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ABSTRACT: Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize more integrated functions of proteins. To test how often synaptic proteins participate in multiple steps in neurotransmission we present a novel probabilistic method to analyze complex functional data from genetic perturbation studies on neuronal secretion. Our method uses a mixture of probabilistic principal component analyzers to cluster genetic perturbations on two distinct steps in synaptic secretion, vesicle priming and fusion, and accounts for the poor standardization between different studies. Clustering data from 121 perturbations revealed that different perturbations of a given protein are often assigned to different steps in the release process. Furthermore, vesicle priming and fusion are inversely correlated for most of those perturbations where a specific protein domain was mutated to create a gain-of-function variant. Finally, two different modes of vesicle release, spontaneous and action potential evoked release, were affected similarly by most perturbations. This data suggests that the presynaptic protein network has evolved as a highly integrated supramolecular machine, which is responsible for both spontaneous and activity induced release, with a group of core proteins using different domains to act on multiple steps in the release process.
PLoS Computational Biology 04/2012; 8(4):e1002450. · 5.22 Impact Factor
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ABSTRACT: Smart premise selection is essential when using automated reasoning as a tool
for large-theory formal proof development. A good method for premise selection
in complex mathematical libraries is the application of machine learning to
large corpora of proofs. This work develops learning-based premise selection in
two ways. First, a newly available minimal dependency analysis of existing
high-level formal mathematical proofs is used to build a large knowledge base
of proof dependencies, providing precise data for ATP-based re-verification and
for training premise selection algorithms. Second, a new machine learning
algorithm for premise selection based on kernel methods is proposed and
implemented. To evaluate the impact of both techniques, a benchmark consisting
of 2078 large-theory mathematical problems is constructed,extending the older
MPTP Challenge benchmark. The combined effect of the techniques results in a
50% improvement on the benchmark over the Vampire/SInE state-of-the-art system
for automated reasoning in large theories.
08/2011;
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Proceedings of the Eleventh SIAM International Conference on Data Mining, SDM 2011, April 28-30, 2011, Mesa, Arizona, USA; 01/2011
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Intelligent Computer Mathematics - 18th Symposium, Calculemus 2011, and 10th International Conference, MKM 2011, Bertinoro, Italy, July 18-23, 2011. Proceedings; 01/2011
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ABSTRACT: In different fields like decision making, psychology, game theory and biology, it has been observed that paired-comparison data like preference relations defined by humans and animals can be intransitive. Intransitive relations cannot be modeled with existing machine learning methods like ranking models, because these models exhibit strong transitivity properties. More specifically, in a stochastic context, where often the reciprocity property characterizes probabilistic relations such as choice probabilities, it has been formally shown that ranking models always satisfy the well-known strong stochastic transitivity property. Given this limitation of ranking models, we present a new kernel function that together with the regularized least-squares algorithm is capable of inferring intransitive reciprocal relations in problems where transitivity violations cannot be considered as noise. In this approach it is the kernel function that defines the transition from learning transitive to learning intransitive relations, and the Kronecker-product is introduced for representing the latter type of relations. In addition, we empirically demonstrate on two benchmark problems, one in game theory and one in theoretical biology, that our algorithm outperforms methods not capable of learning intransitive reciprocal relations.
European Journal of Operational Research.
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