{"class.text":"MISC","text":"although the internet as level topology has been extensively studied over the past few years little is known about the details of the as taxonomy"} {"class.text":"MISC","text":"an as node can represent a wide variety of organizations e g large isp or small private business university with vastly different network characteristics external connectivity patterns network growth tendencies and other properties that we can hardly neglect while working on veracious internet representations in simulation environments"} {"class.text":"AIMX","text":"in this paper we introduce a radically new approach based on machine learning techniques to map all the ases in the internet into a natural as taxonomy"} {"class.text":"OWNX","text":"we believe that this dataset will serve as an invaluable addition to further understanding of the structure and evolution of the internet"} {"class.text":"MISC","text":"the rapid expansion of the internet in the last two decades has produced a large scale system of thousands of diverse independently managed networks that collectively provide global connectivity across a wide spectrum of geopolitical environments"} {"class.text":"MISC","text":"from NUMBER to NUMBER the number of globally routable as identifiers has increased from less than NUMBER NUMBER to more than NUMBER NUMBER exerting significant pressure on interdomain routing as well as other functional and structural parts of the internet"} {"class.text":"MISC","text":"this impressive growth has resulted in a heterogenous and highly complex system that challenges accurate and realistic modeling of the internet infrastructure"} {"class.text":"MISC","text":"in particular the as level topology is an intermix of networks owned and operated by many different organizations e g backbone providers regional providers access providers universities and private companies"} {"class.text":"MISC","text":"in topology modeling knowledge of as types is mandatory for augmenting synthetically constructed or measured as topologies with realistic intra as and inter as router level topologies"} {"class.text":"MISC","text":"the university will likely contain dozens of internal routers thousands of hosts and many other network elements switches servers firewalls"} {"class.text":"MISC","text":"since there is such a diversity among different network types we cannot accurately augment the as level topology with appropriate router level topologies if we cannot MISC\tcharacterize the composing ases"} {"class.text":"MISC","text":"moreover annotating the ases in the as topology with their types is a prerequisite for modeling the evolution of the internet since different types of ases exhibit different growth patterns"} {"class.text":"MISC","text":"for example internet service providers isp grow by attracting new customers and by engaging in business agreements with other isps"} {"class.text":"MISC","text":"on the other hand small companies that connect to the internet through one or few isps do not grow significantly over time"} {"class.text":"MISC","text":"thus categorizing different types of ases in the internet is necessary to identify network evolution patterns and develop accurate evolution models"} {"class.text":"MISC","text":"for example in traffic analysis studies its often required to distinguish between packets that come from home and business users"} {"class.text":"MISC","text":"given an as taxonomy its possible to realize this goal by checking the type of as that originates the prefix in which an ip address lies"} {"class.text":"AIMX","text":"in this work we introduce a radically new approach based on machine learning to construct a representative as taxonomy"} {"class.text":"OWNX","text":"we develop an algorithm to classify ases based on empirically observed differences between as characteristics"} {"class.text":"OWNX","text":"we use a large set of data from the internet routing registries irr CITATION and from routeviews CITATION to identify intrinsic differences between ases of different types"} {"class.text":"AIMX","text":"then we employ a novel machine learning technique to build a classification algorithm that exploits these differences to classify ases into six representative classes that reflect ases with different network properties and infrastructures"} {"class.text":"OWNX","text":"our validation demonstrates that our classification algorithm achieves high accuracy NUMBER NUMBER percent of the examined classifications were correct"} {"class.text":"OWNX","text":"finally we make our results and our classifier publicly available to promote further research and understanding of the internet s structure and evolution"} {"class.text":"OWNX","text":"in section we start with a brief discussion of related work"} {"class.text":"OWNX","text":"section describes the data we used and in section we specify the set of as classes we use in our experiments"} {"class.text":"OWNX","text":"section introduces our classification approach and results"} {"class.text":"OWNX","text":"we validate them in section and conclude in section"} {"class.text":"MISC","text":"although the internet as level topology has been extensively studied over the past few years little is known about the details of the as taxonomy"} {"class.text":"AIMX","text":"in this paper we introduce a radically new approach based on machine learning techniques to map all the ases in the internet into a natural as taxonomy"} {"class.text":"OWNX","text":"we successfully classify NUMBER NUMBER percent of ases with expected accuracy of NUMBER NUMBER percent"} {"class.text":"OWNX","text":"we release to the community the as level topology dataset augmented with NUMBER the as taxonomy information and NUMBER the set of as attributes we used to classify ases"} {"class.text":"MISC","text":"the rapid expansion of the internet in the last two decades has produced a large scale system of thousands of diverse independently managed networks that collectively provide global connectivity across a wide spectrum of geopolitical environments"} {"class.text":"MISC","text":"from NUMBER to NUMBER the number of globally routable as identifiers has increased from less than NUMBER NUMBER to more than NUMBER NUMBER exerting significant pressure on interdomain routing as well as other functional and structural parts of the internet"} {"class.text":"MISC","text":"this impressive growth has resulted in a heterogenous and highly complex system that challenges accurate and realistic modeling of the internet infrastructure"} {"class.text":"MISC","text":"in particular the as level topology is an intermix of networks owned and operated by many different organizations e g backbone providers regional providers access providers universities and private companies"} {"class.text":"MISC","text":"statistical information that faithfully characterizes different as types is on the critical path toward understanding the structure of the internet as well as for modeling its topology and growth"} {"class.text":"MISC","text":"in topology modeling knowledge of as types is mandatory for augmenting synthetically constructed or measured as topologies with realistic intra as and inter as router level topologies"} {"class.text":"MISC","text":"for example we expect the network of a dual homed university to be drastically different from that of a dual homed small company"} {"class.text":"MISC","text":"the university will likely contain dozens of internal routers thousands of hosts and many other network elements switches servers firewalls"} {"class.text":"MISC","text":"on the other hand the small company will most probably have a single router and a simple network topology"} {"class.text":"MISC","text":"since there is such a diversity among different network types we cannot accurately augment the as level topology with appropriate router level topologies if we cannot characterize the composing ases"} {"class.text":"MISC","text":"moreover annotating the ases in the as topology with their types is a prerequisite for modeling the evolution of the internet since different types of ases exhibit different growth patterns"} {"class.text":"MISC","text":"on the other hand small companies that connect to the internet through one or few isps do not grow significantly over time"} {"class.text":"MISC","text":"thus categorizing different types of ases in the internet is necessary to identify network evolution patterns and develop accurate evolution models"} {"class.text":"MISC","text":"for example in traffic analysis studies its often required to distinguish between packets that come from home and business users"} {"class.text":"AIMX","text":"in this work we introduce a radically new approach based on machine learning to construct a representative as taxonomy"} {"class.text":"AIMX","text":"we develop an algorithm to classify ases based on empirically observed differences between as characteristics"} {"class.text":"OWNX","text":"we derive macroscopic statistics on the different types of ases in the internet and validate our results using a sample of NUMBER manually identified as types"} {"class.text":"OWNX","text":"our validation demonstrates that our classification algorithm achieves high accuracy NUMBER NUMBER percent of the examined classifications were correct"} {"class.text":"OWNX","text":"finally we make our results and our classifier publicly available to promote further research and understanding of the internet s structure and evolution"} {"class.text":"BASE","text":"in section we start with a brief discussion of related work"} {"class.text":"OWNX","text":"section describes the data we used and in section we specify the set of as classes we use in our experiments"} {"class.text":"MISC","text":"An AS \"node\" can represent a wide variety of organizations, e g , large ISP, or small private business, university, with vastly different network characteristics, external connectivity patterns, network growth tendencies, and other properties that we can hardly neglect while working on veracious Internet representations in simulation environments"} {"class.text":"AIMX","text":"In this paper, we introduce a radically new approach based on machine learning techniques to map all the ASes in the Internet into a natural AS taxonomy"} {"class.text":"OWNX","text":"We release to the community the AS-level topology dataset augmented with: 1) the AS taxonomy information and 2) the set of AS attributes we used to classify ASes"} {"class.text":"OWNX","text":"We believe that this dataset will serve as an invaluable addition to further understanding of the structure and evolution of the Internet"} {"class.text":"MISC","text":"The rapid expansion of the Internet in the last two decades has produced a large-scale system of thousands of diverse, independently managed networks that collectively provide global connectivity across a wide spectrum of geopolitical environments"} {"class.text":"MISC","text":"From 1997 to 2005 the number of globally routable AS identifiers has increased from less than 2,000 to more than 20,000, exerting significant pressure on interdomain routing as well as other functional and structural parts of the Internet"} {"class.text":"MISC","text":"This impressive growth has resulted in a heterogenous and highly complex system that challenges accurate and realistic modeling of the Internet infrastructure"} {"class.text":"MISC","text":"In particular, the AS-level topology is an intermix of networks owned and operated by many different organizations, e g , backbone providers, regional providers, access providers, universities and private companies"} {"class.text":"MISC","text":"Statistical information that faithfully characterizes different AS types is on the critical path toward understanding the structure of the Internet, as well as for modeling its topology and growth"} {"class.text":"MISC","text":"In topology modeling, knowledge of AS types is mandatory for augmenting synthetically constructed or measured AS topologies with realistic intra-AS and inter-AS router-level topologies"} {"class.text":"MISC","text":"The university will likely contain dozens of internal routers, thousands of hosts, and many other network elements (switches, servers, firewalls)"} {"class.text":"MISC","text":"On the other hand, the small company will most probably have a single router and a simple network topology"} {"class.text":"MISC","text":"Moreover, annotating the ASes in the AS topology with their types is a prerequisite for modeling the evolution of the Internet, since different types of ASes exhibit different growth patterns"} {"class.text":"MISC","text":"For example, Internet Service Providers (ISP) grow by attracting new customers and by engaging in business agreements with other ISPs"} {"class.text":"MISC","text":"On the other hand, small companies that connect to the Internet through one or few ISPs do not grow significantly over time"} {"class.text":"MISC","text":"Thus, categorizing different types of ASes in the Internet is necessary to identify network evolution patterns and develop accurate evolution models"} {"class.text":"MISC","text":"An AS taxonomy is also necessary for mapping IP addresses to different types of users"} {"class.text":"MISC","text":"For example, in traffic analysis studies its often required to distinguish between packets that come from home and business users"} {"class.text":"MISC","text":"Given an AS taxonomy, its possible to realize this goal by checking the type of AS that originates the prefix in which an IP address lies"} {"class.text":"AIMX","text":"In this work, we introduce a radically new approach based on machine learning to construct a representative AS taxonomy"} {"class.text":"OWNX","text":"We develop an algorithm to classify ASes based on empirically observed differences between AS characteristics"} {"class.text":"BASE","text":"We use a large set of data from the Internet Routing Registries~(IRR)~ CITATION and from RouteViews~ CITATION to identify intrinsic differences between ASes of different types"} {"class.text":"OWNX","text":"Then, we employ a novel machine learning technique to build a classification algorithm that exploits these differences to classify ASes into six representative classes that reflect ASes with different network properties and infrastructures"} {"class.text":"OWNX","text":"Our validation demonstrates that our classification algorithm achieves high accuracy:~78 1\\% of the examined classifications were correct"} {"class.text":"OWNX","text":"Finally, we make our results and our classifier publicly available to promote further research and understanding of the Internet's structure and evolution"} {"class.text":"OWNX","text":"Section~ describes the data we used, and in Section~ we specify the set of AS classes we use in our experiments"} {"class.text":"OWNX","text":"Section~ introduces our classification approach and results"} {"class.text":"OWNX","text":"We validate them in Section~ and conclude in Section~"} {"class.text":"MISC","text":"The Minimum Description Length principle for online sequence estimation/prediction in a proper learning setup is studied"} {"class.text":"MISC","text":"If the underlying model class is discrete, then the total expected square loss is a particularly interesting performance measure: (a) this quantity is finitely bounded, implying convergence with probability one, and (b) it additionally specifies the convergence speed"} {"class.text":"MISC","text":"For MDL, in general one can only have loss bounds which are finite but exponentially larger than those for Bayes mixtures"} {"class.text":"AIMX","text":"We show that this is even the case if the model class contains only Bernoulli distributions"} {"class.text":"OWNX","text":"We derive a new upper bound on the prediction error for countable Bernoulli classes"} {"class.text":"OWNX","text":"This implies a small bound (comparable to the one for Bayes mixtures) for certain important model classes"} {"class.text":"OWNX","text":"We discuss the application to Machine Learning tasks such as classification and hypothesis testing, and generalization to countable classes of iid models"} {"class.text":"MISC","text":"``Bayes mixture\", ``Solomonoff induction\", ``marginalization\", all these terms refer to a central induction principle: Obtain a predictive distribution by integrating the product of prior and evidence over the model class"} {"class.text":"CONT","text":"In many cases however, the Bayes mixture is computationally infeasible, and even a sophisticated approximation is expensive"} {"class.text":"MISC","text":"The MDL or MAP (maximum a posteriori) estimator is both a common approximation for the Bayes mixture and interesting for its own sake: Use the model with the largest product of prior and evidence"} {"class.text":"MISC","text":"In practice, the MDL estimator is usually being approximated too, since only a local maximum is determined"} {"class.text":"MISC","text":"How good are the predictions by Bayes mixtures and MDL"} {"class.text":"MISC","text":"This question has attracted much attention"} {"class.text":"MISC","text":"In many cases, an important quality measure is the total or cumulative expected loss of a predictor"} {"class.text":"MISC","text":"In particular the square loss is often considered"} {"class.text":"MISC","text":"Assume that the outcome space is finite, and the model class is continuously parameterized"} {"class.text":"MISC","text":"Then for Bayes mixture prediction, the cumulative expected square loss is usually small but unbounded, growing with SYMBOL , where SYMBOL is the sample size CITATION"} {"class.text":"MISC","text":"This corresponds to an instantaneous loss bound of SYMBOL"} {"class.text":"MISC","text":"For the MDL predictor, the losses behave similarly CITATION under appropriate conditions, in particular with a specific prior"} {"class.text":"MISC","text":"Note that in order to do MDL for continuous model classes, one needs to discretize the parameter space, see also CITATION"} {"class.text":"MISC","text":"On the other hand, if the model class is discrete, then Solomonoff's theorem CITATION bounds the cumulative expected square loss for the Bayes mixture predictions finitely, namely by SYMBOL , where SYMBOL is the prior weight of the ``true\" model SYMBOL"} {"class.text":"MISC","text":"The only necessary assumption is that the true distribution SYMBOL is contained in the model class, ie that we are dealing with proper learning"} {"class.text":"MISC","text":"It has been demonstrated CITATION , that for both Bayes mixture and MDL, the proper learning assumption can be essential: If it is violated, then learning may fail very badly"} {"class.text":"MISC","text":"For MDL predictions in the proper learning case, it has been shown CITATION that a bound of SYMBOL holds"} {"class.text":"MISC","text":"This bound is exponentially larger than the Solomonoff bound, and it is sharp in general"} {"class.text":"MISC","text":"A finite bound on the total expected square loss is particularly interesting: It implies convergence of the predictive to the true probabilities with probability one"} {"class.text":"MISC","text":"In contrast, an instantaneous loss bound of SYMBOL implies only convergence in probability"} {"class.text":"MISC","text":"Additionally, it gives a convergence speed , in the sense that errors of a certain magnitude cannot occur too often"} {"class.text":"MISC","text":"So for both, Bayes mixtures and MDL, convergence with probability one holds, while the convergence speed is exponentially worse for MDL compared to the Bayes mixture"} {"class.text":"MISC","text":"We avoid the term ``convergence rate\" here, since the order of convergence is identical in both cases"} {"class.text":"MISC","text":"It is therefore natural to ask if there are model classes where the cumulative loss of MDL is comparable to that of Bayes mixture predictions"} {"class.text":"AIMX","text":"In the present work, we concentrate on the simplest possible stochastic case, namely discrete Bernoulli classes"} {"class.text":"OWNX","text":"Note that then the MDL ``predictor\" just becomes an estimator, in that it estimates the true parameter and directly uses that for prediction"} {"class.text":"OWNX","text":"Nevertheless, for consistency of terminology, we keep the term predictor"} {"class.text":"MISC","text":"It might be surprising to discover that in general the cumulative loss is still exponential"} {"class.text":"OWNX","text":"On the other hand, we will give mild conditions on the prior guaranteeing a small bound"} {"class.text":"MISC","text":"Moreover, it is well-known that the instantaneous square loss of the Maximum Likelihood estimator decays as SYMBOL in the Bernoulli case"} {"class.text":"MISC","text":"The same holds for MDL, as we will see"} {"class.text":"MISC","text":"If convergence speed is measured in terms of instantaneous losses, then much more general statements are possible CITATION , this is briefly discussed in Section"} {"class.text":"MISC","text":"A particular motivation to consider discrete model classes arises in Algorithmic Information Theory"} {"class.text":"MISC","text":"From a computational point of view, the largest relevant model class is the class of all computable models on some fixed universal Turing machine, precisely prefix machine CITATION"} {"class.text":"MISC","text":"Thus each model corresponds to a program, and there are countably many programs"} {"class.text":"MISC","text":"Moreover, the models are stochastic, precisely they are semimeasures on strings (programs need not halt, otherwise the models were even measures)"} {"class.text":"MISC","text":"Each model has a natural description length, namely the length of the corresponding program"} {"class.text":"MISC","text":"By the Kraft inequality, the priors sum up to at most one"} {"class.text":"MISC","text":"Also the Bernoulli case can be studied in the view of Algorithmic Information Theory"} {"class.text":"MISC","text":"We call this the universal setup : Given a universal Turing machine, the related class of Bernoulli distributions is isomorphic to the countable set of computable reals in SYMBOL"} {"class.text":"MISC","text":"The description length SYMBOL of a parameter SYMBOL is then given by the length of its shortest program"} {"class.text":"MISC","text":"A prior weight may then be defined by SYMBOL"} {"class.text":"MISC","text":"That is, the two-part complexity with respect to the Bernoulli class is the shortest description, save for an additive constant"} {"class.text":"MISC","text":"Many Machine Learning tasks are or can be reduced to sequence prediction tasks"} {"class.text":"MISC","text":"An important example is classification"} {"class.text":"MISC","text":"The task of classifying a new instance SYMBOL after having seen (instance,class) pairs SYMBOL can be phrased as to predict the continuation of the sequence SYMBOL"} {"class.text":"MISC","text":"Typically the (instance,class) pairs are iid"} {"class.text":"MISC","text":"Cumulative loss bounds for prediction usually generalize to prediction conditionalized to some inputs CITATION"} {"class.text":"MISC","text":"Then we can solve classification problems in the standard form"} {"class.text":"OWNX","text":"It is not obvious if and how the proofs in this paper can be conditionalized"} {"class.text":"OWNX","text":"Our main tool for obtaining results is the Kullback-Leibler divergence"} {"class.text":"OWNX","text":"Section shows that the exponential error bound obtained in CITATION is sharp in general"} {"class.text":"OWNX","text":"In Section , we give an upper bound on the instantaneous and the cumulative losses"} {"class.text":"OWNX","text":"The latter bound is small eg under certain conditions on the distribution of the weights, this is the subject of Section"} {"class.text":"MISC","text":"If the underlying model class is discrete, then the total expected square loss is a particularly interesting performance measure: (a) this quantity is finitely bounded, implying convergence with probability one, and (b) it additionally specifies the convergence speed"} {"class.text":"AIMX","text":"We show that this is even the case if the model class contains only Bernoulli distributions"} {"class.text":"OWNX","text":"We derive a new upper bound on the prediction error for countable Bernoulli classes"} {"class.text":"OWNX","text":"We discuss the application to Machine Learning tasks such as classification and hypothesis testing, and generalization to countable classes of iid models"} {"class.text":"MISC","text":"``Bayes mixture\", ``Solomonoff induction\", ``marginalization\", all these terms refer to a central induction principle: Obtain a predictive distribution by integrating the product of prior and evidence over the model class"} {"class.text":"CONT","text":"In many cases however, the Bayes mixture is computationally infeasible, and even a sophisticated approximation is expensive"} {"class.text":"MISC","text":"The MDL or MAP (maximum a posteriori) estimator is both a common approximation for the Bayes mixture and interesting for its own sake: Use the model with the largest product of prior and evidence"} {"class.text":"MISC","text":"In practice, the MDL estimator is usually being approximated too, since only a local maximum is determined"} {"class.text":"MISC","text":"How good are the predictions by Bayes mixtures and MDL"} {"class.text":"MISC","text":"This question has attracted much attention"} {"class.text":"MISC","text":"In many cases, an important quality measure is the total or cumulative expected loss of a predictor"} {"class.text":"MISC","text":"In particular the square loss is often considered"} {"class.text":"MISC","text":"Assume that the outcome space is finite, and the model class is continuously parameterized"} {"class.text":"MISC","text":"This corresponds to an instantaneous loss bound of SYMBOL"} {"class.text":"MISC","text":"For the MDL predictor, the losses behave similarly CITATION under appropriate conditions, in particular with a specific prior"} {"class.text":"MISC","text":"On the other hand, if the model class is discrete, then Solomonoff's theorem CITATION bounds the cumulative expected square loss for the Bayes mixture predictions finitely, namely by SYMBOL , where SYMBOL is the prior weight of the ``true\" model SYMBOL"} {"class.text":"MISC","text":"The only necessary assumption is that the true distribution SYMBOL is contained in the model class, ie that we are dealing with proper learning"} {"class.text":"MISC","text":"This bound is exponentially larger than the Solomonoff bound, and it is sharp in general"} {"class.text":"MISC","text":"A finite bound on the total expected square loss is particularly interesting: It implies convergence of the predictive to the true probabilities with probability one"} {"class.text":"MISC","text":"We avoid the term ``convergence rate\" here, since the order of convergence is identical in both cases"} {"class.text":"MISC","text":"It is therefore natural to ask if there are model classes where the cumulative loss of MDL is comparable to that of Bayes mixture predictions"} {"class.text":"AIMX","text":"In the present work, we concentrate on the simplest possible stochastic case, namely discrete Bernoulli classes"} {"class.text":"OWNX","text":"Note that then the MDL ``predictor\" just becomes an estimator, in that it estimates the true parameter and directly uses that for prediction"} {"class.text":"OWNX","text":"It might be surprising to discover that in general the cumulative loss is still exponential"} {"class.text":"MISC","text":"Moreover, it is well-known that the instantaneous square loss of the Maximum Likelihood estimator decays as SYMBOL in the Bernoulli case"} {"class.text":"MISC","text":"The same holds for MDL, as we will see"} {"class.text":"MISC","text":"If convergence speed is measured in terms of instantaneous losses, then much more general statements are possible CITATION , this is briefly discussed in Section"} {"class.text":"MISC","text":"A particular motivation to consider discrete model classes arises in Algorithmic Information Theory"} {"class.text":"MISC","text":"Thus each model corresponds to a program, and there are countably many programs"} {"class.text":"MISC","text":"Moreover, the models are stochastic, precisely they are semimeasures on strings (programs need not halt, otherwise the models were even measures)"} {"class.text":"MISC","text":"Each model has a natural description length, namely the length of the corresponding program"} {"class.text":"MISC","text":"If we agree that programs are binary strings, then a prior is defined by two to the negative description length"} {"class.text":"MISC","text":"Also the Bernoulli case can be studied in the view of Algorithmic Information Theory"} {"class.text":"MISC","text":"We call this the universal setup : Given a universal Turing machine, the related class of Bernoulli distributions is isomorphic to the countable set of computable reals in SYMBOL"} {"class.text":"MISC","text":"A prior weight may then be defined by SYMBOL"} {"class.text":"MISC","text":"If a string SYMBOL is generated by a Bernoulli distribution with computable parameter SYMBOL , then with high probability the two-part complexity of SYMBOL with respect to the Bernoulli class does not exceed its algorithmic complexity by more than a constant, as shown by Vovk CITATION"} {"class.text":"MISC","text":"Many Machine Learning tasks are or can be reduced to sequence prediction tasks"} {"class.text":"MISC","text":"An important example is classification"} {"class.text":"MISC","text":"The task of classifying a new instance SYMBOL after having seen (instance,class) pairs SYMBOL can be phrased as to predict the continuation of the sequence SYMBOL"} {"class.text":"MISC","text":"Cumulative loss bounds for prediction usually generalize to prediction conditionalized to some inputs CITATION"} {"class.text":"MISC","text":"Then we can solve classification problems in the standard form"} {"class.text":"OWNX","text":"It is not obvious if and how the proofs in this paper can be conditionalized"} {"class.text":"OWNX","text":"Lemmata for this quantity are stated in Section"} {"class.text":"OWNX","text":"Section shows that the exponential error bound obtained in CITATION is sharp in general"} {"class.text":"OWNX","text":"In Section , we give an upper bound on the instantaneous and the cumulative losses"} {"class.text":"OWNX","text":"The latter bound is small eg under certain conditions on the distribution of the weights, this is the subject of Section"} {"class.text":"OWNX","text":"Finally, in Section we discuss the results and give conclusions"} {"class.text":"OWNX","text":"The Minimum Description Length principle for online sequence estimation/prediction in a proper learning setup is studied"} {"class.text":"MISC","text":"If the underlying model class is discrete, then the total expected square loss is a particularly interesting performance measure: (a) this quantity is finitely bounded, implying convergence with probability one, and (b) it additionally specifies the convergence speed"} {"class.text":"MISC","text":"For MDL, in general one can only have loss bounds which are finite but exponentially larger than those for Bayes mixtures"} {"class.text":"AIMX","text":"We show that this is even the case if the model class contains only Bernoulli distributions"} {"class.text":"OWNX","text":"We derive a new upper bound on the prediction error for countable Bernoulli classes"} {"class.text":"OWNX","text":"This implies a small bound (comparable to the one for Bayes mixtures) for certain important model classes"} {"class.text":"OWNX","text":"We discuss the application to Machine Learning tasks such as classification and hypothesis testing, and generalization to countable classes of iid models"} {"class.text":"MISC","text":"``Bayes mixture\", ``Solomonoff induction\", ``marginalization\", all these terms refer to a central induction principle: Obtain a predictive distribution by integrating the product of prior and evidence over the model class"} {"class.text":"MISC","text":"In many cases however, the Bayes mixture is computationally infeasible, and even a sophisticated approximation is expensive"} {"class.text":"MISC","text":"The MDL or MAP (maximum a posteriori) estimator is both a common approximation for the Bayes mixture and interesting for its own sake: Use the model with the largest product of prior and evidence"} {"class.text":"MISC","text":"In practice, the MDL estimator is usually being approximated too, since only a local maximum is determined"} {"class.text":"MISC","text":"How good are the predictions by Bayes mixtures and MDL"} {"class.text":"MISC","text":"This question has attracted much attention"} {"class.text":"MISC","text":"In particular the square loss is often considered"} {"class.text":"MISC","text":"Assume that the outcome space is finite, and the model class is continuously parameterized"} {"class.text":"MISC","text":"Then for Bayes mixture prediction, the cumulative expected square loss is usually small but unbounded, growing with SYMBOL , where SYMBOL is the sample size CITATION"} {"class.text":"MISC","text":"This corresponds to an instantaneous loss bound of SYMBOL"} {"class.text":"MISC","text":"For the MDL predictor, the losses behave similarly CITATION under appropriate conditions, in particular with a specific prior"} {"class.text":"MISC","text":"Note that in order to do MDL for continuous model classes, one needs to discretize the parameter space, see also CITATION"} {"class.text":"MISC","text":"On the other hand, if the model class is discrete, then Solomonoff's theorem CITATION bounds the cumulative expected square loss for the Bayes mixture predictions finitely, namely by SYMBOL , where SYMBOL is the prior weight of the ``true\" model SYMBOL"} {"class.text":"MISC","text":"The only necessary assumption is that the true distribution SYMBOL is contained in the model class, ie that we are dealing with proper learning"} {"class.text":"MISC","text":"It has been demonstrated CITATION , that for both Bayes mixture and MDL, the proper learning assumption can be essential: If it is violated, then learning may fail very badly"} {"class.text":"MISC","text":"This bound is exponentially larger than the Solomonoff bound, and it is sharp in general"} {"class.text":"MISC","text":"A finite bound on the total expected square loss is particularly interesting: It implies convergence of the predictive to the true probabilities with probability one"} {"class.text":"MISC","text":"Additionally, it gives a convergence speed , in the sense that errors of a certain magnitude cannot occur too often"} {"class.text":"MISC","text":"We avoid the term ``convergence rate\" here, since the order of convergence is identical in both cases"} {"class.text":"MISC","text":"It is eg SYMBOL if we additionally assume that the error is monotonically decreasing, which is not necessarily true in general"} {"class.text":"AIMX","text":"In the present work, we concentrate on the simplest possible stochastic case, namely discrete Bernoulli classes"} {"class.text":"OWNX","text":"Note that then the MDL ``predictor\" just becomes an estimator, in that it estimates the true parameter and directly uses that for prediction"} {"class.text":"OWNX","text":"Nevertheless, for consistency of terminology, we keep the term predictor"} {"class.text":"OWNX","text":"It might be surprising to discover that in general the cumulative loss is still exponential"} {"class.text":"OWNX","text":"On the other hand, we will give mild conditions on the prior guaranteeing a small bound"} {"class.text":"MISC","text":"Moreover, it is well-known that the instantaneous square loss of the Maximum Likelihood estimator decays as SYMBOL in the Bernoulli case"} {"class.text":"OWNX","text":"The same holds for MDL, as we will see"} {"class.text":"OWNX","text":"If convergence speed is measured in terms of instantaneous losses, then much more general statements are possible CITATION , this is briefly discussed in Section"} {"class.text":"MISC","text":"A particular motivation to consider discrete model classes arises in Algorithmic Information Theory"} {"class.text":"MISC","text":"From a computational point of view, the largest relevant model class is the class of all computable models on some fixed universal Turing machine, precisely prefix machine CITATION"} {"class.text":"MISC","text":"Thus each model corresponds to a program, and there are countably many programs"} {"class.text":"MISC","text":"Moreover, the models are stochastic, precisely they are semimeasures on strings (programs need not halt, otherwise the models were even measures)"} {"class.text":"MISC","text":"If we agree that programs are binary strings, then a prior is defined by two to the negative description length"} {"class.text":"MISC","text":"By the Kraft inequality, the priors sum up to at most one"} {"class.text":"MISC","text":"Also the Bernoulli case can be studied in the view of Algorithmic Information Theory"} {"class.text":"MISC","text":"The description length SYMBOL of a parameter SYMBOL is then given by the length of its shortest program"} {"class.text":"MISC","text":"If a string SYMBOL is generated by a Bernoulli distribution with computable parameter SYMBOL , then with high probability the two-part complexity of SYMBOL with respect to the Bernoulli class does not exceed its algorithmic complexity by more than a constant, as shown by Vovk CITATION"} {"class.text":"MISC","text":"That is, the two-part complexity with respect to the Bernoulli class is the shortest description, save for an additive constant"} {"class.text":"MISC","text":"The task of classifying a new instance SYMBOL after having seen (instance,class) pairs SYMBOL can be phrased as to predict the continuation of the sequence SYMBOL"} {"class.text":"MISC","text":"Cumulative loss bounds for prediction usually generalize to prediction conditionalized to some inputs CITATION"} {"class.text":"OWNX","text":"Then we can solve classification problems in the standard form"} {"class.text":"OWNX","text":"It is not obvious if and how the proofs in this paper can be conditionalized"} {"class.text":"OWNX","text":"Our main tool for obtaining results is the Kullback-Leibler divergence"} {"class.text":"OWNX","text":"Lemmata for this quantity are stated in Section"} {"class.text":"OWNX","text":"Section shows that the exponential error bound obtained in CITATION is sharp in general"} {"class.text":"OWNX","text":"The latter bound is small eg under certain conditions on the distribution of the weights, this is the subject of Section"} {"class.text":"OWNX","text":"Section treats the universal setup"} {"class.text":"OWNX","text":"Finally, in Section we discuss the results and give conclusions"} {"class.text":"AIMX","text":"in this paper we derive the equations for loop corrected belief propagation on a continuous variable gaussian model"} {"class.text":"OWNX","text":"using the exactness of the averages for belief propagation for gaussian models a different way of obtaining the covariances is found based on belief propagation on cavity graphs"} {"class.text":"OWNX","text":"we discuss the relation of this loop correction algorithm to expectation propagation algorithms for the case in which the model is no longer gaussian but slightly perturbed by nonlinear terms"} {"class.text":"MISC","text":"message passing techniques in graphical models allow for the computation of approximate marginal probabilities in a time interval scaling polynomially in the model size"} {"class.text":"MISC","text":"their discovery has consequently revolutionized several fields of applications in the past years of which error correcting codes and vision are probably the most prominent examples"} {"class.text":"MISC","text":"in many cases the corresponding graphs are loopy implying either that the error resulting from the application of loopy belief propagation bp is negligible for the particular model or it can be tolerated for the particular purpose bp serves"} {"class.text":"MISC","text":"in other cases more sophisticated refinements of bp are necessary taking into account part of the loop errors"} {"class.text":"MISC","text":"finding the optimal treatment of these loop errors motivates an active field of research in which different solutions applying to different model classes are developed"} {"class.text":"MISC","text":"for models involving many short loops like on regular lattices cvm type approaches work well CITATION or tree ep approaches CITATION"} {"class.text":"MISC","text":"the latter may also be applied to correct for an incidental large loop"} {"class.text":"MISC","text":"unifying frameworks like the region graphs of CITATION lead to general strategies for selecting the basic clusters underlying such approaches for general model classes"} {"class.text":"MISC","text":"these quantities are parameterizations of the cavity distributions i e the distribution over neighbor variables of a central variable which has been removed from the graph"} {"class.text":"MISC","text":"the bethe approximation and bp are recovered when this cavity distribution is assumed to factorize whereas the first order correction to the local update equations is obtained when one takes into account the pair cumulants CITATION"} {"class.text":"MISC","text":"estimation of these pair cumulants is possible with extra runs of bp allowing for new polynomial time algorithms reducing errors to order when applying algorithms of which running time scales with an extra factor of CITATION"} {"class.text":"MISC","text":"although this scaling seems heavy the large benefit of the approach is that it does not require selection of basic clusters or underlying tree structures since it takes into account the effect of all loops that contribute to nontrivial correlations in the cavity distribution at once"} {"class.text":"MISC","text":"the above loop correction strategy is applicable in the class of models where a perturbative expansion around the bethe approximation makes sense i e in models with large loops and relatively weak interactions"} {"class.text":"MISC","text":"the principal requirement is that the magnitude of pair variable cumulants of cavity distributions is an order smaller than the single variable cumulants and third order cumulants are even smaller etc"} {"class.text":"MISC","text":"however heuristics based on the strategy allow for other good algorithms performing well outside these parameter regimes CITATION"} {"class.text":"CONT","text":"so far the approach has been developed for discrete variable models on a more abstract CITATION versus practical level CITATION"} {"class.text":"AIMX","text":"in this paper we apply the idea to graphical models for continuous variables"} {"class.text":"OWNX","text":"we derive the loop corrected belief propagation equations for simple tractable gaussian models yielding a message passing scheme that besides the correct average marginals also yields the correct variances"} {"class.text":"OWNX","text":"besides that we discuss some approaches potentially applicable to cases in which extra function approximations are necessary and the relation with expectation propagation"} {"class.text":"CONT","text":"a by product of our loop corrected belief propagation equations is an algorithm that calculates exact covariance matrices for gaussian models like the one discussed in CITATION but without explicitly using linear response"} {"class.text":"OWNX","text":"Using the exactness of the averages for belief propagation for Gaussian models, a different way of obtaining the covariances is found, based on Belief Propagation on cavity graphs"} {"class.text":"AIMX","text":"We discuss the relation of this loop correction algorithm to Expectation Propagation algorithms for the case in which the model is no longer Gaussian, but slightly perturbed by nonlinear terms"} {"class.text":"MISC","text":"Message passing techniques in graphical models allow for the computation of (approximate) marginal probabilities in a time interval scaling polynomially in the model size"} {"class.text":"MISC","text":"Their discovery has consequently revolutionized several fields of applications in the past years, of which error correcting codes and vision are probably the most prominent examples"} {"class.text":"MISC","text":"In many cases, the corresponding graphs are loopy, implying either that the error resulting from the application of loopy belief propagation (BP) is negligible for the particular model, or it can be tolerated for the particular purpose BP serves"} {"class.text":"MISC","text":"In other cases more sophisticated refinements of BP are necessary, taking into account (part of) the loop errors"} {"class.text":"MISC","text":"Finding the optimal treatment of these ``loop errors'' motivates an active field of research, in which different solutions applying to different model classes are developed"} {"class.text":"MISC","text":"For models involving many short loops, like on regular lattices, CVM type approaches work well CITATION , or tree EP approaches CITATION"} {"class.text":"MISC","text":"Unifying frameworks like the Region graphs of CITATION lead to general strategies for selecting the basic clusters underlying such approaches for general model classes"} {"class.text":"MISC","text":"A recent analysis has shown that the local update equations of BP may be interpreted as the zero order term of an expansion in ``cavity connected correlations''"} {"class.text":"MISC","text":"These quantities are parameterizations of the ``cavity distributions'', i e , the distribution over neighbor variables of a central variable which has been removed from the graph"} {"class.text":"MISC","text":"The Bethe approximation and BP are recovered when this cavity distribution is assumed to factorize, whereas the first order correction to the local update equations is obtained when one takes into account the pair cumulants CITATION"} {"class.text":"MISC","text":"The above ``loop correction'' strategy is applicable in the class of models where a perturbative expansion around the Bethe approximation makes sense, i e , in models with large loops and relatively weak interactions"} {"class.text":"MISC","text":"So far the approach has been developed for discrete variable models on a more abstract CITATION versus practical level CITATION"} {"class.text":"OWNX","text":"We derive the loop corrected belief propagation equations for simple tractable Gaussian models, yielding a message passing scheme that, besides the correct average marginals, also yields the correct variances"} {"class.text":"AIMX","text":"Besides that we discuss some approaches potentially applicable to cases in which extra function approximations are necessary, and the relation with expectation propagation"} {"class.text":"OWNX","text":"A by-product of our loop corrected belief propagation equations is an algorithm that calculates exact covariance matrices for Gaussian models like the one discussed in CITATION , but without explicitly using linear response"} {"class.text":"BASE","text":"Using the exactness of the averages for belief propagation for Gaussian models, a different way of obtaining the covariances is found, based on Belief Propagation on cavity graphs"} {"class.text":"OWNX","text":"We discuss the relation of this loop correction algorithm to Expectation Propagation algorithms for the case in which the model is no longer Gaussian, but slightly perturbed by nonlinear terms"} {"class.text":"MISC","text":"Message passing techniques in graphical models allow for the computation of (approximate) marginal probabilities in a time interval scaling polynomially in the model size"} {"class.text":"MISC","text":"Their discovery has consequently revolutionized several fields of applications in the past years, of which error correcting codes and vision are probably the most prominent examples"} {"class.text":"MISC","text":"In many cases, the corresponding graphs are loopy, implying either that the error resulting from the application of loopy belief propagation (BP) is negligible for the particular model, or it can be tolerated for the particular purpose BP serves"} {"class.text":"MISC","text":"In other cases more sophisticated refinements of BP are necessary, taking into account (part of) the loop errors"} {"class.text":"MISC","text":"Finding the optimal treatment of these ``loop errors'' motivates an active field of research, in which different solutions applying to different model classes are developed"} {"class.text":"MISC","text":"For models involving many short loops, like on regular lattices, CVM type approaches work well CITATION , or tree EP approaches CITATION"} {"class.text":"MISC","text":"The latter may also be applied to correct for an incidental large loop"} {"class.text":"MISC","text":"A recent analysis has shown that the local update equations of BP may be interpreted as the zero order term of an expansion in ``cavity connected correlations''"} {"class.text":"MISC","text":"These quantities are parameterizations of the ``cavity distributions'', i e , the distribution over neighbor variables of a central variable which has been removed from the graph"} {"class.text":"MISC","text":"The Bethe approximation and BP are recovered when this cavity distribution is assumed to factorize, whereas the first order correction to the local update equations is obtained when one takes into account the pair cumulants CITATION"} {"class.text":"MISC","text":"Estimation of these pair cumulants is possible with extra runs of BP, allowing for new polynomial time algorithms, reducing errors to order SYMBOL when applying algorithms of which running time scales with an extra factor of SYMBOL CITATION"} {"class.text":"MISC","text":"Although this scaling seems heavy, the large benefit of the approach is that it does not require selection of basic clusters or underlying tree-structures, since it takes into account the effect of all loops that contribute to nontrivial correlations in the cavity distribution at once"} {"class.text":"MISC","text":"The principal requirement is that the magnitude of pair variable cumulants of cavity distributions is an order smaller than the single variable cumulants, and third order cumulants are even smaller, etc"} {"class.text":"MISC","text":"However, heuristics based on the strategy allow for other good algorithms performing well outside these parameter regimes CITATION"} {"class.text":"MISC","text":"So far the approach has been developed for discrete variable models on a more abstract CITATION versus practical level CITATION"} {"class.text":"AIMX","text":"In this paper we apply the idea to graphical models for continuous variables"} {"class.text":"OWNX","text":"Besides that we discuss some approaches potentially applicable to cases in which extra function approximations are necessary, and the relation with expectation propagation"} {"class.text":"BASE","text":"A by-product of our loop corrected belief propagation equations is an algorithm that calculates exact covariance matrices for Gaussian models like the one discussed in CITATION , but without explicitly using linear response"} {"class.text":"MISC","text":"there are two known varieties of defensive forecasting continuous in which sceptic s moves are assumed to depend on the forecasts in a semi continuous manner and which produces deterministic forecasts and randomized in which the dependence of sceptic s moves on the forecasts is arbitrary and forecaster s moves are allowed to be randomized"} {"class.text":"AIMX","text":"this note shows that the randomized variety can be obtained from the continuous variety by smearing sceptic s moves to make them continuous"} {"class.text":"CONT","text":"textbf new as compared to version NUMBER NUMBER august NUMBER of this report the assumption of version NUMBER that the outcome space is finite is relaxed and now it is only assumed to be compact"} {"class.text":"CONT","text":"in the case where is finite it is shown that forecaster can choose his randomized forecasts concentrated on a finite set of cardinality at most"} {"class.text":"CONT","text":"non asymptotic versions of the randomized variety were proposed by sandroni CITATION based on standard measure theoretic probability and vovk and shafer CITATION based on game theoretic probability"} {"class.text":"AIMX","text":"this note states two simple results about defensive forecasting theorem about the continuous variety and theorem about the randomized variety"} {"class.text":"OWNX","text":"the proof of theorem is obtained from the proof of theorem by blurring sceptic s moves"} {"class.text":"OWNX","text":"in our informal discussions we will be assuming that the set of all possible outcomes is finite although we will try to make mathematical statements as general as possible"} {"class.text":"OWNX","text":"the reader who is only interested in the main ideas might choose to specialize theorems and and their proofs to the case of finite"} {"class.text":"MISC","text":"defensive forecasting is a method of transforming laws of probability stated in game theoretic terms as strategies for sceptic into forecasting algorithms"} {"class.text":"MISC","text":"there are two known varieties of defensive forecasting continuous in which sceptic s moves are assumed to depend on the forecasts in a semi continuous manner and which produces deterministic forecasts and randomized in which the dependence of sceptic s moves on the forecasts is arbitrary and forecaster s moves are allowed to be randomized"} {"class.text":"MISC","text":"this note shows that the randomized variety can be obtained from the continuous variety by smearing sceptic s moves to make them continuous"} {"class.text":"OWNX","text":"new as compared to version NUMBER NUMBER august NUMBER of this report the assumption of version NUMBER that the outcome space is finite is relaxed and now it is only assumed to be compact"} {"class.text":"MISC","text":"the continuous variety of defensive forecasting was essentially introduced by levin CITATION but was later rediscovered by kakade and foster CITATION and takemura et al CITATION"} {"class.text":"MISC","text":"the randomized variety was introduced in the case of von mises s version of the game theoretic approach to probability by foster and vohra CITATION and further developed by among others sandroni et al CITATION these papers however were only concerned with asymptotic calibration"} {"class.text":"MISC","text":"non asymptotic versions of the randomized variety were proposed by sandroni CITATION based on standard measure theoretic probability and vovk and shafer CITATION based on game theoretic probability"} {"class.text":"BASE","text":"kakade and foster CITATION noticed that some calibration results require very little randomization this will be an important aspect of our theorem"} {"class.text":"AIMX","text":"this note states two simple results about defensive forecasting theorem about the continuous variety and theorem about the randomized variety"} {"class.text":"AIMX","text":"in our informal discussions we will be assuming that the set of all possible outcomes is finite although we will try to make mathematical statements as general as possible"} {"class.text":"OWNX","text":"the reader who is only interested in the main ideas might choose to specialize theorems and and their proofs to the case of finite"} {"class.text":"AIMX","text":"This note shows that the randomized variety can be obtained from the continuous variety by smearing Sceptic's moves to make them continuous"} {"class.text":"OWNX","text":"New as compared to version 1 (17 August 2007) of this report: The assumption of version 1 that the outcome space SYMBOL is finite is relaxed, and now it is only assumed to be compact"} {"class.text":"OWNX","text":"In the case where SYMBOL is finite, it is shown that Forecaster can choose his randomized forecasts concentrated on a finite set of cardinality at most SYMBOL"} {"class.text":"MISC","text":"The randomized variety was introduced (in the case of von Mises's version of the game-theoretic approach to probability) by Foster and Vohra CITATION and further developed by, among others, Sandroni et al CITATION ; these papers, however, were only concerned with asymptotic calibration"} {"class.text":"BASE","text":"Kakade and Foster CITATION noticed that some calibration results require very little randomization (this will be an important aspect of our Theorem )"} {"class.text":"AIMX","text":"This note states two simple results about defensive forecasting, Theorem about the continuous variety and Theorem about the randomized variety"} {"class.text":"OWNX","text":"In our informal discussions we will be assuming that the set SYMBOL of all possible outcomes is finite, although we will try to make mathematical statements as general as possible"} {"class.text":"MISC","text":"The reader who is only interested in the main ideas might choose to specialize Theorems and and their proofs to the case of finite SYMBOL"} {"class.text":"CONT","text":"most generalization bounds in learning theory are based on some measure of the complexity of the hypothesis class used independently of any algorithm"} {"class.text":"CONT","text":"in contrast the notion of algorithmic stability can be used to derive tight generalization bounds that are tailored to specific learning algorithms by exploiting their particular properties"} {"class.text":"CONT","text":"however as in much of learning theory existing stability analyses and bounds apply only in the scenario where the samples are independently and identically distributed"} {"class.text":"CONT","text":"in many machine learning applications however this assumption does not hold"} {"class.text":"CONT","text":"the observations received by the learning algorithm often have some inherent temporal dependence"} {"class.text":"AIMX","text":"this paper studies the scenario where the observations are drawn from a stationary mixing or mixing sequence a widely adopted assumption in the study of non independent and identically distributed processes that implies a dependence between observations weakening over time"} {"class.text":"OWNX","text":"we prove novel and distinct stability based generalization bounds for stationary mixing and mixing sequences"} {"class.text":"BASE","text":"these bounds strictly generalize the bounds given in the independent and identically distributed case and apply to all stable learning algorithms thereby extending the use of stability bounds to non independent and identically distributed scenarios"} {"class.text":"OWNX","text":"we also illustrate the application of our mixing generalization bounds to general classes of learning algorithms including support vector regression kernel ridge regression and support vector machines and many other kernel regularization based and relative entropy based regularization algorithms"} {"class.text":"OWNX","text":"these novel bounds can thus be viewed as the first theoretical basis for the use of these algorithms in non independent and identically distributed scenarios"} {"class.text":"CONT","text":"most generalization bounds in learning theory are based on some measure of the complexity of the hypothesis class used such as the vc dimension covering numbers or rademacher complexity"} {"class.text":"CONT","text":"these measures characterize a class of hypotheses independently of any algorithm"} {"class.text":"CONT","text":"in contrast the notion of algorithmic stability can be used to derive bounds that are tailored to specific learning algorithms and exploit their particular properties"} {"class.text":"CONT","text":"a learning algorithm is stable if the hypothesis it outputs varies in a limited way in response to small changes made to the training set"} {"class.text":"CONT","text":"algorithmic stability has been used effectively in the past to derive tight generalization bounds CITATION"} {"class.text":"CONT","text":"but as in much of learning theory existing stability analyses and bounds apply only in the scenario where the samples are independently and identically distributed independent and identically distributed"} {"class.text":"CONT","text":"in many machine learning applications this assumption however does not hold in fact the independent and identically distributed assumption is not tested or derived from any data analysis"} {"class.text":"CONT","text":"the observations received by the learning algorithm often have some inherent temporal dependence"} {"class.text":"CONT","text":"this is clear in system diagnosis or time series prediction problems"} {"class.text":"CONT","text":"clearly prices of different stocks on the same day or of the same stock on different days may be dependent"} {"class.text":"CONT","text":"but a less apparent time dependency may affect data sampled in many other tasks as well"} {"class.text":"AIMX","text":"this paper studies the scenario where the observations are drawn from a stationary mixing or mixing sequence a widely adopted assumption in the study of non independent and identically distributed processes that implies a dependence between observations weakening over time CITATION"} {"class.text":"BASE","text":"these bounds strictly generalize the bounds given in the independent and identically distributed case and apply to all stable learning algorithms thereby extending the usefulness of stability bounds to non independent and identically distributed scenarios"} {"class.text":"BASE","text":"our proofs are based on the independent block technique described by CITATION and attributed to CITATION which is commonly used in such contexts"} {"class.text":"CONT","text":"however our analysis differs from previous uses of this technique in that the blocks of points considered are not of equal size"} {"class.text":"OWNX","text":"our generalization bounds for stationary mixing sequences cover a more general non independent and identically distributed scenario and use the standard mcdiarmid s inequality however unlike the mixing case the mixing bound presented here is not a purely exponential bound and contains an additive term depending on the mixing coefficient"} {"class.text":"CONT","text":"algorithms such as support vector regression svr CITATION have been used in the context of time series prediction in which the independent and identically distributed assumption does not hold some with good experimental results CITATION"} {"class.text":"CONT","text":"the stability bounds we give for svr svms and many other kernel regularization based and relative entropy based regularization algorithms can thus be viewed as the first theoretical basis for their use in such scenarios"} {"class.text":"OWNX","text":"the following sections are organized as follows"} {"class.text":"OWNX","text":"section gives our main generalization bounds for stationary mixing sequences based on stability as well as the illustration of its applications to general kernel regularization based algorithms including svr krr and svms as well as to relative entropy based regularization algorithms"} {"class.text":"OWNX","text":"finally section presents the first known stability bounds for the more general stationary mixing scenario"} {"class.text":"MISC","text":"Most generalization bounds in learning theory are based on some measure of the complexity of the hypothesis class used, independently of any algorithm"} {"class.text":"MISC","text":"In contrast, the notion of algorithmic stability can be used to derive tight generalization bounds that are tailored to specific learning algorithms by exploiting their particular properties"} {"class.text":"MISC","text":"However, as in much of learning theory, existing stability analyses and bounds apply only in the scenario where the samples are independently and identically distributed"} {"class.text":"MISC","text":"The observations received by the learning algorithm often have some inherent temporal dependence"} {"class.text":"AIMX","text":"This paper studies the scenario where the observations are drawn from a stationary SYMBOL -mixing or SYMBOL -mixing sequence, a widely adopted assumption in the study of non-iid processes that implies a dependence between observations weakening over time"} {"class.text":"OWNX","text":"These bounds strictly generalize the bounds given in the iid case and apply to all stable learning algorithms, thereby extending the use of stability-bounds to non-iid scenarios"} {"class.text":"OWNX","text":"We also illustrate the application of our SYMBOL -mixing generalization bounds to general classes of learning algorithms, including Support Vector Regression, Kernel Ridge Regression, and Support Vector Machines, and many other kernel regularization-based and relative entropy-based regularization algorithms"} {"class.text":"OWNX","text":"These novel bounds can thus be viewed as the first theoretical basis for the use of these algorithms in non-iid scenarios"} {"class.text":"MISC","text":"Most generalization bounds in learning theory are based on some measure of the complexity of the hypothesis class used, such as the VC-dimension, covering numbers, or Rademacher complexity"} {"class.text":"MISC","text":"In contrast, the notion of algorithmic stability can be used to derive bounds that are tailored to specific learning algorithms and exploit their particular properties"} {"class.text":"MISC","text":"A learning algorithm is stable if the hypothesis it outputs varies in a limited way in response to small changes made to the training set"} {"class.text":"MISC","text":"Algorithmic stability has been used effectively in the past to derive tight generalization bounds CITATION"} {"class.text":"MISC","text":"But, as in much of learning theory, existing stability analyses and bounds apply only in the scenario where the samples are independently and identically distributed (iid)"} {"class.text":"MISC","text":"In many machine learning applications, this assumption, however, does not hold; in fact, the iid assumption is not tested or derived from any data analysis"} {"class.text":"MISC","text":"The observations received by the learning algorithm often have some inherent temporal dependence"} {"class.text":"MISC","text":"This is clear in system diagnosis or time series prediction problems"} {"class.text":"MISC","text":"Clearly, prices of different stocks on the same day, or of the same stock on different days, may be dependent"} {"class.text":"AIMX","text":"This paper studies the scenario where the observations are drawn from a stationary SYMBOL -mixing or SYMBOL -mixing sequence, a widely adopted assumption in the study of non-iid processes that implies a dependence between observations weakening over time CITATION"} {"class.text":"OWNX","text":"These bounds strictly generalize the bounds given in the iid case and apply to all stable learning algorithms, thereby extending the usefulness of stability-bounds to non-iid scenarios"} {"class.text":"BASE","text":"Our proofs are based on the independent block technique described by CITATION and attributed to CITATION , which is commonly used in such contexts"} {"class.text":"CONT","text":"However, our analysis differs from previous uses of this technique in that the blocks of points considered are not of equal size"} {"class.text":"BASE","text":"For our analysis of stationary SYMBOL -mixing sequences, we make use of a generalized version of McDiarmid's inequality CITATION that holds for SYMBOL -mixing sequences"} {"class.text":"BASE","text":"This leads to stability-based generalization bounds with the standard exponential form"} {"class.text":"CONT","text":"Our generalization bounds for stationary SYMBOL -mixing sequences cover a more general non-iid scenario and use the standard McDiarmid's inequality, however, unlike the SYMBOL -mixing case, the SYMBOL -mixing bound presented here is not a purely exponential bound and contains an additive term depending on the mixing coefficient"} {"class.text":"CONT","text":"To our knowledge, the use of these algorithms in non-iid scenarios has not been previously supported by any theoretical analysis"} {"class.text":"OWNX","text":"The stability bounds we give for SVR, SVMs, and many other kernel regularization-based and relative entropy-based regularization algorithms can thus be viewed as the first theoretical basis for their use in such scenarios"} {"class.text":"OWNX","text":"The following sections are organized as follows"} {"class.text":"OWNX","text":"In Section~, we introduce the necessary definitions for the non-iid problems that we are considering and discuss the learning scenarios in that context"} {"class.text":"OWNX","text":"Section~ gives our main generalization bounds for stationary SYMBOL -mixing sequences based on stability, as well as the illustration of its applications to general kernel regularization-based algorithms, including SVR, KRR, and SVMs, as well as to relative entropy-based regularization algorithms"} {"class.text":"OWNX","text":"Finally, Section~ presents the first known stability bounds for the more general stationary SYMBOL -mixing scenario"} {"class.text":"MISC","text":"Most generalization bounds in learning theory are based on some measure of the complexity of the hypothesis class used, independently of any algorithm"} {"class.text":"MISC","text":"In contrast, the notion of algorithmic stability can be used to derive tight generalization bounds that are tailored to specific learning algorithms by exploiting their particular properties"} {"class.text":"MISC","text":"However, as in much of learning theory, existing stability analyses and bounds apply only in the scenario where the samples are independently and identically distributed"} {"class.text":"MISC","text":"In many machine learning applications, however, this assumption does not hold"} {"class.text":"MISC","text":"The observations received by the learning algorithm often have some inherent temporal dependence"} {"class.text":"AIMX","text":"This paper studies the scenario where the observations are drawn from a stationary SYMBOL -mixing or SYMBOL -mixing sequence, a widely adopted assumption in the study of non-iid processes that implies a dependence between observations weakening over time"} {"class.text":"OWNX","text":"We prove novel and distinct stability-based generalization bounds for stationary SYMBOL -mixing and SYMBOL -mixing sequences"} {"class.text":"OWNX","text":"These bounds strictly generalize the bounds given in the iid case and apply to all stable learning algorithms, thereby extending the use of stability-bounds to non-iid scenarios"} {"class.text":"OWNX","text":"We also illustrate the application of our SYMBOL -mixing generalization bounds to general classes of learning algorithms, including Support Vector Regression, Kernel Ridge Regression, and Support Vector Machines, and many other kernel regularization-based and relative entropy-based regularization algorithms"} {"class.text":"OWNX","text":"These novel bounds can thus be viewed as the first theoretical basis for the use of these algorithms in non-iid scenarios"} {"class.text":"MISC","text":"Most generalization bounds in learning theory are based on some measure of the complexity of the hypothesis class used, such as the VC-dimension, covering numbers, or Rademacher complexity"} {"class.text":"MISC","text":"These measures characterize a class of hypotheses, independently of any algorithm"} {"class.text":"MISC","text":"A learning algorithm is stable if the hypothesis it outputs varies in a limited way in response to small changes made to the training set"} {"class.text":"MISC","text":"Algorithmic stability has been used effectively in the past to derive tight generalization bounds CITATION"} {"class.text":"MISC","text":"But, as in much of learning theory, existing stability analyses and bounds apply only in the scenario where the samples are independently and identically distributed (iid)"} {"class.text":"MISC","text":"The observations received by the learning algorithm often have some inherent temporal dependence"} {"class.text":"AIMX","text":"This paper studies the scenario where the observations are drawn from a stationary SYMBOL -mixing or SYMBOL -mixing sequence, a widely adopted assumption in the study of non-iid processes that implies a dependence between observations weakening over time CITATION"} {"class.text":"OWNX","text":"We prove novel and distinct stability-based generalization bounds for stationary SYMBOL -mixing and SYMBOL -mixing sequences"} {"class.text":"OWNX","text":"These bounds strictly generalize the bounds given in the iid case and apply to all stable learning algorithms, thereby extending the usefulness of stability-bounds to non-iid scenarios"} {"class.text":"BASE","text":"Our proofs are based on the independent block technique described by CITATION and attributed to CITATION , which is commonly used in such contextsMISC"} {"class.text":"CONT","text":"However, our analysis differs from previous uses of this technique in that the blocks of points considered are not of equal size"} {"class.text":"BASE","text":"For our analysis of stationary SYMBOL -mixing sequences, we make use of a generalized version of McDiarmid's inequality CITATION that holds for SYMBOL -mixing sequences"} {"class.text":"OWNX","text":"This leads to stability-based generalization bounds with the standard exponential form"} {"class.text":"OWNX","text":"We also illustrate the application of our SYMBOL -mixing generalization bounds to general classes of learning algorithms, including Support Vector Regression (SVR) CITATION , Kernel Ridge Regression CITATION , and Support Vector Machines (SVMs) CITATION"} {"class.text":"MISC","text":"Algorithms such as support vector regression (SVR) CITATION have been used in the context of time series prediction in which the iid assumption does not hold, some with good experimental results CITATION"} {"class.text":"MISC","text":"To our knowledge, the use of these algorithms in non-iid scenarios has not been previously supported by any theoretical analysis"} {"class.text":"OWNX","text":"The stability bounds we give for SVR, SVMs, and many other kernel regularization-based and relative entropy-based regularization algorithms can thus be viewed as the first theoretical basis for their use in such scenarios"} {"class.text":"MISC","text":"The following sections are organized as follows"} {"class.text":"OWNX","text":"In Section~, we introduce the necessary definitions for the non-iid problems that we are considering and discuss the learning scenarios in that context"} {"class.text":"OWNX","text":"Section~ gives our main generalization bounds for stationary SYMBOL -mixing sequences based on stability, as well as the illustration of its applications to general kernel regularization-based algorithms, including SVR, KRR, and SVMs, as well as to relative entropy-based regularization algorithms"} {"class.text":"OWNX","text":"Finally, Section~ presents the first known stability bounds for the more general stationary SYMBOL -mixing scenario"} {"class.text":"OWNX","text":"we derive a qa algorithm for clustering and propose an annealing schedule which is crucial in practice"} {"class.text":"CONT","text":"experiments show the proposed qa algorithm finds better clustering assignments than sa"} {"class.text":"CONT","text":"furthermore qa is as easy as sa to implement"} {"class.text":"MISC","text":"typically clustering problems are formulated as optimization problems which are solved by algorithms for example the em algorithm or convex relaxation"} {"class.text":"MISC","text":"the simulated annealing sa CITATION is a promising candidate"} {"class.text":"MISC","text":"CITATION proved sa was able to find the global optimum with a slow cooling schedule of temperature"} {"class.text":"CONT","text":"although their schedule is in practice too slow for clustering of a large amount of data it is well known that sa still finds a reasonably good solution even with a faster schedule than what citeauthor geman NUMBER proposed"} {"class.text":"CONT","text":"in statistical mechanics quantum annealing qa has been proposed as a novel alternative to sa CITATION"} {"class.text":"CONT","text":"qa adds another dimension to sa for annealing see fig"} {"class.text":"BASE","text":"thus it can be seen as an extension of sa"} {"class.text":"MISC","text":"qa has succeeded in specific problems e g the ising model in statistical mechanics and it is still unclear that qa works better than sa in general"} {"class.text":"MISC","text":"a derived qa algorithm depends on the definition of quantum effect"} {"class.text":"OWNX","text":"we propose quantum effect which leads to a search strategy fit to clustering"} {"class.text":"OWNX","text":"we also show the proposed algorithm is as easy as sa to implement"} {"class.text":"OWNX","text":"\tthe algorithm we propose is a markov chain monte carlo mcmc sampler which we call qa st sampler"} {"class.text":"OWNX","text":"thus we approximate qa by the suzuki trotter st expansion CITATION to derive a tractable sampler which is the qa st sampler"} {"class.text":"OWNX","text":"qa st looks like parallel sas with interaction see fig"} {"class.text":"OWNX","text":"at the beginning of the annealing process qa st is almost the same as sas"} {"class.text":"OWNX","text":"hence qa st finds local optima independently"} {"class.text":"OWNX","text":"as the annealing process continues interaction in fig becomes stronger to move states closer"} {"class.text":"OWNX","text":"qa st at the end picks up the state with the lowest energy in states as the final solution"} {"class.text":"OWNX","text":"qa st with the proposed quantum effect works well for clustering"} {"class.text":"OWNX","text":"fig is an example where data points are grouped into four clusters"} {"class.text":"OWNX","text":"SYMBOL and SYMBOL are locally optimal and is globally optimal"} {"class.text":"OWNX","text":"suppose SYMBOL is equal to two and SYMBOL and SYMBOL in fig correspond to SYMBOL and SYMBOL in fig"} {"class.text":"OWNX","text":"although and are local optima the interaction in fig allows and to search for a better clustering assignment between and"} {"class.text":"OWNX","text":"quantum effect defines the distance metric of clustering assignments"} {"class.text":"OWNX","text":"thus the interaction gives good chance to go to because makes and closer see fig"} {"class.text":"OWNX","text":"the proposed algorithm actually finds from and"} {"class.text":"OWNX","text":"fig is just an example"} {"class.text":"MISC","text":"however a similar situation often occurs in clustering"} {"class.text":"MISC","text":"clustering algorithms in most cases give almost globally optimal solutions like and where the majority of data points are well clustered but some of them are not"} {"class.text":"MISC","text":"note an assignment constructed in such a way is located between the sub optimal ones by the proposed quantum effect so that qa st can find a better assignment between sub optimal ones"} {"class.text":"AIMX","text":"This paper studies quantum annealing (QA) for clustering, which can be seen as an extension of simulated annealing (SA)"} {"class.text":"AIMX","text":"We derive a QA algorithm for clustering and propose an annealing schedule, which is crucial in practice"} {"class.text":"OWNX","text":"Experiments show the proposed QA algorithm finds better clustering assignments than SA"} {"class.text":"OWNX","text":"Furthermore, QA is as easy as SA to implement"} {"class.text":"MISC","text":"Clustering is one of the most popular methods in data mining"} {"class.text":"MISC","text":"Typically, clustering problems are formulated as optimization problems, which are solved by algorithms, for example the EM algorithm or convex relaxation"} {"class.text":"MISC","text":"The simulated annealing (SA) CITATION is a promising candidate"} {"class.text":"MISC","text":"Although their schedule is in practice too slow for clustering of a large amount of data, it is well known that SA still finds a reasonably good solution even with a faster schedule than what CITATION proposed"} {"class.text":"MISC","text":"In statistical mechanics, quantum annealing (QA) has been proposed as a novel alternative to SA CITATION"} {"class.text":"MISC","text":"QA adds another dimension, SYMBOL , to SA for annealing, see Fig"} {"class.text":"MISC","text":"Thus, it can be seen as an extension of SA"} {"class.text":"MISC","text":"QA has succeeded in specific problems, e g the Ising model in statistical mechanics, and it is still unclear that QA works better than SA in general"} {"class.text":"OWNX","text":"We do not actually think QA intuitively helps clustering, but we apply QA to clustering just as procedure to derive an algorithm"} {"class.text":"MISC","text":"A derived QA algorithm depends on the definition of quantum effect SYMBOL"} {"class.text":"AIMX","text":"Our contribution is, 1) to propose a QA-based optimization algorithm for clustering, in particular quantum effect SYMBOL for clustering and a good annealing schedule, which is crucial for applications, 2) and to experimentally show the proposed algorithm optimizes clustering assignments better than SA"} {"class.text":"OWNX","text":"We also show the proposed algorithm is as easy as SA to implement"} {"class.text":"OWNX","text":"The algorithm we propose is a Markov chain Monte Carlo (MCMC) sampler, which we call QA-ST sampler"} {"class.text":"OWNX","text":"As we explain later, a naive QA sampler is intractable even with MCMC"} {"class.text":"AIMX","text":"Thus, we approximate QA by the Suzuki-Trotter (ST) expansion CITATION to derive a tractable sampler, which is the QA-ST sampler"} {"class.text":"OWNX","text":"Hence, QA-ST finds SYMBOL (local) optima independently"} {"class.text":"OWNX","text":"As the annealing process continues, interaction SYMBOL in Fig becomes stronger to move SYMBOL states closer"} {"class.text":"OWNX","text":"QA-ST at the end picks up the state with the lowest energy in SYMBOL states as the final solution"} {"class.text":"OWNX","text":"QA-ST with the proposed quantum effect SYMBOL works well for clustering"} {"class.text":"OWNX","text":"SYMBOL and SYMBOL are locally optimal and SYMBOL is globally optimal"} {"class.text":"OWNX","text":"Suppose SYMBOL is equal to two and SYMBOL and SYMBOL in Fig correspond to SYMBOL and SYMBOL in Fig"} {"class.text":"OWNX","text":"Although SYMBOL and SYMBOL are local optima, the interaction SYMBOL in Fig allows SYMBOL and SYMBOL to search for a better clustering assignment between SYMBOL and SYMBOL"} {"class.text":"OWNX","text":"Quantum effect SYMBOL defines the distance metric of clustering assignments"} {"class.text":"OWNX","text":"In this case, the proposed SYMBOL locates SYMBOL between SYMBOL and SYMBOL"} {"class.text":"OWNX","text":"Thus, the interaction SYMBOL gives good chance to go to SYMBOL because SYMBOL makes SYMBOL and SYMBOL closer (see Fig )"} {"class.text":"MISC","text":"However, a similar situation often occurs in clustering"} {"class.text":"CONT","text":"Clustering algorithms in most cases give ``almost'' globally optimal solutions like SYMBOL and SYMBOL , where the majority of data points are well-clustered, but some of them are not"} {"class.text":"CONT","text":"Thus, a better clustering assignment can be constructed by picking up well-clustered data points from many sub-optimal clustering assignments"} {"class.text":"CONT","text":"Note an assignment constructed in such a way is located between the sub-optimal ones by the proposed quantum effect SYMBOL so that QA-ST can find a better assignment between sub-optimal ones"} {"class.text":"OWNX","text":"This paper studies quantum annealing (QA) for clustering, which can be seen as an extension of simulated annealing (SA)"} {"class.text":"AIMX","text":"We derive a QA algorithm for clustering and propose an annealing schedule, which is crucial in practice"} {"class.text":"OWNX","text":"Furthermore, QA is as easy as SA to implement"} {"class.text":"MISC","text":"Typically, clustering problems are formulated as optimization problems, which are solved by algorithms, for example the EM algorithm or convex relaxation"} {"class.text":"MISC","text":"However, clustering is typically NP-hard"} {"class.text":"MISC","text":"Although their schedule is in practice too slow for clustering of a large amount of data, it is well known that SA still finds a reasonably good solution even with a faster schedule than what CITATION proposed"} {"class.text":"MISC","text":"In statistical mechanics, quantum annealing (QA) has been proposed as a novel alternative to SA CITATION"} {"class.text":"MISC","text":"QA adds another dimension, SYMBOL , to SA for annealing, see Fig"} {"class.text":"MISC","text":"Thus, it can be seen as an extension of SA"} {"class.text":"MISC","text":"QA has succeeded in specific problems, e g the Ising model in statistical mechanics, and it is still unclear that QA works better than SA in general"} {"class.text":"OWNX","text":"We do not actually think QA intuitively helps clustering, but we apply QA to clustering just as procedure to derive an algorithm"} {"class.text":"AIMX","text":"We propose quantum effect SYMBOL , which leads to a search strategy fit to clustering"} {"class.text":"OWNX","text":"We also show the proposed algorithm is as easy as SA to implement"} {"class.text":"OWNX","text":"The algorithm we propose is a Markov chain Monte Carlo (MCMC) sampler, which we call QA-ST sampler"} {"class.text":"OWNX","text":"Thus, we approximate QA by the Suzuki-Trotter (ST) expansion CITATION to derive a tractable sampler, which is the QA-ST sampler"} {"class.text":"OWNX","text":"QA-ST looks like parallel SYMBOL SAs with interaction SYMBOL (see Fig )"} {"class.text":"OWNX","text":"At the beginning of the annealing process, QA-ST is almost the same as SYMBOL SAs"} {"class.text":"OWNX","text":"Hence, QA-ST finds SYMBOL (local) optima independently"} {"class.text":"OWNX","text":"As the annealing process continues, interaction SYMBOL in Fig becomes stronger to move SYMBOL states closer"} {"class.text":"OWNX","text":"QA-ST at the end picks up the state with the lowest energy in SYMBOL states as the final solution"} {"class.text":"OWNX","text":"QA-ST with the proposed quantum effect SYMBOL works well for clustering"} {"class.text":"MISC","text":"Fig is an example where data points are grouped into four clusters"} {"class.text":"MISC","text":"Suppose SYMBOL is equal to two and SYMBOL and SYMBOL in Fig correspond to SYMBOL and SYMBOL in Fig"} {"class.text":"MISC","text":"Although SYMBOL and SYMBOL are local optima, the interaction SYMBOL in Fig allows SYMBOL and SYMBOL to search for a better clustering assignment between SYMBOL and SYMBOL"} {"class.text":"MISC","text":"Quantum effect SYMBOL defines the distance metric of clustering assignments"} {"class.text":"MISC","text":"In this case, the proposed SYMBOL locates SYMBOL between SYMBOL and SYMBOL"} {"class.text":"OWNX","text":"The proposed algorithm actually finds SYMBOL from SYMBOL and SYMBOL"} {"class.text":"MISC","text":"Fig is just an example"} {"class.text":"MISC","text":"However, a similar situation often occurs in clustering"} {"class.text":"MISC","text":"Thus, a better clustering assignment can be constructed by picking up well-clustered data points from many sub-optimal clustering assignments"} {"class.text":"OWNX","text":"Note an assignment constructed in such a way is located between the sub-optimal ones by the proposed quantum effect SYMBOL so that QA-ST can find a better assignment between sub-optimal ones"} {"class.text":"AIMX","text":"we introduce a new principle for model selection in regression and classification"} {"class.text":"MISC","text":"many regression models are controlled by some smoothness or flexibility or complexity parameter e g the number of neighbors to be averaged over in k nearest neighbor knn regression or the polynomial degree in regression with polynomials"} {"class.text":"OWNX","text":"let be the best regressor of complexity on data"} {"class.text":"MISC","text":"a more flexible regressor can fit more data well than a more rigid one"} {"class.text":"OWNX","text":"we define the loss rank of as the number of other fictitious data that are fitted better by than is fitted by"} {"class.text":"OWNX","text":"we suggest selecting the model complexity that has minimal loss rank lorp"} {"class.text":"MISC","text":"it works without a stochastic noise model and is directly applicable to any non parametric regressor like knn"} {"class.text":"OWNX","text":"consider a regression or classification problem in which we want to determine the functional relationship from data i e we seek a function such that is close to the unknown for all"} {"class.text":"MISC","text":"if the class is not too large e g the polynomials of fixed reasonable degree this often works well"} {"class.text":"MISC","text":"what remains is to select the right model complexity like or"} {"class.text":"MISC","text":"this selection cannot be based on the training error since the more complex the model large small the better the fit on perfect for and"} {"class.text":"OWNX","text":"this problem is called overfitting for which various remedies have been suggested we will not discuss empirical test set methods like cross validation but only training set based methods"} {"class.text":"MISC","text":"see e g CITATION for a comparison of cross validation with bayesian model selection"} {"class.text":"MISC","text":"the most popular ones can be regarded as penalized versions of maximum likelihood ml"} {"class.text":"MISC","text":"in addition to the function class one has to specify a sampling model e g that the have independent gaussian distribution with mean"} {"class.text":"MISC","text":"ml chooses penalized ml pml then chooses penalty where the penalty depends on the used approach mdl CITATION bic CITATION aic CITATION"} {"class.text":"MISC","text":"in particular modern mdl CITATION has sound exact foundations and works very well in practice"} {"class.text":"CONT","text":"all pml variants rely on a proper sampling model which may be difficult to establish ignore or at least do not tell how to incorporate a potentially given loss function and are typically limited to semi parametric models"} {"class.text":"MISC","text":"the loss rank is large for regressors fitting not well and for too flexible regressors in both cases the regressor fits many other better"} {"class.text":"MISC","text":"the loss rank has a minimum for not too flexible regressors which fit not too bad"} {"class.text":"OWNX","text":"we claim that minimizing the loss rank is a suitable model selection criterion since it trades off the quality of fit with the flexibility of the model"} {"class.text":"CONT","text":"unlike pml our new loss rank principle lorp works without a noise stochastic sampling model and is directly applicable to any non parametric regressor like knn"} {"class.text":"OWNX","text":"in section after giving a brief introduction to regression we formally state lorp for model selection"} {"class.text":"OWNX","text":"in section we derive explicit expressions for the loss rank for the important class of linear regressors which includes knn polynomial linear basis function lbfr kernel and projective regression"} {"class.text":"OWNX","text":"in section we compare linear lorp to bayesian model selection for linear regression with gaussian noise and prior and in section to pml in particular mdl bic aic and mackay s CITATION and hastie s et al CITATION trace formulas for the effective dimension"} {"class.text":"OWNX","text":"section contains further considerations to be elaborated on in the future"} {"class.text":"OWNX","text":"We introduce a new principle for model selection in regression and classification"} {"class.text":"MISC","text":"Many regression models are controlled by some smoothness or flexibility or complexity parameter SYMBOL , eg the number of neighbors to be averaged over in k nearest neighbor (kNN) regression or the polynomial degree in regression with polynomials"} {"class.text":"MISC","text":"Let SYMBOL be the (best) regressor of complexity SYMBOL on data SYMBOL"} {"class.text":"MISC","text":"A more flexible regressor can fit more data SYMBOL well than a more rigid one"} {"class.text":"MISC","text":"If something (here small loss) is easy to achieve it's typically worth less"} {"class.text":"OWNX","text":"We suggest selecting the model complexity SYMBOL that has minimal loss rank (LoRP)"} {"class.text":"CONT","text":"Unlike most penalized maximum likelihood variants (AIC,BIC,MDL), LoRP only depends on the regression functions and the loss function"} {"class.text":"AIMX","text":"In this paper we formalize, discuss, and motivate LoRP, study it for specific regression problems, in particular linear ones, and compare it to other model selection schemes"} {"class.text":"OWNX","text":"Consider a regression or classification problem in which we want to determine the functional relationship SYMBOL from data SYMBOL , ie we seek a function SYMBOL such that SYMBOL is close to the unknown SYMBOL for all SYMBOL"} {"class.text":"OWNX","text":"One may define regressor SYMBOL directly, eg `average the SYMBOL values of the SYMBOL nearest neighbors (kNN) of SYMBOL in SYMBOL ', or select the SYMBOL from a class of functions SYMBOL that has smallest (training) error on SYMBOL"} {"class.text":"OWNX","text":"What remains is to select the right model complexity SYMBOL , like SYMBOL or SYMBOL"} {"class.text":"OWNX","text":"This selection cannot be based on the training error, since the more complex the model (large SYMBOL , small SYMBOL ) the better the fit on SYMBOL (perfect for SYMBOL and SYMBOL )"} {"class.text":"MISC","text":"This problem is called overfitting, for which various remedies have been suggested: We will not discuss empirical test set methods like cross-validation, but only training set based methods"} {"class.text":"MISC","text":"The most popular ones can be regarded as penalized versions of Maximum Likelihood (ML)"} {"class.text":"OWNX","text":"In addition to the function class SYMBOL , one has to specify a sampling model SYMBOL , eg that the SYMBOL have independent Gaussian distribution with mean SYMBOL"} {"class.text":"OWNX","text":"ML chooses SYMBOL , Penalized ML (PML) then chooses SYMBOL Penalty SYMBOL , where the penalty depends on the used approach (MDL CITATION , BIC CITATION , AIC CITATION )"} {"class.text":"MISC","text":"All PML variants rely on a proper sampling model (which may be difficult to establish), ignore (or at least do not tell how to incorporate) a potentially given loss function, and are typically limited to (semi)parametric models"} {"class.text":"OWNX","text":"The key observation we exploit is that large classes SYMBOL or more flexible regressors SYMBOL can fit more data SYMBOL well than more rigid ones, eg many SYMBOL can be fit well with high order polynomials"} {"class.text":"OWNX","text":"We define the loss rank of SYMBOL as the number of other (fictitious) data SYMBOL that are fitted better by SYMBOL than SYMBOL is fitted by SYMBOL , as measured by some loss function"} {"class.text":"OWNX","text":"The loss rank has a minimum for not too flexible regressors which fit SYMBOL not too bad"} {"class.text":"OWNX","text":"We claim that minimizing the loss rank is a suitable model selection criterion, since it trades off the quality of fit with the flexibility of the model"} {"class.text":"OWNX","text":"Unlike PML, our new Loss Rank Principle (LoRP) works without a noise (stochastic sampling) model, and is directly applicable to any non-parametric regressor, like kNN"} {"class.text":"OWNX","text":"In Section , after giving a brief introduction to regression, we formally state LoRP for model selection"} {"class.text":"OWNX","text":"In Section we compare linear LoRP to Bayesian model selection for linear regression with Gaussian noise and prior, and in Section to PML, in particular MDL, BIC, AIC, and MacKay's CITATION and Hastie's et al CITATION trace formulas for the effective dimension"} {"class.text":"OWNX","text":"In this paper we just scratch at the surface of LoRP"} {"class.text":"OWNX","text":"Section contains further considerations, to be elaborated on in the future"} {"class.text":"AIMX","text":"We introduce a new principle for model selection in regression and classification"} {"class.text":"MISC","text":"Many regression models are controlled by some smoothness or flexibility or complexity parameter SYMBOL , eg the number of neighbors to be averaged over in k nearest neighbor (kNN) regression or the polynomial degree in regression with polynomials"} {"class.text":"MISC","text":"If something (here small loss) is easy to achieve it's typically worth less"} {"class.text":"OWNX","text":"We define the loss rank of SYMBOL as the number of other (fictitious) data SYMBOL that are fitted better by SYMBOL than SYMBOL is fitted by SYMBOL"} {"class.text":"OWNX","text":"We suggest selecting the model complexity SYMBOL that has minimal loss rank (LoRP)"} {"class.text":"CONT","text":"It works without a stochastic noise model, and is directly applicable to any non-parametric regressor, like kNN"} {"class.text":"OWNX","text":"In this paper we formalize, discuss, and motivate LoRP, study it for specific regression problems, in particular linear ones, and compare it to other model selection schemes"} {"class.text":"MISC","text":"Consider a regression or classification problem in which we want to determine the functional relationship SYMBOL from data SYMBOL , ie we seek a function SYMBOL such that SYMBOL is close to the unknown SYMBOL for all SYMBOL"} {"class.text":"MISC","text":"One may define regressor SYMBOL directly, eg `average the SYMBOL values of the SYMBOL nearest neighbors (kNN) of SYMBOL in SYMBOL ', or select the SYMBOL from a class of functions SYMBOL that has smallest (training) error on SYMBOL"} {"class.text":"MISC","text":"If the class SYMBOL is not too large, e g the polynomials of fixed reasonable degree SYMBOL , this often works well"} {"class.text":"MISC","text":"What remains is to select the right model complexity SYMBOL , like SYMBOL or SYMBOL"} {"class.text":"MISC","text":"This selection cannot be based on the training error, since the more complex the model (large SYMBOL , small SYMBOL ) the better the fit on SYMBOL (perfect for SYMBOL and SYMBOL )"} {"class.text":"MISC","text":"This problem is called overfitting, for which various remedies have been suggested: We will not discuss empirical test set methods like cross-validation, but only training set based methods"} {"class.text":"MISC","text":"See eg CITATION for a comparison of cross-validation with Bayesian model selection"} {"class.text":"MISC","text":"Training set based model selection methods allow using all data SYMBOL for regression"} {"class.text":"MISC","text":"The most popular ones can be regarded as penalized versions of Maximum Likelihood (ML)"} {"class.text":"MISC","text":"In addition to the function class SYMBOL , one has to specify a sampling model SYMBOL , eg that the SYMBOL have independent Gaussian distribution with mean SYMBOL"} {"class.text":"MISC","text":"ML chooses SYMBOL , Penalized ML (PML) then chooses SYMBOL Penalty SYMBOL , where the penalty depends on the used approach (MDL CITATION , BIC CITATION , AIC CITATION )"} {"class.text":"MISC","text":"In particular, modern MDL CITATION has sound exact foundations and works very well in practice"} {"class.text":"CONT","text":"All PML variants rely on a proper sampling model (which may be difficult to establish), ignore (or at least do not tell how to incorporate) a potentially given loss function, and are typically limited to (semi)parametric models"} {"class.text":"AIMX","text":"The main goal of the paper is to establish a criterion for selecting the ``best'' model complexity SYMBOL based on regressors SYMBOL given as a black box without insight into the origin or inner structure of SYMBOL , that does not depend on things often not given (like a stochastic noise model), and that exploits what is given (like the loss function)"} {"class.text":"OWNX","text":"The key observation we exploit is that large classes SYMBOL or more flexible regressors SYMBOL can fit more data SYMBOL well than more rigid ones, eg many SYMBOL can be fit well with high order polynomials"} {"class.text":"OWNX","text":"We define the loss rank of SYMBOL as the number of other (fictitious) data SYMBOL that are fitted better by SYMBOL than SYMBOL is fitted by SYMBOL , as measured by some loss function"} {"class.text":"OWNX","text":"The loss rank is large for regressors fitting SYMBOL not well and for too flexible regressors (in both cases the regressor fits many other SYMBOL better)"} {"class.text":"OWNX","text":"The loss rank has a minimum for not too flexible regressors which fit SYMBOL not too bad"} {"class.text":"OWNX","text":"We claim that minimizing the loss rank is a suitable model selection criterion, since it trades off the quality of fit with the flexibility of the model"} {"class.text":"CONT","text":"Unlike PML, our new Loss Rank Principle (LoRP) works without a noise (stochastic sampling) model, and is directly applicable to any non-parametric regressor, like kNN"} {"class.text":"OWNX","text":"In Section we derive explicit expressions for the loss rank for the important class of linear regressors, which includes kNN, polynomial, linear basis function (LBFR), Kernel, and projective regression"} {"class.text":"OWNX","text":"In this paper we just scratch at the surface of LoRP"} {"class.text":"OWNX","text":"Section contains further considerations, to be elaborated on in the future"} {"class.text":"AIMX","text":"we propose a nonparametric bayesian factor regression model that accounts for uncertainty in the number of factors and the relationship between factors"} {"class.text":"OWNX","text":"to accomplish this we propose a sparse variant of the indian buffet process and couple this with a hierarchical model over factors based on kingman s coalescent"} {"class.text":"AIMX","text":"we apply this model to two problems factor analysis and factor regression in gene expression data analysis"} {"class.text":"MISC","text":"factor analysis is the task of explaining data by means of a set of latent factors"} {"class.text":"MISC","text":"the latent factor representation achieves two fold benefits NUMBER discovering the latent process underlying the data NUMBER simpler predictive modeling through a compact data representation"} {"class.text":"MISC","text":"in particular NUMBER is motivated by the problem of prediction in the large p small n paradigm CITATION where the number of features greatly exceeds the number of examples potentially resulting in overfitting"} {"class.text":"CONT","text":"we address three fundamental shortcomings of standard factor analysis approaches CITATION NUMBER we do not assume a known number of factors NUMBER we do not assume factors are independent NUMBER we do not assume all features are relevant to the factor analysis"} {"class.text":"AIMX","text":"our motivation for this work stems from the task of reconstructing regulatory structure from gene expression data"} {"class.text":"MISC","text":"in this context factors correspond to regulatory pathways"} {"class.text":"AIMX","text":"our contributions thus parallel the needs of gene pathway modeling"} {"class.text":"OWNX","text":"our factor regression model is fundamentally nonparametric"} {"class.text":"OWNX","text":"in particular we treat the gene to factor relationship nonparametrically by proposing a sparse variant of the indian buffet process ibp CITATION designed to account for the sparsity of relevant genes features"} {"class.text":"OWNX","text":"the nonparametric nature of our sparse ibp requires that the hierarchical prior also be nonparametric"} {"class.text":"BASE","text":"a natural choice is kingman s coalescent CITATION a popular distribution over infinite binary trees"} {"class.text":"OWNX","text":"since our motivation is an application in bioinformatics our notation and terminology will be drawn from that area"} {"class.text":"OWNX","text":"in particular genes are features samples are examples and pathways are factors"} {"class.text":"OWNX","text":"in this context all three contributions of our model still make sense we do not know how many movie genres there are some genres are closely related romance to comedy versus to action many movies may be spurious"} {"class.text":"AIMX","text":"We propose a nonparametric Bayesian factor regression model that accounts for uncertainty in the number of factors, and the relationship between factors"} {"class.text":"OWNX","text":"To accomplish this, we propose a sparse variant of the Indian Buffet Process and couple this with a hierarchical model over factors, based on Kingman's coalescent"} {"class.text":"OWNX","text":"We apply this model to two problems (factor analysis and factor regression) in gene-expression data analysis"} {"class.text":"MISC","text":"Factor analysis is the task of explaining data by means of a set of latent factors"} {"class.text":"MISC","text":"Factor regression couples this analysis with a prediction task, where the predictions are made solely on the basis of the factor representation"} {"class.text":"AIMX","text":"We address three fundamental shortcomings of standard factor analysis approaches CITATION : (1) we do not assume a known number of factors; (2) we do not assume factors are independent; (3) we do not assume all features are relevant to the factor analysis"} {"class.text":"OWNX","text":"Our motivation for this work stems from the task of reconstructing regulatory structure from gene-expression data"} {"class.text":"OWNX","text":"In this context, factors correspond to regulatory pathways"} {"class.text":"OWNX","text":"Our contributions thus parallel the needs of gene pathway modeling"} {"class.text":"OWNX","text":"In addition, we couple predictive modeling (for factor regression) within the factor analysis framework itself, instead of having to model it separately"} {"class.text":"OWNX","text":"Our factor regression model is fundamentally nonparametric"} {"class.text":"OWNX","text":"In particular, we treat the gene-to-factor relationship nonparametrically by proposing a sparse variant of the Indian Buffet Process (IBP) CITATION , designed to account for the sparsity of relevant genes (features)"} {"class.text":"OWNX","text":"We couple this IBP with a hierarchical prior over the factors"} {"class.text":"OWNX","text":"This prior explains the fact that pathways are fundamentally related: some are involved in transcription, some in signaling, some in synthesis"} {"class.text":"BASE","text":"A natural choice is Kingman's coalescent CITATION , a popular distribution over infinite binary trees"} {"class.text":"OWNX","text":"Since our motivation is an application in bioinformatics, our notation and terminology will be drawn from that area"} {"class.text":"OWNX","text":"In particular, genes are features , samples are examples , and pathways are factors"} {"class.text":"OWNX","text":"However, our model is more general"} {"class.text":"OWNX","text":"An alternative application might be to a collaborative filtering problem, in which case our genes might correspond to movies, our samples might correspond to users and our pathways might correspond to genres"} {"class.text":"AIMX","text":"We propose a nonparametric Bayesian factor regression model that accounts for uncertainty in the number of factors, and the relationship between factors"} {"class.text":"OWNX","text":"We apply this model to two problems (factor analysis and factor regression) in gene-expression data analysis"} {"class.text":"MISC","text":"Factor regression couples this analysis with a prediction task, where the predictions are made solely on the basis of the factor representation"} {"class.text":"MISC","text":"The latent factor representation achieves two-fold benefits: (1) discovering the latent process underlying the data; (2) simpler predictive modeling through a compact data representation"} {"class.text":"MISC","text":"In particular, (2) is motivated by the problem of prediction in the ``large P small N'' paradigm CITATION , where the number of features SYMBOL greatly exceeds the number of examples SYMBOL , potentially resulting in overfitting"} {"class.text":"CONT","text":"We address three fundamental shortcomings of standard factor analysis approaches CITATION : (1) we do not assume a known number of factors; (2) we do not assume factors are independent; (3) we do not assume all features are relevant to the factor analysis"} {"class.text":"OWNX","text":"Our motivation for this work stems from the task of reconstructing regulatory structure from gene-expression data"} {"class.text":"OWNX","text":"In this context, factors correspond to regulatory pathways"} {"class.text":"OWNX","text":"Our contributions thus parallel the needs of gene pathway modeling"} {"class.text":"OWNX","text":"In addition, we couple predictive modeling (for factor regression) within the factor analysis framework itself, instead of having to model it separately"} {"class.text":"OWNX","text":"In particular, we treat the gene-to-factor relationship nonparametrically by proposing a sparse variant of the Indian Buffet Process (IBP) CITATION , designed to account for the sparsity of relevant genes (features)"} {"class.text":"OWNX","text":"We couple this IBP with a hierarchical prior over the factors"} {"class.text":"OWNX","text":"This prior explains the fact that pathways are fundamentally related: some are involved in transcription, some in signaling, some in synthesis"} {"class.text":"OWNX","text":"The nonparametric nature of our sparse IBP requires that the hierarchical prior also be nonparametric"} {"class.text":"MISC","text":"A natural choice is Kingman's coalescent CITATION , a popular distribution over infinite binary trees"} {"class.text":"OWNX","text":"Since our motivation is an application in bioinformatics, our notation and terminology will be drawn from that area"} {"class.text":"OWNX","text":"In particular, genes are features , samples are examples , and pathways are factors"} {"class.text":"OWNX","text":"However, our model is more general"} {"class.text":"OWNX","text":"An alternative application might be to a collaborative filtering problem, in which case our genes might correspond to movies, our samples might correspond to users and our pathways might correspond to genres"} {"class.text":"OWNX","text":"In this context, all three contributions of our model still make sense: we do not know how many movie genres there are; some genres are closely related (romance to comedy versus to action); many movies may be spurious"} {"class.text":"MISC","text":"in the constraint satisfaction problem the aim is to find an assignment of values to a set of variables subject to specified constraints"} {"class.text":"MISC","text":"in the minimum cost homomorphism problem one is additionally given weights for every variable and value and the aim is to find an assignment to the variables that minimizes"} {"class.text":"MISC","text":"let denote the problem parameterized by the set of predicates allowed for constraints"} {"class.text":"AIMX","text":"we show that can be studied by using algebraic methods similar to those used for csps"} {"class.text":"CONT","text":"our result settles a general dichotomy conjecture previously resolved only for certain classes of directed graphs gutin hell rafiey yeo european j of combinatorics NUMBER"} {"class.text":"MISC","text":"constraint satisfaction problems are a natural way of formalizing a large number of computational problems arising in combinatorial optimization artificial intelligence and database theory"} {"class.text":"MISC","text":"this problem has the following two equivalent formulations NUMBER to find an assignment of values to a given set of variables subject to constraints on the values that can be assigned simultaneously to specified subsets of variables and NUMBER to find a homomorphism between two finite relational structures and"} {"class.text":"MISC","text":"considerable attention has been given to the case where the constraints are restricted to a given finite set of relations called a constraint language CITATION"} {"class.text":"MISC","text":"for example when is a constraint language over the boolean set with four ternary predicates we obtain NUMBER sat"} {"class.text":"MISC","text":"this direction of research has been mainly concerned with the computational complexity of as a function of"} {"class.text":"MISC","text":"it has been shown that the complexity of is highly connected with relational clones of universal algebra CITATION"} {"class.text":"MISC","text":"in the minimum cost homomorphism problem we are given variables subject to constraints and additionally costs on variable value pairs"} {"class.text":"MISC","text":"now the task is not just to find any satisfying assignment to the variables but one that minimizes the total cost"} {"class.text":"MISC","text":"was introduced in CITATION where it was motivated by a real world problem in defence logistics"} {"class.text":"MISC","text":"the question for which directed graphs the problem is polynomial time solvable was considered in CITATION"} {"class.text":"OWNX","text":"from this characterization we obtain a dichotomy for i e if is not polynomial time solvable then it is np hard"} {"class.text":"OWNX","text":"of course this dichotomy implies the dichotomy for directed graphs"} {"class.text":"OWNX","text":"in section NUMBER we present some preliminaries together with results connecting the complexity of with conservative algebras"} {"class.text":"OWNX","text":"the main dichotomy theorem is stated in section NUMBER and its proof is divided into several parts which can be found in sections NUMBER NUMBER"} {"class.text":"OWNX","text":"the np hardness results are collected in section NUMBER followed by the building blocks for the tractability result existence of majority polymorphisms section NUMBER and connections with optimization in perfect graphs section NUMBER"} {"class.text":"OWNX","text":"section NUMBER introduces the concept of arithmetical deadlocks which lay the foundation for the final proof in section NUMBER"} {"class.text":"OWNX","text":"in section NUMBER we reformulate our main result in terms of relational clones"} {"class.text":"BASE","text":"finally in section NUMBER we explain the relation of our results to previous research and present directions for future research"} {"class.text":"MISC","text":"In the constraint satisfaction problem ( SYMBOL ), the aim is to find an assignment of values to a set of variables subject to specified constraints"} {"class.text":"MISC","text":"In the minimum cost homomorphism problem ( SYMBOL ), one is additionally given weights SYMBOL for every variable SYMBOL and value SYMBOL , and the aim is to find an assignment SYMBOL to the variables that minimizes SYMBOL"} {"class.text":"OWNX","text":"Let SYMBOL denote the SYMBOL problem parameterized by the set of predicates allowed for constraints"} {"class.text":"OWNX","text":"We show that SYMBOL can be studied by using algebraic methods similar to those used for CSPs"} {"class.text":"OWNX","text":"With the aid of algebraic techniques, we classify the computational complexity of SYMBOL for all choices of SYMBOL"} {"class.text":"AIMX","text":"Our result settles a general dichotomy conjecture previously resolved only for certain classes of directed graphs CITATION"} {"class.text":"MISC","text":"Constraint satisfaction problems ( SYMBOL ) are a natural way of formalizing a large number of computational problems arising in combinatorial optimization, artificial intelligence, and database theory"} {"class.text":"MISC","text":"This problem has the following two equivalent formulations: (1) to find an assignment of values to a given set of variables, subject to constraints on the values that can be assigned simultaneously to specified subsets of variables, and (2) to find a homomorphism between two finite relational structures SYMBOL and SYMBOL"} {"class.text":"MISC","text":"Applications of SYMBOL s arise in the propositional logic, database and graph theory, scheduling and many other areas"} {"class.text":"MISC","text":"During the past 30 years, SYMBOL and its subproblems has been intensively studied by computer scientists and mathematicians"} {"class.text":"MISC","text":"Considerable attention has been given to the case where the constraints are restricted to a given finite set of relations SYMBOL , called a constraint language CITATION"} {"class.text":"MISC","text":"For example, when SYMBOL is a constraint language over the boolean set SYMBOL with four ternary predicates SYMBOL , SYMBOL , SYMBOL , SYMBOL we obtain 3-SAT"} {"class.text":"MISC","text":"This direction of research has been mainly concerned with the computational complexity of SYMBOL as a function of SYMBOL"} {"class.text":"MISC","text":"It has been shown that the complexity of SYMBOL is highly connected with relational clones of universal algebra CITATION"} {"class.text":"MISC","text":"For every constraint language SYMBOL , it has been conjectured that SYMBOL is either in P or NP-complete CITATION"} {"class.text":"MISC","text":"In the minimum cost homomorphism problem ( SYMBOL ), we are given variables subject to constraints and, additionally, costs on variable/value pairs"} {"class.text":"MISC","text":"Now, the task is not just to find any satisfying assignment to the variables, but one that minimizes the total cost"} {"class.text":"MISC","text":"SYMBOL was introduced in CITATION where it was motivated by a real-world problem in defence logistics"} {"class.text":"MISC","text":"The question for which directed graphs SYMBOL the problem SYMBOL is polynomial-time solvable was considered in CITATION"} {"class.text":"AIMX","text":"In this paper, we approach the problem in its most general form by algebraic methods and give a complete algebraic characterization of tractable constraint languages"} {"class.text":"OWNX","text":"From this characterization, we obtain a dichotomy for SYMBOL , i e , if SYMBOL is not polynomial-time solvable, then it is NP-hard"} {"class.text":"OWNX","text":"Of course, this dichotomy implies the dichotomy for directed graphs"} {"class.text":"OWNX","text":"In Section 2, we present some preliminaries together with results connecting the complexity of SYMBOL with conservative algebras"} {"class.text":"OWNX","text":"The main dichotomy theorem is stated in Section 3 and its proof is divided into several parts which can be found in Sections 4-8"} {"class.text":"OWNX","text":"Section 7 introduces the concept of arithmetical deadlocks which lay the foundation for the final proof in Section 8"} {"class.text":"OWNX","text":"In Section 9 we reformulate our main result in terms of relational clones"} {"class.text":"OWNX","text":"Finally, in Section 10 we explain the relation of our results to previous research and present directions for future research"} {"class.text":"MISC","text":"In the constraint satisfaction problem ( SYMBOL ), the aim is to find an assignment of values to a set of variables subject to specified constraints"} {"class.text":"MISC","text":"In the minimum cost homomorphism problem ( SYMBOL ), one is additionally given weights SYMBOL for every variable SYMBOL and value SYMBOL , and the aim is to find an assignment SYMBOL to the variables that minimizes SYMBOL"} {"class.text":"MISC","text":"Let SYMBOL denote the SYMBOL problem parameterized by the set of predicates allowed for constraints"} {"class.text":"MISC","text":"SYMBOL is related to many well-studied combinatorial optimization problems, and concrete applications can be found in, for instance, defence logistics and machine learning"} {"class.text":"AIMX","text":"We show that SYMBOL can be studied by using algebraic methods similar to those used for CSPs"} {"class.text":"OWNX","text":"With the aid of algebraic techniques, we classify the computational complexity of SYMBOL for all choices of SYMBOL"} {"class.text":"OWNX","text":"Our result settles a general dichotomy conjecture previously resolved only for certain classes of directed graphs CITATION"} {"class.text":"MISC","text":"Constraint satisfaction problems ( SYMBOL ) are a natural way of formalizing a large number of computational problems arising in combinatorial optimization, artificial intelligence, and database theory"} {"class.text":"MISC","text":"Applications of SYMBOL s arise in the propositional logic, database and graph theory, scheduling and many other areas"} {"class.text":"MISC","text":"During the past 30 years, SYMBOL and its subproblems has been intensively studied by computer scientists and mathematicians"} {"class.text":"MISC","text":"Considerable attention has been given to the case where the constraints are restricted to a given finite set of relations SYMBOL , called a constraint language CITATION"} {"class.text":"MISC","text":"This direction of research has been mainly concerned with the computational complexity of SYMBOL as a function of SYMBOL"} {"class.text":"MISC","text":"It has been shown that the complexity of SYMBOL is highly connected with relational clones of universal algebra CITATION"} {"class.text":"MISC","text":"For every constraint language SYMBOL , it has been conjectured that SYMBOL is either in P or NP-complete CITATION"} {"class.text":"MISC","text":"Now, the task is not just to find any satisfying assignment to the variables, but one that minimizes the total cost"} {"class.text":"MISC","text":"SYMBOL was introduced in CITATION where it was motivated by a real-world problem in defence logistics"} {"class.text":"MISC","text":"The question for which directed graphs SYMBOL the problem SYMBOL is polynomial-time solvable was considered in CITATION"} {"class.text":"AIMX","text":"In this paper, we approach the problem in its most general form by algebraic methods and give a complete algebraic characterization of tractable constraint languages"} {"class.text":"OWNX","text":"From this characterization, we obtain a dichotomy for SYMBOL , i e , if SYMBOL is not polynomial-time solvable, then it is NP-hard"} {"class.text":"OWNX","text":"In Section 2, we present some preliminaries together with results connecting the complexity of SYMBOL with conservative algebras"} {"class.text":"OWNX","text":"The main dichotomy theorem is stated in Section 3 and its proof is divided into several parts which can be found in Sections 4-8"} {"class.text":"OWNX","text":"The NP-hardness results are collected in Section 4 followed by the building blocks for the tractability result: existence of majority polymorphisms (Section 5) and connections with optimization in perfect graphs (Section 6)"} {"class.text":"OWNX","text":"In Section 9 we reformulate our main result in terms of relational clones"} {"class.text":"OWNX","text":"Finally, in Section 10 we explain the relation of our results to previous research and present directions for future research"} {"class.text":"MISC","text":"Regularized risk minimization with the binary hinge loss and its variants lies at the heart of many machine learning problems"} {"class.text":"MISC","text":"Bundle methods for regularized risk minimization (BMRM) and the closely related SVMStruct are considered the best general purpose solvers to tackle this problem"} {"class.text":"MISC","text":"It was recently shown that BMRM requires SYMBOL iterations to converge to an SYMBOL accurate solution"} {"class.text":"AIMX","text":"In the first part of the paper we use the Hadamard matrix to construct a regularized risk minimization problem and show that these rates cannot be improved"} {"class.text":"OWNX","text":"We then show how one can exploit the structure of the objective function to devise an algorithm for the binary hinge loss which converges to an SYMBOL accurate solution in SYMBOL iterations"} {"class.text":"MISC","text":"Let SYMBOL denote samples and SYMBOL be the corresponding labels"} {"class.text":"MISC","text":"Given a training set of SYMBOL sample label pairs SYMBOL , drawn i i d from a joint probability distribution on SYMBOL , many machine learning algorithms solve the following regularized risk minimization problem:"} {"class.text":"MISC","text":"Here SYMBOL denotes the loss on instance SYMBOL using the current model SYMBOL and SYMBOL , the empirical risk, is the average loss on the training set"} {"class.text":"MISC","text":"The regularizer SYMBOL acts as a penalty on the complexity of the classifier and prevents overfitting"} {"class.text":"MISC","text":"Usually the loss is convex in SYMBOL but can be nonsmooth while the regularizer is usually a smooth strongly convex function"} {"class.text":"MISC","text":"Binary Support Vector Machines (SVMs) are a prototypical example of such regularized risk minimization problems where SYMBOL and the loss considered is the binary hinge loss:"} {"class.text":"MISC","text":"Recently, a number of solvers have been proposed for the regularized risk minimization problem"} {"class.text":"MISC","text":"The convergence analysis of SVMStruct was improved to SYMBOL iterations by CITATION"} {"class.text":"MISC","text":"In fact, CITATION showed that their convergence analysis holds for a more general solver than SVMStruct namely BMRM (Bundle method for regularized risk minimization)"} {"class.text":"MISC","text":"At every iteration BMRM replaces SYMBOL by a piecewise linear lower bound SYMBOL and optimizes to obtain the next iterate SYMBOL"} {"class.text":"MISC","text":"Here SYMBOL denotes an arbitrary subgradient of SYMBOL at SYMBOL (see Section ) and SYMBOL"} {"class.text":"MISC","text":"The piecewise linear lower bound is successively tightened until the gap falls below a predefined tolerance SYMBOL"} {"class.text":"CONT","text":"Even though BMRM solves an expensive optimization problem at every iteration, the convergence analysis only uses a simple one-dimensional line search to bound the decrease in SYMBOL"} {"class.text":"CONT","text":"Furthermore, the empirical convergence behavior of BMRM is much better than the theoretically predicted rates on a number of real life problems"} {"class.text":"MISC","text":"It was therefore conjectured that the rates of convergence of BMRM could be improved"} {"class.text":"AIMX","text":"In this paper we answer this question in the negative by explicitly constructing a regularized risk minimization problem for which BMRM takes at least SYMBOL iterations"} {"class.text":"OWNX","text":"Using a very old result of Nesterov CITATION we obtain an algorithm for SVMs which only requires SYMBOL iterations to converge to an SYMBOL accurate solution; each iteration of the algorithm requires SYMBOL work"} {"class.text":"OWNX","text":"Although we primarily focus on the regularized risk minimization with the binary hinge loss, our algorithm can also be used whenever the empirical risk is piecewise linear and contains a small number of pieces"} {"class.text":"OWNX","text":"Examples of this include multiclass, multi-label, and ordinal regression hinge loss and other related losses"} {"class.text":"MISC","text":"Regularized risk minimization with the binary hinge loss and its variants lies at the heart of many machine learning problems"} {"class.text":"MISC","text":"Bundle methods for regularized risk minimization (BMRM) and the closely related SVMStruct are considered the best general purpose solvers to tackle this problem"} {"class.text":"MISC","text":"It was recently shown that BMRM requires SYMBOL iterations to converge to an SYMBOL accurate solution"} {"class.text":"OWNX","text":"In the first part of the paper we use the Hadamard matrix to construct a regularized risk minimization problem and show that these rates cannot be improved"} {"class.text":"AIMX","text":"We then show how one can exploit the structure of the objective function to devise an algorithm for the binary hinge loss which converges to an SYMBOL accurate solution in SYMBOL iterations"} {"class.text":"MISC","text":"Let SYMBOL denote samples and SYMBOL be the corresponding labels"} {"class.text":"MISC","text":"Given a training set of SYMBOL sample label pairs SYMBOL , drawn iid from a joint probability distribution on SYMBOL , many machine learning algorithms solve the following regularized risk minimization problem:"} {"class.text":"MISC","text":"Here SYMBOL denotes the loss on instance SYMBOL using the current model SYMBOL and SYMBOL , the empirical risk, is the average loss on the training set"} {"class.text":"MISC","text":"The regularizer SYMBOL acts as a penalty on the complexity of the classifier and prevents overfitting"} {"class.text":"MISC","text":"Usually the loss is convex in SYMBOL but can be nonsmooth while the regularizer is usually a smooth strongly convex function"} {"class.text":"MISC","text":"Binary Support Vector Machines (SVMs) are a prototypical example of such regularized risk minimization problems where SYMBOL and the loss considered is the binary hinge loss:"} {"class.text":"MISC","text":"Recently, a number of solvers have been proposed for the regularized risk minimization problem"} {"class.text":"MISC","text":"The first and perhaps the best known solver is SVMStruct CITATION , which was shown to converge in SYMBOL iterations to an SYMBOL accurate solution"} {"class.text":"MISC","text":"The convergence analysis of SVMStruct was improved to SYMBOL iterations by CITATION"} {"class.text":"MISC","text":"In fact, CITATION showed that their convergence analysis holds for a more general solver than SVMStruct namely BMRM (Bundle method for regularized risk minimization)"} {"class.text":"MISC","text":"At every iteration BMRM replaces SYMBOL by a piecewise linear lower bound SYMBOL and optimizes to obtain the next iterate SYMBOL"} {"class.text":"MISC","text":"Here SYMBOL denotes an arbitrary subgradient of SYMBOL at SYMBOL (see Section ) and SYMBOL"} {"class.text":"MISC","text":"Furthermore, the empirical convergence behavior of BMRM is much better than the theoretically predicted rates on a number of real life problems"} {"class.text":"MISC","text":"It was therefore conjectured that the rates of convergence of BMRM could be improved"} {"class.text":"AIMX","text":"In this paper we answer this question in the negative by explicitly constructing a regularized risk minimization problem for which BMRM takes at least SYMBOL iterations"} {"class.text":"OWNX","text":"One possible way to circumvent the SYMBOL lower bound is to solve the problem in the dual"} {"class.text":"OWNX","text":"Although we primarily focus on the regularized risk minimization with the binary hinge loss, our algorithm can also be used whenever the empirical risk is piecewise linear and contains a small number of pieces"} {"class.text":"OWNX","text":"Examples of this include multiclass, multi-label, and ordinal regression hinge loss and other related losses"} {"class.text":"MISC","text":"Bundle methods for regularized risk minimization (BMRM) and the closely related SVMStruct are considered the best general purpose solvers to tackle this problem"} {"class.text":"MISC","text":"It was recently shown that BMRM requires SYMBOL iterations to converge to an SYMBOL accurate solution"} {"class.text":"AIMX","text":"In the first part of the paper we use the Hadamard matrix to construct a regularized risk minimization problem and show that these rates cannot be improved"} {"class.text":"AIMX","text":"We then show how one can exploit the structure of the objective function to devise an algorithm for the binary hinge loss which converges to an SYMBOL accurate solution in SYMBOL iterations"} {"class.text":"MISC","text":"Given a training set of SYMBOL sample label pairs SYMBOL , drawn iid from a joint probability distribution on SYMBOL , many machine learning algorithms solve the following regularized risk minimization problem:"} {"class.text":"MISC","text":"Here SYMBOL denotes the loss on instance SYMBOL using the current model SYMBOL and SYMBOL , the empirical risk, is the average loss on the training set"} {"class.text":"MISC","text":"Usually the loss is convex in SYMBOL but can be nonsmooth while the regularizer is usually a smooth strongly convex function"} {"class.text":"MISC","text":"Recently, a number of solvers have been proposed for the regularized risk minimization problem"} {"class.text":"MISC","text":"The first and perhaps the best known solver is SVMStruct CITATION , which was shown to converge in SYMBOL iterations to an SYMBOL accurate solution"} {"class.text":"MISC","text":"At every iteration BMRM replaces SYMBOL by a piecewise linear lower bound SYMBOL and optimizes to obtain the next iterate SYMBOL"} {"class.text":"MISC","text":"Here SYMBOL denotes an arbitrary subgradient of SYMBOL at SYMBOL (see Section ) and SYMBOL"} {"class.text":"MISC","text":"The piecewise linear lower bound is successively tightened until the gap falls below a predefined tolerance SYMBOL"} {"class.text":"MISC","text":"Furthermore, the empirical convergence behavior of BMRM is much better than the theoretically predicted rates on a number of real life problems"} {"class.text":"MISC","text":"It was therefore conjectured that the rates of convergence of BMRM could be improved"} {"class.text":"AIMX","text":"In this paper we answer this question in the negative by explicitly constructing a regularized risk minimization problem for which BMRM takes at least SYMBOL iterations"} {"class.text":"MISC","text":"One possible way to circumvent the SYMBOL lower bound is to solve the problem in the dual"} {"class.text":"OWNX","text":"Using a very old result of Nesterov CITATION we obtain an algorithm for SVMs which only requires SYMBOL iterations to converge to an SYMBOL accurate solution; each iteration of the algorithm requires SYMBOL work"} {"class.text":"OWNX","text":"Although we primarily focus on the regularized risk minimization with the binary hinge loss, our algorithm can also be used whenever the empirical risk is piecewise linear and contains a small number of pieces"} {"class.text":"MISC","text":"Examples of this include multiclass, multi-label, and ordinal regression hinge loss and other related losses"} {"class.text":"MISC","text":"similar to research on risky choice, the traditional analysis of intertemporal choice takes the view that an individual behaves so as to maximize the discounted sum of all future utilities"} {"class.text":"MISC","text":"the well-known allais paradox contradicts the fundamental postulates of maximizing the expected value or utility of a risky option"} {"class.text":"MISC","text":"in the field of intertemporal choice, the discounted-utility du theory proposed by paul samuelson in 1937 was presented not only as a valid normative standard but also as a descriptive theory of actual intertemporal choice behavior CITATION"} {"class.text":"MISC","text":"in its general form, the du theory proposes that the value of an option, x; t, is the product of its present utility, ux, and an exponential temporal discounting function, ft, where t is the time at which x is acquired"} {"class.text":"MISC","text":"the overall value of a mixed option, a = {x, t, x, t, }, denoted va, is simply the sum of these products"} {"class.text":"MISC","text":"that is, va = sigma ux ft"} {"class.text":"MISC","text":"an option a will be preferred to an option b if and only if va greater than vb"} {"class.text":"MISC","text":"however, a large body of empirical evidence demonstrates that people systematically violate this theory"} {"class.text":"MISC","text":"this includes the common difference effect, the magnitude effect, the gain-loss asymmetry, the delay-speedup asymmetry, and so on CITATION"} {"class.text":"MISC","text":"this situation has led researchers to consider extensions and modifications of the du theory to reconcile it with the experimental data"} {"class.text":"MISC","text":"the most prominent idea to account for these anomalies is the hyperbolic discounting model CITATION"} {"class.text":"MISC","text":"this model suggests that the discount rate is not dynamically consistent but that the rate is higher between the present and near future and lower between the near and far distant future"} {"class.text":"MISC","text":"however, these models focus on intertemporal choice between pairs of single-dated outcomes represented as pure gains or losses"} {"class.text":"MISC","text":"when these models are applied to intertemporal choice between pairs of multiple-dated outcomes in mixed contexts, there is general agreement on the additive assumption and the independence assumption"} {"class.text":"MISC","text":"with an apt transformation of the discounting rate, the additive assumption means that preferences for outcome sequences are based on a simple aggregation of their individual components within intertemporal choice CITATION"} {"class.text":"MISC","text":"the independence assumption means that the value or utility of an outcome in one period is independent of outcomes in other periods CITATION"} {"class.text":"MISC","text":"because risk and delay might be psychologically equivalent, or at least analogous, and because similar psychological processes might underlie risk and intertemporal choice CITATION , theoretical development in intertemporal choice has progressed steadily along a similar route as that of risky choice CITATION"} {"class.text":"MISC","text":"both lines of research have spawned a large number of variant models"} {"class.text":"MISC","text":"although the functional forms differ, most theories assume a maximization principle; that is, people calculate the mathematical expectation of each outcome and add them together before choosing the option that maximizes overall value or utility"} {"class.text":"CONT","text":"for example, research on risky decision making does not treat risky choice as limited to pure gains or pure losses but has been extended to include mixed outcomes involving both gains and losses"} {"class.text":"MISC","text":"the well-known allais paradox CITATION contradicts the fundamental postulates of maximizing the expected utility of a risky option"} {"class.text":"MISC","text":"the paradox presents a violation of the cancellation axiom, which asserts that, if two options have a common consequence under a particular event, the preference order of the options should be independent of the value of that consequence CITATION"} {"class.text":"MISC","text":"most models of intertemporal choice have not yet abandoned the additive assumption and the independence assumption"} {"class.text":"MISC","text":"these two assumptions would lead to the cancellation axiom, which indicates that a preference between two sequences with elements in common does not depend on the nature of the common elements"} {"class.text":"MISC","text":"table 1 illustrates an example of the multiple-dated outcomes problem, which would be used to test the cancellation axiom"} {"class.text":"MISC","text":"the violation of cancellation would be observed if the preference orderings were different between problem i and problem i"} {"class.text":"MISC","text":"however, if allais's proposition applies to intertemporal choice, we will eventually encounter an intertemporal version of the allais paradox"} {"class.text":"AIMX","text":"we first illustrate our point with a paradox that is an intertemporal-type violation of the cancellation axiom"} {"class.text":"MISC","text":"similar to research on risky choice, the traditional analysis of intertemporal choice takes the view that an individual behaves so as to maximize the discounted sum of all future utilities"} {"class.text":"MISC","text":"the overall value of a mixed option, a = {x, t, x, t, }, denoted va, is simply the sum of these products"} {"class.text":"MISC","text":"that is, va = sigma ux ft"} {"class.text":"MISC","text":"an option a will be preferred to an option b if and only if va greater than vb"} {"class.text":"MISC","text":"however, a large body of empirical evidence demonstrates that people systematically violate this theory"} {"class.text":"MISC","text":"this includes the common difference effect, the magnitude effect, the gain-loss asymmetry, the delay-speedup asymmetry, and so on CITATION"} {"class.text":"MISC","text":"this situation has led researchers to consider extensions and modifications of the du theory to reconcile it with the experimental data"} {"class.text":"MISC","text":"this model suggests that the discount rate is not dynamically consistent but that the rate is higher between the present and near future and lower between the near and far distant future"} {"class.text":"MISC","text":"however, these models focus on intertemporal choice between pairs of single-dated outcomes represented as pure gains or losses"} {"class.text":"MISC","text":"when these models are applied to intertemporal choice between pairs of multiple-dated outcomes in mixed contexts, there is general agreement on the additive assumption and the independence assumption"} {"class.text":"MISC","text":"with an apt transformation of the discounting rate, the additive assumption means that preferences for outcome sequences are based on a simple aggregation of their individual components within intertemporal choice CITATION"} {"class.text":"MISC","text":"the independence assumption means that the value or utility of an outcome in one period is independent of outcomes in other periods CITATION"} {"class.text":"MISC","text":"because risk and delay might be psychologically equivalent, or at least analogous, and because similar psychological processes might underlie risk and intertemporal choice CITATION , theoretical development in intertemporal choice has progressed steadily along a similar route as that of risky choice CITATION"} {"class.text":"MISC","text":"both lines of research have spawned a large number of variant models"} {"class.text":"MISC","text":"for example, research on risky decision making does not treat risky choice as limited to pure gains or pure losses but has been extended to include mixed outcomes involving both gains and losses"} {"class.text":"MISC","text":"examples include the sign-dependent utility model CITATION , the rank- and sign-dependent utility model CITATION , and the transfer of attention exchange model CITATION"} {"class.text":"MISC","text":"the well-known allais paradox CITATION contradicts the fundamental postulates of maximizing the expected utility of a risky option"} {"class.text":"MISC","text":"the paradox presents a violation of the cancellation axiom, which asserts that, if two options have a common consequence under a particular event, the preference order of the options should be independent of the value of that consequence CITATION"} {"class.text":"MISC","text":"since then, many new descriptive theories of risky choice have abandoned the maximization assumption CITATION"} {"class.text":"MISC","text":"most models of intertemporal choice have not yet abandoned the additive assumption and the independence assumption"} {"class.text":"MISC","text":"these two assumptions would lead to the cancellation axiom, which indicates that a preference between two sequences with elements in common does not depend on the nature of the common elements"} {"class.text":"OWNX","text":"in problem i, the additive models predict that adding a common element x at time 2 to both option a and option b would not change the preference orderings"} {"class.text":"OWNX","text":"however, if allais's proposition applies to intertemporal choice, we will eventually encounter an intertemporal version of the allais paradox"} {"class.text":"OWNX","text":"we first illustrate our point with a paradox that is an intertemporal-type violation of the cancellation axiom"} {"class.text":"MISC","text":"similar to research on risky choice, the traditional analysis of intertemporal choice takes the view that an individual behaves so as to maximize the discounted sum of all future utilities"} {"class.text":"MISC","text":"the well-known allais paradox contradicts the fundamental postulates of maximizing the expected value or utility of a risky option"} {"class.text":"AIMX","text":"we describe a violation of the law of diminishing marginal utility as well as an intertemporal version of the allais paradox"} {"class.text":"MISC","text":"in the field of intertemporal choice, the discounted-utility du theory proposed by paul samuelson in 1937 was presented not only as a valid normative standard but also as a descriptive theory of actual intertemporal choice behavior CITATION"} {"class.text":"MISC","text":"in its general form, the du theory proposes that the value of an option, x; t, is the product of its present utility, ux, and an exponential temporal discounting function, ft, where t is the time at which x is acquired"} {"class.text":"MISC","text":"the overall value of a mixed option, a = {x, t, x, t, }, denoted va, is simply the sum of these products"} {"class.text":"CONT","text":"however, a large body of empirical evidence demonstrates that people systematically violate this theory"} {"class.text":"MISC","text":"this includes the common difference effect, the magnitude effect, the gain-loss asymmetry, the delay-speedup asymmetry, and so on CITATION"} {"class.text":"MISC","text":"this situation has led researchers to consider extensions and modifications of the du theory to reconcile it with the experimental data"} {"class.text":"MISC","text":"the most prominent idea to account for these anomalies is the hyperbolic discounting model CITATION"} {"class.text":"MISC","text":"numerous theories have been developed by transforming the discount function to other forms, from one-parameter hyperbolic discounting CITATION to generalized hyperbolic discounting CITATION , to proportional discounting CITATION , and to quasi-hyperbolic discounting CITATION"} {"class.text":"MISC","text":"however, these models focus on intertemporal choice between pairs of single-dated outcomes represented as pure gains or losses"} {"class.text":"MISC","text":"when these models are applied to intertemporal choice between pairs of multiple-dated outcomes in mixed contexts, there is general agreement on the additive assumption and the independence assumption"} {"class.text":"MISC","text":"with an apt transformation of the discounting rate, the additive assumption means that preferences for outcome sequences are based on a simple aggregation of their individual components within intertemporal choice CITATION"} {"class.text":"MISC","text":"the independence assumption means that the value or utility of an outcome in one period is independent of outcomes in other periods CITATION"} {"class.text":"MISC","text":"because risk and delay might be psychologically equivalent, or at least analogous, and because similar psychological processes might underlie risk and intertemporal choice CITATION , theoretical development in intertemporal choice has progressed steadily along a similar route as that of risky choice CITATION"} {"class.text":"MISC","text":"both lines of research have spawned a large number of variant models"} {"class.text":"MISC","text":"although the functional forms differ, most theories assume a maximization principle; that is, people calculate the mathematical expectation of each outcome and add them together before choosing the option that maximizes overall value or utility"} {"class.text":"MISC","text":"a minor difference is that the existing models of intertemporal choice are relatively underdeveloped and are less flexible in dealing with empirical challenges"} {"class.text":"MISC","text":"the well-known allais paradox CITATION contradicts the fundamental postulates of maximizing the expected utility of a risky option"} {"class.text":"MISC","text":"the paradox presents a violation of the cancellation axiom, which asserts that, if two options have a common consequence under a particular event, the preference order of the options should be independent of the value of that consequence CITATION"} {"class.text":"CONT","text":"most models of intertemporal choice have not yet abandoned the additive assumption and the independence assumption"} {"class.text":"MISC","text":"these two assumptions would lead to the cancellation axiom, which indicates that a preference between two sequences with elements in common does not depend on the nature of the common elements"} {"class.text":"MISC","text":"in problem i, the additive models predict that adding a common element x at time 2 to both option a and option b would not change the preference orderings"} {"class.text":"MISC","text":"the violation of cancellation would be observed if the preference orderings were different between problem i and problem i"} {"class.text":"MISC","text":"however, if allais's proposition applies to intertemporal choice, we will eventually encounter an intertemporal version of the allais paradox"} {"class.text":"OWNX","text":"we first illustrate our point with a paradox that is an intertemporal-type violation of the cancellation axiom"} {"class.text":"OWNX","text":"this study was designed to assess sex-related differences in the selection of an appropriate strategy when facing novelty"} {"class.text":"OWNX","text":"\ta simple visuo-spatial task was used to investigate exploratory behavior as a specific response to novelty"} {"class.text":"OWNX","text":"the exploration task was followed by a visual discrimination task and the responses were analyzed using signal detection theory"} {"class.text":"OWNX","text":"during exploration women selected a local searching strategy in which the metric distance between what is already known and what is unknown was reduced whereas men adopted a global strategy based on an approximately uniform distribution of choices"} {"class.text":"OWNX","text":"women's exploratory behavior gives rise to a notion of a secure base warranting a sense of safety while men's behavior does not appear to be influenced by risk"} {"class.text":"OWNX","text":"this sex-related difference was interpreted as a difference in beliefs concerning the likelihood of uncertain events influencing risk evaluation"} {"class.text":"MISC","text":"males and females seem to differ in spatial abilities and styles CITATION"} {"class.text":"MISC","text":"generally studies involving navigational problems showed that female cognitive style relies more on detailed information while male style relies more on global information CITATION"} {"class.text":"MISC","text":"evolutionary mechanisms could potentially account for sex differences in spatial behavior"} {"class.text":"MISC","text":"for example these behavioral differences may be due to mating patterns that induced a selection of large-range navigation in males CITATION"} {"class.text":"MISC","text":"mating patterns or mating strategies are linked to the dynamics of reproduction and sexual selection CITATION and sexual selection is restricted to characteristics that influence mate choice and competition for mates"} {"class.text":"MISC","text":"typically males have to compete through extensive ranging for access to mates while females have to choose mating partners according to reproductive success CITATION"} {"class.text":"MISC","text":"another proposition but exclusively directed at humans suggested that the division of labor game hunting and plant gathering would have put greater selection pressure on females' spatial memory because females sustained gathering duties CITATION"} {"class.text":"MISC","text":"however as argued by ecuyer-dab and robert CITATION the selection of male characteristics depends on females' choice for mates"} {"class.text":"MISC","text":"in females however spatial cognition would have been primarily shaped by the natural selection of a strong concern for survival both of self and of offspring"} {"class.text":"MISC","text":"this concern would have compelled them to favor low-risk strategies like concentrating on proximal spatial cues when coping with space-related problems"} {"class.text":"MISC","text":"such focusing would have enabled secure navigation based on detailed landmark encoding as well as in certain species regular feeding based on remembering the exact locations of potential resources p NUMBER"} {"class.text":"MISC","text":"thus the hypothesis of labor division would be a by-product of sexual selection and not the cause of sex differences in spatial behavior"} {"class.text":"MISC","text":"in that context spatial skills play a crucial role since they increase reproductive success and the accessibility to food resource but at the same time multiply the risks of getting lost being killed or consumed by other animals predation"} {"class.text":"CONT","text":"experimental investigations of sex differences in spatial abilities yield apparently disparate results CITATION"} {"class.text":"MISC","text":"this might be partly due to the complexity of contemporary experimental designs but also to a lack of investigations concerning decision-making processes involved in the selection of strategies"} {"class.text":"OWNX","text":"the current study investigates sex differences in basic behaviors like exploration detection and discrimination involving the selection of strategies when coping with uncertainty"} {"class.text":"OWNX","text":"following the above quotation from ecuyer-dab and robert's the hypothesis is that women compared to men should favor low-risk strategies when coping with space-related problems"} {"class.text":"OWNX","text":"to test this i used a simple spontaneous two-dimensional exploratory task"} {"class.text":"OWNX","text":"this choice relies on the fact that exploration is a natural behavior and that it is fundamental in acquiring spatial knowledge"} {"class.text":"MISC","text":"it seems to be based on driving factors such as curiosity comfort or mastery over one's environment"} {"class.text":"MISC","text":"moreover it is commonly defined as serving to reduce uncertainty and thus allow coping with fear CITATION"} {"class.text":"MISC","text":"exploration is mainly characterized by a succession of progressions and stops CITATION and the selection of exploration could rely on its capacity to act as a regulator of uncertainty"} {"class.text":"MISC","text":"indeed progressions are based on decisions taken during stops and stops correspond to choice points allowing decisions"} {"class.text":"OWNX","text":"in order to assess risk-taking a classical visual discrimination task based on the stimuli observed during the exploration task was used"} {"class.text":"AIMX","text":"this study was designed to assess sex-related differences in the selection of an appropriate strategy when facing novelty"} {"class.text":"OWNX","text":"a simple visuo-spatial task was used to investigate exploratory behavior as a specific response to novelty"} {"class.text":"OWNX","text":"during exploration women selected a local searching strategy in which the metric distance between what is already known and what is unknown was reduced whereas men adopted a global strategy based on an approximately uniform distribution of choices"} {"class.text":"OWNX","text":"women's exploratory behavior gives rise to a notion of a secure base warranting a sense of safety while men's behavior does not appear to be influenced by risk"} {"class.text":"OWNX","text":"this sex-related difference was interpreted as a difference in beliefs concerning the likelihood of uncertain events influencing risk evaluation"} {"class.text":"MISC","text":"males and females seem to differ in spatial abilities and styles CITATION"} {"class.text":"MISC","text":"generally studies involving navigational problems showed that female cognitive style relies more on detailed information while male style relies more on global information CITATION"} {"class.text":"MISC","text":"for example these behavioral differences may be due to mating patterns that induced a selection of large-range navigation in males CITATION"} {"class.text":"MISC","text":"mating patterns or mating strategies are linked to the dynamics of reproduction and sexual selection CITATION and sexual selection is restricted to characteristics that influence mate choice and competition for mates"} {"class.text":"MISC","text":"typically males have to compete through extensive ranging for access to mates while females have to choose mating partners according to reproductive success CITATION"} {"class.text":"MISC","text":"another proposition but exclusively directed at humans suggested that the division of labor game hunting and plant gathering would have put greater selection pressure on females' spatial memory because females sustained gathering duties CITATION"} {"class.text":"MISC","text":"however as argued by ecuyer-dab and robert CITATION the selection of male characteristics depends on females' choice for mates"} {"class.text":"MISC","text":"this concern would have compelled them to favor low-risk strategies like concentrating on proximal spatial cues when coping with space-related problems"} {"class.text":"MISC","text":"such focusing would have enabled secure navigation based on detailed landmark encoding as well as in certain species regular feeding based on remembering the exact locations of potential resources p NUMBER"} {"class.text":"MISC","text":"thus the hypothesis of labor division would be a by-product of sexual selection and not the cause of sex differences in spatial behavior"} {"class.text":"MISC","text":"taken together the literature seems to indicate that the key to understanding the evolution of behavioral sex differences relies on the relative costs and benefits of producing offspring CITATION"} {"class.text":"MISC","text":"this might be partly due to the complexity of contemporary experimental designs but also to a lack of investigations concerning decision-making processes involved in the selection of strategies"} {"class.text":"AIMX","text":"the current study investigates sex differences in basic behaviors like exploration detection and discrimination involving the selection of strategies when coping with uncertainty"} {"class.text":"AIMX","text":"following the above quotation from ecuyer-dab and robert's the hypothesis is that women compared to men should favor low-risk strategies when coping with space-related problems"} {"class.text":"OWNX","text":"to test this i used a simple spontaneous two-dimensional exploratory task"} {"class.text":"MISC","text":"this choice relies on the fact that exploration is a natural behavior and that it is fundamental in acquiring spatial knowledge"} {"class.text":"MISC","text":"it seems to be based on driving factors such as curiosity comfort or mastery over one's environment"} {"class.text":"MISC","text":"moreover it is commonly defined as serving to reduce uncertainty and thus allow coping with fear CITATION"} {"class.text":"MISC","text":"exploration is mainly characterized by a succession of progressions and stops CITATION and the selection of exploration could rely on its capacity to act as a regulator of uncertainty"} {"class.text":"MISC","text":"indeed progressions are based on decisions taken during stops and stops correspond to choice points allowing decisions"} {"class.text":"BASE","text":"voss CITATION refers to the exploration process as the generation and testing of hypotheses concerning the object's meaning and potential use"} {"class.text":"OWNX","text":"in order to assess risk-taking a classical visual discrimination task based on the stimuli observed during the exploration task was used"} {"class.text":"OWNX","text":"the results were analyzed with signal detection theory"} {"class.text":"AIMX","text":"this study was designed to assess sex-related differences in the selection of an appropriate strategy when facing novelty"} {"class.text":"OWNX","text":"a simple visuo-spatial task was used to investigate exploratory behavior as a specific response to novelty"} {"class.text":"OWNX","text":"the exploration task was followed by a visual discrimination task and the responses were analyzed using signal detection theory"} {"class.text":"OWNX","text":"during exploration women selected a local searching strategy in which the metric distance between what is already known and what is unknown was reduced whereas men adopted a global strategy based on an approximately uniform distribution of choices"} {"class.text":"OWNX","text":"women's exploratory behavior gives rise to a notion of a secure base warranting a sense of safety while men's behavior does not appear to be influenced by risk"} {"class.text":"OWNX","text":"this sex-related difference was interpreted as a difference in beliefs concerning the likelihood of uncertain events influencing risk evaluation"} {"class.text":"MISC","text":"males and females seem to differ in spatial abilities and styles CITATION"} {"class.text":"MISC","text":"generally studies involving navigational problems showed that female cognitive style relies more on detailed information while male style relies more on global information CITATION"} {"class.text":"MISC","text":"for example these behavioral differences may be due to mating patterns that induced a selection of large-range navigation in males CITATION"} {"class.text":"MISC","text":"mating patterns or mating strategies are linked to the dynamics of reproduction and sexual selection CITATION and sexual selection is restricted to characteristics that influence mate choice and competition for mates"} {"class.text":"MISC","text":"typically males have to compete through extensive ranging for access to mates while females have to choose mating partners according to reproductive success CITATION"} {"class.text":"MISC","text":"another proposition but exclusively directed at humans suggested that the division of labor game hunting and plant gathering would have put greater selection pressure on females' spatial memory because females sustained gathering duties CITATION"} {"class.text":"MISC","text":"in females however spatial cognition would have been primarily shaped by the natural selection of a strong concern for survival both of self and of offspring"} {"class.text":"MISC","text":"this concern would have compelled them to favor low-risk strategies like concentrating on proximal spatial cues when coping with space-related problems"} {"class.text":"MISC","text":"thus the hypothesis of labor division would be a by-product of sexual selection and not the cause of sex differences in spatial behavior"} {"class.text":"MISC","text":"taken together the literature seems to indicate that the key to understanding the evolution of behavioral sex differences relies on the relative costs and benefits of producing offspring CITATION"} {"class.text":"MISC","text":"in that context spatial skills play a crucial role since they increase reproductive success and the accessibility to food resource but at the same time multiply the risks of getting lost being killed or consumed by other animals predation"} {"class.text":"MISC","text":"experimental investigations of sex differences in spatial abilities yield apparently disparate results CITATION"} {"class.text":"OWNX","text":"following the above quotation from ecuyer-dab and robert's the hypothesis is that women compared to men should favor low-risk strategies when coping with space-related problems"} {"class.text":"OWNX","text":"to test this i used a simple spontaneous two-dimensional exploratory task"} {"class.text":"MISC","text":"this choice relies on the fact that exploration is a natural behavior and that it is fundamental in acquiring spatial knowledge"} {"class.text":"MISC","text":"it seems to be based on driving factors such as curiosity comfort or mastery over one's environment"} {"class.text":"MISC","text":"moreover it is commonly defined as serving to reduce uncertainty and thus allow coping with fear CITATION"} {"class.text":"MISC","text":"exploration is mainly characterized by a succession of progressions and stops CITATION and the selection of exploration could rely on its capacity to act as a regulator of uncertainty"} {"class.text":"MISC","text":"indeed progressions are based on decisions taken during stops and stops correspond to choice points allowing decisions"} {"class.text":"MISC","text":"voss CITATION refers to the exploration process as the generation and testing of hypotheses concerning the object's meaning and potential use"} {"class.text":"OWNX","text":"in order to assess risk-taking a classical visual discrimination task based on the stimuli observed during the exploration task was used"} {"class.text":"OWNX","text":"the results were analyzed with signal detection theory"} {"class.text":"AIMX","text":"the paper extends research on fixed-pie perceptions by suggesting that disputants may prefer proposals that are perceived to be equally attractive to both parties i e , balanced rather than one-sided, because balanced agreements are seen as more likely to be successfully implemented"} {"class.text":"OWNX","text":"we test our predictions using data on israeli support for the geneva accords, an agreement for a two state solution negotiated by unofficial delegations of israel and the palestinian authority in 2003"} {"class.text":"OWNX","text":"we show that implementation concerns create a demand among israelis for balance in the degree to which each side favors or opposes the agreement"} {"class.text":"OWNX","text":"the effect of balance is noteworthy in that it creates considerable support for proposals even when a majority of israelis and palestinians oppose the deal"} {"class.text":"MISC","text":"normative models of bargaining and negotiation suggest that if there is potential for mutual benefit, conflicting parties should be able to achieve it CITATION"} {"class.text":"CONT","text":"descriptive accounts and empirical investigations of negotiation behavior CITATION , however, suggest that a number of psychological barriers to conflict resolution are likely to make efficient deal making difficult CITATION"} {"class.text":"MISC","text":"the fixed-pie bias refers to the belief that any gain for one party will be associated with an equivalent loss to the other party"} {"class.text":"MISC","text":"a large body of research finds that negotiators are susceptible to the fixed-pie bias prior to, during, and even after negotiations CITATION"} {"class.text":"BASE","text":"in the current paper we investigate and extend research on fixed pie bias in the context of protracted intergroup conflict"} {"class.text":"AIMX","text":"the paper extends research on fixed-pie perceptions by suggesting that disputants may prefer proposals that are perceived to be equally attractive to both parties i e , balanced rather than one-sided, because balanced agreements are seen as more likely to be successfully implemented"} {"class.text":"OWNX","text":"we test our predictions using data on israeli support for the geneva accords, an agreement for a two state solution negotiated by unofficial delegations of israel and the palestinian authority in 2003"} {"class.text":"AIMX","text":"we show that implementation concerns create a demand among israelis for balance in the degree to which each side favors or opposes the agreement"} {"class.text":"OWNX","text":"the effect of balance is noteworthy in that it creates considerable support for proposals even when a majority of israelis and palestinians oppose the deal"} {"class.text":"CONT","text":"descriptive accounts and empirical investigations of negotiation behavior CITATION , however, suggest that a number of psychological barriers to conflict resolution are likely to make efficient deal making difficult CITATION"} {"class.text":"MISC","text":"for example, research on cognitive biases associated with egocentric perceptions suggests that negotiators and evaluators of negotiated agreements are likely to exhibit a \"fixed-pie bias\" CITATION"} {"class.text":"MISC","text":"the fixed-pie bias refers to the belief that any gain for one party will be associated with an equivalent loss to the other party"} {"class.text":"CONT","text":"this belief is a \"bias\" when it persists even in contexts where there is a possibility of compatible interests or mutual benefit"} {"class.text":"AIMX","text":"in the current paper we investigate and extend research on fixed pie bias in the context of protracted intergroup conflict"} {"class.text":"AIMX","text":"the paper extends research on fixed-pie perceptions by suggesting that disputants may prefer proposals that are perceived to be equally attractive to both parties i e , balanced rather than one-sided, because balanced agreements are seen as more likely to be successfully implemented"} {"class.text":"OWNX","text":"we test our predictions using data on israeli support for the geneva accords, an agreement for a two state solution negotiated by unofficial delegations of israel and the palestinian authority in 2003"} {"class.text":"OWNX","text":"the results demonstrate that israelis are more likely to support agreements that are seen favorably by other israelis, but - contrary to fixed-pie predictions - israeli support for the accords does not diminish simply because a majority of palestinians favors rather than opposes the accords"} {"class.text":"OWNX","text":"we show that implementation concerns create a demand among israelis for balance in the degree to which each side favors or opposes the agreement"} {"class.text":"OWNX","text":"the effect of balance is noteworthy in that it creates considerable support for proposals even when a majority of israelis and palestinians oppose the deal"} {"class.text":"MISC","text":"for example, research on cognitive biases associated with egocentric perceptions suggests that negotiators and evaluators of negotiated agreements are likely to exhibit a \"fixed-pie bias\" CITATION"} {"class.text":"MISC","text":"the fixed-pie bias refers to the belief that any gain for one party will be associated with an equivalent loss to the other party"} {"class.text":"MISC","text":"this belief is a \"bias\" when it persists even in contexts where there is a possibility of compatible interests or mutual benefit"} {"class.text":"OWNX","text":"we manipulated the likelihood that individuals would identify self-control conflict, and we measured their trait ability to implement self-control strategies"} {"class.text":"OWNX","text":"our analysis reveals a positive and significant correlation between trait self-control and pro-social behavior in the treatment where we expected a relatively high likelihood of conflict identification-but not in the treatment where we expected a low likelihood"} {"class.text":"OWNX","text":"the magnitude of the effect is of economic significance"} {"class.text":"MISC","text":"lured by temptation, individuals may find themselves acting against their better judgment"} {"class.text":"MISC","text":"for example, the dieter faced with the opportunity to indulge in a delicious creamy cake may perceive a conflict between indulging and maintaining a good figure"} {"class.text":"MISC","text":"the student may feel conflicted between the desire to go to the cinema and her better judgment to stay home and study"} {"class.text":"MISC","text":"and, similarly, the fashionista might feel conflicted between the temptation to purchase new boots and her better judgment to maintain a responsible budget"} {"class.text":"MISC","text":"perhaps less intuitively, but no less importantly, the question of pro-social versus selfish behavior may be understood in similar terms"} {"class.text":"MISC","text":"this conceptualization may help reconcile conflicting notions in economics of selfish and pro-social motivations"} {"class.text":"MISC","text":"that individuals should care much about their own self-interest seems almost tautological and requires little further exposition, but that individuals also should care about the interest of others-at the expense of that of their own-has attracted considerable attention CITATION"} {"class.text":"MISC","text":"for example, many individuals voluntarily contribute to charity or to public goods e g , recycling, and they pay their taxes despite low likelihood of punishment for failing to do so"} {"class.text":"MISC","text":"nonetheless, one could imagine that even individuals of generally pro-social inclination on occasion may feel tempted to act selfishly and hence underreport income to the authorities"} {"class.text":"MISC","text":"that is, pro-social preferences potentially fly in the face of basic urges for personal gain-or greed-and the individual may thus experience a self-control conflict between better judgment to act pro-socially and the temptation to act selfishly"} {"class.text":"MISC","text":"a multitude of conceptualizations exist, many of which are complementary"} {"class.text":"MISC","text":"willpower, then, represents the combined resources that the executive function-or the planner, in the parlance of thaler and shefrin CITATION -brings to bear in a deliberate struggle against temptation CITATION"} {"class.text":"MISC","text":"such resources may include cognitive strategies to divert attention away from temptation CITATION , strategies of pre-commitment CITATION , or possibly the sheer strength of mind to hold back from the song of the sirens"} {"class.text":"MISC","text":"our conceptualization of self-control mirrors these"} {"class.text":"MISC","text":"only recently has the psychological literature started to explore how the question of pro-social versus selfish behavior relates to that of self-control"} {"class.text":"MISC","text":"loewenstein CITATION suggests that selfish behavior may be motivated by visceral urges or drive-states, resembling cravings for relief from hunger, pain, and sexual deprivation"} {"class.text":"MISC","text":"o'donoghue and loewenstein CITATION argue that such selfish urges may conflict with the \"colder\", more abstract preferences for altruism, as visceral urges for sweets may conflict with more abstract preferences for a fine figure or good health"} {"class.text":"CONT","text":"at present, there is but indirect evidence for this idea"} {"class.text":"MISC","text":"albrecht et al CITATION report consistent results; individuals who choose between immediate and delayed rewards for themselves exhibit less patience and more affective involvement activation in the dopaminergic reward system than do individuals who make such choices for others-or for themselves in the future"} {"class.text":"MISC","text":"that is, more \"impatient\" individuals contributed less to the public good than did \"patient\" ones"} {"class.text":"MISC","text":"furthermore, burks et al CITATION find that \"short-term\" patience-the beta in the beta -δ model-is positively associated with cooperative behavior in a sequential prisoner's dilemma"} {"class.text":"MISC","text":"however, duffy and smith CITATION report no effect of cognitive load-a manipulation intended to deplete cognitive resources and thereby impair self-control-on outcomes across treatments in a repeated multi-player prisoner's dilemma"} {"class.text":"MISC","text":"an emerging literature on the \"default\" response in games of trust and reciprocity lends further credence to the notion that altruistic responses require self-control"} {"class.text":"MISC","text":"achtziger et al CITATION subjected players in an ultimatum game to cognitive resource depletion, and show that depleted proposers made lower offers-they became less altruistic"} {"class.text":"MISC","text":"moreover, depleted responders were more likely to reject offers that were unfair to themselves-they exhibited \"altruistic punishment\""} {"class.text":"MISC","text":"halali et al CITATION report the same for responders, but with a different depletion task"} {"class.text":"MISC","text":"using a trust game, knoch et al CITATION subjected trustees' right lateral prefrontal cortex to transcranial magnetic stimulation, which reduces functioning in the targeted brain region"} {"class.text":"MISC","text":"trustees, though cognizant that returning a share of the investments was both strategic and norm-compliant, were unable to do so under impaired executive functioning; self-control seems necessary to act on the better judgment to resist the temptation to keep the received investment entirely for oneself"} {"class.text":"MISC","text":"one interpretation of their results is that the default behavior is to act selfishly and that pro-social behavior requires the successful resolution of a self-control conflict, which slows the response time"} {"class.text":"MISC","text":"such successful resolution of conflict would require cognitive resources, but hauge et al CITATION report no effect of cognitive load on players in one-shot dictator games"} {"class.text":"AIMX","text":"in this paper we attempt a more direct test of the hypothesis that pro-social versus selfish behavior may represent a self-control problem"} {"class.text":"OWNX","text":"we employ a standard measure of pure pro-social behavior, the one-shot dictator game, which invokes neither concerns for strategy nor for reciprocity; and a well-grounded psychometric measure of self-control, the rosenbaum self-control schedule CITATION"} {"class.text":"OWNX","text":"further, we explore the conditions under which we expect an association between self-control and pro-social behavior"} {"class.text":"BASE","text":"in so doing, we rely on two conditions necessary for successfully exercising restraint in the face of temptation; myrseth and fishbach CITATION propose a two-stage model of self-control, which postulates that an individual in the face of temptation first identifies conflict or not between indulging and pursuing a higher-order goal and, second, that the individual next employs self-control strategies if and only if conflict was identified at the first stage see figure 1"} {"class.text":"MISC","text":"determinants of conflict identification in the face of temptation have been explored only recently"} {"class.text":"MISC","text":"in some contexts, the question is almost trivial and identification of conflict virtually obvious"} {"class.text":"MISC","text":"for example, the diabetic dieter probably knows that having even a single, tempting chocolate may incur major costs"} {"class.text":"MISC","text":"however, the question of self-control conflict is more ambiguous for the non-diabetic dieter, who faces the same chocolate"} {"class.text":"MISC","text":"having this one chocolate alone will not incur major costs, but doing so regularly might"} {"class.text":"MISC","text":"similarly, the good citizen may find that a general failure to act generously would represent a major threat to his self-image, but being stingy on just a couple of occasions is a more ambiguous matter"} {"class.text":"MISC","text":"myrseth and fishbach CITATION use the term epsilon cost temptation to denote tempting opportunities that incur nothing but trivial costs when consumed in small amounts, but potentially serious costs when consumed extensively"} {"class.text":"MISC","text":"they argue that individuals identify self-control conflict in the face of epsilon cost temptation if and only if two conditions are met: a the focal consumption opportunity must be viewed in relation to multiple additional opportunities, and b the decision maker must assume that similar choices are made for each opportunity CITATION"} {"class.text":"MISC","text":"that is, considering the question of whether or not to have a delicious creamy cake will evoke self-control conflict in the dieter if the dining opportunity is viewed in relation to future opportunities for dessert consumption, but not if the dining opportunity is viewed in isolation, as a singular episode"} {"class.text":"MISC","text":"similarly, the question of whether or not to be generous-to donate to a charitable organization-may elicit self-control conflict if the decision is viewed in relation to future decisions, but not if the decision is viewed in isolation"} {"class.text":"MISC","text":"if viewed in relation to future decisions, the question of how much to donate on a single occasion may have bearing on the decision maker's self-image; donating now-and in the future-indicates a generous character, whereas keeping the money for oneself does not"} {"class.text":"MISC","text":"however, if viewed in isolation, the question of how much to donate has little bearing on self-image; the present decision of how much to donate is considered only in light of immediate consequences, leaving self-image out of the equation"} {"class.text":"MISC","text":"because a consistent self-image represents an important motivator for pro-social behavior CITATION , we expect that individuals are more likely to identify self-control conflict between selfish and pro-social behavior if the allocation decision is seen in relation to future opportunities than if it is seen in isolation"} {"class.text":"MISC","text":"they find that presenting a calendar displaying the current month, with a grid separating the dates, raised participants' subsequent consumption of potato chips relative to that of participants whom were presented a calendar without a grid"} {"class.text":"MISC","text":"they argue that the gridded calendar activated an isolated versus interrelated frame of the choice opportunity; it made participants more likely to isolate the date in question and thus less likely to see the decision task in relation to similar future opportunities"} {"class.text":"MISC","text":"consequently, the grid reduced the likelihood that participants would identify a conflict between the temptation to have chips and the better judgment to maintain a fine figure and good health"} {"class.text":"MISC","text":"indeed, participants who viewed the gridded calendar reported experiencing less conflict during their decision to have chips or not than did those who viewed the non-gridded calendar"} {"class.text":"OWNX","text":"to explore our hypothesis that the problem of pro-social versus selfish behavior may represent one of self-control, we have applied the empirical strategy from myrseth and fishbach CITATION in the dictator game-a participant is granted an endowment and asked to split it between herself and a recipient CITATION , and in our case the red cross featured as recipient CITATION"} {"class.text":"OWNX","text":"if pro-social versus selfish behavior could represent a self-control conflict, we would expect participants' trait self-control, as measured by rosenbaum's CITATION scale, to correlate positively with pro-social behavior for participants who have just previously viewed a calendar without a grid, but less so or not at all for participants who have viewed a calendar with"} {"class.text":"OWNX","text":"in the case of low likelihood, the slope is expected to be weakly positive"} {"class.text":"OWNX","text":"in the case of the higher likelihood, however, the slope is expected to be strictly greater than that in the case of low likelihood"} {"class.text":"OWNX","text":"this means that for a given level of self-control, one might observe substantially different donation behavior depending on whether conflict was identified or not"} {"class.text":"AIMX","text":"we test in the context of a dictator game the proposition that individuals may experience a self-control conflict between the temptation to act selfishly and the better judgment to act pro-socially"} {"class.text":"OWNX","text":"our analysis reveals a positive and significant correlation between trait self-control and pro-social behavior in the treatment where we expected a relatively high likelihood of conflict identification-but not in the treatment where we expected a low likelihood"} {"class.text":"MISC","text":"the magnitude of the effect is of economic significance"} {"class.text":"OWNX","text":"we conclude that subtle cues might prove sufficient to alter individuals' perception of allocation opportunities, thereby prompting individuals to draw on their own cognitive resources to act pro-socially"} {"class.text":"MISC","text":"self-control failure, famously termed akrasia in plato's protagoras CITATION , persists throughout domains of daily life and represents a central issue of both philosophy and modern-day social sciences"} {"class.text":"MISC","text":"for example, the dieter faced with the opportunity to indulge in a delicious creamy cake may perceive a conflict between indulging and maintaining a good figure"} {"class.text":"MISC","text":"the student may feel conflicted between the desire to go to the cinema and her better judgment to stay home and study"} {"class.text":"MISC","text":"perhaps less intuitively, but no less importantly, the question of pro-social versus selfish behavior may be understood in similar terms"} {"class.text":"MISC","text":"this conceptualization may help reconcile conflicting notions in economics of selfish and pro-social motivations"} {"class.text":"MISC","text":"that individuals should care much about their own self-interest seems almost tautological and requires little further exposition, but that individuals also should care about the interest of others-at the expense of that of their own-has attracted considerable attention CITATION"} {"class.text":"MISC","text":"nonetheless, one could imagine that even individuals of generally pro-social inclination on occasion may feel tempted to act selfishly and hence underreport income to the authorities"} {"class.text":"MISC","text":"that is, pro-social preferences potentially fly in the face of basic urges for personal gain-or greed-and the individual may thus experience a self-control conflict between better judgment to act pro-socially and the temptation to act selfishly"} {"class.text":"MISC","text":"self-control-our capacity to overrule temptation-is no less complex than it is important"} {"class.text":"MISC","text":"a multitude of conceptualizations exist, many of which are complementary"} {"class.text":"MISC","text":"typically, and in line with classic ideas of the conflict between reason and passion, authors view self-control as a \"cold\" executive function that guides behavior in the face of \"hot\" impulses to act against better judgment CITATION"} {"class.text":"MISC","text":"willpower, then, represents the combined resources that the executive function-or the planner, in the parlance of thaler and shefrin CITATION -brings to bear in a deliberate struggle against temptation CITATION"} {"class.text":"MISC","text":"such resources may include cognitive strategies to divert attention away from temptation CITATION , strategies of pre-commitment CITATION , or possibly the sheer strength of mind to hold back from the song of the sirens"} {"class.text":"OWNX","text":"our conceptualization of self-control mirrors these"} {"class.text":"MISC","text":"only recently has the psychological literature started to explore how the question of pro-social versus selfish behavior relates to that of self-control"} {"class.text":"MISC","text":"loewenstein CITATION suggests that selfish behavior may be motivated by visceral urges or drive-states, resembling cravings for relief from hunger, pain, and sexual deprivation"} {"class.text":"CONT","text":"at present, there is but indirect evidence for this idea"} {"class.text":"MISC","text":"for example, pronin et al CITATION show that decisions about others resemble decisions about \"future selves\", both classes of which contrast to decisions about less abstract \"present selves\""} {"class.text":"MISC","text":"albrecht et al CITATION report consistent results; individuals who choose between immediate and delayed rewards for themselves exhibit less patience and more affective involvement activation in the dopaminergic reward system than do individuals who make such choices for others-or for themselves in the future"} {"class.text":"MISC","text":"moreover, curry et al CITATION find in a standard public goods game that individuals' discount rates are negatively associated with their contributions to the public good"} {"class.text":"MISC","text":"arriving at similar results, fehr and leibbrandt CITATION report that patient vs impatient fishermen, whose time preferences were elicited in the lab, exhibited more cooperative behavior in a common resource problem and were in the field less likely to over-exploit the common pool resource"} {"class.text":"MISC","text":"furthermore, burks et al CITATION find that \"short-term\" patience-the beta in the beta -δ model-is positively associated with cooperative behavior in a sequential prisoner's dilemma"} {"class.text":"MISC","text":"however, duffy and smith CITATION report no effect of cognitive load-a manipulation intended to deplete cognitive resources and thereby impair self-control-on outcomes across treatments in a repeated multi-player prisoner's dilemma"} {"class.text":"MISC","text":"an emerging literature on the \"default\" response in games of trust and reciprocity lends further credence to the notion that altruistic responses require self-control"} {"class.text":"MISC","text":"achtziger et al CITATION subjected players in an ultimatum game to cognitive resource depletion, and show that depleted proposers made lower offers-they became less altruistic"} {"class.text":"MISC","text":"moreover, depleted responders were more likely to reject offers that were unfair to themselves-they exhibited \"altruistic punishment\""} {"class.text":"MISC","text":"halali et al CITATION report the same for responders, but with a different depletion task"} {"class.text":"MISC","text":"crockett et al CITATION subjected responders to acute tryptophan depletion-a procedure that temporarily reduces serotonin levels in the brain and thereby impairs self-control CITATION ; reduced serotonin levels raised rejection rates and this reduction is positively correlated with impulsive choice in a delay-discounting task CITATION"} {"class.text":"MISC","text":"using a trust game, knoch et al CITATION subjected trustees' right lateral prefrontal cortex to transcranial magnetic stimulation, which reduces functioning in the targeted brain region"} {"class.text":"MISC","text":"trustees, though cognizant that returning a share of the investments was both strategic and norm-compliant, were unable to do so under impaired executive functioning; self-control seems necessary to act on the better judgment to resist the temptation to keep the received investment entirely for oneself"} {"class.text":"BASE","text":"closest to our domain of inquiry, piovesan and wengstrom CITATION measured response times of participants in a repeated dictator game, lasting 24 periods"} {"class.text":"MISC","text":"they find both across and within participants that lower response times are associated with more selfish choices"} {"class.text":"MISC","text":"one interpretation of their results is that the default behavior is to act selfishly and that pro-social behavior requires the successful resolution of a self-control conflict, which slows the response time"} {"class.text":"MISC","text":"such successful resolution of conflict would require cognitive resources, but hauge et al CITATION report no effect of cognitive load on players in one-shot dictator games"} {"class.text":"AIMX","text":"in this paper we attempt a more direct test of the hypothesis that pro-social versus selfish behavior may represent a self-control problem"} {"class.text":"OWNX","text":"we employ a standard measure of pure pro-social behavior, the one-shot dictator game, which invokes neither concerns for strategy nor for reciprocity; and a well-grounded psychometric measure of self-control, the rosenbaum self-control schedule CITATION"} {"class.text":"OWNX","text":"further, we explore the conditions under which we expect an association between self-control and pro-social behavior"} {"class.text":"MISC","text":"critically, self-control strategies are relevant to the decision to indulge only when the individual has identified self-control conflict"} {"class.text":"MISC","text":"therefore, one strategy for investigating whether the problem of pro-social versus selfish behavior resembles one of self-control is to test whether the tendency to apply self-control strategies is positively associated with pro-social behavior when individuals have identified self-control conflict, but less so or not at all when individuals have not"} {"class.text":"MISC","text":"determinants of conflict identification in the face of temptation have been explored only recently"} {"class.text":"MISC","text":"for example, the diabetic dieter probably knows that having even a single, tempting chocolate may incur major costs"} {"class.text":"MISC","text":"however, the question of self-control conflict is more ambiguous for the non-diabetic dieter, who faces the same chocolate"} {"class.text":"MISC","text":"having this one chocolate alone will not incur major costs, but doing so regularly might"} {"class.text":"MISC","text":"similarly, the good citizen may find that a general failure to act generously would represent a major threat to his self-image, but being stingy on just a couple of occasions is a more ambiguous matter"} {"class.text":"MISC","text":"myrseth and fishbach CITATION use the term epsilon cost temptation to denote tempting opportunities that incur nothing but trivial costs when consumed in small amounts, but potentially serious costs when consumed extensively"} {"class.text":"MISC","text":"they argue that individuals identify self-control conflict in the face of epsilon cost temptation if and only if two conditions are met: a the focal consumption opportunity must be viewed in relation to multiple additional opportunities, and b the decision maker must assume that similar choices are made for each opportunity CITATION"} {"class.text":"MISC","text":"that is, considering the question of whether or not to have a delicious creamy cake will evoke self-control conflict in the dieter if the dining opportunity is viewed in relation to future opportunities for dessert consumption, but not if the dining opportunity is viewed in isolation, as a singular episode"} {"class.text":"MISC","text":"similarly, the question of whether or not to be generous-to donate to a charitable organization-may elicit self-control conflict if the decision is viewed in relation to future decisions, but not if the decision is viewed in isolation"} {"class.text":"MISC","text":"if viewed in relation to future decisions, the question of how much to donate on a single occasion may have bearing on the decision maker's self-image; donating now-and in the future-indicates a generous character, whereas keeping the money for oneself does not"} {"class.text":"MISC","text":"however, if viewed in isolation, the question of how much to donate has little bearing on self-image; the present decision of how much to donate is considered only in light of immediate consequences, leaving self-image out of the equation"} {"class.text":"MISC","text":"because a consistent self-image represents an important motivator for pro-social behavior CITATION , we expect that individuals are more likely to identify self-control conflict between selfish and pro-social behavior if the allocation decision is seen in relation to future opportunities than if it is seen in isolation"} {"class.text":"MISC","text":"myrseth and fishbach CITATION show that subtle framing manipulations are sufficient to influence identification of self-control conflict in the face of epsilon cost temptation"} {"class.text":"MISC","text":"they find that presenting a calendar displaying the current month, with a grid separating the dates, raised participants' subsequent consumption of potato chips relative to that of participants whom were presented a calendar without a grid"} {"class.text":"MISC","text":"they argue that the gridded calendar activated an isolated versus interrelated frame of the choice opportunity; it made participants more likely to isolate the date in question and thus less likely to see the decision task in relation to similar future opportunities"} {"class.text":"MISC","text":"consequently, the grid reduced the likelihood that participants would identify a conflict between the temptation to have chips and the better judgment to maintain a fine figure and good health"} {"class.text":"MISC","text":"indeed, participants who viewed the gridded calendar reported experiencing less conflict during their decision to have chips or not than did those who viewed the non-gridded calendar"} {"class.text":"MISC","text":"furthermore, participants' trait ability to implement self-control strategies, measured by rosenbaum's CITATION psychometric scale, was positively associated with chips consumption for those who viewed the calendar without the grid and who were more likely to identify conflict, but not for others who viewed the calendar with and who were less likely to identify conflict"} {"class.text":"BASE","text":"to explore our hypothesis that the problem of pro-social versus selfish behavior may represent one of self-control, we have applied the empirical strategy from myrseth and fishbach CITATION in the dictator game-a participant is granted an endowment and asked to split it between herself and a recipient CITATION , and in our case the red cross featured as recipient CITATION"} {"class.text":"OWNX","text":"the game thus pits pro-social motivations against self-interest"} {"class.text":"OWNX","text":"if pro-social versus selfish behavior could represent a self-control conflict, we would expect participants' trait self-control, as measured by rosenbaum's CITATION scale, to correlate positively with pro-social behavior for participants who have just previously viewed a calendar without a grid, but less so or not at all for participants who have viewed a calendar with"} {"class.text":"OWNX","text":"the graph in figure 2 displays donation, as a function of level of self-control, for two different levels of identification likelihood"} {"class.text":"OWNX","text":"in the case of low likelihood, the slope is expected to be weakly positive"} {"class.text":"OWNX","text":"in the case of the higher likelihood, however, the slope is expected to be strictly greater than that in the case of low likelihood"} {"class.text":"OWNX","text":"we manipulated the likelihood that individuals would identify self-control conflict, and we measured their trait ability to implement self-control strategies"} {"class.text":"OWNX","text":"our analysis reveals a positive and significant correlation between trait self-control and pro-social behavior in the treatment where we expected a relatively high likelihood of conflict identification-but not in the treatment where we expected a low likelihood"} {"class.text":"MISC","text":"lured by temptation, individuals may find themselves acting against their better judgment"} {"class.text":"MISC","text":"self-control failure, famously termed akrasia in plato's protagoras CITATION , persists throughout domains of daily life and represents a central issue of both philosophy and modern-day social sciences"} {"class.text":"MISC","text":"for example, the dieter faced with the opportunity to indulge in a delicious creamy cake may perceive a conflict between indulging and maintaining a good figure"} {"class.text":"MISC","text":"the student may feel conflicted between the desire to go to the cinema and her better judgment to stay home and study"} {"class.text":"MISC","text":"perhaps less intuitively, but no less importantly, the question of pro-social versus selfish behavior may be understood in similar terms"} {"class.text":"MISC","text":"this conceptualization may help reconcile conflicting notions in economics of selfish and pro-social motivations"} {"class.text":"MISC","text":"that individuals should care much about their own self-interest seems almost tautological and requires little further exposition, but that individuals also should care about the interest of others-at the expense of that of their own-has attracted considerable attention CITATION"} {"class.text":"MISC","text":"for example, many individuals voluntarily contribute to charity or to public goods e g , recycling, and they pay their taxes despite low likelihood of punishment for failing to do so"} {"class.text":"MISC","text":"that is, pro-social preferences potentially fly in the face of basic urges for personal gain-or greed-and the individual may thus experience a self-control conflict between better judgment to act pro-socially and the temptation to act selfishly"} {"class.text":"MISC","text":"a multitude of conceptualizations exist, many of which are complementary"} {"class.text":"MISC","text":"willpower, then, represents the combined resources that the executive function-or the planner, in the parlance of thaler and shefrin CITATION -brings to bear in a deliberate struggle against temptation CITATION"} {"class.text":"MISC","text":"such resources may include cognitive strategies to divert attention away from temptation CITATION , strategies of pre-commitment CITATION , or possibly the sheer strength of mind to hold back from the song of the sirens"} {"class.text":"OWNX","text":"our conceptualization of self-control mirrors these"} {"class.text":"MISC","text":"only recently has the psychological literature started to explore how the question of pro-social versus selfish behavior relates to that of self-control"} {"class.text":"MISC","text":"o'donoghue and loewenstein CITATION argue that such selfish urges may conflict with the \"colder\", more abstract preferences for altruism, as visceral urges for sweets may conflict with more abstract preferences for a fine figure or good health"} {"class.text":"MISC","text":"at present, there is but indirect evidence for this idea"} {"class.text":"MISC","text":"for example, pronin et al CITATION show that decisions about others resemble decisions about \"future selves\", both classes of which contrast to decisions about less abstract \"present selves\""} {"class.text":"MISC","text":"albrecht et al CITATION report consistent results; individuals who choose between immediate and delayed rewards for themselves exhibit less patience and more affective involvement activation in the dopaminergic reward system than do individuals who make such choices for others-or for themselves in the future"} {"class.text":"MISC","text":"moreover, curry et al CITATION find in a standard public goods game that individuals' discount rates are negatively associated with their contributions to the public good"} {"class.text":"MISC","text":"that is, more \"impatient\" individuals contributed less to the public good than did \"patient\" ones"} {"class.text":"MISC","text":"arriving at similar results, fehr and leibbrandt CITATION report that patient vs impatient fishermen, whose time preferences were elicited in the lab, exhibited more cooperative behavior in a common resource problem and were in the field less likely to over-exploit the common pool resource"} {"class.text":"MISC","text":"furthermore, burks et al CITATION find that \"short-term\" patience-the beta in the beta -δ model-is positively associated with cooperative behavior in a sequential prisoner's dilemma"} {"class.text":"MISC","text":"however, duffy and smith CITATION report no effect of cognitive load-a manipulation intended to deplete cognitive resources and thereby impair self-control-on outcomes across treatments in a repeated multi-player prisoner's dilemma"} {"class.text":"MISC","text":"an emerging literature on the \"default\" response in games of trust and reciprocity lends further credence to the notion that altruistic responses require self-control"} {"class.text":"MISC","text":"halali et al CITATION report the same for responders, but with a different depletion task"} {"class.text":"MISC","text":"crockett et al CITATION subjected responders to acute tryptophan depletion-a procedure that temporarily reduces serotonin levels in the brain and thereby impairs self-control CITATION ; reduced serotonin levels raised rejection rates and this reduction is positively correlated with impulsive choice in a delay-discounting task CITATION"} {"class.text":"MISC","text":"using a trust game, knoch et al CITATION subjected trustees' right lateral prefrontal cortex to transcranial magnetic stimulation, which reduces functioning in the targeted brain region"} {"class.text":"MISC","text":"trustees, though cognizant that returning a share of the investments was both strategic and norm-compliant, were unable to do so under impaired executive functioning; self-control seems necessary to act on the better judgment to resist the temptation to keep the received investment entirely for oneself"} {"class.text":"MISC","text":"they find both across and within participants that lower response times are associated with more selfish choices"} {"class.text":"MISC","text":"one interpretation of their results is that the default behavior is to act selfishly and that pro-social behavior requires the successful resolution of a self-control conflict, which slows the response time"} {"class.text":"MISC","text":"such successful resolution of conflict would require cognitive resources, but hauge et al CITATION report no effect of cognitive load on players in one-shot dictator games"} {"class.text":"AIMX","text":"in this paper we attempt a more direct test of the hypothesis that pro-social versus selfish behavior may represent a self-control problem"} {"class.text":"OWNX","text":"we employ a standard measure of pure pro-social behavior, the one-shot dictator game, which invokes neither concerns for strategy nor for reciprocity; and a well-grounded psychometric measure of self-control, the rosenbaum self-control schedule CITATION"} {"class.text":"BASE","text":"in so doing, we rely on two conditions necessary for successfully exercising restraint in the face of temptation; myrseth and fishbach CITATION propose a two-stage model of self-control, which postulates that an individual in the face of temptation first identifies conflict or not between indulging and pursuing a higher-order goal and, second, that the individual next employs self-control strategies if and only if conflict was identified at the first stage see figure 1"} {"class.text":"MISC","text":"critically, self-control strategies are relevant to the decision to indulge only when the individual has identified self-control conflict"} {"class.text":"MISC","text":"therefore, one strategy for investigating whether the problem of pro-social versus selfish behavior resembles one of self-control is to test whether the tendency to apply self-control strategies is positively associated with pro-social behavior when individuals have identified self-control conflict, but less so or not at all when individuals have not"} {"class.text":"MISC","text":"determinants of conflict identification in the face of temptation have been explored only recently"} {"class.text":"MISC","text":"in some contexts, the question is almost trivial and identification of conflict virtually obvious"} {"class.text":"MISC","text":"for example, the diabetic dieter probably knows that having even a single, tempting chocolate may incur major costs"} {"class.text":"MISC","text":"however, the question of self-control conflict is more ambiguous for the non-diabetic dieter, who faces the same chocolate"} {"class.text":"MISC","text":"having this one chocolate alone will not incur major costs, but doing so regularly might"} {"class.text":"MISC","text":"similarly, the good citizen may find that a general failure to act generously would represent a major threat to his self-image, but being stingy on just a couple of occasions is a more ambiguous matter"} {"class.text":"MISC","text":"myrseth and fishbach CITATION use the term epsilon cost temptation to denote tempting opportunities that incur nothing but trivial costs when consumed in small amounts, but potentially serious costs when consumed extensively"} {"class.text":"MISC","text":"they argue that individuals identify self-control conflict in the face of epsilon cost temptation if and only if two conditions are met: a the focal consumption opportunity must be viewed in relation to multiple additional opportunities, and b the decision maker must assume that similar choices are made for each opportunity CITATION"} {"class.text":"MISC","text":"that is, considering the question of whether or not to have a delicious creamy cake will evoke self-control conflict in the dieter if the dining opportunity is viewed in relation to future opportunities for dessert consumption, but not if the dining opportunity is viewed in isolation, as a singular episode"} {"class.text":"MISC","text":"similarly, the question of whether or not to be generous-to donate to a charitable organization-may elicit self-control conflict if the decision is viewed in relation to future decisions, but not if the decision is viewed in isolation"} {"class.text":"MISC","text":"however, if viewed in isolation, the question of how much to donate has little bearing on self-image; the present decision of how much to donate is considered only in light of immediate consequences, leaving self-image out of the equation"} {"class.text":"OWNX","text":"because a consistent self-image represents an important motivator for pro-social behavior CITATION , we expect that individuals are more likely to identify self-control conflict between selfish and pro-social behavior if the allocation decision is seen in relation to future opportunities than if it is seen in isolation"} {"class.text":"MISC","text":"myrseth and fishbach CITATION show that subtle framing manipulations are sufficient to influence identification of self-control conflict in the face of epsilon cost temptation"} {"class.text":"MISC","text":"they argue that the gridded calendar activated an isolated versus interrelated frame of the choice opportunity; it made participants more likely to isolate the date in question and thus less likely to see the decision task in relation to similar future opportunities"} {"class.text":"MISC","text":"consequently, the grid reduced the likelihood that participants would identify a conflict between the temptation to have chips and the better judgment to maintain a fine figure and good health"} {"class.text":"MISC","text":"furthermore, participants' trait ability to implement self-control strategies, measured by rosenbaum's CITATION psychometric scale, was positively associated with chips consumption for those who viewed the calendar without the grid and who were more likely to identify conflict, but not for others who viewed the calendar with and who were less likely to identify conflict"} {"class.text":"BASE","text":"to explore our hypothesis that the problem of pro-social versus selfish behavior may represent one of self-control, we have applied the empirical strategy from myrseth and fishbach CITATION in the dictator game-a participant is granted an endowment and asked to split it between herself and a recipient CITATION , and in our case the red cross featured as recipient CITATION"} {"class.text":"OWNX","text":"the game thus pits pro-social motivations against self-interest"} {"class.text":"OWNX","text":"if pro-social versus selfish behavior could represent a self-control conflict, we would expect participants' trait self-control, as measured by rosenbaum's CITATION scale, to correlate positively with pro-social behavior for participants who have just previously viewed a calendar without a grid, but less so or not at all for participants who have viewed a calendar with"} {"class.text":"OWNX","text":"the graph in figure 2 displays donation, as a function of level of self-control, for two different levels of identification likelihood"} {"class.text":"OWNX","text":"in the case of low likelihood, the slope is expected to be weakly positive"} {"class.text":"OWNX","text":"in the case of the higher likelihood, however, the slope is expected to be strictly greater than that in the case of low likelihood"} {"class.text":"OWNX","text":"this means that for a given level of self-control, one might observe substantially different donation behavior depending on whether conflict was identified or not"} {"class.text":"MISC--the","text":"prospect theory editing operation, by which a decision maker's reference point is determined, can have important effects on the disutility of the test"} {"class.text":"AIMX--on","text":"the basis of the prospect theory value function, this paper develops two approaches to reducing disutility by directing the decision maker's attention to either actual past or expected future losses that result in shifted reference points"} {"class.text":"OWNX--after","text":"providing a graphical description of the approaches and a mathematical proof of the direction of their effect on judgment, we briefly illustrate the potential value of these approaches with examples from qualitative research on prostate cancer treatment decisions"} {"class.text":"MISC--in","text":"preventative health decisions, such as the decision to undergo an invasive screening test or treatment, people may be deterred from selecting the test because its disutility relative to not testing is greater than the utility associated with prevention of possible disease"} {"class.text":"MISC--the","text":"prospect theory editing operation CITATION , by which a decision maker's reference point is determined, can have important impacts on the perceived disutility of the test"} {"class.text":"MISC--the","text":"work of rothman, salovey, and colleagues on message framing has tested prospect theory predictions of how the description of test outcomes as gains or losses as well as the conceptualization of the purpose of the test as preventative vs diagnostic and the consequent perception of whether the test is \"safe\" or \"risky\" can affect test rates CITATION"} {"class.text":"MISC--specifically,","text":"message framing theories predict that when a procedure is perceived as risky e g , cancer screening tests may cause a patient to find out that they have cancer, loss-framed messages will promote testing more strongly than gain-framed messages, because people favor risky prospects over sure prospects in the domain of losses"} {"class.text":"MISC--on","text":"the other hand, when a procedure is perceived as safe e g , sunscreen prevents sunburn and skin cancer, gain-framed messages are predicted to be more effective because people prefer sure prospects to risky prospects in the domain of gains"} {"class.text":"MISC--several","text":"public health intervention studies have examined message framing and generally found evidence favoring the predictions CITATION"} {"class.text":"AIMX--on","text":"the basis of the prospect theory value function, this paper develops two approaches to reducing perceived disutility by directing the decision maker's attention to either actual past or expected future losses that can serve as reference points and are not consequences of the test itself"} {"class.text":"CONT--these","text":"approaches thus differ from message framing, which focuses on how the test outcomes are described and manipulates gain and loss framing"} {"class.text":"OWNX--we","text":"instead derive the potential impact of directly refocusing the decision maker's reference point"} {"class.text":"MISC--in","text":"preventative health decisions, such as the decision to undergo an invasive screening test or treatment, people may be deterred from selecting the test because its perceived disutility relative to not testing is greater than the utility associated with prevention of possible disease"} {"class.text":"MISC--the","text":"prospect theory editing operation, by which a decision maker's reference point is determined, can have important effects on the disutility of the test"} {"class.text":"AIMX--on","text":"the basis of the prospect theory value function, this paper develops two approaches to reducing disutility by directing the decision maker's attention to either actual past or expected future losses that result in shifted reference points"} {"class.text":"OWNX--after","text":"providing a graphical description of the approaches and a mathematical proof of the direction of their effect on judgment, we briefly illustrate the potential value of these approaches with examples from qualitative research on prostate cancer treatment decisions"} {"class.text":"MISC--in","text":"preventative health decisions, such as the decision to undergo an invasive screening test or treatment, people may be deterred from selecting the test because its disutility relative to not testing is greater than the utility associated with prevention of possible disease"} {"class.text":"MISC--for","text":"example, people may feel that the anticipated disutility of a colonoscopy for colorectal cancer screening is great enough relative to the expected utilty of prevention of possible colorectal cancer to dissuade them from seeking colonoscopy"} {"class.text":"MISC--the","text":"prospect theory editing operation CITATION , by which a decision maker's reference point is determined, can have important impacts on the perceived disutility of the test"} {"class.text":"MISC--the","text":"work of rothman, salovey, and colleagues on message framing has tested prospect theory predictions of how the description of test outcomes as gains or losses as well as the conceptualization of the purpose of the test as preventative vs diagnostic and the consequent perception of whether the test is \"safe\" or \"risky\" can affect test rates CITATION"} {"class.text":"MISC--specifically,","text":"message framing theories predict that when a procedure is perceived as risky e g , cancer screening tests may cause a patient to find out that they have cancer, loss-framed messages will promote testing more strongly than gain-framed messages, because people favor risky prospects over sure prospects in the domain of losses"} {"class.text":"MISC--on","text":"the other hand, when a procedure is perceived as safe e g , sunscreen prevents sunburn and skin cancer, gain-framed messages are predicted to be more effective because people prefer sure prospects to risky prospects in the domain of gains"} {"class.text":"MISC--several","text":"public health intervention studies have examined message framing and generally found evidence favoring the predictions CITATION"} {"class.text":"AIMX--on","text":"the basis of the prospect theory value function, this paper develops two approaches to reducing perceived disutility by directing the decision maker's attention to either actual past or expected future losses that can serve as reference points and are not consequences of the test itself"} {"class.text":"OWNX--we","text":"instead derive the potential impact of directly refocusing the decision maker's reference point"} {"class.text":"MISC","text":"in preventative health decisions, such as the decision to undergo an invasive screening test or treatment, people may be deterred from selecting the test because its perceived disutility relative to not testing is greater than the utility associated with prevention of possible disease"} {"class.text":"MISC","text":"in preventative health decisions, such as the decision to undergo an invasive screening test or treatment, people may be deterred from selecting the test because its disutility relative to not testing is greater than the utility associated with prevention of possible disease"} {"class.text":"MISC","text":"for example, people may feel that the anticipated disutility of a colonoscopy for colorectal cancer screening is great enough relative to the expected utilty of prevention of possible colorectal cancer to dissuade them from seeking colonoscopy"} {"class.text":"MISC","text":"the prospect theory editing operation CITATION , by which a decision maker's reference point is determined, can have important impacts on the perceived disutility of the test"} {"class.text":"MISC","text":"the work of rothman, salovey, and colleagues on message framing has tested prospect theory predictions of how the description of test outcomes as gains or losses as well as the conceptualization of the purpose of the test as preventative vs diagnostic and the consequent perception of whether the test is \"safe\" or \"risky\" can affect test rates CITATION"} {"class.text":"MISC","text":"specifically, message framing theories predict that when a procedure is perceived as risky e g , cancer screening tests may cause a patient to find out that they have cancer, loss-framed messages will promote testing more strongly than gain-framed messages, because people favor risky prospects over sure prospects in the domain of losses"} {"class.text":"MISC","text":"on the other hand, when a procedure is perceived as safe e g , sunscreen prevents sunburn and skin cancer, gain-framed messages are predicted to be more effective because people prefer sure prospects to risky prospects in the domain of gains"} {"class.text":"CONT","text":"these approaches thus differ from message framing, which focuses on how the test outcomes are described and manipulates gain and loss framing"} {"class.text":"OWNX","text":"we instead derive the potential impact of directly refocusing the decision maker's reference point"} {"class.text":"MISC","text":"previous tests of cumulative prospect theory cpt and of the priority heuristic ph found evidence contradicting these two models of risky decision making."} {"class.text":"CONT","text":"however, those tests were criticized because they had characteristics that might \"trigger\" use of other heuristics."} {"class.text":"AIMX","text":"this paper presents new tests that avoid those characteristics."} {"class.text":"OWNX","text":"expected values of the gambles are nearly equal in each choice."} {"class.text":"OWNX","text":"in addition, if a person followed expected value ev, expected utility eu, cpt, or ph in these tests, she would shift her preferences in the same direction as shifts in ev or eu"} {"class.text":"OWNX","text":"new tests of probability-consequence interaction were also conducted"} {"class.text":"OWNX","text":"strong interactions were observed, contrary to ph"} {"class.text":"AIMX","text":"this paper compares three models that attempt to describe risky decision making"} {"class.text":"AIMX","text":"these models are cumulative prospect theory cpt CITATION , birnbaum's CITATION transfer of attention exchange model tax, and the priority heuristic ph of brandstatter, gigerenzer, and hertwig CITATION"} {"class.text":"MISC","text":"the ph model is based on the idea that people compare one attribute at a time, such as the minimum prizes"} {"class.text":"BASE","text":"in addition, the similarity model of rubinstein CITATION as modified by leland CITATION is also relevant to these studies, although these studies were not designed to test that model"} {"class.text":"MISC","text":"birnbaum CITATION reviewed a number of critical tests that refute any rank dependent utility rdu model CITATION including rank and sign-dependent utility CITATION , cpt, and expected utility eu"} {"class.text":"MISC","text":"birnbaum CITATION noted that many of the same tests that refute cpt also contradict the priority heuristic"} {"class.text":"MISC","text":"some of these choices included cases where 90% or more of the participants satisfied stochastic dominance but the priority heuristic predicts indifference"} {"class.text":"MISC","text":"in other choices, significantly more than half of the participants about 70% of undergraduates violated stochastic dominance, but the priority heuristic predicts that people should satisfy it"} {"class.text":"MISC","text":"brandstatter, gigerenzer, and hertwig CITATION responded that properties of these choices may have induced people to use other heuristics drawn from a person's \"adaptive toolbox"} {"class.text":"MISC","text":"presumably, decision makers first decide what rule to use, then they either apply that rule or choose to use another rule"} {"class.text":"CONT","text":"the mechanism that decides what rule to use has not yet been specified; it is described instead with lists of \"triggering conditions,\" which are estimated from data like parameters"} {"class.text":"MISC","text":"in addition, brandstatter et al CITATION argued that certain choices reviewed by birnbaum CITATION used gambles that differed in expected value ev"} {"class.text":"CONT","text":"brandstatter et al CITATION presented a figure to show that the priority heuristic is not accurate when expected values evs differ, which led them to suppose that two strategies are at work, one for \"easy\" choices that differ in ev and one for \"harder\" choices where evs are nearly equal"} {"class.text":"MISC","text":"brandstatter et al consider ev ratio as a proxy for the \"difficulty\" of a choice, but do not necessarily hold that people actually compute ratios of ev"} {"class.text":"MISC","text":"they argued that the priority heuristic is accurate for \"difficult\" choices in which evs are nearly equal"} {"class.text":"MISC","text":"to account for the results, brandstatter et al noted that birnbaum and navarrete CITATION used many choices in which both gambles of a choice had the same probability distribution and in some choices two branches had the same probability"} {"class.text":"CONT","text":"ph was not accurate for such choices, so brandstatter, et al CITATION theorized that people use a \"toting up\" heuristic for choices in which two branches had the same probability"} {"class.text":"MISC","text":"in some of the choices in birnbaum and navarrete CITATION , there was a common probability-consequence branch in both choices, which was theorized to trigger editing rules and other heuristics that were called up to account for the failures of the priority heuristic"} {"class.text":"CONT","text":"the arguments of brandstatter et al CITATION might also provide excuses for previous failures of cpt as well"} {"class.text":"AIMX","text":"this paper devises a new type of test that avoids the exceptions stated above"} {"class.text":"OWNX","text":"in these tests, one alternative does not stochastically dominate the other, there are no common probability-consequence branches, probabilities of the consequences are not equal, and expected values are nearly equal"} {"class.text":"CONT","text":"in addition, unlike previous tests, the new tests use shifts in expected value and expected utility to \"help\" predictions of ph and cpt"} {"class.text":"OWNX","text":"that is, expected value and expected utility are both manipulated such that, if a person shifts his or her judgments in the same direction as the changes in eu or ev, his or her choices will appear consistent with ph and cpt"} {"class.text":"OWNX","text":"however, the choices are designed so that the tax model with parameters typical of previous research predicts that people will shift their choices in the opposite direction of ev, eu, cpt, and ph"} {"class.text":"MISC","text":"previous tests of cumulative prospect theory cpt and of the priority heuristic ph found evidence contradicting these two models of risky decision making."} {"class.text":"CONT","text":"however, those tests were criticized because they had characteristics that might \"trigger\" use of other heuristics."} {"class.text":"OWNX","text":"expected values of the gambles are nearly equal in each choice."} {"class.text":"OWNX","text":"in addition, if a person followed expected value ev, expected utility eu, cpt, or ph in these tests, she would shift her preferences in the same direction as shifts in ev or eu"} {"class.text":"OWNX","text":"in contrast, the transfer of attention exchange model tax and a similarity model predict that people will reverse preferences in the opposite direction"} {"class.text":"OWNX","text":"results contradict the ph, even when ph is modified to include a preliminary similarity evaluation using the ph parameters"} {"class.text":"OWNX","text":"new tests of probability-consequence interaction were also conducted"} {"class.text":"OWNX","text":"strong interactions were observed, contrary to ph"} {"class.text":"OWNX","text":"these results add to the growing bodies of evidence showing that neither cpt nor ph is an accurate description of risky decision making"} {"class.text":"AIMX","text":"this paper compares three models that attempt to describe risky decision making"} {"class.text":"AIMX","text":"these models are cumulative prospect theory cpt CITATION , birnbaum's CITATION transfer of attention exchange model tax, and the priority heuristic ph of brandstatter, gigerenzer, and hertwig CITATION"} {"class.text":"MISC","text":"the ph model is based on the idea that people compare one attribute at a time, such as the minimum prizes"} {"class.text":"MISC","text":"birnbaum CITATION noted that many of the same tests that refute cpt also contradict the priority heuristic"} {"class.text":"MISC","text":"for example, the priority heuristic predicted fewer than half of the modal choices analyzed by birnbaum CITATION , by birnbaum CITATION , and by birnbaum and navarrete CITATION"} {"class.text":"MISC","text":"some of these choices included cases where 90% or more of the participants satisfied stochastic dominance but the priority heuristic predicts indifference"} {"class.text":"MISC","text":"in other choices, significantly more than half of the participants about 70% of undergraduates violated stochastic dominance, but the priority heuristic predicts that people should satisfy it"} {"class.text":"MISC","text":"brandstatter, gigerenzer, and hertwig CITATION responded that properties of these choices may have induced people to use other heuristics drawn from a person's \"adaptive toolbox"} {"class.text":"MISC","text":"presumably, decision makers first decide what rule to use, then they either apply that rule or choose to use another rule"} {"class.text":"CONT","text":"the mechanism that decides what rule to use has not yet been specified; it is described instead with lists of \"triggering conditions,\" which are estimated from data like parameters"} {"class.text":"MISC","text":"brandstatter et al CITATION concluded that the priority heuristic does not apply when there is a stochastic dominance relation in the choice"} {"class.text":"CONT","text":"brandstatter et al CITATION presented a figure to show that the priority heuristic is not accurate when expected values evs differ, which led them to suppose that two strategies are at work, one for \"easy\" choices that differ in ev and one for \"harder\" choices where evs are nearly equal"} {"class.text":"MISC","text":"from the data, brandstatter et al CITATION estimated that, when the ratio of ev exceeds 2, people act as if they choose the gamble with the higher ev"} {"class.text":"MISC","text":"brandstatter et al consider ev ratio as a proxy for the \"difficulty\" of a choice, but do not necessarily hold that people actually compute ratios of ev"} {"class.text":"MISC","text":"they argued that the priority heuristic is accurate for \"difficult\" choices in which evs are nearly equal"} {"class.text":"CONT","text":"however, birnbaum CITATION noted that ev ratios in birnbaum and navarrete CITATION had been inside the region where ph is supposed to apply; in that study, the priority heuristic failed to reproduce even half of the modal choices correctly"} {"class.text":"MISC","text":"to account for the results, brandstatter et al noted that birnbaum and navarrete CITATION used many choices in which both gambles of a choice had the same probability distribution and in some choices two branches had the same probability"} {"class.text":"CONT","text":"ph was not accurate for such choices, so brandstatter, et al CITATION theorized that people use a \"toting up\" heuristic for choices in which two branches had the same probability"} {"class.text":"MISC","text":"in some of the choices in birnbaum and navarrete CITATION , there was a common probability-consequence branch in both choices, which was theorized to trigger editing rules and other heuristics that were called up to account for the failures of the priority heuristic"} {"class.text":"CONT","text":"the arguments of brandstatter et al CITATION might also provide excuses for previous failures of cpt as well"} {"class.text":"AIMX","text":"this paper devises a new type of test that avoids the exceptions stated above"} {"class.text":"OWNX","text":"in these tests, one alternative does not stochastically dominate the other, there are no common probability-consequence branches, probabilities of the consequences are not equal, and expected values are nearly equal"} {"class.text":"CONT","text":"in addition, unlike previous tests, the new tests use shifts in expected value and expected utility to \"help\" predictions of ph and cpt"} {"class.text":"OWNX","text":"that is, expected value and expected utility are both manipulated such that, if a person shifts his or her judgments in the same direction as the changes in eu or ev, his or her choices will appear consistent with ph and cpt"} {"class.text":"OWNX","text":"however, the choices are designed so that the tax model with parameters typical of previous research predicts that people will shift their choices in the opposite direction of ev, eu, cpt, and ph"} {"class.text":"MISC","text":"previous tests of cumulative prospect theory cpt and of the priority heuristic ph found evidence contradicting these two models of risky decision making"} {"class.text":"MISC","text":"however, those tests were criticized because they had characteristics that might \"trigger\" use of other heuristics"} {"class.text":"AIMX","text":"this paper presents new tests that avoid those characteristics"} {"class.text":"OWNX","text":"expected values of the gambles are nearly equal in each choice"} {"class.text":"OWNX","text":"in addition, if a person followed expected value ev, expected utility eu, cpt, or ph in these tests, she would shift her preferences in the same direction as shifts in ev or eu"} {"class.text":"CONT","text":"results contradict the ph, even when ph is modified to include a preliminary similarity evaluation using the ph parameters"} {"class.text":"OWNX","text":"new tests of probability-consequence interaction were also conducted"} {"class.text":"OWNX","text":"strong interactions were observed, contrary to ph"} {"class.text":"OWNX","text":"these results add to the growing bodies of evidence showing that neither cpt nor ph is an accurate description of risky decision making"} {"class.text":"AIMX","text":"this paper compares three models that attempt to describe risky decision making"} {"class.text":"MISC","text":"these models are cumulative prospect theory cpt CITATION , birnbaum's CITATION transfer of attention exchange model tax, and the priority heuristic ph of brandstatter, gigerenzer, and hertwig CITATION"} {"class.text":"MISC","text":"the ph model is based on the idea that people compare one attribute at a time, such as the minimum prizes"} {"class.text":"MISC","text":"in addition, the similarity model of rubinstein CITATION as modified by leland CITATION is also relevant to these studies, although these studies were not designed to test that model"} {"class.text":"MISC","text":"birnbaum CITATION reviewed a number of critical tests that refute any rank dependent utility rdu model CITATION including rank and sign-dependent utility CITATION , cpt, and expected utility eu"} {"class.text":"MISC","text":"birnbaum CITATION noted that many of the same tests that refute cpt also contradict the priority heuristic"} {"class.text":"MISC","text":"for example, the priority heuristic predicted fewer than half of the modal choices analyzed by birnbaum CITATION , by birnbaum CITATION , and by birnbaum and navarrete CITATION"} {"class.text":"MISC","text":"some of these choices included cases where 90% or more of the participants satisfied stochastic dominance but the priority heuristic predicts indifference"} {"class.text":"MISC","text":"in other choices, significantly more than half of the participants about 70% of undergraduates violated stochastic dominance, but the priority heuristic predicts that people should satisfy it"} {"class.text":"MISC","text":"brandstatter, gigerenzer, and hertwig CITATION responded that properties of these choices may have induced people to use other heuristics drawn from a person's \"adaptive toolbox\""} {"class.text":"MISC","text":"presumably, decision makers first decide what rule to use, then they either apply that rule or choose to use another rule"} {"class.text":"MISC","text":"the mechanism that decides what rule to use has not yet been specified; it is described instead with lists of \"triggering conditions,\" which are estimated from data like parameters"} {"class.text":"MISC","text":"brandstatter et al CITATION concluded that the priority heuristic does not apply when there is a stochastic dominance relation in the choice"} {"class.text":"MISC","text":"in addition, brandstatter et al CITATION argued that certain choices reviewed by birnbaum CITATION used gambles that differed in expected value ev"} {"class.text":"MISC","text":"brandstatter et al CITATION presented a figure to show that the priority heuristic is not accurate when expected values evs differ, which led them to suppose that two strategies are at work, one for \"easy\" choices that differ in ev and one for \"harder\" choices where evs are nearly equal"} {"class.text":"MISC","text":"from the data, brandstatter et al CITATION estimated that, when the ratio of ev exceeds 2, people act as if they choose the gamble with the higher ev"} {"class.text":"MISC","text":"they argued that the priority heuristic is accurate for \"difficult\" choices in which evs are nearly equal"} {"class.text":"MISC","text":"brandstatter et al CITATION replicated part of that study and their results confirmed that the priority heuristic reproduced fewer than half of the modal choices that they chose for replication CITATION"} {"class.text":"MISC","text":"to account for the results, brandstatter et al noted that birnbaum and navarrete CITATION used many choices in which both gambles of a choice had the same probability distribution and in some choices two branches had the same probability"} {"class.text":"MISC","text":"in some of the choices in birnbaum and navarrete CITATION , there was a common probability-consequence branch in both choices, which was theorized to trigger editing rules and other heuristics that were called up to account for the failures of the priority heuristic"} {"class.text":"AIMX","text":"this paper devises a new type of test that avoids the exceptions stated above"} {"class.text":"CONT","text":"in addition, unlike previous tests, the new tests use shifts in expected value and expected utility to \"help\" predictions of ph and cpt"} {"class.text":"OWNX","text":"that is, expected value and expected utility are both manipulated such that, if a person shifts his or her judgments in the same direction as the changes in eu or ev, his or her choices will appear consistent with ph and cpt"} {"class.text":"OWNX","text":"however, the choices are designed so that the tax model with parameters typical of previous research predicts that people will shift their choices in the opposite direction of ev, eu, cpt, and ph"} {"class.text":"AIMX","text":"this paper extends previous research showing that experienced difficulty of recall can influence evaluative judgments CITATION to a field study of university students rating a course"} {"class.text":"OWNX","text":"students completed a mid-course evaluation form in which they were asked to list either NUMBER ways in which the course could be improved a relatively easy task or NUMBER ways in which the course could be improved a relatively difficult task"} {"class.text":"OWNX","text":"an internal analysis suggests that the number of critiques solicited provides a frame against which accessibility of instances is evaluated"} {"class.text":"OWNX","text":"the paper concludes with a discussion of implications of the present results and possible directions for future research"} {"class.text":"MISC","text":"this process has generally been demonstrated by asking participants to assess the relative likelihood of two categories in which instances of the first category are more difficult to recall than instances of the second category despite the fact that instances of the first category are more common in the world"} {"class.text":"MISC","text":"for instance kahneman and tversky CITATION found that most people think the letter r more often appears in english words as the first letter than the third letter presumably because the first letter provides a better cue for recalling instances of words than does the third letter"} {"class.text":"MISC","text":"in fact it turns out that r appears more often as the third than first letter in english words"} {"class.text":"MISC","text":"schwarz et al CITATION observed that the classic studies demonstrating the availability heuristic failed to distinguish an interpretation based on ease of retrieval from an alternative interpretation based on content of retrieval in which an event is judged more common when a larger number of examples come to mind"} {"class.text":"MISC","text":"to tease apart these accounts schwarz et al CITATION asked participants in one study to list either NUMBER or NUMBER examples of assertive or unassertive behavior that they have exhibited and then rate themselves on their overall degree of assertiveness"} {"class.text":"MISC","text":"thus an abundance of data supports the original interpretation of the availability heuristic categories are judged to be more common when instances more easily come to mind even when a smaller absolute number of instances are generated"} {"class.text":"MISC","text":"this program has been extended from frequency-based judgments to evaluative judgments of such targets as public transportation CITATION luxury automobiles CITATION and one's own childhood CITATION"} {"class.text":"MISC","text":"for instance winkielman and schwarz CITATION asked participants to recall either NUMBER childhood events an easy task or NUMBER childhood events a difficult task"} {"class.text":"MISC","text":"some participants were then led to believe that memories from pleasant periods tend to fade while others were led to believe that memories from unpleasant periods tend to fade"} {"class.text":"MISC","text":"when later asked to evaluate their childhood participants believed that pleasant memories fade rated their childhood more favorably when they completed the difficult task NUMBER events than the easy task NUMBER events participants who believed that unpleasant memories fade rated their childhood more favorably when they completed the easy rather than difficult task"} {"class.text":"MISC","text":"previous studies of the availability heuristic using the paradigm of schwarz et al CITATION have turned up impressive and robust results"} {"class.text":"MISC","text":"however these demonstrations have been restricted primarily to laboratory surveys in which task of recalling examples then making an overall assessment may seem somewhat artificial to participants and the responses of little consequence"} {"class.text":"MISC","text":"hence ratings of respondents may be especially susceptible to superficial cues-such as the accessibility of instances-when mapping their beliefs and attitudes onto an unfamiliar response scale"} {"class.text":"OWNX","text":"the present investigation overcomes these limitations through a field study of students evaluating a course"} {"class.text":"MISC","text":"first evaluations are a normal facet of most university courses in which students are commonly asked to list specific suggestions and also provide a global assessment"} {"class.text":"MISC","text":"moreover course evaluations are consequential as they can influence future course offerings and course staffing promotion and tenure decisions and provide information to future prospective students of the target course"} {"class.text":"MISC","text":"second students at universities quickly become familiar with standard course evaluation scales and how ratings are distributed across classes often relying on these scores in choosing among elective courses"} {"class.text":"MISC","text":"the study of course evaluations is also interesting in its own right"} {"class.text":"MISC","text":"a number of recent papers have questioned the validity of these ratings and a lively debate appeared some years ago in the american psychologist CITATION"} {"class.text":"MISC","text":"thus far questions of discriminant validity have mainly focused on the correlation between teaching ratings and apparently irrelevant factors such as the students' expected grades or the course workload"} {"class.text":"MISC","text":"to date there have been few published investigations of the relationship between the design of course feedback forms and summary course evaluations"} {"class.text":"AIMX","text":"the present study attempts to answer the following provocative question can one paradoxically obtain higher course ratings by soliciting a greater number of critical comments from students"} {"class.text":"BASE","text":"this paper extends previous research showing that experienced difficulty of recall can influence evaluative judgments CITATION to a field study of university students rating a course"} {"class.text":"OWNX","text":"respondents who had been asked for NUMBER critical comments subsequently rated the course more favorably than respondents who had been asked for NUMBER critical comments"} {"class.text":"OWNX","text":"an internal analysis suggests that the number of critiques solicited provides a frame against which accessibility of instances is evaluated"} {"class.text":"OWNX","text":"the paper concludes with a discussion of implications of the present results and possible directions for future research"} {"class.text":"MISC","text":"according to tversky and kahneman's CITATION availability heuristic people sometimes judge the frequency of events in the world by the ease with which examples come to mind"} {"class.text":"MISC","text":"for instance kahneman and tversky CITATION found that most people think the letter r more often appears in english words as the first letter than the third letter presumably because the first letter provides a better cue for recalling instances of words than does the third letter"} {"class.text":"MISC","text":"in fact it turns out that r appears more often as the third than first letter in english words"} {"class.text":"MISC","text":"schwarz et al CITATION observed that the classic studies demonstrating the availability heuristic failed to distinguish an interpretation based on ease of retrieval from an alternative interpretation based on content of retrieval in which an event is judged more common when a larger number of examples come to mind"} {"class.text":"MISC","text":"to tease apart these accounts schwarz et al CITATION asked participants in one study to list either NUMBER or NUMBER examples of assertive or unassertive behavior that they have exhibited and then rate themselves on their overall degree of assertiveness"} {"class.text":"MISC","text":"participants rated themselves as more assertive after they had listed NUMBER examples of assertive behavior a relatively easy task rather than NUMBER examples a relatively difficult task similarly they rated themselves as less assertive i e more unassertive after they had listed NUMBER rather than NUMBER examples of unassertive behavior"} {"class.text":"MISC","text":"similar patterns of results have been observed in many other studies of frequency-related judgments including the rate at which a particular letter occurs in various positions of words CITATION the quality of one's own memory CITATION the frequency of one's own past behaviors CITATION one's susceptibility to heart disease CITATION and one's susceptibility to sexual assault CITATION"} {"class.text":"MISC","text":"for a review of this literature see schwarz CITATION"} {"class.text":"MISC","text":"thus an abundance of data supports the original interpretation of the availability heuristic categories are judged to be more common when instances more easily come to mind even when a smaller absolute number of instances are generated"} {"class.text":"MISC","text":"this program has been extended from frequency-based judgments to evaluative judgments of such targets as public transportation CITATION luxury automobiles CITATION and one's own childhood CITATION"} {"class.text":"MISC","text":"for instance winkielman and schwarz CITATION asked participants to recall either NUMBER childhood events an easy task or NUMBER childhood events a difficult task"} {"class.text":"MISC","text":"some participants were then led to believe that memories from pleasant periods tend to fade while others were led to believe that memories from unpleasant periods tend to fade"} {"class.text":"MISC","text":"when later asked to evaluate their childhood participants believed that pleasant memories fade rated their childhood more favorably when they completed the difficult task NUMBER events than the easy task NUMBER events participants who believed that unpleasant memories fade rated their childhood more favorably when they completed the easy rather than difficult task"} {"class.text":"MISC","text":"previous studies of the availability heuristic using the paradigm of schwarz et al CITATION have turned up impressive and robust results"} {"class.text":"CONT","text":"however these demonstrations have been restricted primarily to laboratory surveys in which task of recalling examples then making an overall assessment may seem somewhat artificial to participants and the responses of little consequence"} {"class.text":"MISC","text":"more important most participants in previous studies presumably had little prior experience with the particular likert scale that served as the dependent measure e g most had never before rated their childhood or public transportation on a NUMBER -point scale"} {"class.text":"CONT","text":"hence ratings of respondents may be especially susceptible to superficial cues-such as the accessibility of instances-when mapping their beliefs and attitudes onto an unfamiliar response scale"} {"class.text":"AIMX","text":"the present investigation overcomes these limitations through a field study of students evaluating a course"} {"class.text":"OWNX","text":"first evaluations are a normal facet of most university courses in which students are commonly asked to list specific suggestions and also provide a global assessment"} {"class.text":"OWNX","text":"moreover course evaluations are consequential as they can influence future course offerings and course staffing promotion and tenure decisions and provide information to future prospective students of the target course"} {"class.text":"OWNX","text":"second students at universities quickly become familiar with standard course evaluation scales and how ratings are distributed across classes often relying on these scores in choosing among elective courses"} {"class.text":"OWNX","text":"the study of course evaluations is also interesting in its own right"} {"class.text":"OWNX","text":"a number of recent papers have questioned the validity of these ratings and a lively debate appeared some years ago in the american psychologist CITATION"} {"class.text":"OWNX","text":"thus far questions of discriminant validity have mainly focused on the correlation between teaching ratings and apparently irrelevant factors such as the students' expected grades or the course workload"} {"class.text":"MISC","text":"to date there have been few published investigations of the relationship between the design of course feedback forms and summary course evaluations"} {"class.text":"OWNX","text":"the present study attempts to answer the following provocative question can one paradoxically obtain higher course ratings by soliciting a greater number of critical comments from students"} {"class.text":"AIMX","text":"this paper extends previous research showing that experienced difficulty of recall can influence evaluative judgments CITATION to a field study of university students rating a course"} {"class.text":"OWNX","text":"students completed a mid-course evaluation form in which they were asked to list either NUMBER ways in which the course could be improved a relatively easy task or NUMBER ways in which the course could be improved a relatively difficult task"} {"class.text":"OWNX","text":"respondents who had been asked for NUMBER critical comments subsequently rated the course more favorably than respondents who had been asked for NUMBER critical comments"} {"class.text":"OWNX","text":"an internal analysis suggests that the number of critiques solicited provides a frame against which accessibility of instances is evaluated"} {"class.text":"OWNX","text":"the paper concludes with a discussion of implications of the present results and possible directions for future research"} {"class.text":"MISC","text":"according to tversky and kahneman's CITATION availability heuristic people sometimes judge the frequency of events in the world by the ease with which examples come to mind"} {"class.text":"MISC","text":"for instance kahneman and tversky CITATION found that most people think the letter r more often appears in english words as the first letter than the third letter presumably because the first letter provides a better cue for recalling instances of words than does the third letter"} {"class.text":"MISC","text":"in fact it turns out that r appears more often as the third than first letter in english words"} {"class.text":"MISC","text":"schwarz et al CITATION observed that the classic studies demonstrating the availability heuristic failed to distinguish an interpretation based on ease of retrieval from an alternative interpretation based on content of retrieval in which an event is judged more common when a larger number of examples come to mind"} {"class.text":"MISC","text":"to tease apart these accounts schwarz et al CITATION asked participants in one study to list either NUMBER or NUMBER examples of assertive or unassertive behavior that they have exhibited and then rate themselves on their overall degree of assertiveness"} {"class.text":"MISC","text":"similar patterns of results have been observed in many other studies of frequency-related judgments including the rate at which a particular letter occurs in various positions of words CITATION the quality of one's own memory CITATION the frequency of one's own past behaviors CITATION one's susceptibility to heart disease CITATION and one's susceptibility to sexual assault CITATION"} {"class.text":"MISC","text":"thus an abundance of data supports the original interpretation of the availability heuristic categories are judged to be more common when instances more easily come to mind even when a smaller absolute number of instances are generated"} {"class.text":"MISC","text":"this program has been extended from frequency-based judgments to evaluative judgments of such targets as public transportation CITATION luxury automobiles CITATION and one's own childhood CITATION"} {"class.text":"MISC","text":"for instance winkielman and schwarz CITATION asked participants to recall either NUMBER childhood events an easy task or NUMBER childhood events a difficult task"} {"class.text":"MISC","text":"some participants were then led to believe that memories from pleasant periods tend to fade while others were led to believe that memories from unpleasant periods tend to fade"} {"class.text":"MISC","text":"when later asked to evaluate their childhood participants believed that pleasant memories fade rated their childhood more favorably when they completed the difficult task NUMBER events than the easy task NUMBER events participants who believed that unpleasant memories fade rated their childhood more favorably when they completed the easy rather than difficult task"} {"class.text":"MISC","text":"previous studies of the availability heuristic using the paradigm of schwarz et al CITATION have turned up impressive and robust results"} {"class.text":"MISC","text":"hence ratings of respondents may be especially susceptible to superficial cues-such as the accessibility of instances-when mapping their beliefs and attitudes onto an unfamiliar response scale"} {"class.text":"MISC","text":"first evaluations are a normal facet of most university courses in which students are commonly asked to list specific suggestions and also provide a global assessment"} {"class.text":"MISC","text":"moreover course evaluations are consequential as they can influence future course offerings and course staffing promotion and tenure decisions and provide information to future prospective students of the target course"} {"class.text":"MISC","text":"second students at universities quickly become familiar with standard course evaluation scales and how ratings are distributed across classes often relying on these scores in choosing among elective courses"} {"class.text":"MISC","text":"the study of course evaluations is also interesting in its own right"} {"class.text":"MISC","text":"a number of recent papers have questioned the validity of these ratings and a lively debate appeared some years ago in the american psychologist CITATION"} {"class.text":"MISC","text":"to date there have been few published investigations of the relationship between the design of course feedback forms and summary course evaluations"} {"class.text":"AIMX","text":"the present study attempts to answer the following provocative question can one paradoxically obtain higher course ratings by soliciting a greater number of critical comments from students"} {"class.text":"MISC","text":"feelings of anger in response to norm violations are assumed to motivate third-party sanctions, yet there is only sparse and indirect support for this idea"} {"class.text":"AIMX","text":"we investigated the impact of both anger and guilt feelings on third-party sanctions"} {"class.text":"OWNX","text":"in two studies both emotions were independently manipulated"} {"class.text":"OWNX","text":"results show that anger and guilt independently constitute sufficient but not necessary causes of punishment"} {"class.text":"OWNX","text":"low levels of punishment are observed only when neither emotion is elicited"} {"class.text":"MISC","text":"they stand up for their friends if someone speaks ill about them in their absence"} {"class.text":"MISC","text":"they do not tolerate a colleague being bullied at work"} {"class.text":"MISC","text":"they boycott consumer products that are produced using child labor"} {"class.text":"MISC","text":"some even come to the aid of a stranger who is being physically harassed, in spite of obvious personal danger"} {"class.text":"MISC","text":"however, punishing norm-violations is costly in terms of time and energy"} {"class.text":"MISC","text":"it may even impose physical risks"} {"class.text":"MISC","text":"punishing injustice is therefore considered to be a moral act, particularly when it is performed on behalf of others CITATION"} {"class.text":"AIMX","text":"this begs the question of what incites third-party sanctions, as they usually oppose self-interest"} {"class.text":"CONT","text":"feelings of anger in response to norm violations are assumed to motivate third-party sanctions, yet there is only sparse and indirect support for this idea"} {"class.text":"OWNX","text":"we investigated the impact of both anger and guilt feelings on third-party sanctions"} {"class.text":"OWNX","text":"in two studies both emotions were independently manipulated"} {"class.text":"OWNX","text":"results show that anger and guilt independently constitute sufficient but not necessary causes of punishment"} {"class.text":"AIMX","text":"we discuss the implications of these findings for the functions of altruistic sanctions"} {"class.text":"MISC","text":"people often defend the interests of others"} {"class.text":"MISC","text":"they stand up for their friends if someone speaks ill about them in their absence"} {"class.text":"MISC","text":"they do not tolerate a colleague being bullied at work"} {"class.text":"MISC","text":"they boycott consumer products that are produced using child labor"} {"class.text":"MISC","text":"however, punishing norm-violations is costly in terms of time and energy"} {"class.text":"MISC","text":"it may even impose physical risks"} {"class.text":"MISC","text":"punishing injustice is therefore considered to be a moral act, particularly when it is performed on behalf of others CITATION"} {"class.text":"AIMX","text":"this begs the question of what incites third-party sanctions, as they usually oppose self-interest"} {"class.text":"MISC","text":"third-party punishment has recently received attention as an explanation for human altruism"} {"class.text":"CONT","text":"feelings of anger in response to norm violations are assumed to motivate third-party sanctions, yet there is only sparse and indirect support for this idea"} {"class.text":"AIMX","text":"we investigated the impact of both anger and guilt feelings on third-party sanctions"} {"class.text":"OWNX","text":"in two studies both emotions were independently manipulated"} {"class.text":"OWNX","text":"results show that anger and guilt independently constitute sufficient but not necessary causes of punishment"} {"class.text":"OWNX","text":"we discuss the implications of these findings for the functions of altruistic sanctions"} {"class.text":"MISC","text":"people often defend the interests of others"} {"class.text":"MISC","text":"they stand up for their friends if someone speaks ill about them in their absence"} {"class.text":"MISC","text":"they do not tolerate a colleague being bullied at work"} {"class.text":"MISC","text":"they boycott consumer products that are produced using child labor"} {"class.text":"MISC","text":"some even come to the aid of a stranger who is being physically harassed, in spite of obvious personal danger"} {"class.text":"MISC","text":"in general, people retaliate against injustice even if they are not directly victimized"} {"class.text":"MISC","text":"sanctioning of norm-violations is vital for prosocial behavior to be sustained CITATION"} {"class.text":"MISC","text":"this begs the question of what incites third-party sanctions, as they usually oppose self-interest"} {"class.text":"OWNX","text":"participants initially showed robust sces, but they also showed a significant reduction in bias after only one round of feedback"} {"class.text":"MISC","text":"when resources are at a premium, it is optimal to enter into competitive environments in which we are certain to fare well and to avoid those in which we are doomed to fail"} {"class.text":"MISC","text":"however, when people evaluate their likelihood of success in competitions, they are subject to a robust bias: a competitor should consider the strengths and weaknesses of the self and the other competitors CITATION , but people often give too much weight to evidence related to their own strengths and weaknesses and too little weight to such evidence about the competitor CITATION"} {"class.text":"MISC","text":"this egocentrism results in overoptimism when the circumstances of the competition are favorable, such as when competitors in a trivia game learn that the questions will be from an easy category-even though they'll be easy for everyone CITATION"} {"class.text":"MISC","text":"egocentrism also results in overpessimism when the circumstances are unfavorable e g , a difficult trivia category"} {"class.text":"MISC","text":"this phenomenon of being more optimistic when shared competitive circumstances are favorable than when they are not has been dubbed the shared-circumstance effect CITATION , and it has been replicated across a variety of settings e g , general knowledge tasks, card games, athletic competitions"} {"class.text":"MISC","text":"in most previous studies on the sce, participants were presented with novel, non-repeated competitive situations"} {"class.text":"MISC","text":"for example, when a tennis tournament is played during a string of windy days, players can have several opportunities to observe how the weather affects themselves and their competitors"} {"class.text":"MISC","text":"to examine whether egocentrism and sces persist in repeated-play contexts, rose and windschitl CITATION had pairs of participants compete against each other in multiple rounds of a trivia contest that involved easy and hard categories"} {"class.text":"MISC","text":"in each round, participants estimated their likelihood of beating their competitor, answered trivia questions, and received feedback about who won"} {"class.text":"MISC","text":"in initial rounds, there were robust sces; participants were much more optimistic about winning easy categories than hard ones"} {"class.text":"MISC","text":"if they encountered the same hard and easy categories across rounds, the participants learned from feedback"} {"class.text":"MISC","text":"that is, the sce shrank-but slowly-across six rounds with the same categories"} {"class.text":"MISC","text":"the sce for that round dramatically and fully rebounded; it was every bit as large as observed for round 1"} {"class.text":"MISC","text":"these results provide a bleak view of how well people can learn from feedback and avoid sces"} {"class.text":"MISC","text":"CITATION are people's abilities to learn to avoid sces-based on feedback-really as bleak as this prior research might suggest"} {"class.text":"AIMX","text":"we argue that some shared circumstances are more transparently shared than others, and this may affect how readily people learn to avoid the bias that creates sces-and how easily they can transfer this learning to a slightly new set of shared circumstances"} {"class.text":"OWNX","text":"by transparently shared, we are referring to how obvious it is that a circumstance that is helpful or hindering to the self will affect others in largely the same way"} {"class.text":"OWNX","text":"in the present study, we examined the influence of repeated feedback on sces"} {"class.text":"CONT","text":"however, unlike past research, we used a competition in which the difficulty of the shared circumstance relative to competitions, for example, involving easy and hard trivia categories is more transparently shared"} {"class.text":"OWNX","text":"in a multi-round paradigm, participants competed in object-tossing competitions"} {"class.text":"OWNX","text":"in each round, two competitors each had 8 throws per object-attempting to land the object inside a target area"} {"class.text":"OWNX","text":"there was always one easy-to-aim object e g , a beanbag and one hard-to-aim object e g , a paper plate, which constituted our shared-circumstance manipulation"} {"class.text":"OWNX","text":"full feedback was given during and after each round, and predictions were solicited before each round and also before a final round with novel objects"} {"class.text":"OWNX","text":"we suspected that a tossing competition, rather than a trivia competition, would produce less bleak results about the debiasing of sces through repeated play"} {"class.text":"MISC","text":"in the case of trivia, watching one's competitor fail to answer trivia questions doesn't give any insight about why the category is difficult for that person"} {"class.text":"MISC","text":"also, knowing that one's competitor struggled on a difficult category does not provide obvious information about why he or she might struggle on another difficult category"} {"class.text":"MISC","text":"however, in the case of throwing, watching a competitor fail when tossing an object probably illuminates the relevance of specific shared, situational circumstances i e , the properties of the specific objects as well as a more general awareness of the relevance that object properties have on throwing success-for anyone"} {"class.text":"MISC","text":"for example, seeing a paper plate fly unpredictably will likely give an observer a clear impression that the object will fly unpredictably regardless of who is throwing it"} {"class.text":"MISC","text":"for participants, this enhances the appreciation that one's struggles are not primarily due to personal characteristics but to properties of the tossed objects; this would then be useful in mitigating egocentrism and sces, even when new objects are introduced"} {"class.text":"OWNX","text":"consequently, we expected that, even though participants might reveal a robust sce at round 1 prior to any feedback or observations regarding their competitor, they would show a pronounced learning effect after the feedback and observations of round 1"} {"class.text":"OWNX","text":"that is, they would show significantly reduced sces starting immediately after round 1"} {"class.text":"MISC","text":"when judging their likelihood of success in competitive tasks, people tend to be overoptimistic for easy tasks and overpessimistic for hard tasks the shared circumstance effect; sce"} {"class.text":"MISC","text":"previous research has shown that feedback and experience from repeated-play competitions has a limited impact on sces"} {"class.text":"OWNX","text":"pairs of participants competed in, made predictions about, and received feedback on, multiple rounds of a throwing task involving both easy- and hard-to-aim objects"} {"class.text":"OWNX","text":"participants initially showed robust sces, but they also showed a significant reduction in bias after only one round of feedback"} {"class.text":"OWNX","text":"these and other results support a more positive view than suggested from past research on the potential for sces to be debiased through outcome feedback"} {"class.text":"MISC","text":"competition abounds in everyday life, where we contend with others for top grades, jobs, trophies, and mates"} {"class.text":"MISC","text":"this egocentrism results in overoptimism when the circumstances of the competition are favorable, such as when competitors in a trivia game learn that the questions will be from an easy category-even though they'll be easy for everyone CITATION"} {"class.text":"MISC","text":"egocentrism also results in overpessimism when the circumstances are unfavorable e g , a difficult trivia category"} {"class.text":"MISC","text":"this phenomenon of being more optimistic when shared competitive circumstances are favorable than when they are not has been dubbed the shared-circumstance effect CITATION , and it has been replicated across a variety of settings e g , general knowledge tasks, card games, athletic competitions"} {"class.text":"MISC","text":"in most previous studies on the sce, participants were presented with novel, non-repeated competitive situations"} {"class.text":"MISC","text":"these situations did not allow people to learn from past experiences or from feedback within the immediate competitive context"} {"class.text":"MISC","text":"for example, when a tennis tournament is played during a string of windy days, players can have several opportunities to observe how the weather affects themselves and their competitors"} {"class.text":"MISC","text":"to examine whether egocentrism and sces persist in repeated-play contexts, rose and windschitl CITATION had pairs of participants compete against each other in multiple rounds of a trivia contest that involved easy and hard categories"} {"class.text":"MISC","text":"in each round, participants estimated their likelihood of beating their competitor, answered trivia questions, and received feedback about who won"} {"class.text":"MISC","text":"in initial rounds, there were robust sces; participants were much more optimistic about winning easy categories than hard ones"} {"class.text":"MISC","text":"if they encountered the same hard and easy categories across rounds, the participants learned from feedback"} {"class.text":"MISC","text":"that is, the sce shrank-but slowly-across six rounds with the same categories"} {"class.text":"MISC","text":"the sce was never eliminated, even after six rounds"} {"class.text":"MISC","text":"also, for a seventh round, participants were told there would be new categories"} {"class.text":"MISC","text":"the sce for that round dramatically and fully rebounded; it was every bit as large as observed for round 1"} {"class.text":"MISC","text":"these results provide a bleak view of how well people can learn from feedback and avoid sces"} {"class.text":"MISC","text":"moreover, results from a study by moore and cain CITATION , which also used repeated plays with feedback, suggest an even bleaker view"} {"class.text":"MISC","text":"those researchers also used easy and difficult quizzes as shared-circumstance manipulations, but found virtually no reduction in sces after numerous rounds with feedback"} {"class.text":"MISC","text":"CITATION are people's abilities to learn to avoid sces-based on feedback-really as bleak as this prior research might suggest"} {"class.text":"AIMX","text":"we argue that some shared circumstances are more transparently shared than others, and this may affect how readily people learn to avoid the bias that creates sces-and how easily they can transfer this learning to a slightly new set of shared circumstances"} {"class.text":"OWNX","text":"by transparently shared, we are referring to how obvious it is that a circumstance that is helpful or hindering to the self will affect others in largely the same way"} {"class.text":"OWNX","text":"in the present study, we examined the influence of repeated feedback on sces"} {"class.text":"OWNX","text":"however, unlike past research, we used a competition in which the difficulty of the shared circumstance relative to competitions, for example, involving easy and hard trivia categories is more transparently shared"} {"class.text":"OWNX","text":"in a multi-round paradigm, participants competed in object-tossing competitions"} {"class.text":"OWNX","text":"in each round, two competitors each had 8 throws per object-attempting to land the object inside a target area"} {"class.text":"OWNX","text":"there was always one easy-to-aim object e g , a beanbag and one hard-to-aim object e g , a paper plate, which constituted our shared-circumstance manipulation"} {"class.text":"OWNX","text":"full feedback was given during and after each round, and predictions were solicited before each round and also before a final round with novel objects"} {"class.text":"OWNX","text":"we suspected that a tossing competition, rather than a trivia competition, would produce less bleak results about the debiasing of sces through repeated play"} {"class.text":"OWNX","text":"in the case of trivia, watching one's competitor fail to answer trivia questions doesn't give any insight about why the category is difficult for that person"} {"class.text":"OWNX","text":"however, in the case of throwing, watching a competitor fail when tossing an object probably illuminates the relevance of specific shared, situational circumstances i e , the properties of the specific objects as well as a more general awareness of the relevance that object properties have on throwing success-for anyone"} {"class.text":"OWNX","text":"for example, seeing a paper plate fly unpredictably will likely give an observer a clear impression that the object will fly unpredictably regardless of who is throwing it"} {"class.text":"OWNX","text":"for participants, this enhances the appreciation that one's struggles are not primarily due to personal characteristics but to properties of the tossed objects; this would then be useful in mitigating egocentrism and sces, even when new objects are introduced"} {"class.text":"OWNX","text":"consequently, we expected that, even though participants might reveal a robust sce at round 1 prior to any feedback or observations regarding their competitor, they would show a pronounced learning effect after the feedback and observations of round 1"} {"class.text":"OWNX","text":"that is, they would show significantly reduced sces starting immediately after round 1"} {"class.text":"OWNX","text":"we also expected that this learning would be generally transferable"} {"class.text":"MISC","text":"when judging their likelihood of success in competitive tasks, people tend to be overoptimistic for easy tasks and overpessimistic for hard tasks the shared circumstance effect; sce"} {"class.text":"MISC","text":"previous research has shown that feedback and experience from repeated-play competitions has a limited impact on sces"} {"class.text":"AIMX","text":"however, in this paper, we suggest that competitive situations, in which the shared difficulty or easiness of the task is more transparent, will be more amenable to debiasing via repeated play"} {"class.text":"OWNX","text":"pairs of participants competed in, made predictions about, and received feedback on, multiple rounds of a throwing task involving both easy- and hard-to-aim objects"} {"class.text":"OWNX","text":"participants initially showed robust sces, but they also showed a significant reduction in bias after only one round of feedback"} {"class.text":"OWNX","text":"these and other results support a more positive view than suggested from past research on the potential for sces to be debiased through outcome feedback"} {"class.text":"MISC","text":"competition abounds in everyday life, where we contend with others for top grades, jobs, trophies, and mates"} {"class.text":"MISC","text":"when resources are at a premium, it is optimal to enter into competitive environments in which we are certain to fare well and to avoid those in which we are doomed to fail"} {"class.text":"MISC","text":"this egocentrism results in overoptimism when the circumstances of the competition are favorable, such as when competitors in a trivia game learn that the questions will be from an easy category-even though they'll be easy for everyone CITATION"} {"class.text":"MISC","text":"egocentrism also results in overpessimism when the circumstances are unfavorable e g , a difficult trivia category"} {"class.text":"MISC","text":"in most previous studies on the sce, participants were presented with novel, non-repeated competitive situations"} {"class.text":"MISC","text":"these situations did not allow people to learn from past experiences or from feedback within the immediate competitive context"} {"class.text":"MISC","text":"however, in everyday contexts there are often opportunities to learn how a shared circumstance tends to affect the self, others, and outcomes"} {"class.text":"MISC","text":"for example, when a tennis tournament is played during a string of windy days, players can have several opportunities to observe how the weather affects themselves and their competitors"} {"class.text":"MISC","text":"to examine whether egocentrism and sces persist in repeated-play contexts, rose and windschitl CITATION had pairs of participants compete against each other in multiple rounds of a trivia contest that involved easy and hard categories"} {"class.text":"MISC","text":"in each round, participants estimated their likelihood of beating their competitor, answered trivia questions, and received feedback about who won"} {"class.text":"MISC","text":"in initial rounds, there were robust sces; participants were much more optimistic about winning easy categories than hard ones"} {"class.text":"MISC","text":"if they encountered the same hard and easy categories across rounds, the participants learned from feedback"} {"class.text":"MISC","text":"that is, the sce shrank-but slowly-across six rounds with the same categories"} {"class.text":"MISC","text":"the sce was never eliminated, even after six rounds"} {"class.text":"MISC","text":"also, for a seventh round, participants were told there would be new categories"} {"class.text":"MISC","text":"the sce for that round dramatically and fully rebounded; it was every bit as large as observed for round 1"} {"class.text":"MISC","text":"these results provide a bleak view of how well people can learn from feedback and avoid sces"} {"class.text":"MISC","text":"moreover, results from a study by moore and cain CITATION , which also used repeated plays with feedback, suggest an even bleaker view"} {"class.text":"MISC","text":"those researchers also used easy and difficult quizzes as shared-circumstance manipulations, but found virtually no reduction in sces after numerous rounds with feedback CITATION"} {"class.text":"MISC","text":"are people's abilities to learn to avoid sces-based on feedback-really as bleak as this prior research might suggest"} {"class.text":"AIMX","text":"we argue that some shared circumstances are more transparently shared than others, and this may affect how readily people learn to avoid the bias that creates sces-and how easily they can transfer this learning to a slightly new set of shared circumstances"} {"class.text":"OWNX","text":"by transparently shared, we are referring to how obvious it is that a circumstance that is helpful or hindering to the self will affect others in largely the same way"} {"class.text":"AIMX","text":"in the present study, we examined the influence of repeated feedback on sces"} {"class.text":"OWNX","text":"in a multi-round paradigm, participants competed in object-tossing competitions"} {"class.text":"OWNX","text":"in each round, two competitors each had 8 throws per object-attempting to land the object inside a target area"} {"class.text":"OWNX","text":"there was always one easy-to-aim object e g , a beanbag and one hard-to-aim object e g , a paper plate, which constituted our shared-circumstance manipulation"} {"class.text":"OWNX","text":"full feedback was given during and after each round, and predictions were solicited before each round and also before a final round with novel objects"} {"class.text":"OWNX","text":"we suspected that a tossing competition, rather than a trivia competition, would produce less bleak results about the debiasing of sces through repeated play"} {"class.text":"MISC","text":"also, knowing that one's competitor struggled on a difficult category does not provide obvious information about why he or she might struggle on another difficult category"} {"class.text":"MISC","text":"however, in the case of throwing, watching a competitor fail when tossing an object probably illuminates the relevance of specific shared, situational circumstances i e , the properties of the specific objects as well as a more general awareness of the relevance that object properties have on throwing success-for anyone"} {"class.text":"MISC","text":"for example, seeing a paper plate fly unpredictably will likely give an observer a clear impression that the object will fly unpredictably regardless of who is throwing it"} {"class.text":"OWNX","text":"that is, they would show significantly reduced sces starting immediately after round 1"} {"class.text":"OWNX","text":"we also expected that this learning would be generally transferable"} {"class.text":"MISC","text":"previous research on anchoring has shown this heuristic to be a very robust psychological phenomenon ubiquitous across many domains of human judgment and decision-making"} {"class.text":"CONT","text":"despite the prevalence of anchoring effects researchers have only recently begun to investigate the underlying factors responsible for how and in what ways a person is susceptible to them"} {"class.text":"AIMX","text":"this paper examines how one such factor the big-five personality trait of openness-to-experience influences the effect of previously presented anchors on participants' judgments"} {"class.text":"OWNX","text":"our findings indicate that participants high in openness-to-experience were significantly more influenced by anchoring cues relative to participants low in this trait"} {"class.text":"MISC","text":"the anchoring effect CITATION refers to the adjustment of one's assessment higher or lower based upon previously presented external information or an anchor"} {"class.text":"MISC","text":"the anchoring heuristic appears to be prevalent throughout human decision processes and has been shown to reliably influence judgments in a variety of domains including probability estimates CITATION negotiation CITATION legal judgments CITATION and general knowledge CITATION"} {"class.text":"MISC","text":"further anchoring effects appear viable across most situations for both novices and experts CITATION and seem to be effective under conditions of monetary incentives CITATION and in real-world settings CITATION"} {"class.text":"MISC","text":"anchoring thus appears to be a very robust psychological phenomenon"} {"class.text":"MISC","text":"however not all individuals may be equally influenced by anchoring cues"} {"class.text":"MISC","text":"tversky and kahneman CITATION pointed to the important role of personal characteristics of the decision maker in risky choice situations"} {"class.text":"MISC","text":"later work by stanovich and west CITATION suggested that intellectual traits influence decision making and consequential choice preference"} {"class.text":"MISC","text":"recently individual differences have been found in numerical reliance CITATION ambiguity CITATION preference for actions or inactions CITATION and the optimistic bias CITATION"} {"class.text":"MISC","text":"the big-five personality traits CITATION have proven to be important individual difference factors for understanding decision choices"} {"class.text":"MISC","text":"further attesting to the importance of individual differences levin and hart CITATION demonstrated that individual differences in preference appear to originate at a very early age"} {"class.text":"MISC","text":"taken together these findings suggest that the impact of individual difference factors on decision-making is both profound and pervasive"} {"class.text":"MISC","text":"in the last couple of decades the five-factor model of personality has become the most widely tested and well-regarded personality trait model"} {"class.text":"MISC","text":"a great deal of research has supported this model's validity and reliability CITATION"} {"class.text":"CONT","text":"while most research has agreed on the nature of the first four factors the nature of the fifth factor has been controversial a controversy predominately based upon whether a lexical approach derived from language frequency within the lexicon of a particular language CITATION or a questionnaire approach CITATION should be used to measure it"} {"class.text":"MISC","text":"individuals scoring high on this dimension are more open to new ideas CITATION and motivated to seek variety and external experience"} {"class.text":"MISC","text":"individuals scoring low tend to be less inclined to consider alternative opinions and are more steadfast in their own beliefs CITATION making them more likely to rely upon information that is familiar and conventional CITATION"} {"class.text":"MISC","text":"a fundamental aspect of the anchoring effect is that individuals are sensitive to information which they have experienced"} {"class.text":"MISC","text":"specifically as research has shown the openness trait reflects individual propensities to adjust one's beliefs CITATION and to consider external information CITATION"} {"class.text":"OWNX","text":"therefore based upon the nature of the openness-to-experience trait and the processes involved in the anchoring effect we hypothesize that individual differences in openness-to-experience will influence susceptibility to anchoring effects"} {"class.text":"OWNX","text":"to test this hypothesis we first measured individual levels of the personality trait of openness-to-experience"} {"class.text":"OWNX","text":"we then provided participants with an anchoring task involving either the mississippi river study NUMBER or african nations in the un study NUMBER"} {"class.text":"MISC","text":"previous research on anchoring has shown this heuristic to be a very robust psychological phenomenon ubiquitous across many domains of human judgment and decision-making."} {"class.text":"MISC","text":"despite the prevalence of anchoring effects researchers have only recently begun to investigate the underlying factors responsible for how and in what ways a person is susceptible to them."} {"class.text":"AIMX","text":"this paper examines how one such factor the big-five personality trait of openness-to-experience influences the effect of previously presented anchors on participants' judgments."} {"class.text":"OWNX","text":"our findings indicate that participants high in openness-to-experience were significantly more influenced by anchoring cues relative to participants low in this trait."} {"class.text":"OWNX","text":"these findings were consistent across two different types of anchoring tasks providing convergent evidence for our hypothesis"} {"class.text":"MISC","text":"the anchoring effect CITATION refers to the adjustment of one's assessment higher or lower based upon previously presented external information or an anchor."} {"class.text":"MISC","text":"the anchoring heuristic appears to be prevalent throughout human decision processes and has been shown to reliably influence judgments in a variety of domains including probability estimates CITATION negotiation CITATION legal judgments CITATION and general knowledge CITATION."} {"class.text":"MISC","text":"further anchoring effects appear viable across most situations for both novices and experts CITATION and seem to be effective under conditions of monetary incentives CITATION and in real-world settings CITATION."} {"class.text":"MISC","text":"anchoring thus appears to be a very robust psychological phenomenon."} {"class.text":"MISC","text":"however not all individuals may be equally influenced by anchoring cues."} {"class.text":"MISC","text":"identification of factors that influence how and in what ways a person is susceptible to this heuristic should further the understanding of the process."} {"class.text":"MISC","text":"one avenue of approach is to investigate the role of individual difference factors."} {"class.text":"MISC","text":"tversky and kahneman CITATION pointed to the important role of personal characteristics of the decision maker in risky choice situations."} {"class.text":"MISC","text":"later work by stanovich and west CITATION suggested that intellectual traits influence decision making and consequential choice preference."} {"class.text":"MISC","text":"recently individual differences have been found in numerical reliance CITATION ambiguity CITATION preference for actions or inactions CITATION and the optimistic bias CITATION."} {"class.text":"MISC","text":"the big-five personality traits CITATION have proven to be important individual difference factors for understanding decision choices."} {"class.text":"MISC","text":"further attesting to the importance of individual differences levin and hart CITATION demonstrated that individual differences in preference appear to originate at a very early age."} {"class.text":"AIMX","text":"the purpose of the current study is to investigate how one individual difference factor may influence the strength of the anchoring effect."} {"class.text":"AIMX","text":"specifically we are interested in how individual differences in the personality trait of openness-to-experience influences anchoring effects."} {"class.text":"MISC","text":"in the last couple of decades the five-factor model of personality has become the most widely tested and well-regarded personality trait model."} {"class.text":"MISC","text":"while most research has agreed on the nature of the first four factors the nature of the fifth factor has been controversial; a controversy predominately based upon whether a lexical approach derived from language frequency within the lexicon of a particular language CITATION or a questionnaire approach CITATION should be used to measure it."} {"class.text":"MISC","text":"the fifth factor is often labeled openness-to-experience which refers to a propensity to adjust beliefs and behaviors when exposed to new types of information or ideas CITATION."} {"class.text":"MISC","text":"individuals scoring high on this dimension are more open to new ideas CITATION and motivated to seek variety and external experience."} {"class.text":"MISC","text":"individuals scoring low tend to be less inclined to consider alternative opinions and are more steadfast in their own beliefs CITATION making them more likely to rely upon information that is familiar and conventional CITATION."} {"class.text":"MISC","text":"a fundamental aspect of the anchoring effect is that individuals are sensitive to information which they have experienced."} {"class.text":"MISC","text":"this change in judgment which is based upon external cues seems particularly relevant and related to the openness-to-experience personality trait."} {"class.text":"MISC","text":"specifically as research has shown the openness trait reflects individual propensities to adjust one's beliefs CITATION and to consider external information CITATION."} {"class.text":"AIMX","text":"therefore based upon the nature of the openness-to-experience trait and the processes involved in the anchoring effect we hypothesize that individual differences in openness-to-experience will influence susceptibility to anchoring effects."} {"class.text":"AIMX","text":"specifically we hypothesize that the judgments of those individuals high in this trait will be more influenced by previously presented anchors whereas those individuals low in this trait will be less influenced by the anchor."} {"class.text":"OWNX","text":"to test this hypothesis we first measured individual levels of the personality trait of openness-to-experience."} {"class.text":"OWNX","text":"we then provided participants with an anchoring task involving either the mississippi river study NUMBER or african nations in the un study NUMBER"} {"class.text":"MISC","text":"despite the prevalence of anchoring effects researchers have only recently begun to investigate the underlying factors responsible for how and in what ways a person is susceptible to them"} {"class.text":"AIMX","text":"this paper examines how one such factor the big-five personality trait of openness-to-experience influences the effect of previously presented anchors on participants' judgments"} {"class.text":"OWNX","text":"our findings indicate that participants high in openness-to-experience were significantly more influenced by anchoring cues relative to participants low in this trait"} {"class.text":"OWNX","text":"these findings were consistent across two different types of anchoring tasks providing convergent evidence for our hypothesis"} {"class.text":"MISC","text":"the anchoring effect CITATION refers to the adjustment of one's assessment higher or lower based upon previously presented external information or an anchor"} {"class.text":"MISC","text":"the anchoring heuristic appears to be prevalent throughout human decision processes and has been shown to reliably influence judgments in a variety of domains including probability estimates CITATION negotiation CITATION legal judgments CITATION and general knowledge CITATION"} {"class.text":"MISC","text":"further anchoring effects appear viable across most situations for both novices and experts CITATION and seem to be effective under conditions of monetary incentives CITATION and in real-world settings CITATION"} {"class.text":"MISC","text":"anchoring thus appears to be a very robust psychological phenomenon"} {"class.text":"MISC","text":"however not all individuals may be equally influenced by anchoring cues"} {"class.text":"MISC","text":"identification of factors that influence how and in what ways a person is susceptible to this heuristic should further the understanding of the process"} {"class.text":"MISC","text":"later work by stanovich and west CITATION suggested that intellectual traits influence decision making and consequential choice preference"} {"class.text":"MISC","text":"recently individual differences have been found in numerical reliance CITATION ambiguity CITATION preference for actions or inactions CITATION and the optimistic bias CITATION"} {"class.text":"MISC","text":"the big-five personality traits CITATION have proven to be important individual difference factors for understanding decision choices"} {"class.text":"MISC","text":"taken together these findings suggest that the impact of individual difference factors on decision-making is both profound and pervasive"} {"class.text":"AIMX","text":"the purpose of the current study is to investigate how one individual difference factor may influence the strength of the anchoring effect"} {"class.text":"MISC","text":"in the last couple of decades the five-factor model of personality has become the most widely tested and well-regarded personality trait model"} {"class.text":"MISC","text":"a great deal of research has supported this model's validity and reliability CITATION"} {"class.text":"MISC","text":"while most research has agreed on the nature of the first four factors the nature of the fifth factor has been controversial a controversy predominately based upon whether a lexical approach derived from language frequency within the lexicon of a particular language CITATION or a questionnaire approach CITATION should be used to measure it"} {"class.text":"MISC","text":"individuals scoring high on this dimension are more open to new ideas CITATION and motivated to seek variety and external experience"} {"class.text":"MISC","text":"individuals scoring low tend to be less inclined to consider alternative opinions and are more steadfast in their own beliefs CITATION making them more likely to rely upon information that is familiar and conventional CITATION"} {"class.text":"MISC","text":"this change in judgment which is based upon external cues seems particularly relevant and related to the openness-to-experience personality trait"} {"class.text":"OWNX","text":"therefore based upon the nature of the openness-to-experience trait and the processes involved in the anchoring effect we hypothesize that individual differences in openness-to-experience will influence susceptibility to anchoring effects"} {"class.text":"OWNX","text":"to test this hypothesis we first measured individual levels of the personality trait of openness-to-experience"} {"class.text":"OWNX","text":"we then provided participants with an anchoring task involving either the mississippi river study NUMBER or african nations in the un study NUMBER"} {"class.text":"MISC","text":"Expansion of polyglutamine tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases."} {"class.text":"MISC","text":"Disease age of onset is correlated with the polyQ insert length above a critical value of 35 40 glutamines."} {"class.text":"MISC","text":"The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence."} {"class.text":"AIMX","text":"Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel -helix."} {"class.text":"MISC","text":"This transition occurs selectively in peptides longer than 37 glutamines."} {"class.text":"OWNX","text":"In the -helices observed in simulations, all residues adopt -strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 2 residues per turn."} {"class.text":"OWNX","text":"We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel -hairpins in their ground state, in agreement with experiments."} {"class.text":"OWNX","text":"The lower stability of mutant -helices explains their lower aggregation rates compared to wild type."} {"class.text":"OWNX","text":"Our results provide a molecular mechanism for polyQ-mediated aggregation."} {"class.text":"MISC","text":"Intranuclear inclusion bodies containing polyQ aggregates have been found in vitro CITATION, CITATION, in cell cultures, animal models, and affected patients CITATION, CITATION."} {"class.text":"MISC","text":"The aggregates are known to have a characteristic amyloid topology CITATION."} {"class.text":"MISC","text":"The inhibition of oligomerization by the azo-dye Congo red, or by the Hsp70/Hsp40 chaperone system, exerts marked protective effects in vivo and in vitro CITATION, CITATION."} {"class.text":"MISC","text":"Aggregation and disease are observed if the number of glutamines in the expansion, n, exceeds a critical value, n C CITATION."} {"class.text":"MISC","text":"The nearly universal existence of this criticality in all polyQ-related diseases suggests that when the polyQ insert length exceeds a critical value, a pathological change, largely independent of the host protein, occurs in the polyQ insert itself."} {"class.text":"MISC","text":"Therefore, isolated polyQ peptides have been used as model systems for studying polyQ aggregation CITATION, CITATION, CITATION, and it is known that: The nuclear uptake of polyQ peptide aggregates prepared in vitro is cytotoxic in cell cultures CITATION, isolated polyQ peptides have in vitro aggregation properties similar to the corresponding full-length proteins containing the polyQ insert CITATION, CITATION, peptide aggregation follows a nucleated mechanism showing characteristic lag and growth phases CITATION, CITATION, and the glutamine tract-length dependence of the lag-time interval correlates well with the age of onset of disease CITATION."} {"class.text":"MISC","text":"Longer peptides have progressively smaller lag times of aggregation, and a correspondingly early age of onset of the disease CITATION ."} {"class.text":"MISC","text":"Unaggregated polyQ peptides form random coil structures, whereas aggregates are composed of amyloid-like -strands CITATION."} {"class.text":"MISC","text":"The conversion of random coil to -strand occurs in an individual polyQ chain CITATION, and fibril formation occurs by addition of other polyQ chains to these monomeric -strand nuclei."} {"class.text":"MISC","text":"Therefore, the conformational dynamics of an individual polyQ chain determines both its aggregation mechanism and the structure of the final aggregates."} {"class.text":"MISC","text":"Expansion of polyglutamine tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases."} {"class.text":"MISC","text":"The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence."} {"class.text":"MISC","text":"While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood."} {"class.text":"OWNX","text":"This transition occurs selectively in peptides longer than 37 glutamines."} {"class.text":"OWNX","text":"In the -helices observed in simulations, all residues adopt -strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 2 residues per turn."} {"class.text":"OWNX","text":"We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel -hairpins in their ground state, in agreement with experiments."} {"class.text":"OWNX","text":"The lower stability of mutant -helices explains their lower aggregation rates compared to wild type."} {"class.text":"MISC","text":"Intranuclear inclusion bodies containing polyQ aggregates have been found in vitro CITATION, CITATION, in cell cultures, animal models, and affected patients CITATION, CITATION."} {"class.text":"MISC","text":"The aggregates are known to have a characteristic amyloid topology CITATION."} {"class.text":"MISC","text":"The inhibition of oligomerization by the azo-dye Congo red, or by the Hsp70/Hsp40 chaperone system, exerts marked protective effects in vivo and in vitro CITATION, CITATION."} {"class.text":"MISC","text":"Aggregation and disease are observed if the number of glutamines in the expansion, n, exceeds a critical value, n C CITATION."} {"class.text":"MISC","text":"The nearly universal existence of this criticality in all polyQ-related diseases suggests that when the polyQ insert length exceeds a critical value, a pathological change, largely independent of the host protein, occurs in the polyQ insert itself."} {"class.text":"MISC","text":"Therefore, isolated polyQ peptides have been used as model systems for studying polyQ aggregation CITATION, CITATION, CITATION, and it is known that: The nuclear uptake of polyQ peptide aggregates prepared in vitro is cytotoxic in cell cultures CITATION, isolated polyQ peptides have in vitro aggregation properties similar to the corresponding full-length proteins containing the polyQ insert CITATION, CITATION, peptide aggregation follows a nucleated mechanism showing characteristic lag and growth phases CITATION, CITATION, and the glutamine tract-length dependence of the lag-time interval correlates well with the age of onset of disease CITATION."} {"class.text":"MISC","text":"Peptides of subcritical lengths have long lag times of aggregation and a corresponding age of onset later than the typical life span of a person."} {"class.text":"MISC","text":"Longer peptides have progressively smaller lag times of aggregation, and a correspondingly early age of onset of the disease CITATION ."} {"class.text":"MISC","text":"Unaggregated polyQ peptides form random coil structures, whereas aggregates are composed of amyloid-like -strands CITATION."} {"class.text":"MISC","text":"The conversion of random coil to -strand occurs in an individual polyQ chain CITATION, and fibril formation occurs by addition of other polyQ chains to these monomeric -strand nuclei."} {"class.text":"MISC","text":"Therefore, the conformational dynamics of an individual polyQ chain determines both its aggregation mechanism and the structure of the final aggregates."} {"class.text":"MISC","text":"The details of the conformational dynamics of polyQ and the length dependence of the dynamics are not well understood CITATION ."} {"class.text":"MISC","text":"Expansion of polyglutamine tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases."} {"class.text":"MISC","text":"Disease age of onset is correlated with the polyQ insert length above a critical value of 35 40 glutamines."} {"class.text":"MISC","text":"The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence."} {"class.text":"CONT","text":"While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood."} {"class.text":"AIMX","text":"Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel -helix."} {"class.text":"OWNX","text":"This transition occurs selectively in peptides longer than 37 glutamines."} {"class.text":"OWNX","text":"In the -helices observed in simulations, all residues adopt -strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 2 residues per turn."} {"class.text":"OWNX","text":"We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel -hairpins in their ground state, in agreement with experiments."} {"class.text":"OWNX","text":"The lower stability of mutant -helices explains their lower aggregation rates compared to wild type."} {"class.text":"OWNX","text":"Our results provide a molecular mechanism for polyQ-mediated aggregation."} {"class.text":"MISC","text":"The appearance of polyglutamine -containing aggregates CITATION CITATION is a hallmark of disease progression in all diseases in which CAG-expansions occur in genes CITATION."} {"class.text":"MISC","text":"Intranuclear inclusion bodies containing polyQ aggregates have been found in vitro CITATION, CITATION, in cell cultures, animal models, and affected patients CITATION, CITATION."} {"class.text":"MISC","text":"The inhibition of oligomerization by the azo-dye Congo red, or by the Hsp70/Hsp40 chaperone system, exerts marked protective effects in vivo and in vitro CITATION, CITATION."} {"class.text":"MISC","text":"The nearly universal existence of this criticality in all polyQ-related diseases suggests that when the polyQ insert length exceeds a critical value, a pathological change, largely independent of the host protein, occurs in the polyQ insert itself."} {"class.text":"MISC","text":"Peptides of subcritical lengths have long lag times of aggregation and a corresponding age of onset later than the typical life span of a person."} {"class.text":"MISC","text":"Longer peptides have progressively smaller lag times of aggregation, and a correspondingly early age of onset of the disease CITATION ."} {"class.text":"MISC","text":"The conversion of random coil to -strand occurs in an individual polyQ chain CITATION, and fibril formation occurs by addition of other polyQ chains to these monomeric -strand nuclei."} {"class.text":"MISC","text":"Therefore, the conformational dynamics of an individual polyQ chain determines both its aggregation mechanism and the structure of the final aggregates."} {"class.text":"CONT","text":"The details of the conformational dynamics of polyQ and the length dependence of the dynamics are not well understood CITATION ."} {"class.text":"AIMX","text":"A new theoretical survey of proteins' resistance to constant speed stretching is performed for a set of 17 134 proteins as described by a structure-based model."} {"class.text":"MISC","text":"Our previous studies have dealt with 7510 proteins of no more than 150 amino acids."} {"class.text":"MISC","text":"The proteins are ranked according to the strength of the resistance."} {"class.text":"MISC","text":"Most of the predicted top-strength proteins have not yet been studied experimentally."} {"class.text":"MISC","text":"Architectures and folds which are likely to yield large forces are identified."} {"class.text":"MISC","text":"New types of potent force clamps are discovered."} {"class.text":"MISC","text":"An effective energy parameter of the model is estimated by comparing the theoretical data on characteristic forces to the corresponding experimental values combined with an extrapolation of the theoretical data to the experimental pulling speeds."} {"class.text":"MISC","text":"These studies provide guidance for future experiments on single molecule manipulation and should lead to selection of proteins for applications."} {"class.text":"MISC","text":"A new class of proteins, involving cystein slipknots, is identified as one that is expected to lead to the strongest force clamps known."} {"class.text":"MISC","text":"Atomic force microscopy, optical tweezers, and other tools of nanotechnology have enabled induction and monitoring of large conformational changes in biomolecules."} {"class.text":"MISC","text":"Such studies are performed to assess structure of the biomolecules, their elastic properties, and ability to act as nanomachines in a cell."} {"class.text":"MISC","text":"Stretching studies of proteins CITATION are of a particular current interest and they have been performed for under a hundred of systems."} {"class.text":"CONT","text":"They are limited by of order 100 ns time scales and thus require using unrealistically large constant pulling speeds."} {"class.text":"MISC","text":"However, they often elucidate the nature of the force clamp the region responsible for the largest force of resistance to pulling, FORMULA."} {"class.text":"MISC","text":"All of the experimental and all-atom simulational studies address merely a tiny fraction of proteins that are stored in the Protein Data Bank CITATION."} {"class.text":"MISC","text":"Thus it appears worthwhile to consider a large set of proteins and determine their FORMULA within an approximate model that allows for fast and yet reasonably accurate calculations."} {"class.text":"MISC","text":"Structure-based models of proteins, as pioneered by Go and his collaborators CITATION and used in several implementations CITATION CITATION, seem to be suited to this task especially well since they are defined in terms of the native structures away from which stretching is imposed."} {"class.text":"MISC","text":"There are many ways, all phenomenological, to construct a structure-based model of a protein."} {"class.text":"MISC","text":"504 of possible variants are enumerated and 62 are studied in details in ref. CITATION."} {"class.text":"MISC","text":"The variants differ by the choice of effective potentials, nature of the local backbone stiffness, energy-related parameters, and of the coarse-grained degrees of freedom."} {"class.text":"MISC","text":"Comparing FORMULA to the corresponding experimental values in 36 available cases selects several optimal models CITATION."} {"class.text":"MISC","text":"Among them, there is one which is very simple and which describes a protein in terms of its FORMULA atoms, as labeled by the sequential index FORMULA."} {"class.text":"MISC","text":"The contact map is determined by assigning the van der Waals spheres to the heavy atoms and by checking whether spheres belonging to different amino acids overlap in the native state CITATION, CITATION."} {"class.text":"MISC","text":"Non-native contacts are considered repulsive."} {"class.text":"MISC","text":"Application of this criterion frequently selects the FORMULA contacts as native."} {"class.text":"MISC","text":"If the contact map includes these contacts the resulting model will be denoted here as FORMULA."} {"class.text":"MISC","text":"Thus the FORMULA couplings should better be removed from the contact map ."} {"class.text":"MISC","text":"The survey to determine FORMULA in 7510 model proteins with the number of amino acids, FORMULA, not exceeding 150 and 239 longer proteins has been accomplished twice."} {"class.text":"MISC","text":"First within the FORMULA model CITATION and soon afterwords within the FORMULA model CITATION."} {"class.text":"MISC","text":"The two surveys are compared in more details in refs. CITATION, CITATION."} {"class.text":"MISC","text":"The results differ, particularly when it comes to ranking of the proteins according to the value of FORMULA, but they mutually provide the error bars on the findings."} {"class.text":"MISC","text":"They both agree, however, on predicting that there are many proteins whose strength should be considerably larger than the frequently studied benchmark the sarcomere protein titin."} {"class.text":"MISC","text":"Near the top of the list, there is the scaffoldin protein c7A which has been recently measured to have FORMULA of about 480 pN CITATION."} {"class.text":"MISC","text":"Other findings include establishing correlations with the CATH hierarchical classification scheme CITATION, CITATION, such as that there are no strong FORMULA proteins, and identification of several types of the force clamps."} {"class.text":"MISC","text":"The large forces most commonly originate in parallel FORMULA that are sheared CITATION."} {"class.text":"MISC","text":"However, there are also clamps with antiparallel FORMULA, unstructured strands, and other kinds."} {"class.text":"MISC","text":"Here, we present results of still another survey which is based on a download of December 18, 2008 which contains 54 807 structure files and leads to 17 134 acceptable structures with FORMULA not exceeding 250."} {"class.text":"MISC","text":"These structures are then analyzed through simulations based on the FORMULA model."} {"class.text":"MISC","text":"The numerical code has been improved to allow for acceleration of calculations by a factor of 2."} {"class.text":"MISC","text":"The 190 structures with the top values of FORMULA in units of FORMULA are shown in Table 1 and Table S1 of the SI, together with the values of titin and ubiquitin to provide a scale."} {"class.text":"MISC","text":"As argued in the Materials and Methods section section, the unit of force, FORMULA, is now estimated to be of order 110 pN."} {"class.text":"MISC","text":"All of the corresponding proteins are predicted to be much stronger than titin and none but two of them have been studied experimentally yet."} {"class.text":"OWNX","text":"One of them involves a cysteine slipknot and is found to be operational in all of the 13 top strength proteins."} {"class.text":"OWNX","text":"In this motif, a slip-loop is pulled out of a cysteine knot-loop."} {"class.text":"OWNX","text":"The two mechanisms are similar in spirit since both involve dragging of the backbone."} {"class.text":"OWNX","text":"However, in the CSK case, two fragments of the backbone are participating."} {"class.text":"OWNX","text":"The previous surveys did not relate to the SCOP scheme."} {"class.text":"MISC","text":"A general observation, however, is that each such group of structures may also include examples of proteins that unravel easily."} {"class.text":"MISC","text":"The dynamics of a protein are very sensitive to mechanical details that are largely captured by the contact map and not just by the appearance of a structure."} {"class.text":"MISC","text":"On the other hand, if one were to look for mechanically strong proteins then the architectures and folds identified by us should provide a good starting point."} {"class.text":"OWNX","text":"We also study the dependence of FORMULA on the pulling velocity and characterize the dependence on FORMULA through distributions of the forces."} {"class.text":"MISC","text":"The current third survey has been performed within the same FORMULA model as the second survey CITATION."} {"class.text":"BASE","text":"However, we reuse and extend it here because the editors of Biophysical Journal retracted the second survey CITATION."} {"class.text":"OWNX","text":"All of the values of FORMULA are deposited at the website LINK and can by accessed by through the PDB structure code."} {"class.text":"AIMX","text":"A new theoretical survey of proteins' resistance to constant speed stretching is performed for a set of 17 134 proteins as described by a structure-based model."} {"class.text":"MISC","text":"Our previous studies have dealt with 7510 proteins of no more than 150 amino acids."} {"class.text":"MISC","text":"Most of the predicted top-strength proteins have not yet been studied experimentally."} {"class.text":"MISC","text":"They involve disulphide bridges and, in particular, cysteine slipknots."} {"class.text":"MISC","text":"An effective energy parameter of the model is estimated by comparing the theoretical data on characteristic forces to the corresponding experimental values combined with an extrapolation of the theoretical data to the experimental pulling speeds."} {"class.text":"MISC","text":"A new class of proteins, involving cystein slipknots, is identified as one that is expected to lead to the strongest force clamps known."} {"class.text":"MISC","text":"This class is characterized through molecular dynamics simulations."} {"class.text":"MISC","text":"Atomic force microscopy, optical tweezers, and other tools of nanotechnology have enabled induction and monitoring of large conformational changes in biomolecules."} {"class.text":"MISC","text":"Interpretation of some of these experiments has been helped by all-atom simulations, such as reported in refs. CITATION, CITATION."} {"class.text":"CONT","text":"They are limited by of order 100 ns time scales and thus require using unrealistically large constant pulling speeds."} {"class.text":"MISC","text":"However, they often elucidate the nature of the force clamp the region responsible for the largest force of resistance to pulling, FORMULA."} {"class.text":"MISC","text":"Structure-based models of proteins, as pioneered by Go and his collaborators CITATION and used in several implementations CITATION CITATION, seem to be suited to this task especially well since they are defined in terms of the native structures away from which stretching is imposed."} {"class.text":"MISC","text":"There are many ways, all phenomenological, to construct a structure-based model of a protein."} {"class.text":"MISC","text":"504 of possible variants are enumerated and 62 are studied in details in ref. CITATION."} {"class.text":"MISC","text":"The variants differ by the choice of effective potentials, nature of the local backbone stiffness, energy-related parameters, and of the coarse-grained degrees of freedom."} {"class.text":"MISC","text":"Comparing FORMULA to the corresponding experimental values in 36 available cases selects several optimal models CITATION."} {"class.text":"MISC","text":"Among them, there is one which is very simple and which describes a protein in terms of its FORMULA atoms, as labeled by the sequential index FORMULA."} {"class.text":"MISC","text":"This model is denoted by FORMULA which stands for, respectively, the Lennard-Jones native contact potentials, local backbone stiffness represented by harmonic terms that favor the native values of local chiralities, the contact map in which there are no FORMULA contacts, and the amplitude of the Lennard-Jones potential, FORMULA, is uniform."} {"class.text":"MISC","text":"The contact map is determined by assigning the van der Waals spheres to the heavy atoms and by checking whether spheres belonging to different amino acids overlap in the native state CITATION, CITATION."} {"class.text":"MISC","text":"If they do, a contact is declared as native."} {"class.text":"MISC","text":"Non-native contacts are considered repulsive."} {"class.text":"MISC","text":"If the contact map includes these contacts the resulting model will be denoted here as FORMULA."} {"class.text":"MISC","text":"On average, it performs worse than FORMULA because the FORMULA contacts usually correspond to the weak van der Waals couplings as can be demonstrated in a sample of proteins by using a software CITATION which analyses atomic configurations from the chemical perspective on molecular bonds."} {"class.text":"MISC","text":"Thus the FORMULA couplings should better be removed from the contact map ."} {"class.text":"MISC","text":"First within the FORMULA model CITATION and soon afterwords within the FORMULA model CITATION."} {"class.text":"MISC","text":"The first survey also comes with many details of the methodology whereas the second just presents the outcomes."} {"class.text":"MISC","text":"The two surveys are compared in more details in refs. CITATION, CITATION."} {"class.text":"MISC","text":"Near the top of the list, there is the scaffoldin protein c7A which has been recently measured to have FORMULA of about 480 pN CITATION."} {"class.text":"MISC","text":"However, there are also clamps with antiparallel FORMULA, unstructured strands, and other kinds."} {"class.text":"MISC","text":"The two surveys have been based on the structure download made on July 26, 2005 when the PDB comprised 29 385 entries."} {"class.text":"MISC","text":"Many of them correspond to nucleic acids, complexes with nucleic acids and with other proteins, carbohydrates, or come with incomplete files and hence the much smaller number of proteins that could be used in the molecular dynamics studies."} {"class.text":"MISC","text":"Here, we present results of still another survey which is based on a download of December 18, 2008 which contains 54 807 structure files and leads to 17 134 acceptable structures with FORMULA not exceeding 250."} {"class.text":"MISC","text":"The numerical code has been improved to allow for acceleration of calculations by a factor of 2."} {"class.text":"MISC","text":"The 190 structures with the top values of FORMULA in units of FORMULA are shown in Table 1 and Table S1 of the SI, together with the values of titin and ubiquitin to provide a scale."} {"class.text":"MISC","text":"As argued in the Materials and Methods section section, the unit of force, FORMULA, is now estimated to be of order 110 pN."} {"class.text":"MISC","text":"All of the corresponding proteins are predicted to be much stronger than titin and none but two of them have been studied experimentally yet."} {"class.text":"OWNX","text":"In addition to the types of force clamps identified before, we have discovered two new mechanisms of sturdiness."} {"class.text":"OWNX","text":"One of them involves a cysteine slipknot and is found to be operational in all of the 13 top strength proteins."} {"class.text":"OWNX","text":"In this motif, a slip-loop is pulled out of a cysteine knot-loop."} {"class.text":"OWNX","text":"Another involves dragging of a single fragment of the main chain across a cysteine knot-loop."} {"class.text":"OWNX","text":"The two mechanisms are similar in spirit since both involve dragging of the backbone."} {"class.text":"OWNX","text":"However, in the CSK case, two fragments of the backbone are participating."} {"class.text":"AIMX","text":"We make a more systematic identification of the CATH-classified architectures that are linked to mechanical strength and then analyze correlations of the data to the SCOP-based grouping CITATION CITATION."} {"class.text":"OWNX","text":"The previous surveys did not relate to the SCOP scheme."} {"class.text":"OWNX","text":"We identify the CATH-based architectures and SCOP-based folds that are associated with the occurrence of a strong resistance to pulling."} {"class.text":"MISC","text":"The dynamics of a protein are very sensitive to mechanical details that are largely captured by the contact map and not just by the appearance of a structure."} {"class.text":"OWNX","text":"We also study the dependence of FORMULA on the pulling velocity and characterize the dependence on FORMULA through distributions of the forces."} {"class.text":"MISC","text":"The current third survey has been performed within the same FORMULA model as the second survey CITATION."} {"class.text":"BASE","text":"However, we reuse and extend it here because the editors of Biophysical Journal retracted the second survey CITATION."} {"class.text":"OWNX","text":"All of the values of FORMULA are deposited at the website LINK and can by accessed by through the PDB structure code."} {"class.text":"OWNX","text":"The proteins selected have no gaps in their structure determination and consist of no more than 250 amino acids."} {"class.text":"MISC","text":"Our previous studies have dealt with 7510 proteins of no more than 150 amino acids."} {"class.text":"OWNX","text":"The proteins are ranked according to the strength of the resistance."} {"class.text":"OWNX","text":"They involve disulphide bridges and, in particular, cysteine slipknots."} {"class.text":"OWNX","text":"An effective energy parameter of the model is estimated by comparing the theoretical data on characteristic forces to the corresponding experimental values combined with an extrapolation of the theoretical data to the experimental pulling speeds."} {"class.text":"OWNX","text":"These studies provide guidance for future experiments on single molecule manipulation and should lead to selection of proteins for applications."} {"class.text":"OWNX","text":"A new class of proteins, involving cystein slipknots, is identified as one that is expected to lead to the strongest force clamps known."} {"class.text":"OWNX","text":"This class is characterized through molecular dynamics simulations."} {"class.text":"MISC","text":"Atomic force microscopy, optical tweezers, and other tools of nanotechnology have enabled induction and monitoring of large conformational changes in biomolecules."} {"class.text":"MISC","text":"Such studies are performed to assess structure of the biomolecules, their elastic properties, and ability to act as nanomachines in a cell."} {"class.text":"MISC","text":"Stretching studies of proteins CITATION are of a particular current interest and they have been performed for under a hundred of systems."} {"class.text":"CONT","text":"They are limited by of order 100 ns time scales and thus require using unrealistically large constant pulling speeds."} {"class.text":"MISC","text":"However, they often elucidate the nature of the force clamp the region responsible for the largest force of resistance to pulling, FORMULA."} {"class.text":"CONT","text":"All of the experimental and all-atom simulational studies address merely a tiny fraction of proteins that are stored in the Protein Data Bank CITATION."} {"class.text":"MISC","text":"Thus it appears worthwhile to consider a large set of proteins and determine their FORMULA within an approximate model that allows for fast and yet reasonably accurate calculations."} {"class.text":"MISC","text":"There are many ways, all phenomenological, to construct a structure-based model of a protein."} {"class.text":"MISC","text":"504 of possible variants are enumerated and 62 are studied in details in ref. CITATION."} {"class.text":"MISC","text":"The variants differ by the choice of effective potentials, nature of the local backbone stiffness, energy-related parameters, and of the coarse-grained degrees of freedom."} {"class.text":"MISC","text":"The most crucial choice relates to making a decision about which interactions between amino acids count as native contacts."} {"class.text":"MISC","text":"Comparing FORMULA to the corresponding experimental values in 36 available cases selects several optimal models CITATION."} {"class.text":"MISC","text":"Among them, there is one which is very simple and which describes a protein in terms of its FORMULA atoms, as labeled by the sequential index FORMULA."} {"class.text":"MISC","text":"This model is denoted by FORMULA which stands for, respectively, the Lennard-Jones native contact potentials, local backbone stiffness represented by harmonic terms that favor the native values of local chiralities, the contact map in which there are no FORMULA contacts, and the amplitude of the Lennard-Jones potential, FORMULA, is uniform."} {"class.text":"MISC","text":"The contact map is determined by assigning the van der Waals spheres to the heavy atoms and by checking whether spheres belonging to different amino acids overlap in the native state CITATION, CITATION."} {"class.text":"MISC","text":"If they do, a contact is declared as native."} {"class.text":"MISC","text":"Non-native contacts are considered repulsive."} {"class.text":"MISC","text":"Application of this criterion frequently selects the FORMULA contacts as native."} {"class.text":"MISC","text":"If the contact map includes these contacts the resulting model will be denoted here as FORMULA."} {"class.text":"MISC","text":"Thus the FORMULA couplings should better be removed from the contact map ."} {"class.text":"MISC","text":"The survey to determine FORMULA in 7510 model proteins with the number of amino acids, FORMULA, not exceeding 150 and 239 longer proteins has been accomplished twice."} {"class.text":"MISC","text":"First within the FORMULA model CITATION and soon afterwords within the FORMULA model CITATION."} {"class.text":"MISC","text":"The first survey also comes with many details of the methodology whereas the second just presents the outcomes."} {"class.text":"MISC","text":"The two surveys are compared in more details in refs. CITATION, CITATION."} {"class.text":"MISC","text":"The results differ, particularly when it comes to ranking of the proteins according to the value of FORMULA, but they mutually provide the error bars on the findings."} {"class.text":"MISC","text":"They both agree, however, on predicting that there are many proteins whose strength should be considerably larger than the frequently studied benchmark the sarcomere protein titin."} {"class.text":"MISC","text":"Other findings include establishing correlations with the CATH hierarchical classification scheme CITATION, CITATION, such as that there are no strong FORMULA proteins, and identification of several types of the force clamps."} {"class.text":"MISC","text":"The large forces most commonly originate in parallel FORMULA that are sheared CITATION."} {"class.text":"MISC","text":"The two surveys have been based on the structure download made on July 26, 2005 when the PDB comprised 29 385 entries."} {"class.text":"MISC","text":"Many of them correspond to nucleic acids, complexes with nucleic acids and with other proteins, carbohydrates, or come with incomplete files and hence the much smaller number of proteins that could be used in the molecular dynamics studies."} {"class.text":"AIMX","text":"Here, we present results of still another survey which is based on a download of December 18, 2008 which contains 54 807 structure files and leads to 17 134 acceptable structures with FORMULA not exceeding 250."} {"class.text":"OWNX","text":"These structures are then analyzed through simulations based on the FORMULA model."} {"class.text":"OWNX","text":"The numerical code has been improved to allow for acceleration of calculations by a factor of 2."} {"class.text":"OWNX","text":"As argued in the Materials and Methods section section, the unit of force, FORMULA, is now estimated to be of order 110 pN."} {"class.text":"OWNX","text":"All of the corresponding proteins are predicted to be much stronger than titin and none but two of them have been studied experimentally yet."} {"class.text":"OWNX","text":"In addition to the types of force clamps identified before, we have discovered two new mechanisms of sturdiness."} {"class.text":"OWNX","text":"One of them involves a cysteine slipknot and is found to be operational in all of the 13 top strength proteins."} {"class.text":"OWNX","text":"In this motif, a slip-loop is pulled out of a cysteine knot-loop."} {"class.text":"OWNX","text":"Another involves dragging of a single fragment of the main chain across a cysteine knot-loop."} {"class.text":"OWNX","text":"The two mechanisms are similar in spirit since both involve dragging of the backbone."} {"class.text":"OWNX","text":"However, in the CSK case, two fragments of the backbone are participating."} {"class.text":"OWNX","text":"We make a more systematic identification of the CATH-classified architectures that are linked to mechanical strength and then analyze correlations of the data to the SCOP-based grouping CITATION CITATION."} {"class.text":"CONT","text":"The previous surveys did not relate to the SCOP scheme."} {"class.text":"OWNX","text":"A general observation, however, is that each such group of structures may also include examples of proteins that unravel easily."} {"class.text":"OWNX","text":"The dynamics of a protein are very sensitive to mechanical details that are largely captured by the contact map and not just by the appearance of a structure."} {"class.text":"OWNX","text":"On the other hand, if one were to look for mechanically strong proteins then the architectures and folds identified by us should provide a good starting point."} {"class.text":"OWNX","text":"We also study the dependence of FORMULA on the pulling velocity and characterize the dependence on FORMULA through distributions of the forces."} {"class.text":"MISC","text":"The current third survey has been performed within the same FORMULA model as the second survey CITATION."} {"class.text":"BASE","text":"However, we reuse and extend it here because the editors of Biophysical Journal retracted the second survey CITATION."} {"class.text":"OWNX","text":"All of the values of FORMULA are deposited at the website LINK and can by accessed by through the PDB structure code."} {"class.text":"AIMX","text":"Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction maintenance therapies might be optimized."} {"class.text":"OWNX","text":"Our model suggests that under a variety of biologically plausible conditions, 6 10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen."} {"class.text":"OWNX","text":"For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal."} {"class.text":"OWNX","text":"The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated."} {"class.text":"OWNX","text":"These observations have implications for both the timing and the kinds of drugs selected for induction maintenance and therapy-intensification strategies."} {"class.text":"MISC","text":"In therapy-naive patients without clinically apparent resistance mutations, triple-drug therapy with two nucleoside analog reverse transcriptase inhibitors and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor is standard CITATION."} {"class.text":"MISC","text":"In these patients, treatment success rates, defined as viral load 50 copies/ml at 48 wk, range from 70 percent to 80 percent 85 percent."} {"class.text":"MISC","text":"However, in patients with previous regimen failure requiring salvage therapy, response rates are usually considerably lower CITATION CITATION, and it is frequently not possible to assemble a three-drug regimen with uncompromised activity against all viral strains present."} {"class.text":"MISC","text":"In these individuals, treatment failure often occurs after an initial period of response to a new regimen, and is usually associated with the appearance of multiply drug-resistant viral strains."} {"class.text":"MISC","text":"This has led to attempts to treat highly experienced patients with various deep salvage regimens consisting of four, five, or six individual drugs CITATION CITATION."} {"class.text":"MISC","text":"The need to minimize drug resistance while reducing treatment-related toxicities has engendered an interest in induction maintenance strategies, in which a period of intensified antiretroviral therapy is followed by a simplified long-term regimen CITATION CITATION."} {"class.text":"CONT","text":"Most such trials have yielded higher failure rates in the treatment group than in controls receiving conventional therapy."} {"class.text":"CONT","text":"One weakness of existing studies has been that induction therapy consisted of standard three-drug antiretroviral therapy regimens in common clinical use at the time of the study, under conditions now recognized to permit subclinical viral replication CITATION, CITATION."} {"class.text":"MISC","text":"However, two recent studies have shown the apparent effectiveness of induction therapy for 48 wk followed by maintenance therapy with atazanavir CITATION or lopinvir/ritonavir CITATION, CITATION, and this has led to new optimism concerning IM approaches."} {"class.text":"OWNX","text":"To explore this hypothesis quantitatively, we constructed a detailed computer simulation model of the dynamics of sensitive and resistant viruses during a hypothetical IM regimen."} {"class.text":"OWNX","text":"We show that the timing and duration of induction therapy relative to maintenance therapy can affect the probability that viruses resistant to the maintenance regimen will be eradicated in ways that are somewhat counterintuitive."} {"class.text":"OWNX","text":"Under biologically plausible conditions, we find that 6 10 mo of induction therapy are required to maximize the probability of eradicating these resistant viruses."} {"class.text":"OWNX","text":"For shorter induction periods, we find that it is optimal to use a delayed-induction regimen administered several days to weeks after the start of the intended long-term maintenance therapy."} {"class.text":"MISC","text":"The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies."} {"class.text":"AIMX","text":"Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction maintenance therapies might be optimized."} {"class.text":"OWNX","text":"Our model suggests that under a variety of biologically plausible conditions, 6 10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen."} {"class.text":"OWNX","text":"For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal."} {"class.text":"OWNX","text":"The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated."} {"class.text":"MISC","text":"The failure of antiretroviral therapies to completely suppress viral replication in some patients represents a major difficulty in the management of HIV infection."} {"class.text":"MISC","text":"In therapy-naive patients without clinically apparent resistance mutations, triple-drug therapy with two nucleoside analog reverse transcriptase inhibitors and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor is standard CITATION."} {"class.text":"MISC","text":"In these individuals, treatment failure often occurs after an initial period of response to a new regimen, and is usually associated with the appearance of multiply drug-resistant viral strains."} {"class.text":"MISC","text":"This has led to attempts to treat highly experienced patients with various deep salvage regimens consisting of four, five, or six individual drugs CITATION CITATION."} {"class.text":"MISC","text":"These patients are particularly vulnerable to the many drug interactions CITATION and adverse metabolic, hematologic, neurologic, cardiovascular, and gastrointestinal side effects that complicate HIV therapy and seriously undermine the success of clinical management CITATION CITATION ."} {"class.text":"MISC","text":"Failure typically occurs during maintenance therapy, and has been attributed to poor regimen adherence CITATION and recrudescence of resistance mutations present before institution of induction therapy CITATION."} {"class.text":"CONT","text":"One weakness of existing studies has been that induction therapy consisted of standard three-drug antiretroviral therapy regimens in common clinical use at the time of the study, under conditions now recognized to permit subclinical viral replication CITATION, CITATION."} {"class.text":"CONT","text":"Moreover, in these early studies, the induction phase only lasted between 3 to 6 mo, which may be insufficient."} {"class.text":"MISC","text":"However, two recent studies have shown the apparent effectiveness of induction therapy for 48 wk followed by maintenance therapy with atazanavir CITATION or lopinvir/ritonavir CITATION, CITATION, and this has led to new optimism concerning IM approaches."} {"class.text":"OWNX","text":"We have hypothesized that a longer period of a highly suppressive induction therapy that is appropriately timed relative to the start of maintenance therapy may allow minority resistant variants to decay below a stochastic extinction threshold, allowing for successful long-term treatment with simpler and better-tolerated regimens."} {"class.text":"AIMX","text":"To explore this hypothesis quantitatively, we constructed a detailed computer simulation model of the dynamics of sensitive and resistant viruses during a hypothetical IM regimen."} {"class.text":"OWNX","text":"We show that the timing and duration of induction therapy relative to maintenance therapy can affect the probability that viruses resistant to the maintenance regimen will be eradicated in ways that are somewhat counterintuitive."} {"class.text":"OWNX","text":"Under biologically plausible conditions, we find that 6 10 mo of induction therapy are required to maximize the probability of eradicating these resistant viruses."} {"class.text":"MISC","text":"The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies."} {"class.text":"AIMX","text":"Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction maintenance therapies might be optimized."} {"class.text":"OWNX","text":"Our model suggests that under a variety of biologically plausible conditions, 6 10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen."} {"class.text":"OWNX","text":"The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated."} {"class.text":"OWNX","text":"These observations have implications for both the timing and the kinds of drugs selected for induction maintenance and therapy-intensification strategies."} {"class.text":"MISC","text":"The failure of antiretroviral therapies to completely suppress viral replication in some patients represents a major difficulty in the management of HIV infection."} {"class.text":"MISC","text":"In therapy-naive patients without clinically apparent resistance mutations, triple-drug therapy with two nucleoside analog reverse transcriptase inhibitors and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor is standard CITATION."} {"class.text":"MISC","text":"In these patients, treatment success rates, defined as viral load 50 copies/ml at 48 wk, range from 70 percent to 80 percent 85 percent."} {"class.text":"MISC","text":"This has led to attempts to treat highly experienced patients with various deep salvage regimens consisting of four, five, or six individual drugs CITATION CITATION."} {"class.text":"MISC","text":"These patients are particularly vulnerable to the many drug interactions CITATION and adverse metabolic, hematologic, neurologic, cardiovascular, and gastrointestinal side effects that complicate HIV therapy and seriously undermine the success of clinical management CITATION CITATION ."} {"class.text":"MISC","text":"The need to minimize drug resistance while reducing treatment-related toxicities has engendered an interest in induction maintenance strategies, in which a period of intensified antiretroviral therapy is followed by a simplified long-term regimen CITATION CITATION."} {"class.text":"CONT","text":"One weakness of existing studies has been that induction therapy consisted of standard three-drug antiretroviral therapy regimens in common clinical use at the time of the study, under conditions now recognized to permit subclinical viral replication CITATION, CITATION."} {"class.text":"CONT","text":"Moreover, in these early studies, the induction phase only lasted between 3 to 6 mo, which may be insufficient."} {"class.text":"MISC","text":"However, two recent studies have shown the apparent effectiveness of induction therapy for 48 wk followed by maintenance therapy with atazanavir CITATION or lopinvir/ritonavir CITATION, CITATION, and this has led to new optimism concerning IM approaches."} {"class.text":"OWNX","text":"We have hypothesized that a longer period of a highly suppressive induction therapy that is appropriately timed relative to the start of maintenance therapy may allow minority resistant variants to decay below a stochastic extinction threshold, allowing for successful long-term treatment with simpler and better-tolerated regimens."} {"class.text":"AIMX","text":"To explore this hypothesis quantitatively, we constructed a detailed computer simulation model of the dynamics of sensitive and resistant viruses during a hypothetical IM regimen."} {"class.text":"OWNX","text":"We show that the timing and duration of induction therapy relative to maintenance therapy can affect the probability that viruses resistant to the maintenance regimen will be eradicated in ways that are somewhat counterintuitive."} {"class.text":"OWNX","text":"Under biologically plausible conditions, we find that 6 10 mo of induction therapy are required to maximize the probability of eradicating these resistant viruses."} {"class.text":"OWNX","text":"For shorter induction periods, we find that it is optimal to use a delayed-induction regimen administered several days to weeks after the start of the intended long-term maintenance therapy."} {"class.text":"MISC","text":"The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20 29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics simulations with explicit solvent model."} {"class.text":"MISC","text":"hIAPP20 29 fragments aggregate into partially ordered -sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel -sheet oligomers in mixed in-register and out-of-register patterns."} {"class.text":"AIMX","text":"Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides."} {"class.text":"MISC","text":"A range of human diseases including Alzheimer's disease, Parkinson's disease, the spongiform encephalopathy and type 2 diabetes mellitus is associated with amyloid deposits of normally soluble proteins or peptides CITATION CITATION."} {"class.text":"MISC","text":"In T2DM, the main protein component of fibrillar protein deposits in the pancreatic islets of langerhans has been identified as a 37-residue hormone referred to as islet amyloid polypeptide or amylin CITATION, which is synthesized in -cells of the pancreas and cosecreted with insulin CITATION, CITATION."} {"class.text":"MISC","text":"There are convincing evidences that the toxicity of amyloid related diseases may be caused by the soluble intermediate oligomers instead of mature fibrils CITATION CITATION, and the interaction between lipid bilayer and these soluble oligomer CITATION CITATION."} {"class.text":"MISC","text":"Moreover, up to 10 percent components in amyloid deposits from patient tissues were lipid molecules, indicating that the lipids can be uptaken from membranes and then wrapped into fibrillar amyloid CITATION CITATION."} {"class.text":"CONT","text":"There is, however, missing information about how individual lipid molecule involving in the peptide aggregation process."} {"class.text":"AIMX","text":"It will then be beneficial to understand the molecular details of how single lipid molecule influences the assembly process of amyloidogenic peptides which is the main focus of the current study."} {"class.text":"MISC","text":"Besides the external factors, such as lipid bilayer, pH value, the sequences of peptide themselves have great effects on the aggregation behaviors."} {"class.text":"MISC","text":"The rIAPP differs from hIAPP in six amino acids and five of them are clustered in a short decapeptide, which is considered to be strongly amyloidogenic and forms similar unbranched fibrils itself to the full-length hIAPP CITATION, CITATION."} {"class.text":"MISC","text":"The three proline substitutions in rIAPP20 29 are believed to be highly responsible for the lacking of the amyloidogenic property of the segment or full-length peptide CITATION."} {"class.text":"CONT","text":"Although rIAPP has been intensively applied in experimental research acting as a potential peptide inhibitor for peptide aggregation CITATION, CITATION, the molecular mechanism of its resistance to amyloid is still not crystal clear."} {"class.text":"MISC","text":"Here, the aggregation of rIAPP20 29 segments is subjected to the same simulation condition as hIAPP20 29 to explore the non-amyloidogenic properties of the peptide and meanwhile to evaluate the simulation results as a negative control."} {"class.text":"MISC","text":"Thus, the computational approaches have been employed to complement experimental investigations to gain the insight into the aggregation mechanisms CITATION CITATION."} {"class.text":"MISC","text":"Santini et al. performed ART-OPEP simulations on trimer of A 16 22 by treating side chains as a bead and solvent implicitly CITATION."} {"class.text":"MISC","text":"A novel mechanism for single -strand to surmount unnatural registry without dissociation, referred to as reptation was proposed before experimental characterization CITATION."} {"class.text":"MISC","text":"Cheon et al. used ProFASi package to reduce the bonded potential energy to include torsional angles only and treated hydrogen bonds explicitly CITATION."} {"class.text":"MISC","text":"They were able to carry out two series of 100 Monte Carlo simulations on 20 copies of two fragments A 16 22 and A 25 35."} {"class.text":"MISC","text":"In these studies, simulations were usually started with randomly oriented, extended or random-coiled peptides which underwent ab initio folding to form -sheet oligomers."} {"class.text":"MISC","text":"Albeit simplified models allow studying large-scale systems CITATION or observing more events in limited simulation time CITATION, all-atom explicit solvent models can reproduce amyloid aggregation in aqueous environment more accurately and supply more information on sidechain contacts CITATION."} {"class.text":"MISC","text":"Nguyen et al. prolonged a series of conventional MD simulations to 300 ns on A 16 22 of 3 6 oligomer size with explicit solvent CITATION."} {"class.text":"MISC","text":"The extensive simulations were able to probe the interpeptide sidechain contacts and large conformational fluctuations upon monomer addition to preformed -sheet oligomers in a dock-lock mechanism."} {"class.text":"OWNX","text":"In our studies, an enhanced-sampling method, replica exchange molecular dynamics CITATION was implemented CITATION, and all water and peptide atoms are treated explicitly by applying OPLS-AA force field CITATION."} {"class.text":"OWNX","text":"The four copies of amyloidogenic segment hIAPP20 29 and an extra dioleoylphosphatidylcholine lipid molecule were initially set in extended conformation and dispersed in simulation boxes."} {"class.text":"OWNX","text":"The formation of -sheet containing tetramers, was observed within 100 ns ab initio REMD folding simulations."} {"class.text":"OWNX","text":"The acquirement of abundant intermediate states suggested two possible -sheet transition pathways."} {"class.text":"OWNX","text":"Simulation of four hIAPP peptides without lipid molecule was also performed."} {"class.text":"OWNX","text":"Nonamyloidogenic rat IAPP segments were studied as a negative control with the aim of understanding the inhibitory effect of three proline substitutions."} {"class.text":"MISC","text":"The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20 29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics simulations with explicit solvent model."} {"class.text":"MISC","text":"hIAPP20 29 fragments aggregate into partially ordered -sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel -sheet oligomers in mixed in-register and out-of-register patterns."} {"class.text":"MISC","text":"The hydrophobic interaction between lipid tails and residues at positions 23 25 is found to stabilize the ordered -sheet structure, indicating a catalysis role of lipid molecules in hIAPP20 29 self-assembly."} {"class.text":"MISC","text":"The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies."} {"class.text":"AIMX","text":"Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides."} {"class.text":"MISC","text":"In T2DM, the main protein component of fibrillar protein deposits in the pancreatic islets of langerhans has been identified as a 37-residue hormone referred to as islet amyloid polypeptide or amylin CITATION, which is synthesized in -cells of the pancreas and cosecreted with insulin CITATION, CITATION."} {"class.text":"MISC","text":"There are convincing evidences that the toxicity of amyloid related diseases may be caused by the soluble intermediate oligomers instead of mature fibrils CITATION CITATION, and the interaction between lipid bilayer and these soluble oligomer CITATION CITATION."} {"class.text":"MISC","text":"Moreover, up to 10 percent components in amyloid deposits from patient tissues were lipid molecules, indicating that the lipids can be uptaken from membranes and then wrapped into fibrillar amyloid CITATION CITATION."} {"class.text":"MISC","text":"Most studies so far treated the lipid bilayer as a template to exert its influences on the conformation and aggregation properties of peptides CITATION CITATION."} {"class.text":"MISC","text":"There is, however, missing information about how individual lipid molecule involving in the peptide aggregation process."} {"class.text":"OWNX","text":"It will then be beneficial to understand the molecular details of how single lipid molecule influences the assembly process of amyloidogenic peptides which is the main focus of the current study."} {"class.text":"MISC","text":"Besides the external factors, such as lipid bilayer, pH value, the sequences of peptide themselves have great effects on the aggregation behaviors."} {"class.text":"MISC","text":"Several other species such as non-human primates CITATION, cats CITATION, raccoons CITATION, and rodent species can produce IAPP, but the primary sequence of IAPP varies slightly among species."} {"class.text":"MISC","text":"The rIAPP differs from hIAPP in six amino acids and five of them are clustered in a short decapeptide, which is considered to be strongly amyloidogenic and forms similar unbranched fibrils itself to the full-length hIAPP CITATION, CITATION."} {"class.text":"MISC","text":"The three proline substitutions in rIAPP20 29 are believed to be highly responsible for the lacking of the amyloidogenic property of the segment or full-length peptide CITATION."} {"class.text":"MISC","text":"Although rIAPP has been intensively applied in experimental research acting as a potential peptide inhibitor for peptide aggregation CITATION, CITATION, the molecular mechanism of its resistance to amyloid is still not crystal clear."} {"class.text":"MISC","text":"Here, the aggregation of rIAPP20 29 segments is subjected to the same simulation condition as hIAPP20 29 to explore the non-amyloidogenic properties of the peptide and meanwhile to evaluate the simulation results as a negative control."} {"class.text":"MISC","text":"Due to the metastable and short-lived nature of soluble pre-fibril oligomers at the early steps of fibril formation, experimental data are usually difficult to obtain CITATION, CITATION."} {"class.text":"MISC","text":"Thus, the computational approaches have been employed to complement experimental investigations to gain the insight into the aggregation mechanisms CITATION CITATION."} {"class.text":"MISC","text":"Considering multiple copies of peptides needed due to the self-assembly nature of amyloid formation, various simplified representations of molecular systems using implicit solvent models were preferred rather than all-atom models."} {"class.text":"MISC","text":"Santini et al. performed ART-OPEP simulations on trimer of A 16 22 by treating side chains as a bead and solvent implicitly CITATION."} {"class.text":"MISC","text":"Cheon et al. used ProFASi package to reduce the bonded potential energy to include torsional angles only and treated hydrogen bonds explicitly CITATION."} {"class.text":"MISC","text":"They were able to carry out two series of 100 Monte Carlo simulations on 20 copies of two fragments A 16 22 and A 25 35."} {"class.text":"MISC","text":"They observed early-stage events and obtained an atomic-detailed description of nucleated conformational conversion CITATION model for amyloid aggregation."} {"class.text":"MISC","text":"In these studies, simulations were usually started with randomly oriented, extended or random-coiled peptides which underwent ab initio folding to form -sheet oligomers."} {"class.text":"MISC","text":"Albeit simplified models allow studying large-scale systems CITATION or observing more events in limited simulation time CITATION, all-atom explicit solvent models can reproduce amyloid aggregation in aqueous environment more accurately and supply more information on sidechain contacts CITATION."} {"class.text":"MISC","text":"Nguyen et al. prolonged a series of conventional MD simulations to 300 ns on A 16 22 of 3 6 oligomer size with explicit solvent CITATION."} {"class.text":"MISC","text":"The extensive simulations were able to probe the interpeptide sidechain contacts and large conformational fluctuations upon monomer addition to preformed -sheet oligomers in a dock-lock mechanism."} {"class.text":"OWNX","text":"In our studies, an enhanced-sampling method, replica exchange molecular dynamics CITATION was implemented CITATION, and all water and peptide atoms are treated explicitly by applying OPLS-AA force field CITATION."} {"class.text":"OWNX","text":"The four copies of amyloidogenic segment hIAPP20 29 and an extra dioleoylphosphatidylcholine lipid molecule were initially set in extended conformation and dispersed in simulation boxes."} {"class.text":"OWNX","text":"The formation of -sheet containing tetramers, was observed within 100 ns ab initio REMD folding simulations."} {"class.text":"OWNX","text":"Simulation of four hIAPP peptides without lipid molecule was also performed."} {"class.text":"OWNX","text":"Nonamyloidogenic rat IAPP segments were studied as a negative control with the aim of understanding the inhibitory effect of three proline substitutions."} {"class.text":"MISC","text":"The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20 29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics simulations with explicit solvent model."} {"class.text":"MISC","text":"hIAPP20 29 fragments aggregate into partially ordered -sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel -sheet oligomers in mixed in-register and out-of-register patterns."} {"class.text":"MISC","text":"The hydrophobic interaction between lipid tails and residues at positions 23 25 is found to stabilize the ordered -sheet structure, indicating a catalysis role of lipid molecules in hIAPP20 29 self-assembly."} {"class.text":"MISC","text":"The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies."} {"class.text":"AIMX","text":"Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides."} {"class.text":"MISC","text":"A range of human diseases including Alzheimer's disease, Parkinson's disease, the spongiform encephalopathy and type 2 diabetes mellitus is associated with amyloid deposits of normally soluble proteins or peptides CITATION CITATION."} {"class.text":"MISC","text":"There are convincing evidences that the toxicity of amyloid related diseases may be caused by the soluble intermediate oligomers instead of mature fibrils CITATION CITATION, and the interaction between lipid bilayer and these soluble oligomer CITATION CITATION."} {"class.text":"MISC","text":"For example, channel-like annular structures of oligomers of several amyloidogenic peptides have been observed on the lipid membrane CITATION, CITATION, and have been studied by molecular dynamics simulations as well CITATION, CITATION."} {"class.text":"MISC","text":"Most studies so far treated the lipid bilayer as a template to exert its influences on the conformation and aggregation properties of peptides CITATION CITATION."} {"class.text":"AIMX","text":"It will then be beneficial to understand the molecular details of how single lipid molecule influences the assembly process of amyloidogenic peptides which is the main focus of the current study."} {"class.text":"MISC","text":"Besides the external factors, such as lipid bilayer, pH value, the sequences of peptide themselves have great effects on the aggregation behaviors."} {"class.text":"MISC","text":"Several other species such as non-human primates CITATION, cats CITATION, raccoons CITATION, and rodent species can produce IAPP, but the primary sequence of IAPP varies slightly among species."} {"class.text":"MISC","text":"Importantly, IAPP from rodent species, such as rat/mouse IAPP lose capacities of aggregating into amyloid fibrils CITATION, but transgenic mouse models that express human IAPP develop islet deposits CITATION."} {"class.text":"MISC","text":"The rIAPP differs from hIAPP in six amino acids and five of them are clustered in a short decapeptide, which is considered to be strongly amyloidogenic and forms similar unbranched fibrils itself to the full-length hIAPP CITATION, CITATION."} {"class.text":"MISC","text":"The three proline substitutions in rIAPP20 29 are believed to be highly responsible for the lacking of the amyloidogenic property of the segment or full-length peptide CITATION."} {"class.text":"CONT","text":"Although rIAPP has been intensively applied in experimental research acting as a potential peptide inhibitor for peptide aggregation CITATION, CITATION, the molecular mechanism of its resistance to amyloid is still not crystal clear."} {"class.text":"MISC","text":"Due to the metastable and short-lived nature of soluble pre-fibril oligomers at the early steps of fibril formation, experimental data are usually difficult to obtain CITATION, CITATION."} {"class.text":"OWNX","text":"Thus, the computational approaches have been employed to complement experimental investigations to gain the insight into the aggregation mechanisms CITATION CITATION."} {"class.text":"OWNX","text":"Considering multiple copies of peptides needed due to the self-assembly nature of amyloid formation, various simplified representations of molecular systems using implicit solvent models were preferred rather than all-atom models."} {"class.text":"MISC","text":"Santini et al. performed ART-OPEP simulations on trimer of A 16 22 by treating side chains as a bead and solvent implicitly CITATION."} {"class.text":"MISC","text":"A novel mechanism for single -strand to surmount unnatural registry without dissociation, referred to as reptation was proposed before experimental characterization CITATION."} {"class.text":"MISC","text":"Cheon et al. used ProFASi package to reduce the bonded potential energy to include torsional angles only and treated hydrogen bonds explicitly CITATION."} {"class.text":"MISC","text":"They observed early-stage events and obtained an atomic-detailed description of nucleated conformational conversion CITATION model for amyloid aggregation."} {"class.text":"MISC","text":"Albeit simplified models allow studying large-scale systems CITATION or observing more events in limited simulation time CITATION, all-atom explicit solvent models can reproduce amyloid aggregation in aqueous environment more accurately and supply more information on sidechain contacts CITATION."} {"class.text":"MISC","text":"Nguyen et al. prolonged a series of conventional MD simulations to 300 ns on A 16 22 of 3 6 oligomer size with explicit solvent CITATION."} {"class.text":"MISC","text":"The extensive simulations were able to probe the interpeptide sidechain contacts and large conformational fluctuations upon monomer addition to preformed -sheet oligomers in a dock-lock mechanism."} {"class.text":"OWNX","text":"In our studies, an enhanced-sampling method, replica exchange molecular dynamics CITATION was implemented CITATION, and all water and peptide atoms are treated explicitly by applying OPLS-AA force field CITATION."} {"class.text":"OWNX","text":"The formation of -sheet containing tetramers, was observed within 100 ns ab initio REMD folding simulations."} {"class.text":"OWNX","text":"Simulation of four hIAPP peptides without lipid molecule was also performed."} {"class.text":"OWNX","text":"Nonamyloidogenic rat IAPP segments were studied as a negative control with the aim of understanding the inhibitory effect of three proline substitutions."} {"class.text":"MISC","text":"Numerous psychophysical experiments found that humans preferably rely on a narrow band of spatial frequencies for recognition of face identity."} {"class.text":"OWNX","text":"A recently conducted theoretical study by the author suggests that this frequency preference reflects an adaptation of the brain's face processing machinery to this specific stimulus class."} {"class.text":"OWNX","text":"The purpose of the present study is to examine this property in greater detail and to specifically elucidate the implication of internal face features."} {"class.text":"OWNX","text":"To this end, I parameterized Gabor filters to match the spatial receptive field of contrast sensitive neurons in the primary visual cortex."} {"class.text":"OWNX","text":"Filter responses to a large number of face images were computed, aligned for internal face features, and response-equalized."} {"class.text":"OWNX","text":"The results demonstrate that the frequency preference is caused by internal face features."} {"class.text":"OWNX","text":"Thus, the psychophysically observed human frequency bias for face processing seems to be specifically caused by the intrinsic spatial frequency content of internal face features."} {"class.text":"MISC","text":"Taking advantage of these statistical regularities contributes to an optimal encoding of sensory signals in neuronal responses, in the sense that the code conveys the highest information with respect to specific constraints CITATION CITATION."} {"class.text":"MISC","text":"Among the various constraints which were formulated we find, for example, keeping metabolic energy consumption as low as possible CITATION CITATION, or keeping total wiring length between processing units at a minimum CITATION, or maximizing the suppression of spatio-temporal redundancy in the input signal CITATION, CITATION CITATION ."} {"class.text":"MISC","text":"As for visual stimuli, natural images reveal a conspicuous statistical regularity that comes as an approximately linear decrease of their amplitude spectra as a function of spatial frequency CITATION CITATION."} {"class.text":"MISC","text":"This means that pairs of luminance values are strongly correlated CITATION, and this property could be exploited for gain controlling of visual neurons."} {"class.text":"MISC","text":"According to this response equalization hypothesis, gain should thus be incremented with increasing spatial frequency, such that the distribution of response amplitudes of frequency-tuned neurons to a typical natural image is flat."} {"class.text":"MISC","text":"An argument in favor of employing response equalization is that it would lead to an improvement of information transmission from one neuronal stage to another, because the output of one stage would match the limited dynamic range of a second one CITATION ."} {"class.text":"AIMX","text":"The present article builds upon previously reported results for whitened amplitude spectra of face images CITATION : the whitened spectra reveal a spatial frequency maximum at 10 15 cycles per face, but only if external face features are suppressed."} {"class.text":"BASE","text":"The predicted frequency maximum nevertheless agrees well with numerous psychophysical experiments, which found that face identity is preferably processed in a narrow band of spatial frequencies from 8 to 16 cycles per face CITATION CITATION ."} {"class.text":"MISC","text":"Despite of it all, the results presented in CITATION indicate that the maxima in the amplitude spectra are caused by the compound effect of horizontally oriented internal face features."} {"class.text":"MISC","text":"Quantitatively, the maxima thus occur in units of cycles per face height, whereas most psychophysical studies instead measure their results in terms of cycles per face width."} {"class.text":"MISC","text":"Furthermore, although a clear enhancement of horizontal amplitudes could be observed in the spectra, horizontal amplitudes showed a somewhat noisy dependence on spatial frequency."} {"class.text":"MISC","text":"Both effects are a consequence of that face features were not considered individually, what causes a mixing of the spatial frequency content of individual face features in the spectra."} {"class.text":"MISC","text":"The mixing leads to averaging-out effects such that any possible enhancement of spectral amplitudes at other than the horizontal orientation goes unnoticed, but also may cause interference effects which lead to the mentioned noisy dependence of amplitudes on spatial frequency."} {"class.text":"OWNX","text":"The present study addresses the two issues by means of an extensive analysis of face images by means of Gabor filters."} {"class.text":"OWNX","text":"The filters were thereby parameterized to match the spatial receptive field of band-limited, oriented and contrast sensitive neurons in the primary visual cortex CITATION CITATION."} {"class.text":"OWNX","text":"Great care has been taken to guarantee the correct alignment of filter responses with respect to the position of internal face features prior to their averaging."} {"class.text":"OWNX","text":"Doing so permits to precisely elucidate how the frequency dependence of Gabor responses is related to each of the four internal face features."} {"class.text":"OWNX","text":"The resulting graphs of whitened Gabor amplitudes versus spatial frequency are smooth and reveal distinct maxima at nearly all orientations."} {"class.text":"OWNX","text":"The most stable maxima, however, are observed at horizontal feature orientations in the first place, but also at vertical orientations."} {"class.text":"OWNX","text":"This observation holds true for all of the internal face features."} {"class.text":"MISC","text":"Numerous psychophysical experiments found that humans preferably rely on a narrow band of spatial frequencies for recognition of face identity."} {"class.text":"OWNX","text":"To this end, I parameterized Gabor filters to match the spatial receptive field of contrast sensitive neurons in the primary visual cortex."} {"class.text":"OWNX","text":"The results demonstrate that the frequency preference is caused by internal face features."} {"class.text":"MISC","text":"In the brain, the structure of neuronal circuits for processing sensory information matches the statistical properties of the sensory signals CITATION."} {"class.text":"MISC","text":"Taking advantage of these statistical regularities contributes to an optimal encoding of sensory signals in neuronal responses, in the sense that the code conveys the highest information with respect to specific constraints CITATION CITATION."} {"class.text":"MISC","text":"Among the various constraints which were formulated we find, for example, keeping metabolic energy consumption as low as possible CITATION CITATION, or keeping total wiring length between processing units at a minimum CITATION, or maximizing the suppression of spatio-temporal redundancy in the input signal CITATION, CITATION CITATION ."} {"class.text":"MISC","text":"As for visual stimuli, natural images reveal a conspicuous statistical regularity that comes as an approximately linear decrease of their amplitude spectra as a function of spatial frequency CITATION CITATION."} {"class.text":"MISC","text":"Then, visual neurons would have equal sensitivities or response amplitudes independent of their spatial frequency preference CITATION."} {"class.text":"MISC","text":"According to this response equalization hypothesis, gain should thus be incremented with increasing spatial frequency, such that the distribution of response amplitudes of frequency-tuned neurons to a typical natural image is flat."} {"class.text":"MISC","text":"An argument in favor of employing response equalization is that it would lead to an improvement of information transmission from one neuronal stage to another, because the output of one stage would match the limited dynamic range of a second one CITATION ."} {"class.text":"MISC","text":"The predicted frequency maximum nevertheless agrees well with numerous psychophysical experiments, which found that face identity is preferably processed in a narrow band of spatial frequencies from 8 to 16 cycles per face CITATION CITATION ."} {"class.text":"MISC","text":"Despite of it all, the results presented in CITATION indicate that the maxima in the amplitude spectra are caused by the compound effect of horizontally oriented internal face features."} {"class.text":"MISC","text":"Quantitatively, the maxima thus occur in units of cycles per face height, whereas most psychophysical studies instead measure their results in terms of cycles per face width."} {"class.text":"MISC","text":"Furthermore, although a clear enhancement of horizontal amplitudes could be observed in the spectra, horizontal amplitudes showed a somewhat noisy dependence on spatial frequency."} {"class.text":"MISC","text":"Both effects are a consequence of that face features were not considered individually, what causes a mixing of the spatial frequency content of individual face features in the spectra."} {"class.text":"MISC","text":"The mixing leads to averaging-out effects such that any possible enhancement of spectral amplitudes at other than the horizontal orientation goes unnoticed, but also may cause interference effects which lead to the mentioned noisy dependence of amplitudes on spatial frequency."} {"class.text":"AIMX","text":"The present study addresses the two issues by means of an extensive analysis of face images by means of Gabor filters."} {"class.text":"OWNX","text":"Great care has been taken to guarantee the correct alignment of filter responses with respect to the position of internal face features prior to their averaging."} {"class.text":"OWNX","text":"The resulting graphs of whitened Gabor amplitudes versus spatial frequency are smooth and reveal distinct maxima at nearly all orientations."} {"class.text":"OWNX","text":"The most stable maxima, however, are observed at horizontal feature orientations in the first place, but also at vertical orientations."} {"class.text":"OWNX","text":"This observation holds true for all of the internal face features."} {"class.text":"OWNX","text":"The present study therefore shows how the individual internal face features contribute to the psychophysically observed frequency preference, and proposes concrete mechanisms of how higher amplitudes of whitened cell responses at an early level could possibly lead to the psychophysically measured effects."} {"class.text":"MISC","text":"Numerous psychophysical experiments found that humans preferably rely on a narrow band of spatial frequencies for recognition of face identity."} {"class.text":"MISC","text":"A recently conducted theoretical study by the author suggests that this frequency preference reflects an adaptation of the brain's face processing machinery to this specific stimulus class."} {"class.text":"OWNX","text":"To this end, I parameterized Gabor filters to match the spatial receptive field of contrast sensitive neurons in the primary visual cortex."} {"class.text":"OWNX","text":"Filter responses to a large number of face images were computed, aligned for internal face features, and response-equalized."} {"class.text":"OWNX","text":"The results demonstrate that the frequency preference is caused by internal face features."} {"class.text":"OWNX","text":"Thus, the psychophysically observed human frequency bias for face processing seems to be specifically caused by the intrinsic spatial frequency content of internal face features."} {"class.text":"MISC","text":"In the brain, the structure of neuronal circuits for processing sensory information matches the statistical properties of the sensory signals CITATION."} {"class.text":"MISC","text":"Taking advantage of these statistical regularities contributes to an optimal encoding of sensory signals in neuronal responses, in the sense that the code conveys the highest information with respect to specific constraints CITATION CITATION."} {"class.text":"OWNX","text":"Among the various constraints which were formulated we find, for example, keeping metabolic energy consumption as low as possible CITATION CITATION, or keeping total wiring length between processing units at a minimum CITATION, or maximizing the suppression of spatio-temporal redundancy in the input signal CITATION, CITATION CITATION ."} {"class.text":"MISC","text":"As for visual stimuli, natural images reveal a conspicuous statistical regularity that comes as an approximately linear decrease of their amplitude spectra as a function of spatial frequency CITATION CITATION."} {"class.text":"MISC","text":"This means that pairs of luminance values are strongly correlated CITATION, and this property could be exploited for gain controlling of visual neurons."} {"class.text":"MISC","text":"According to this response equalization hypothesis, gain should thus be incremented with increasing spatial frequency, such that the distribution of response amplitudes of frequency-tuned neurons to a typical natural image is flat."} {"class.text":"MISC","text":"An argument in favor of employing response equalization is that it would lead to an improvement of information transmission from one neuronal stage to another, because the output of one stage would match the limited dynamic range of a second one CITATION ."} {"class.text":"BASE","text":"The present article builds upon previously reported results for whitened amplitude spectra of face images CITATION : the whitened spectra reveal a spatial frequency maximum at 10 15 cycles per face, but only if external face features are suppressed."} {"class.text":"MISC","text":"The predicted frequency maximum nevertheless agrees well with numerous psychophysical experiments, which found that face identity is preferably processed in a narrow band of spatial frequencies from 8 to 16 cycles per face CITATION CITATION ."} {"class.text":"MISC","text":"Despite of it all, the results presented in CITATION indicate that the maxima in the amplitude spectra are caused by the compound effect of horizontally oriented internal face features."} {"class.text":"MISC","text":"Quantitatively, the maxima thus occur in units of cycles per face height, whereas most psychophysical studies instead measure their results in terms of cycles per face width."} {"class.text":"MISC","text":"Furthermore, although a clear enhancement of horizontal amplitudes could be observed in the spectra, horizontal amplitudes showed a somewhat noisy dependence on spatial frequency."} {"class.text":"MISC","text":"Both effects are a consequence of that face features were not considered individually, what causes a mixing of the spatial frequency content of individual face features in the spectra."} {"class.text":"MISC","text":"The mixing leads to averaging-out effects such that any possible enhancement of spectral amplitudes at other than the horizontal orientation goes unnoticed, but also may cause interference effects which lead to the mentioned noisy dependence of amplitudes on spatial frequency."} {"class.text":"AIMX","text":"The present study addresses the two issues by means of an extensive analysis of face images by means of Gabor filters."} {"class.text":"OWNX","text":"Great care has been taken to guarantee the correct alignment of filter responses with respect to the position of internal face features prior to their averaging."} {"class.text":"MISC","text":"Doing so permits to precisely elucidate how the frequency dependence of Gabor responses is related to each of the four internal face features."} {"class.text":"OWNX","text":"The resulting graphs of whitened Gabor amplitudes versus spatial frequency are smooth and reveal distinct maxima at nearly all orientations."} {"class.text":"OWNX","text":"The most stable maxima, however, are observed at horizontal feature orientations in the first place, but also at vertical orientations."} {"class.text":"OWNX","text":"This observation holds true for all of the internal face features."} {"class.text":"MISC","text":"The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli."} {"class.text":"MISC","text":"It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location."} {"class.text":"MISC","text":"These findings have led to the hypothesis that the hippocampus operates using a dual coding system."} {"class.text":"AIMX","text":"We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues."} {"class.text":"BASE","text":"This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology."} {"class.text":"OWNX","text":"Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain."} {"class.text":"MISC","text":"The hippocampus and surrounding medial temporal lobe are implicated in declarative memory function in humans and other mammals CITATION."} {"class.text":"MISC","text":"Electrophysiology studies in a range of species have demonstrated that the activity of single pyramidal cells within this region can encode for the presence of both spatial and non-spatial stimuli CITATION."} {"class.text":"MISC","text":"The majority of empirical investigation has focussed on place cells neurons whose firing rate is directly correlated with an animal's spatial location within the corresponding place field CITATION."} {"class.text":"MISC","text":"Subsequent research has identified similar single cell responses to a variety of non-spatial cues including odour CITATION, complex visual images CITATION, CITATION, CITATION, running speed CITATION and the concept of a bed or nest CITATION."} {"class.text":"MISC","text":"It has also been demonstrated that the exact timing of place cell discharge, relative to the theta oscillation which dominates the hippocampal EEG during learning, correlates with distance travelled through a place field CITATION, CITATION, CITATION CITATION."} {"class.text":"MISC","text":"These findings have led to the hypothesis that the hippocampus operates using a dual rate and temporal coding system CITATION, CITATION."} {"class.text":"OWNX","text":"Here we present a spiking neural network model which utilises a dual coding system in order to encode and recall both symmetric and asymmetric connections between neurons that exhibit repeated synchronous and asynchronous firing patterns respectively."} {"class.text":"MISC","text":"The postulated mnemonic function of the hippocampus has been extensively modelled using recurrent neural networks, and this approach is supported by empirical data CITATION CITATION."} {"class.text":"MISC","text":"The biological correlate of these models is widely believed to be the CA3 region, which exhibits dense recurrent connectivity and wherein synaptic plasticity can be easily and reliably induced."} {"class.text":"MISC","text":"Pharmacological and genetic knockout studies have demonstrated that NMDAr-dependent synaptic plasticity in CA3 is critical for the rapid encoding of novel information, and synaptic output from CA3 critical for its retrieval CITATION, CITATION."} {"class.text":"MISC","text":"Recurrent neural network models of hippocampal mnemonic function have generally utilised rate-coded Hebbian learning rules to generate reciprocal associations between neurons with concurrently elevated firing rates CITATION, CITATION."} {"class.text":"MISC","text":"Hypothetically, this corresponds to the presence of either multiple stimuli or multiple overlapping place fields encountered at a single location CITATION CITATION."} {"class.text":"MISC","text":"The hippocampus is also implicated in sequence learning, and temporally asymmetric plasticity rules have subsequently been employed in recurrent network models to generate hetero-associative connections between neurons that fire with repeated temporal correlation CITATION CITATION."} {"class.text":"MISC","text":"Hypothetically, this corresponds to a sequence of place fields being traversed or stimuli being encountered on a behavioural timescale CITATION."} {"class.text":"MISC","text":"Importantly, previous computational models of hetero-associative learning have typically encoded each successive stage of a learned sequence with the activity of a single neuron, while empirical studies estimate that place fields are typically encoded by an ensemble of several hundred place cells CITATION, CITATION CITATION."} {"class.text":"CONT","text":"No computational model has thus far integrated auto- and hetero- associative learning in order to simultaneously generate both bi-directional and asymmetric connections between neurons that are active at the same and successive theta phases respectively using a single temporally asymmetric synaptic plasticity rule."} {"class.text":"MISC","text":"It is not yet clear if rate-coded auto-associative network models of hippocampal mnemonic function are compatible with STDP or theta coded neural dynamics."} {"class.text":"AIMX","text":"Here, we examine the synaptic dynamics generated by several different STDP rules in a spiking recurrent neural network model of CA3 during the encoding of temporal, rate and dual coded activity patterns created by a phenomenological model of phase precession."} {"class.text":"OWNX","text":"We demonstrate that under certain conditions - the STDP rule can generate both bi-directional connections between neurons which burst at concurrent theta phase and asymmetric connections between neurons which fire at consecutive theta phase."} {"class.text":"OWNX","text":"Interestingly, these neural dynamics are reminiscent of sharp wave ripple activity observed in vivo CITATION CITATION."} {"class.text":"OWNX","text":"These findings demonstrate that STDP and theta coded neural dynamics are compatible with rate-coded auto-associative network models of hippocampal function."} {"class.text":"MISC","text":"It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location."} {"class.text":"OWNX","text":"To investigate the phenomenon of dual coding in the hippocampus, we examine a spiking recurrent network model with theta coded neural dynamics and an STDP rule that mediates rate-coded Hebbian learning when pre- and post-synaptic firing is stochastic."} {"class.text":"AIMX","text":"We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues."} {"class.text":"BASE","text":"This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology."} {"class.text":"OWNX","text":"Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain."} {"class.text":"MISC","text":"The hippocampus and surrounding medial temporal lobe are implicated in declarative memory function in humans and other mammals CITATION."} {"class.text":"MISC","text":"Electrophysiology studies in a range of species have demonstrated that the activity of single pyramidal cells within this region can encode for the presence of both spatial and non-spatial stimuli CITATION."} {"class.text":"MISC","text":"The majority of empirical investigation has focussed on place cells neurons whose firing rate is directly correlated with an animal's spatial location within the corresponding place field CITATION."} {"class.text":"MISC","text":"Subsequent research has identified similar single cell responses to a variety of non-spatial cues including odour CITATION, complex visual images CITATION, CITATION, CITATION, running speed CITATION and the concept of a bed or nest CITATION."} {"class.text":"MISC","text":"It has also been demonstrated that the exact timing of place cell discharge, relative to the theta oscillation which dominates the hippocampal EEG during learning, correlates with distance travelled through a place field CITATION, CITATION, CITATION CITATION."} {"class.text":"OWNX","text":"Here we present a spiking neural network model which utilises a dual coding system in order to encode and recall both symmetric and asymmetric connections between neurons that exhibit repeated synchronous and asynchronous firing patterns respectively."} {"class.text":"MISC","text":"The postulated mnemonic function of the hippocampus has been extensively modelled using recurrent neural networks, and this approach is supported by empirical data CITATION CITATION."} {"class.text":"MISC","text":"The biological correlate of these models is widely believed to be the CA3 region, which exhibits dense recurrent connectivity and wherein synaptic plasticity can be easily and reliably induced."} {"class.text":"MISC","text":"Pharmacological and genetic knockout studies have demonstrated that NMDAr-dependent synaptic plasticity in CA3 is critical for the rapid encoding of novel information, and synaptic output from CA3 critical for its retrieval CITATION, CITATION."} {"class.text":"MISC","text":"Recurrent neural network models of hippocampal mnemonic function have generally utilised rate-coded Hebbian learning rules to generate reciprocal associations between neurons with concurrently elevated firing rates CITATION, CITATION."} {"class.text":"MISC","text":"Hypothetically, this corresponds to a sequence of place fields being traversed or stimuli being encountered on a behavioural timescale CITATION."} {"class.text":"MISC","text":"It is not yet clear if rate-coded auto-associative network models of hippocampal mnemonic function are compatible with STDP or theta coded neural dynamics."} {"class.text":"AIMX","text":"Here, we examine the synaptic dynamics generated by several different STDP rules in a spiking recurrent neural network model of CA3 during the encoding of temporal, rate and dual coded activity patterns created by a phenomenological model of phase precession."} {"class.text":"OWNX","text":"We demonstrate that under certain conditions - the STDP rule can generate both bi-directional connections between neurons which burst at concurrent theta phase and asymmetric connections between neurons which fire at consecutive theta phase."} {"class.text":"OWNX","text":"Subsequent superthreshold stimulation of a small number of simulated neurons generates putative recall activity, driven by recurrent excitation, that corresponds to pattern completion and/or sequence prediction in auto- and/or hetero- associative connections respectively."} {"class.text":"OWNX","text":"These findings demonstrate that STDP and theta coded neural dynamics are compatible with rate-coded auto-associative network models of hippocampal function."} {"class.text":"MISC","text":"The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli."} {"class.text":"MISC","text":"It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location."} {"class.text":"OWNX","text":"We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues."} {"class.text":"OWNX","text":"This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology."} {"class.text":"MISC","text":"Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain."} {"class.text":"MISC","text":"The hippocampus and surrounding medial temporal lobe are implicated in declarative memory function in humans and other mammals CITATION."} {"class.text":"MISC","text":"It has also been demonstrated that the exact timing of place cell discharge, relative to the theta oscillation which dominates the hippocampal EEG during learning, correlates with distance travelled through a place field CITATION, CITATION, CITATION CITATION."} {"class.text":"MISC","text":"These findings have led to the hypothesis that the hippocampus operates using a dual rate and temporal coding system CITATION, CITATION."} {"class.text":"MISC","text":"The postulated mnemonic function of the hippocampus has been extensively modelled using recurrent neural networks, and this approach is supported by empirical data CITATION CITATION."} {"class.text":"MISC","text":"The biological correlate of these models is widely believed to be the CA3 region, which exhibits dense recurrent connectivity and wherein synaptic plasticity can be easily and reliably induced."} {"class.text":"MISC","text":"Pharmacological and genetic knockout studies have demonstrated that NMDAr-dependent synaptic plasticity in CA3 is critical for the rapid encoding of novel information, and synaptic output from CA3 critical for its retrieval CITATION, CITATION."} {"class.text":"MISC","text":"Hypothetically, this corresponds to the presence of either multiple stimuli or multiple overlapping place fields encountered at a single location CITATION CITATION."} {"class.text":"MISC","text":"The hippocampus is also implicated in sequence learning, and temporally asymmetric plasticity rules have subsequently been employed in recurrent network models to generate hetero-associative connections between neurons that fire with repeated temporal correlation CITATION CITATION."} {"class.text":"MISC","text":"Hypothetically, this corresponds to a sequence of place fields being traversed or stimuli being encountered on a behavioural timescale CITATION."} {"class.text":"MISC","text":"Empirical data indicates that changes in the strength of synapses within the hippocampus can depend upon temporal correlations in pre- and post- synaptic firing according to a spike-timing dependent plasticity rule CITATION CITATION."} {"class.text":"MISC","text":"It is not yet clear if rate-coded auto-associative network models of hippocampal mnemonic function are compatible with STDP or theta coded neural dynamics."} {"class.text":"AIMX","text":"Here, we examine the synaptic dynamics generated by several different STDP rules in a spiking recurrent neural network model of CA3 during the encoding of temporal, rate and dual coded activity patterns created by a phenomenological model of phase precession."} {"class.text":"OWNX","text":"We demonstrate that under certain conditions - the STDP rule can generate both bi-directional connections between neurons which burst at concurrent theta phase and asymmetric connections between neurons which fire at consecutive theta phase."} {"class.text":"OWNX","text":"Subsequent superthreshold stimulation of a small number of simulated neurons generates putative recall activity, driven by recurrent excitation, that corresponds to pattern completion and/or sequence prediction in auto- and/or hetero- associative connections respectively."} {"class.text":"MISC","text":"Interestingly, these neural dynamics are reminiscent of sharp wave ripple activity observed in vivo CITATION CITATION."} {"class.text":"OWNX","text":"These findings demonstrate that STDP and theta coded neural dynamics are compatible with rate-coded auto-associative network models of hippocampal function."} {"class.text":"OWNX","text":"Furthermore, the encoding and reactivation of dual coded Hebbian phase sequences of activity in mutually exciting neuronal ensembles demonstrated here has been proposed as a general neural coding mechanism for cognitive processing CITATION, CITATION CITATION ."} {"class.text":"MISC","text":"Metabolic network reconstructions represent valuable scaffolds for -omics data integration and are used to computationally interrogate network properties."} {"class.text":"MISC","text":"However, they do not explicitly account for the synthesis of macromolecules."} {"class.text":"OWNX","text":"Here, we present the first genome-scale, fine-grained reconstruction of Escherichia coli's transcriptional and translational machinery, which produces 423 functional gene products in a sequence-specific manner and accounts for all necessary chemical transformations."} {"class.text":"BASE","text":"Legacy data from over 500 publications and three databases were reviewed, and many pathways were considered, including stable RNA maturation and modification, protein complex formation, and iron sulfur cluster biogenesis."} {"class.text":"OWNX","text":"This reconstruction represents the most comprehensive knowledge base for these important cellular functions in E. coli and is unique in its scope."} {"class.text":"OWNX","text":"Furthermore, it was converted into a mathematical model and used to: quantitatively integrate gene expression data as reaction constraints and compute functional network states, which were compared to reported experimental data."} {"class.text":"OWNX","text":"For example, the model predicted accurately the ribosome production, without any parameterization."} {"class.text":"OWNX","text":"Also, in silico rRNA operon deletion suggested that a high RNA polymerase density on the remaining rRNA operons is needed to reproduce the reported experimental ribosome numbers."} {"class.text":"OWNX","text":"This genome-scale reconstruction of E. coli's transcriptional and translational machinery presents a milestone in systems biology because it will enable quantitative integration of -omics datasets and thus the study of the mechanistic principles underlying the genotype phenotype relationship."} {"class.text":"MISC","text":"High-throughput experimental technologies enable the production of heterogeneous data, such as expression profiles and proteomic data, for almost any organism of interest."} {"class.text":"MISC","text":"A detailed mathematical representation of the in vivo cellular network is required to obtain a holistic understanding of cellular processes from these data sets and to quantitatively integrate them into a biological context."} {"class.text":"MISC","text":"One such approach is the bottom-up network reconstruction, which builds manually networks in a brick-by-brick manner using genome annotation and component-specific information CITATION, CITATION."} {"class.text":"MISC","text":"This reconstruction procedure is well established for metabolic reaction networks and has been applied to many organisms, including Human CITATION, Saccharomyces cerevisiae CITATION, CITATION, Leishmani major CITATION, Escherichia coli CITATION, Helicobacter pylori CITATION, Pseudomonas aeruginosa CITATION, and Pseudomonas putida CITATION, CITATION ."} {"class.text":"MISC","text":"These bottom-up metabolic networks differ from other network reconstructions as they are tailored to the genomic content of the target organism and built manually using biochemical, physiological, and other experimental information in addition to the genome annotation."} {"class.text":"MISC","text":"The reconstruction and modeling procedure is a 4-step process: obtaining a draft reaction list based on genome annotation and biochemical databases, refinement of reaction list using experimental information, conversion of the reaction list into a computable format and application of systems boundaries to define condition-specific models, and the evaluation and validation of the model content using various mathematical methods."} {"class.text":"MISC","text":"By iterating step 2 to 4, reconstructions that are self-consistent within their defined scope can be generated."} {"class.text":"MISC","text":"Metabolic network reconstruction have demonstrated to be useful in at least 5 areas of applications CITATION : biological discovery CITATION, phenotypic behavior CITATION, bacterial evolution CITATION, network analysis CITATION, and metabolic engineering CITATION."} {"class.text":"MISC","text":"This wide range of applications of the metabolic reconstructions is possible because they can be readily converted into predictive, condition-specific models."} {"class.text":"MISC","text":"Unlike more traditional approaches to modeling metabolism, the constraint-based modeling approach requires few, if any, parameters CITATION, CITATION."} {"class.text":"MISC","text":"The stoichiometric information encoded in the reconstruction can be represented mathematically as a stoichiometric matrix, S, where the rows correspond to the components and the columns correspond to the reactions ."} {"class.text":"OWNX","text":"This reconstruction enables quantitative integration of high-throughput data such as gene expression, proteomic, and mRNA degradation data."} {"class.text":"OWNX","text":"Moreover, proteins are produced in high copy numbers in growing cells; thus, any quantitative mechanistic modeling and analysis of high-throughput data needs to account for the synthesis cost associated with these molecules."} {"class.text":"MISC","text":"Numerous studies have been published that investigate protein synthesis using kinetic models CITATION CITATION."} {"class.text":"CONT","text":"These models are generally tailored to the questions they address making it difficult to readily apply them for modified problems."} {"class.text":"MISC","text":"Since stoichiometric relationships are a common requisite for any type of mechanistic modeling, organism-specific BiGG knowledge bases can be used as templates to derive problem-specific, mechanistic models."} {"class.text":"MISC","text":"In fact, network stoichiometry is a dominant feature of kinetic models as well CITATION."} {"class.text":"AIMX","text":"In this study, we present a new generation of network reconstructions, which directly account for the synthesis of individual mRNA and proteins."} {"class.text":"OWNX","text":"We named the mathematical representation of this reconstruction the Expression matrix, or E-matrix, since it encodes the expression of mRNA and proteins."} {"class.text":"OWNX","text":"All network reactions were formulated to account for gene-specific and E. coli-specific details, such as nucleotide composition, operon association, and sigma factor usage."} {"class.text":"OWNX","text":"This reconstruction is the first comprehensive database detailing the available information for these cellular functions and can thus be deemed a knowledge base."} {"class.text":"OWNX","text":"After conversion of the E-matrix reconstruction into condition-specific models corresponding to different doubling times, we were able to accurately predict the ribosome production reported in literature, without any parameterization."} {"class.text":"OWNX","text":"Furthermore, we show that the E-matrix can be used to study the effect of rRNA operon deletion."} {"class.text":"OWNX","text":"Our results predict that a high density of RNA polymerases is required on the remaining rRNA operons, to achieve the reported ribosome numbers."} {"class.text":"OWNX","text":"Finally, we show that proteins used in the E-matrix could be grouped into functional modules which lead to a more simplified view of the network."} {"class.text":"MISC","text":"Metabolic network reconstructions represent valuable scaffolds for -omics data integration and are used to computationally interrogate network properties."} {"class.text":"MISC","text":"However, they do not explicitly account for the synthesis of macromolecules."} {"class.text":"OWNX","text":"Here, we present the first genome-scale, fine-grained reconstruction of Escherichia coli's transcriptional and translational machinery, which produces 423 functional gene products in a sequence-specific manner and accounts for all necessary chemical transformations."} {"class.text":"BASE","text":"Legacy data from over 500 publications and three databases were reviewed, and many pathways were considered, including stable RNA maturation and modification, protein complex formation, and iron sulfur cluster biogenesis."} {"class.text":"OWNX","text":"Furthermore, it was converted into a mathematical model and used to: quantitatively integrate gene expression data as reaction constraints and compute functional network states, which were compared to reported experimental data."} {"class.text":"OWNX","text":"For example, the model predicted accurately the ribosome production, without any parameterization."} {"class.text":"OWNX","text":"Also, in silico rRNA operon deletion suggested that a high RNA polymerase density on the remaining rRNA operons is needed to reproduce the reported experimental ribosome numbers."} {"class.text":"OWNX","text":"Moreover, functional protein modules were determined, and many were found to contain gene products from multiple subsystems, highlighting the functional interaction of these proteins."} {"class.text":"OWNX","text":"This genome-scale reconstruction of E. coli's transcriptional and translational machinery presents a milestone in systems biology because it will enable quantitative integration of -omics datasets and thus the study of the mechanistic principles underlying the genotype phenotype relationship."} {"class.text":"MISC","text":"High-throughput experimental technologies enable the production of heterogeneous data, such as expression profiles and proteomic data, for almost any organism of interest."} {"class.text":"MISC","text":"A detailed mathematical representation of the in vivo cellular network is required to obtain a holistic understanding of cellular processes from these data sets and to quantitatively integrate them into a biological context."} {"class.text":"MISC","text":"One such approach is the bottom-up network reconstruction, which builds manually networks in a brick-by-brick manner using genome annotation and component-specific information CITATION, CITATION."} {"class.text":"MISC","text":"This reconstruction procedure is well established for metabolic reaction networks and has been applied to many organisms, including Human CITATION, Saccharomyces cerevisiae CITATION, CITATION, Leishmani major CITATION, Escherichia coli CITATION, Helicobacter pylori CITATION, Pseudomonas aeruginosa CITATION, and Pseudomonas putida CITATION, CITATION ."} {"class.text":"MISC","text":"These bottom-up metabolic networks differ from other network reconstructions as they are tailored to the genomic content of the target organism and built manually using biochemical, physiological, and other experimental information in addition to the genome annotation."} {"class.text":"MISC","text":"Hence, these reconstructions can be thought of as biochemically, genetically, and genomically structured knowledge bases CITATION."} {"class.text":"MISC","text":"The reconstruction and modeling procedure is a 4-step process: obtaining a draft reaction list based on genome annotation and biochemical databases, refinement of reaction list using experimental information, conversion of the reaction list into a computable format and application of systems boundaries to define condition-specific models, and the evaluation and validation of the model content using various mathematical methods."} {"class.text":"MISC","text":"By iterating step 2 to 4, reconstructions that are self-consistent within their defined scope can be generated."} {"class.text":"MISC","text":"Metabolic network reconstruction have demonstrated to be useful in at least 5 areas of applications CITATION : biological discovery CITATION, phenotypic behavior CITATION, bacterial evolution CITATION, network analysis CITATION, and metabolic engineering CITATION."} {"class.text":"MISC","text":"This wide range of applications of the metabolic reconstructions is possible because they can be readily converted into predictive, condition-specific models."} {"class.text":"MISC","text":"Unlike more traditional approaches to modeling metabolism, the constraint-based modeling approach requires few, if any, parameters CITATION, CITATION."} {"class.text":"MISC","text":"While the COBRA approach has been successfully applied to metabolic networks, the same principles and assumptions can be also employed to reconstruct and model other cellular functions, such as signaling CITATION CITATION, regulation CITATION, and protein synthesis CITATION."} {"class.text":"BASE","text":"In this study, we extended and refined earlier work by Allen et al., which proposed a stoichiometric formalism to model protein synthesis and illustrated it on some E. coli genes and operons CITATION."} {"class.text":"OWNX","text":"We created a more detailed, gene-specific representation of the transcriptional and translational processes, which explicitly accounts for the sequence-specific synthesis of DNA, mRNA, and proteins."} {"class.text":"OWNX","text":"This reconstruction enables quantitative integration of high-throughput data such as gene expression, proteomic, and mRNA degradation data."} {"class.text":"OWNX","text":"Moreover, proteins are produced in high copy numbers in growing cells; thus, any quantitative mechanistic modeling and analysis of high-throughput data needs to account for the synthesis cost associated with these molecules."} {"class.text":"MISC","text":"Numerous studies have been published that investigate protein synthesis using kinetic models CITATION CITATION."} {"class.text":"CONT","text":"These models are generally tailored to the questions they address making it difficult to readily apply them for modified problems."} {"class.text":"MISC","text":"In fact, network stoichiometry is a dominant feature of kinetic models as well CITATION."} {"class.text":"MISC","text":"Thus, network reconstruction serves as a platform for steady-state and kinetic modeling ."} {"class.text":"AIMX","text":"In this study, we present a new generation of network reconstructions, which directly account for the synthesis of individual mRNA and proteins."} {"class.text":"OWNX","text":"Furthermore, we used information from three databases and more than 500 scientific publications to formulate mechanistically detailed and accurate reactions."} {"class.text":"OWNX","text":"This reconstruction is the first comprehensive database detailing the available information for these cellular functions and can thus be deemed a knowledge base."} {"class.text":"OWNX","text":"Furthermore, we show that the E-matrix can be used to study the effect of rRNA operon deletion."} {"class.text":"OWNX","text":"Our results predict that a high density of RNA polymerases is required on the remaining rRNA operons, to achieve the reported ribosome numbers."} {"class.text":"OWNX","text":"Finally, we show that proteins used in the E-matrix could be grouped into functional modules which lead to a more simplified view of the network."} {"class.text":"MISC","text":"Metabolic network reconstructions represent valuable scaffolds for -omics data integration and are used to computationally interrogate network properties."} {"class.text":"CONT","text":"However, they do not explicitly account for the synthesis of macromolecules."} {"class.text":"AIMX","text":"Here, we present the first genome-scale, fine-grained reconstruction of Escherichia coli's transcriptional and translational machinery, which produces 423 functional gene products in a sequence-specific manner and accounts for all necessary chemical transformations."} {"class.text":"OWNX","text":"This reconstruction represents the most comprehensive knowledge base for these important cellular functions in E. coli and is unique in its scope."} {"class.text":"AIMX","text":"Furthermore, it was converted into a mathematical model and used to: quantitatively integrate gene expression data as reaction constraints and compute functional network states, which were compared to reported experimental data."} {"class.text":"OWNX","text":"For example, the model predicted accurately the ribosome production, without any parameterization."} {"class.text":"OWNX","text":"Moreover, functional protein modules were determined, and many were found to contain gene products from multiple subsystems, highlighting the functional interaction of these proteins."} {"class.text":"MISC","text":"High-throughput experimental technologies enable the production of heterogeneous data, such as expression profiles and proteomic data, for almost any organism of interest."} {"class.text":"MISC","text":"A detailed mathematical representation of the in vivo cellular network is required to obtain a holistic understanding of cellular processes from these data sets and to quantitatively integrate them into a biological context."} {"class.text":"MISC","text":"One such approach is the bottom-up network reconstruction, which builds manually networks in a brick-by-brick manner using genome annotation and component-specific information CITATION, CITATION."} {"class.text":"MISC","text":"This reconstruction procedure is well established for metabolic reaction networks and has been applied to many organisms, including Human CITATION, Saccharomyces cerevisiae CITATION, CITATION, Leishmani major CITATION, Escherichia coli CITATION, Helicobacter pylori CITATION, Pseudomonas aeruginosa CITATION, and Pseudomonas putida CITATION, CITATION ."} {"class.text":"MISC","text":"These bottom-up metabolic networks differ from other network reconstructions as they are tailored to the genomic content of the target organism and built manually using biochemical, physiological, and other experimental information in addition to the genome annotation."} {"class.text":"MISC","text":"Hence, these reconstructions can be thought of as biochemically, genetically, and genomically structured knowledge bases CITATION."} {"class.text":"MISC","text":"The reconstruction and modeling procedure is a 4-step process: obtaining a draft reaction list based on genome annotation and biochemical databases, refinement of reaction list using experimental information, conversion of the reaction list into a computable format and application of systems boundaries to define condition-specific models, and the evaluation and validation of the model content using various mathematical methods."} {"class.text":"MISC","text":"By iterating step 2 to 4, reconstructions that are self-consistent within their defined scope can be generated."} {"class.text":"MISC","text":"Metabolic network reconstruction have demonstrated to be useful in at least 5 areas of applications CITATION : biological discovery CITATION, phenotypic behavior CITATION, bacterial evolution CITATION, network analysis CITATION, and metabolic engineering CITATION."} {"class.text":"MISC","text":"This wide range of applications of the metabolic reconstructions is possible because they can be readily converted into predictive, condition-specific models."} {"class.text":"CONT","text":"Unlike more traditional approaches to modeling metabolism, the constraint-based modeling approach requires few, if any, parameters CITATION, CITATION."} {"class.text":"MISC","text":"While the COBRA approach has been successfully applied to metabolic networks, the same principles and assumptions can be also employed to reconstruct and model other cellular functions, such as signaling CITATION CITATION, regulation CITATION, and protein synthesis CITATION."} {"class.text":"BASE","text":"In this study, we extended and refined earlier work by Allen et al., which proposed a stoichiometric formalism to model protein synthesis and illustrated it on some E. coli genes and operons CITATION."} {"class.text":"OWNX","text":"We created a more detailed, gene-specific representation of the transcriptional and translational processes, which explicitly accounts for the sequence-specific synthesis of DNA, mRNA, and proteins."} {"class.text":"OWNX","text":"This reconstruction enables quantitative integration of high-throughput data such as gene expression, proteomic, and mRNA degradation data."} {"class.text":"MISC","text":"Moreover, proteins are produced in high copy numbers in growing cells; thus, any quantitative mechanistic modeling and analysis of high-throughput data needs to account for the synthesis cost associated with these molecules."} {"class.text":"CONT","text":"These models are generally tailored to the questions they address making it difficult to readily apply them for modified problems."} {"class.text":"MISC","text":"Since stoichiometric relationships are a common requisite for any type of mechanistic modeling, organism-specific BiGG knowledge bases can be used as templates to derive problem-specific, mechanistic models."} {"class.text":"MISC","text":"In fact, network stoichiometry is a dominant feature of kinetic models as well CITATION."} {"class.text":"MISC","text":"Thus, network reconstruction serves as a platform for steady-state and kinetic modeling ."} {"class.text":"AIMX","text":"In this study, we present a new generation of network reconstructions, which directly account for the synthesis of individual mRNA and proteins."} {"class.text":"OWNX","text":"We named the mathematical representation of this reconstruction the Expression matrix, or E-matrix, since it encodes the expression of mRNA and proteins."} {"class.text":"OWNX","text":"All network reactions were formulated to account for gene-specific and E. coli-specific details, such as nucleotide composition, operon association, and sigma factor usage."} {"class.text":"OWNX","text":"Furthermore, we used information from three databases and more than 500 scientific publications to formulate mechanistically detailed and accurate reactions."} {"class.text":"OWNX","text":"This reconstruction is the first comprehensive database detailing the available information for these cellular functions and can thus be deemed a knowledge base."} {"class.text":"OWNX","text":"After conversion of the E-matrix reconstruction into condition-specific models corresponding to different doubling times, we were able to accurately predict the ribosome production reported in literature, without any parameterization."} {"class.text":"OWNX","text":"Furthermore, we show that the E-matrix can be used to study the effect of rRNA operon deletion."} {"class.text":"OWNX","text":"Our results predict that a high density of RNA polymerases is required on the remaining rRNA operons, to achieve the reported ribosome numbers."} {"class.text":"OWNX","text":"Finally, we show that proteins used in the E-matrix could be grouped into functional modules which lead to a more simplified view of the network."} {"class.text":"MISC","text":"Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels."} {"class.text":"MISC","text":"While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology."} {"class.text":"OWNX","text":"Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location."} {"class.text":"OWNX","text":"For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability."} {"class.text":"OWNX","text":"Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one."} {"class.text":"OWNX","text":"At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model."} {"class.text":"OWNX","text":"Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites."} {"class.text":"MISC","text":"The appropriate level of physical detail required to understand how complex processes such as cognition and behavior emerge from more simple biological structures is unclear CITATION, CITATION."} {"class.text":"CONT","text":"For example, while it is possible to account for certain aspects of nervous system function using models that represent each neuron as a simple integrate and fire device, it is increasingly clear that this approach does not capture the full range of computations that many real neurons carry out CITATION, CITATION."} {"class.text":"MISC","text":"Dendritic and axonal morphology are defining features of neuronal cell types and have important influences on the computations that a neuron performs CITATION."} {"class.text":"BASE","text":"Cable theory and compartmental modeling provide a foundation for predicting the propagation of electrical signals in the dendrites and axons of neurons CITATION, CITATION."} {"class.text":"MISC","text":"However, while the assumption that transitions between open and closed states of ion channels can be treated as a deterministic process may be sufficient for some purposes, recent evidence suggests that stochastic transitions between the states of individual ion channels could influence computations carried out by neurons CITATION CITATION."} {"class.text":"CONT","text":"While cable theory suggests that fluctuations of this kind might be particularly important in fine structures such as axons and dendrites CITATION, we nevertheless know very little about how neuronal morphology and stochastic gating of ion channels interact to determine how neurons respond to synaptic input."} {"class.text":"MISC","text":"Given the difficulty of reducing detailed morphological models to simple analytical forms that could also incorporate stochastic gating of individual ion channels CITATION, experimentally constrained numerical simulations will be important to enable these issues to be explored systematically."} {"class.text":"CONT","text":"Investigation of stochastic ion channel gating using numerical simulations has been limited by trades-offs between simulation accuracy and computation time CITATION."} {"class.text":"MISC","text":"A simple approach is to add noise sources to deterministic models."} {"class.text":"CONT","text":"However, as ion channels have multiple functional states with transitions that often depend on the membrane voltage CITATION, CITATION, CITATION, CITATION, this may not accurately account for the noise introduced by ion channel currents."} {"class.text":"MISC","text":"A more accurate alternative is to explicitly model transitions between different functional states for each ion channel on a neuron's membrane."} {"class.text":"CONT","text":"However, for neurons with complex axonal or dendritic architectures there are two substantial obstacles to this approach."} {"class.text":"CONT","text":"First, typical central neurons express large numbers of ion channels and simulations must be repeated many times to obtain statistically valid descriptions CITATION."} {"class.text":"CONT","text":"Second, each neuronal ion channel occupies a specific location on the extra-cellular membrane, whereas most neuronal models represent the distribution of ion channels as the density of a deterministic conductance across an area of membrane."} {"class.text":"CONT","text":"Although this formalism has been successful for simulating many aspects of neuronal activity, it is of less use for models that explore the consequences of the localization of individual ion channels, for example to evaluate the macroscopic effects of short range interactions between ion channels and other signaling molecules CITATION, or the consequences of spatially heterogeneous distributions of ion channels within relatively small sub-cellular structures such as dendritic spines and axon terminals CITATION, CITATION ."} {"class.text":"AIMX","text":"To address the functional consequences of stochastic ion channel gating in neurons with extensive dendritic or axonal arborizations we developed a parallel stochastic ion channel simulator, which enables efficient simulation of the electrical activity of neurons with complex morphologies and arbitrary localization of stochastic ion channels on the extracellular membrane, while also addressing limitations of previous approaches."} {"class.text":"OWNX","text":"Here, we illustrate the use of PSICS and ICING, outline the computational strategies used and provide benchmark data for evaluation."} {"class.text":"OWNX","text":"We then identify previously unappreciated differences between the effects of stochastic ion channel gating on somatic and dendritic membrane potential activity in several different morphological classes of neuron."} {"class.text":"OWNX","text":"We show that the consequences of stochastic gating depend on dendritic morphology and suggest novel functional roles for the kinetics of ion channel gating."} {"class.text":"OWNX","text":"We show that stochastic gating of axonal or dendritic ion channels substantially modifies synaptically driven dendritic and axonal spike output, with stochastic gating of voltage-dependent sodium and potassium channels having the greatest impact and hyperpolarization-activated channels the least."} {"class.text":"OWNX","text":"Full documentation for PSICS/ICING as well as the software, source code and examples are available from the project website ."} {"class.text":"MISC","text":"While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology."} {"class.text":"AIMX","text":"We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes."} {"class.text":"OWNX","text":"Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location."} {"class.text":"OWNX","text":"For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability."} {"class.text":"OWNX","text":"Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one."} {"class.text":"OWNX","text":"At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model."} {"class.text":"OWNX","text":"These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments."} {"class.text":"OWNX","text":"Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites."} {"class.text":"MISC","text":"The appropriate level of physical detail required to understand how complex processes such as cognition and behavior emerge from more simple biological structures is unclear CITATION, CITATION."} {"class.text":"CONT","text":"For example, while it is possible to account for certain aspects of nervous system function using models that represent each neuron as a simple integrate and fire device, it is increasingly clear that this approach does not capture the full range of computations that many real neurons carry out CITATION, CITATION."} {"class.text":"MISC","text":"Dendritic and axonal morphology are defining features of neuronal cell types and have important influences on the computations that a neuron performs CITATION."} {"class.text":"MISC","text":"Differences in morphology determine how neurons respond to synaptic input and are sufficient to produce distinct patterns of spontaneous activity CITATION and degrees of action potential back-propagation from the soma into the dendrites CITATION."} {"class.text":"BASE","text":"Cable theory and compartmental modeling provide a foundation for predicting the propagation of electrical signals in the dendrites and axons of neurons CITATION, CITATION."} {"class.text":"MISC","text":"However, while the assumption that transitions between open and closed states of ion channels can be treated as a deterministic process may be sufficient for some purposes, recent evidence suggests that stochastic transitions between the states of individual ion channels could influence computations carried out by neurons CITATION CITATION."} {"class.text":"MISC","text":"Stochastic opening and closing of ion channels causes noisy fluctuations in the current or voltage recorded from a neuron CITATION CITATION."} {"class.text":"CONT","text":"While cable theory suggests that fluctuations of this kind might be particularly important in fine structures such as axons and dendrites CITATION, we nevertheless know very little about how neuronal morphology and stochastic gating of ion channels interact to determine how neurons respond to synaptic input."} {"class.text":"MISC","text":"Given the difficulty of reducing detailed morphological models to simple analytical forms that could also incorporate stochastic gating of individual ion channels CITATION, experimentally constrained numerical simulations will be important to enable these issues to be explored systematically."} {"class.text":"CONT","text":"Investigation of stochastic ion channel gating using numerical simulations has been limited by trades-offs between simulation accuracy and computation time CITATION."} {"class.text":"MISC","text":"A simple approach is to add noise sources to deterministic models."} {"class.text":"CONT","text":"However, as ion channels have multiple functional states with transitions that often depend on the membrane voltage CITATION, CITATION, CITATION, CITATION, this may not accurately account for the noise introduced by ion channel currents."} {"class.text":"MISC","text":"A more accurate alternative is to explicitly model transitions between different functional states for each ion channel on a neuron's membrane."} {"class.text":"CONT","text":"However, for neurons with complex axonal or dendritic architectures there are two substantial obstacles to this approach."} {"class.text":"CONT","text":"This is a formidable computational task and even relatively straightforward simulations of the consequences of stochastic channel gating can require substantial computing time."} {"class.text":"CONT","text":"Second, each neuronal ion channel occupies a specific location on the extra-cellular membrane, whereas most neuronal models represent the distribution of ion channels as the density of a deterministic conductance across an area of membrane."} {"class.text":"CONT","text":"Although this formalism has been successful for simulating many aspects of neuronal activity, it is of less use for models that explore the consequences of the localization of individual ion channels, for example to evaluate the macroscopic effects of short range interactions between ion channels and other signaling molecules CITATION, or the consequences of spatially heterogeneous distributions of ion channels within relatively small sub-cellular structures such as dendritic spines and axon terminals CITATION, CITATION ."} {"class.text":"AIMX","text":"To address the functional consequences of stochastic ion channel gating in neurons with extensive dendritic or axonal arborizations we developed a parallel stochastic ion channel simulator, which enables efficient simulation of the electrical activity of neurons with complex morphologies and arbitrary localization of stochastic ion channels on the extracellular membrane, while also addressing limitations of previous approaches."} {"class.text":"OWNX","text":"We have also developed an interactive tool for visualization and development of models of neurons containing uniquely located ion channels."} {"class.text":"OWNX","text":"Here, we illustrate the use of PSICS and ICING, outline the computational strategies used and provide benchmark data for evaluation."} {"class.text":"OWNX","text":"We then identify previously unappreciated differences between the effects of stochastic ion channel gating on somatic and dendritic membrane potential activity in several different morphological classes of neuron."} {"class.text":"OWNX","text":"We show that the consequences of stochastic gating depend on dendritic morphology and suggest novel functional roles for the kinetics of ion channel gating."} {"class.text":"BASE","text":"Using a previously well-validated realistic model of a CA1 pyramidal neuron we demonstrate that stochastic ion channel gating influences spike output in response to dendritic synaptic input."} {"class.text":"OWNX","text":"We show that stochastic gating of axonal or dendritic ion channels substantially modifies synaptically driven dendritic and axonal spike output, with stochastic gating of voltage-dependent sodium and potassium channels having the greatest impact and hyperpolarization-activated channels the least."} {"class.text":"OWNX","text":"By demonstrating that neuronal responses to dendritic synaptic input can be intrinsically probabilistic, these results offer a new and general perspective on synaptic integration by central neurons."} {"class.text":"OWNX","text":"Full documentation for PSICS/ICING as well as the software, source code and examples are available from the project website ."} {"class.text":"MISC","text":"Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels."} {"class.text":"AIMX","text":"We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes."} {"class.text":"OWNX","text":"Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location."} {"class.text":"MISC","text":"For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability."} {"class.text":"OWNX","text":"Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one."} {"class.text":"OWNX","text":"At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model."} {"class.text":"OWNX","text":"These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments."} {"class.text":"OWNX","text":"Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites."} {"class.text":"MISC","text":"The appropriate level of physical detail required to understand how complex processes such as cognition and behavior emerge from more simple biological structures is unclear CITATION, CITATION."} {"class.text":"MISC","text":"For example, while it is possible to account for certain aspects of nervous system function using models that represent each neuron as a simple integrate and fire device, it is increasingly clear that this approach does not capture the full range of computations that many real neurons carry out CITATION, CITATION."} {"class.text":"MISC","text":"Dendritic and axonal morphology are defining features of neuronal cell types and have important influences on the computations that a neuron performs CITATION."} {"class.text":"MISC","text":"Differences in morphology determine how neurons respond to synaptic input and are sufficient to produce distinct patterns of spontaneous activity CITATION and degrees of action potential back-propagation from the soma into the dendrites CITATION."} {"class.text":"MISC","text":"Cable theory and compartmental modeling provide a foundation for predicting the propagation of electrical signals in the dendrites and axons of neurons CITATION, CITATION."} {"class.text":"MISC","text":"Stochastic opening and closing of ion channels causes noisy fluctuations in the current or voltage recorded from a neuron CITATION CITATION."} {"class.text":"CONT","text":"While cable theory suggests that fluctuations of this kind might be particularly important in fine structures such as axons and dendrites CITATION, we nevertheless know very little about how neuronal morphology and stochastic gating of ion channels interact to determine how neurons respond to synaptic input."} {"class.text":"MISC","text":"Given the difficulty of reducing detailed morphological models to simple analytical forms that could also incorporate stochastic gating of individual ion channels CITATION, experimentally constrained numerical simulations will be important to enable these issues to be explored systematically."} {"class.text":"CONT","text":"Investigation of stochastic ion channel gating using numerical simulations has been limited by trades-offs between simulation accuracy and computation time CITATION."} {"class.text":"MISC","text":"A simple approach is to add noise sources to deterministic models."} {"class.text":"CONT","text":"However, as ion channels have multiple functional states with transitions that often depend on the membrane voltage CITATION, CITATION, CITATION, CITATION, this may not accurately account for the noise introduced by ion channel currents."} {"class.text":"MISC","text":"A more accurate alternative is to explicitly model transitions between different functional states for each ion channel on a neuron's membrane."} {"class.text":"CONT","text":"However, for neurons with complex axonal or dendritic architectures there are two substantial obstacles to this approach."} {"class.text":"CONT","text":"This is a formidable computational task and even relatively straightforward simulations of the consequences of stochastic channel gating can require substantial computing time."} {"class.text":"CONT","text":"Second, each neuronal ion channel occupies a specific location on the extra-cellular membrane, whereas most neuronal models represent the distribution of ion channels as the density of a deterministic conductance across an area of membrane."} {"class.text":"CONT","text":"Although this formalism has been successful for simulating many aspects of neuronal activity, it is of less use for models that explore the consequences of the localization of individual ion channels, for example to evaluate the macroscopic effects of short range interactions between ion channels and other signaling molecules CITATION, or the consequences of spatially heterogeneous distributions of ion channels within relatively small sub-cellular structures such as dendritic spines and axon terminals CITATION, CITATION ."} {"class.text":"AIMX","text":"To address the functional consequences of stochastic ion channel gating in neurons with extensive dendritic or axonal arborizations we developed a parallel stochastic ion channel simulator, which enables efficient simulation of the electrical activity of neurons with complex morphologies and arbitrary localization of stochastic ion channels on the extracellular membrane, while also addressing limitations of previous approaches."} {"class.text":"OWNX","text":"Here, we illustrate the use of PSICS and ICING, outline the computational strategies used and provide benchmark data for evaluation."} {"class.text":"OWNX","text":"We then identify previously unappreciated differences between the effects of stochastic ion channel gating on somatic and dendritic membrane potential activity in several different morphological classes of neuron."} {"class.text":"OWNX","text":"We show that the consequences of stochastic gating depend on dendritic morphology and suggest novel functional roles for the kinetics of ion channel gating."} {"class.text":"BASE","text":"Using a previously well-validated realistic model of a CA1 pyramidal neuron we demonstrate that stochastic ion channel gating influences spike output in response to dendritic synaptic input."} {"class.text":"OWNX","text":"We show that stochastic gating of axonal or dendritic ion channels substantially modifies synaptically driven dendritic and axonal spike output, with stochastic gating of voltage-dependent sodium and potassium channels having the greatest impact and hyperpolarization-activated channels the least."} {"class.text":"OWNX","text":"By demonstrating that neuronal responses to dendritic synaptic input can be intrinsically probabilistic, these results offer a new and general perspective on synaptic integration by central neurons."} {"class.text":"MISC","text":"Alternative splicing contributes to both gene regulation and protein diversity."} {"class.text":"AIMX","text":"To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome."} {"class.text":"OWNX","text":"In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40 percent of the 6,216 alternative events we could detect."} {"class.text":"OWNX","text":"Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle."} {"class.text":"OWNX","text":"By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation."} {"class.text":"OWNX","text":"Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5 splice site of exons included in muscle."} {"class.text":"OWNX","text":"Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern."} {"class.text":"OWNX","text":"While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families."} {"class.text":"MISC","text":"Splicing is an essential process that constructs protein coding messenger RNA sequences using tiny segments of information buried in the much larger primary transcripts of the eukaryotic gene."} {"class.text":"MISC","text":"Splicing patterns seem distinct in the vertebrate nervous system compared to other tissues CITATION, CITATION, and it is tempting to hypothesize that neural alternative splicing contributed to the rapid evolution of the vertebrate brain without large increases in gene number CITATION ."} {"class.text":"MISC","text":"Biochemical analysis of alternative splicing has shown that numerous RNA binding proteins influence the use of specific splice sites to stimulate splicing events that lead to particular mRNA isoforms CITATION, CITATION."} {"class.text":"MISC","text":"These RNA binding proteins may activate or repress the use of splice sites by binding to nearby sequences in the exon or in the intron."} {"class.text":"MISC","text":"In many cases, multiple RNA binding proteins combine to create repressing and activating influences that produce patterns of splicing control CITATION, CITATION."} {"class.text":"MISC","text":"Some proteins, such as SR proteins and the CELF proteins, have mostly activating roles, whereas others, such as hnRNP A1, PTB, and nPTB, have mostly repressing roles."} {"class.text":"MISC","text":"Certain proteins can either activate or repress splicing in different contexts, depending on the position of their binding sites or the expression of other RNA binding proteins CITATION, CITATION ."} {"class.text":"MISC","text":"A complete catalog of the RNA sequences corresponding to the enhancers and silencers bound by splicing regulatory proteins would greatly aid the understanding of splicing regulatory networks."} {"class.text":"MISC","text":"Thus far, there are only a handful of splicing regulators whose corresponding RNA binding motifs have been identified, whereas there may be many splicing regulators among the hundreds of RNA binding proteins encoded by the mouse genome."} {"class.text":"MISC","text":"Adding to this complexity is the tendency for the mRNAs of RNA binding proteins to be alternatively spliced, leading to multiple RNA binding protein isoforms with potentially different functions."} {"class.text":"CONT","text":"Currently, the methods available for expanding the list of known regulators and their target sequences are limited, and the development of this catalog is in the early stage CITATION ."} {"class.text":"MISC","text":"Much of the available genomic information on alternative splicing is derived by the alignment of large numbers of expressed sequence tags and messenger RNAs to genome sequences."} {"class.text":"MISC","text":"The analysis of exons that appear to be constitutive or alternative has led to the successful identification of many distinguishing features of alternatively spliced regions CITATION CITATION, even allowing their accurate prediction without cDNA evidence CITATION, CITATION, CITATION."} {"class.text":"CONT","text":"Although cDNA libraries have been invaluable for discovering general features of alternatively spliced exons, it is difficult to connect specific regulatory sequences to specific biological conditions with confidence due to variable and sometimes missing information about the source materials and methods of cDNA library construction."} {"class.text":"CONT","text":"The relatively low number of transcripts present from any one gene also makes it difficult to estimate differences in expression levels using library representation as a measure."} {"class.text":"MISC","text":"Thus, more direct methods are needed to associate alternative splicing events with underlying biological conditions."} {"class.text":"MISC","text":"The recent application of microarray technology to questions of splicing and splicing regulation promises to reveal parallel connections between many splicing events and specific biological or experimental conditions CITATION CITATION."} {"class.text":"MISC","text":"Analysis of experimental changes in splicing for many genes simultaneously should reveal biological conditions necessary for proper splicing regulation in a way that analysis of cDNA libraries cannot, and with breadth that cannot be achieved by analysis of a reporter construct or a few endogenous target genes."} {"class.text":"OWNX","text":"To demonstrate this, we constructed a DNA microarray designed to capture splicing information for about 6,200 alternative events in the mouse transcriptome, using a combination of splice junction and exon probes, and have hybridized RNA from 22 adult mouse tissues."} {"class.text":"AIMX","text":"We examine splicing in these tissues by asking three questions."} {"class.text":"OWNX","text":"First we ask, Which RNA isoforms are present in a particular tissue sample?"} {"class.text":"OWNX","text":"To answer this simple question, we used a new method based on comparing the intensity of the probes in a probe set to the distribution of intensities from all probes with similar G C level."} {"class.text":"BASE","text":"This is similar in spirit although different in approach to the present-absent calls from Affymetrix MAS 5.0 algorithms CITATION, as this microarray did not contain mismatch probes."} {"class.text":"OWNX","text":"Using RT-PCR, we show that this method has a true-positive rate of 85 percent."} {"class.text":"OWNX","text":"Second we ask, Which RNA isoforms are differentially expressed across the tissues examined?"} {"class.text":"BASE","text":"For each RNA isoform, the intensities of the isoform-specific junction probes were examined across tissues using the Kruskal-Wallis statistical test."} {"class.text":"OWNX","text":"After correcting for multiple testing, about 40 percent of the 6,216 total alternative splicing events examined were found to have more than one RNA form that was differentially expressed, indicating widespread tissue differences in splicing over the tissues."} {"class.text":"OWNX","text":"To answer this, we used a regression-based bootstrapping method, which also allows an estimate of the relative change in skipping and inclusion in the two sample groups."} {"class.text":"OWNX","text":"We analyzed the intron sequences associated with exon skipping events that are differentially regulated in brain or muscle relative to other tissues and found unusual patterns of sequence conservation that provide new information about tissue regulation of alternative splicing and its evolution."} {"class.text":"AIMX","text":"To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome."} {"class.text":"OWNX","text":"In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40 percent of the 6,216 alternative events we could detect."} {"class.text":"OWNX","text":"A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons."} {"class.text":"OWNX","text":"By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation."} {"class.text":"OWNX","text":"Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5 splice site of exons included in muscle."} {"class.text":"OWNX","text":"Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern."} {"class.text":"OWNX","text":"While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families."} {"class.text":"MISC","text":"Regulated alternative splicing can create different protein coding sequences under different biological circumstances, allowing the production of functionally related but distinct proteins."} {"class.text":"MISC","text":"In addition, alternative splicing can mediate the repression of gene expression by stimulating the formation of transcripts subject to nonsense-mediated decay CITATION CITATION."} {"class.text":"MISC","text":"Splicing patterns seem distinct in the vertebrate nervous system compared to other tissues CITATION, CITATION, and it is tempting to hypothesize that neural alternative splicing contributed to the rapid evolution of the vertebrate brain without large increases in gene number CITATION ."} {"class.text":"MISC","text":"Biochemical analysis of alternative splicing has shown that numerous RNA binding proteins influence the use of specific splice sites to stimulate splicing events that lead to particular mRNA isoforms CITATION, CITATION."} {"class.text":"MISC","text":"These RNA binding proteins may activate or repress the use of splice sites by binding to nearby sequences in the exon or in the intron."} {"class.text":"MISC","text":"Some proteins, such as SR proteins and the CELF proteins, have mostly activating roles, whereas others, such as hnRNP A1, PTB, and nPTB, have mostly repressing roles."} {"class.text":"MISC","text":"Certain proteins can either activate or repress splicing in different contexts, depending on the position of their binding sites or the expression of other RNA binding proteins CITATION, CITATION ."} {"class.text":"MISC","text":"A complete catalog of the RNA sequences corresponding to the enhancers and silencers bound by splicing regulatory proteins would greatly aid the understanding of splicing regulatory networks."} {"class.text":"MISC","text":"In addition, several related but distinct genes produce proteins that bind the same or overlapping sets of sequences; for example, Fox-1 and RBM9 each bind UGCAUG CITATION, CITATION, and the branchpoint binding protein SF1 and the protein quaking each bind UACUAAC-like motifs CITATION CITATION."} {"class.text":"CONT","text":"Currently, the methods available for expanding the list of known regulators and their target sequences are limited, and the development of this catalog is in the early stage CITATION ."} {"class.text":"MISC","text":"Much of the available genomic information on alternative splicing is derived by the alignment of large numbers of expressed sequence tags and messenger RNAs to genome sequences."} {"class.text":"MISC","text":"The analysis of exons that appear to be constitutive or alternative has led to the successful identification of many distinguishing features of alternatively spliced regions CITATION CITATION, even allowing their accurate prediction without cDNA evidence CITATION, CITATION, CITATION."} {"class.text":"CONT","text":"Although cDNA libraries have been invaluable for discovering general features of alternatively spliced exons, it is difficult to connect specific regulatory sequences to specific biological conditions with confidence due to variable and sometimes missing information about the source materials and methods of cDNA library construction."} {"class.text":"CONT","text":"The relatively low number of transcripts present from any one gene also makes it difficult to estimate differences in expression levels using library representation as a measure."} {"class.text":"MISC","text":"Thus, more direct methods are needed to associate alternative splicing events with underlying biological conditions."} {"class.text":"MISC","text":"The recent application of microarray technology to questions of splicing and splicing regulation promises to reveal parallel connections between many splicing events and specific biological or experimental conditions CITATION CITATION."} {"class.text":"MISC","text":"Analysis of experimental changes in splicing for many genes simultaneously should reveal biological conditions necessary for proper splicing regulation in a way that analysis of cDNA libraries cannot, and with breadth that cannot be achieved by analysis of a reporter construct or a few endogenous target genes."} {"class.text":"OWNX","text":"To demonstrate this, we constructed a DNA microarray designed to capture splicing information for about 6,200 alternative events in the mouse transcriptome, using a combination of splice junction and exon probes, and have hybridized RNA from 22 adult mouse tissues."} {"class.text":"OWNX","text":"First we ask, Which RNA isoforms are present in a particular tissue sample?"} {"class.text":"OWNX","text":"To answer this simple question, we used a new method based on comparing the intensity of the probes in a probe set to the distribution of intensities from all probes with similar G C level."} {"class.text":"BASE","text":"This is similar in spirit although different in approach to the present-absent calls from Affymetrix MAS 5.0 algorithms CITATION, as this microarray did not contain mismatch probes."} {"class.text":"OWNX","text":"Second we ask, Which RNA isoforms are differentially expressed across the tissues examined?"} {"class.text":"BASE","text":"For each RNA isoform, the intensities of the isoform-specific junction probes were examined across tissues using the Kruskal-Wallis statistical test."} {"class.text":"OWNX","text":"Third we ask, Which cassette exons are included differentially between brain and nonbrain tissues?"} {"class.text":"OWNX","text":"To answer this, we used a regression-based bootstrapping method, which also allows an estimate of the relative change in skipping and inclusion in the two sample groups."} {"class.text":"OWNX","text":"We analyzed the intron sequences associated with exon skipping events that are differentially regulated in brain or muscle relative to other tissues and found unusual patterns of sequence conservation that provide new information about tissue regulation of alternative splicing and its evolution."} {"class.text":"MISC","text":"Alternative splicing contributes to both gene regulation and protein diversity."} {"class.text":"AIMX","text":"To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome."} {"class.text":"OWNX","text":"Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle."} {"class.text":"OWNX","text":"A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons."} {"class.text":"OWNX","text":"By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation."} {"class.text":"OWNX","text":"Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5 splice site of exons included in muscle."} {"class.text":"OWNX","text":"Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern."} {"class.text":"MISC","text":"Splicing is an essential process that constructs protein coding messenger RNA sequences using tiny segments of information buried in the much larger primary transcripts of the eukaryotic gene."} {"class.text":"MISC","text":"Regulated alternative splicing can create different protein coding sequences under different biological circumstances, allowing the production of functionally related but distinct proteins."} {"class.text":"MISC","text":"Splicing patterns seem distinct in the vertebrate nervous system compared to other tissues CITATION, CITATION, and it is tempting to hypothesize that neural alternative splicing contributed to the rapid evolution of the vertebrate brain without large increases in gene number CITATION ."} {"class.text":"MISC","text":"Biochemical analysis of alternative splicing has shown that numerous RNA binding proteins influence the use of specific splice sites to stimulate splicing events that lead to particular mRNA isoforms CITATION, CITATION."} {"class.text":"MISC","text":"These RNA binding proteins may activate or repress the use of splice sites by binding to nearby sequences in the exon or in the intron."} {"class.text":"MISC","text":"In many cases, multiple RNA binding proteins combine to create repressing and activating influences that produce patterns of splicing control CITATION, CITATION."} {"class.text":"MISC","text":"Certain proteins can either activate or repress splicing in different contexts, depending on the position of their binding sites or the expression of other RNA binding proteins CITATION, CITATION ."} {"class.text":"MISC","text":"A complete catalog of the RNA sequences corresponding to the enhancers and silencers bound by splicing regulatory proteins would greatly aid the understanding of splicing regulatory networks."} {"class.text":"MISC","text":"Thus far, there are only a handful of splicing regulators whose corresponding RNA binding motifs have been identified, whereas there may be many splicing regulators among the hundreds of RNA binding proteins encoded by the mouse genome."} {"class.text":"MISC","text":"Adding to this complexity is the tendency for the mRNAs of RNA binding proteins to be alternatively spliced, leading to multiple RNA binding protein isoforms with potentially different functions."} {"class.text":"CONT","text":"Currently, the methods available for expanding the list of known regulators and their target sequences are limited, and the development of this catalog is in the early stage CITATION ."} {"class.text":"MISC","text":"Much of the available genomic information on alternative splicing is derived by the alignment of large numbers of expressed sequence tags and messenger RNAs to genome sequences."} {"class.text":"CONT","text":"Although cDNA libraries have been invaluable for discovering general features of alternatively spliced exons, it is difficult to connect specific regulatory sequences to specific biological conditions with confidence due to variable and sometimes missing information about the source materials and methods of cDNA library construction."} {"class.text":"CONT","text":"The relatively low number of transcripts present from any one gene also makes it difficult to estimate differences in expression levels using library representation as a measure."} {"class.text":"CONT","text":"Thus, more direct methods are needed to associate alternative splicing events with underlying biological conditions."} {"class.text":"CONT","text":"Analysis of experimental changes in splicing for many genes simultaneously should reveal biological conditions necessary for proper splicing regulation in a way that analysis of cDNA libraries cannot, and with breadth that cannot be achieved by analysis of a reporter construct or a few endogenous target genes."} {"class.text":"AIMX","text":"To demonstrate this, we constructed a DNA microarray designed to capture splicing information for about 6,200 alternative events in the mouse transcriptome, using a combination of splice junction and exon probes, and have hybridized RNA from 22 adult mouse tissues."} {"class.text":"AIMX","text":"We examine splicing in these tissues by asking three questions."} {"class.text":"OWNX","text":"First we ask, Which RNA isoforms are present in a particular tissue sample?"} {"class.text":"OWNX","text":"To answer this simple question, we used a new method based on comparing the intensity of the probes in a probe set to the distribution of intensities from all probes with similar G C level."} {"class.text":"BASE","text":"This is similar in spirit although different in approach to the present-absent calls from Affymetrix MAS 5.0 algorithms CITATION, as this microarray did not contain mismatch probes."} {"class.text":"OWNX","text":"Second we ask, Which RNA isoforms are differentially expressed across the tissues examined?"} {"class.text":"OWNX","text":"After correcting for multiple testing, about 40 percent of the 6,216 total alternative splicing events examined were found to have more than one RNA form that was differentially expressed, indicating widespread tissue differences in splicing over the tissues."} {"class.text":"OWNX","text":"Third we ask, Which cassette exons are included differentially between brain and nonbrain tissues?"} {"class.text":"OWNX","text":"To answer this, we used a regression-based bootstrapping method, which also allows an estimate of the relative change in skipping and inclusion in the two sample groups."} {"class.text":"OWNX","text":"We analyzed the intron sequences associated with exon skipping events that are differentially regulated in brain or muscle relative to other tissues and found unusual patterns of sequence conservation that provide new information about tissue regulation of alternative splicing and its evolution."} {"class.text":"MISC","text":"Recently, a new class of antiretroviral drugs has entered clinical practice that specifically bind to the co-receptor CCR5, and thus inhibit virus entry."} {"class.text":"MISC","text":"Accurate prediction of the co-receptor used by the virus in the patient is important as it allows for personalized selection of effective drugs and prognosis of disease progression."} {"class.text":"OWNX","text":"The two-level method predicts usage of CXCR4 co-receptor for new V3 sequences within seconds, with an area under the ROC curve of 0.937 0.004."} {"class.text":"OWNX","text":"For instance, it quantifies the importance for co-receptor usage of a pocket that probably is responsible for binding sulfated tyrosine."} {"class.text":"MISC","text":"Specific protein interactions are central to biological processes, and the infection of cells with viruses is no exception there."} {"class.text":"MISC","text":"In the case of pathogenic viruses, such protein interactions are potential targets for medical intervention."} {"class.text":"MISC","text":"An example of particularly high relevance is Human Immunodeficiency Virus 1."} {"class.text":"MISC","text":"HIV-1 enters human cells in a process that comprises several steps, including the binding of the viral gp120 protein to the cellular receptor protein CD4 and a co-receptor protein, usually one of the two chemokine receptors CCR5 and CXCR4 CITATION."} {"class.text":"MISC","text":"The type of co-receptor used by the virus, the so-called co-receptor tropism, has a prognostic value, since patients with a CXCR4-tropic virus progress faster to Acquired Immunodeficiency Syndrome compared to patients with a CCR5-tropic virus CITATION."} {"class.text":"MISC","text":"In addition to the purely X4- and R5-tropic viruses, there are also dual-tropic strains, able to use both co-receptors."} {"class.text":"MISC","text":"This has made the determination of co-receptor tropism directly relevant to anti-retroviral treatment, as CCR5-inhibitors are of course inactive against X4 virus."} {"class.text":"MISC","text":"The standard way of determining co-receptor tropism is by cell-based assays CITATION, CITATION."} {"class.text":"CONT","text":"The main drawbacks of these assays are that they are currently only carried out by a handful of specialized laboratories worldwide, and that the overall procedure typically takes several weeks."} {"class.text":"MISC","text":"This is a relatively fast and cheap standard procedure established in many clinics."} {"class.text":"MISC","text":"At first glance, genotypic testing for co-receptor tropism seems to be possible since the main molecular determinant of tropism is known to be the third variable loop of the viral glycoprotein gp120 CITATION, a peptide stretch of about 35 amino-acids with a disulfide bridge connecting the terminal cysteins."} {"class.text":"CONT","text":"Unfortunately, as suggested by its name, V3 is notorious for its high sequence variability CITATION including also some variability in length, and this has made it difficult to use it as a basis for genotypic co-receptor tropism testing."} {"class.text":"MISC","text":"Nevertheless, the relevance of the quest has prompted many groups to develop models that link properties of V3 to co-receptor tropism."} {"class.text":"MISC","text":"The importance of electrostatics for co-receptor tropism has been recognized early on, and the best-known model, the so-called 11/25-rule, refers to charges of V3-residues 11 and 25: if one of these is positive, then the virus is CXCR4-tropic CITATION, CITATION."} {"class.text":"MISC","text":"This rule has a specificity of more than 0.9, but only a low to moderate sensitivity of about 0.4 0.6, depending on the test data, which is not satisfactory for routine clinical application."} {"class.text":"CONT","text":"Still, prediction accuracies fall short of what seems reasonable for regular clinical use CITATION."} {"class.text":"MISC","text":"It is unclear whether the limited accuracies are the footprint of tropism-determinants outside V3, or the consequence of model imperfections."} {"class.text":"MISC","text":"A milestone for the understanding of co-receptor tropism was the X-ray structure of gp120 with the V3 loop in a biological context CITATION."} {"class.text":"MISC","text":"This paved the way for the development of prediction methods that use, in addition to V3 sequence, structural information."} {"class.text":"MISC","text":"To our knowledge, the first of these methods has been that of Sander et al. CITATION, which was mainly based on geometric distances of amino-acid pairs within the structure of V3."} {"class.text":"OWNX","text":"By the latter we consider a seemingly trivial but fundamental fact that so far has not been thoroughly exploited: although V3 is highly variable, all X4-tropic V3 loops share one property, namely, they preferentially have a physical binding interaction with CXCR4, while R5-tropic V3 loops preferably interacts with CCR5."} {"class.text":"MISC","text":"Human Immunodeficiency Virus 1 uses for entry into host cells a receptor and one of two co-receptors."} {"class.text":"MISC","text":"Recently, a new class of antiretroviral drugs has entered clinical practice that specifically bind to the co-receptor CCR5, and thus inhibit virus entry."} {"class.text":"AIMX","text":"We have investigated whether it is possible to predict co-receptor usage accurately by analyzing the amino acid sequence of the main determinant of co-receptor usage, i.e., the third variable loop V3 of the gp120 protein."} {"class.text":"OWNX","text":"We developed a two-level machine learning approach that in the first level considers two different properties important for protein-protein binding derived from structural models of V3 and V3 sequences."} {"class.text":"OWNX","text":"The second level combines the two predictions of the first level."} {"class.text":"OWNX","text":"The two-level method predicts usage of CXCR4 co-receptor for new V3 sequences within seconds, with an area under the ROC curve of 0.937 0.004."} {"class.text":"OWNX","text":"Moreover, it is relatively robust against insertions and deletions, which frequently occur in V3."} {"class.text":"OWNX","text":"The approach could help clinicians to find optimal personalized treatments, and it offers new insights into the molecular basis of co-receptor usage."} {"class.text":"MISC","text":"Specific protein interactions are central to biological processes, and the infection of cells with viruses is no exception there."} {"class.text":"MISC","text":"In the case of pathogenic viruses, such protein interactions are potential targets for medical intervention."} {"class.text":"MISC","text":"An example of particularly high relevance is Human Immunodeficiency Virus 1."} {"class.text":"MISC","text":"HIV-1 enters human cells in a process that comprises several steps, including the binding of the viral gp120 protein to the cellular receptor protein CD4 and a co-receptor protein, usually one of the two chemokine receptors CCR5 and CXCR4 CITATION."} {"class.text":"MISC","text":"The type of co-receptor used by the virus, the so-called co-receptor tropism, has a prognostic value, since patients with a CXCR4-tropic virus progress faster to Acquired Immunodeficiency Syndrome compared to patients with a CCR5-tropic virus CITATION."} {"class.text":"MISC","text":"In addition to the purely X4- and R5-tropic viruses, there are also dual-tropic strains, able to use both co-receptors."} {"class.text":"MISC","text":"Recently, the first drug that binds to CCR5, and thus inhibits productive binding of gp120, has been approved by regulatory authorities in several countries."} {"class.text":"MISC","text":"This has made the determination of co-receptor tropism directly relevant to anti-retroviral treatment, as CCR5-inhibitors are of course inactive against X4 virus."} {"class.text":"MISC","text":"The standard way of determining co-receptor tropism is by cell-based assays CITATION, CITATION."} {"class.text":"CONT","text":"The main drawbacks of these assays are that they are currently only carried out by a handful of specialized laboratories worldwide, and that the overall procedure typically takes several weeks."} {"class.text":"MISC","text":"These impediments to the wide application of entry inhibitors could be overcome by an approach similar to genotypic drug resistance testing CITATION, where drug resistance of a viral strain is inferred from comparison of mutational patterns obtained from sequencing parts of the genome of that strain with patterns of validated resistance mutations."} {"class.text":"MISC","text":"This is a relatively fast and cheap standard procedure established in many clinics."} {"class.text":"MISC","text":"At first glance, genotypic testing for co-receptor tropism seems to be possible since the main molecular determinant of tropism is known to be the third variable loop of the viral glycoprotein gp120 CITATION, a peptide stretch of about 35 amino-acids with a disulfide bridge connecting the terminal cysteins."} {"class.text":"MISC","text":"Nevertheless, the relevance of the quest has prompted many groups to develop models that link properties of V3 to co-receptor tropism."} {"class.text":"MISC","text":"The importance of electrostatics for co-receptor tropism has been recognized early on, and the best-known model, the so-called 11/25-rule, refers to charges of V3-residues 11 and 25: if one of these is positive, then the virus is CXCR4-tropic CITATION, CITATION."} {"class.text":"MISC","text":"To improve predictions from sequence, several groups have applied machine learning methods, such as artificial neural networks CITATION, position specific scoring matrices CITATION, decision trees, or support vector machines CITATION."} {"class.text":"CONT","text":"Still, prediction accuracies fall short of what seems reasonable for regular clinical use CITATION."} {"class.text":"MISC","text":"It is unclear whether the limited accuracies are the footprint of tropism-determinants outside V3, or the consequence of model imperfections."} {"class.text":"MISC","text":"A milestone for the understanding of co-receptor tropism was the X-ray structure of gp120 with the V3 loop in a biological context CITATION."} {"class.text":"MISC","text":"This paved the way for the development of prediction methods that use, in addition to V3 sequence, structural information."} {"class.text":"BASE","text":"Although our method, detailed in the following, relies on the same experimental structure by Huang et al. CITATION, it differs from that of Sander et al. in several respects, e.g. it deals with indels, and, perhaps most crucially, it uses as descriptors properties that directly determine interaction of V3 with the co-receptors."} {"class.text":"OWNX","text":"By the latter we consider a seemingly trivial but fundamental fact that so far has not been thoroughly exploited: although V3 is highly variable, all X4-tropic V3 loops share one property, namely, they preferentially have a physical binding interaction with CXCR4, while R5-tropic V3 loops preferably interacts with CCR5."} {"class.text":"MISC","text":"Human Immunodeficiency Virus 1 uses for entry into host cells a receptor and one of two co-receptors."} {"class.text":"MISC","text":"Recently, a new class of antiretroviral drugs has entered clinical practice that specifically bind to the co-receptor CCR5, and thus inhibit virus entry."} {"class.text":"MISC","text":"Accurate prediction of the co-receptor used by the virus in the patient is important as it allows for personalized selection of effective drugs and prognosis of disease progression."} {"class.text":"OWNX","text":"The second level combines the two predictions of the first level."} {"class.text":"OWNX","text":"The two-level method predicts usage of CXCR4 co-receptor for new V3 sequences within seconds, with an area under the ROC curve of 0.937 0.004."} {"class.text":"OWNX","text":"Moreover, it is relatively robust against insertions and deletions, which frequently occur in V3."} {"class.text":"OWNX","text":"The approach could help clinicians to find optimal personalized treatments, and it offers new insights into the molecular basis of co-receptor usage."} {"class.text":"OWNX","text":"For instance, it quantifies the importance for co-receptor usage of a pocket that probably is responsible for binding sulfated tyrosine."} {"class.text":"MISC","text":"Specific protein interactions are central to biological processes, and the infection of cells with viruses is no exception there."} {"class.text":"MISC","text":"In the case of pathogenic viruses, such protein interactions are potential targets for medical intervention."} {"class.text":"MISC","text":"An example of particularly high relevance is Human Immunodeficiency Virus 1."} {"class.text":"MISC","text":"HIV-1 enters human cells in a process that comprises several steps, including the binding of the viral gp120 protein to the cellular receptor protein CD4 and a co-receptor protein, usually one of the two chemokine receptors CCR5 and CXCR4 CITATION."} {"class.text":"MISC","text":"In addition to the purely X4- and R5-tropic viruses, there are also dual-tropic strains, able to use both co-receptors."} {"class.text":"MISC","text":"Recently, the first drug that binds to CCR5, and thus inhibits productive binding of gp120, has been approved by regulatory authorities in several countries."} {"class.text":"MISC","text":"This has made the determination of co-receptor tropism directly relevant to anti-retroviral treatment, as CCR5-inhibitors are of course inactive against X4 virus."} {"class.text":"MISC","text":"The standard way of determining co-receptor tropism is by cell-based assays CITATION, CITATION."} {"class.text":"CONT","text":"The main drawbacks of these assays are that they are currently only carried out by a handful of specialized laboratories worldwide, and that the overall procedure typically takes several weeks."} {"class.text":"MISC","text":"These impediments to the wide application of entry inhibitors could be overcome by an approach similar to genotypic drug resistance testing CITATION, where drug resistance of a viral strain is inferred from comparison of mutational patterns obtained from sequencing parts of the genome of that strain with patterns of validated resistance mutations."} {"class.text":"MISC","text":"This is a relatively fast and cheap standard procedure established in many clinics."} {"class.text":"MISC","text":"At first glance, genotypic testing for co-receptor tropism seems to be possible since the main molecular determinant of tropism is known to be the third variable loop of the viral glycoprotein gp120 CITATION, a peptide stretch of about 35 amino-acids with a disulfide bridge connecting the terminal cysteins."} {"class.text":"MISC","text":"Unfortunately, as suggested by its name, V3 is notorious for its high sequence variability CITATION including also some variability in length, and this has made it difficult to use it as a basis for genotypic co-receptor tropism testing."} {"class.text":"MISC","text":"The importance of electrostatics for co-receptor tropism has been recognized early on, and the best-known model, the so-called 11/25-rule, refers to charges of V3-residues 11 and 25: if one of these is positive, then the virus is CXCR4-tropic CITATION, CITATION."} {"class.text":"CONT","text":"This rule has a specificity of more than 0.9, but only a low to moderate sensitivity of about 0.4 0.6, depending on the test data, which is not satisfactory for routine clinical application."} {"class.text":"MISC","text":"To improve predictions from sequence, several groups have applied machine learning methods, such as artificial neural networks CITATION, position specific scoring matrices CITATION, decision trees, or support vector machines CITATION."} {"class.text":"MISC","text":"It is unclear whether the limited accuracies are the footprint of tropism-determinants outside V3, or the consequence of model imperfections."} {"class.text":"MISC","text":"A milestone for the understanding of co-receptor tropism was the X-ray structure of gp120 with the V3 loop in a biological context CITATION."} {"class.text":"MISC","text":"This paved the way for the development of prediction methods that use, in addition to V3 sequence, structural information."} {"class.text":"MISC","text":"To our knowledge, the first of these methods has been that of Sander et al. CITATION, which was mainly based on geometric distances of amino-acid pairs within the structure of V3."} {"class.text":"OWNX","text":"By the latter we consider a seemingly trivial but fundamental fact that so far has not been thoroughly exploited: although V3 is highly variable, all X4-tropic V3 loops share one property, namely, they preferentially have a physical binding interaction with CXCR4, while R5-tropic V3 loops preferably interacts with CCR5."} {"class.text":"OWNX","text":"The accuracy of the method makes it attractive as clinical tool for patient tailored decisions on treatment with entry inhibitors, and it suggests that co-receptor tropism can be explained almost exclusively based on V3."}