ALBERT

Description: Healthcare facilities are constantly deteriorating due to tight budgets allocated to the upkeep of building assets. This entails the need for improved deterioration modeling of such buildings in order to enforce a predictive maintenance approach that decreases the unexpected occurrence of failures and the corresponding downtime elapsed to repair or replace the faulty asset components. Currently, hospitals utilize subjective deterioration prediction methodologies that mostly rely on age as the sole indicator of degradation to forecast the useful lives of the building components. Thus, this paper aims at formulating a more efficient stochastic deterioration prediction model that integrates the latest observed condition into the forecasting procedure to overcome the subjectivity and uncertainties associated with the currently employed methods. This is achieved by means of developing a hybrid genetic algorithm-based fuzzy Markovian model that simulates the deterioration process given the scarcity of available data demonstrating the condition assessment and evaluation for such critical facilities. A nonhomogeneous transition probability matrix (TPM) based on fuzzy membership functions representing the condition, age and relative deterioration rate of the hospital systems is utilized to address the inherited uncertainties. The TPM is further calibrated by means of a genetic algorithm to circumvent the drawbacks of the expert-based models. A sensitivity analysis was carried out to analyze the possible changes in the output resulting from predefined modifications to the input parameters in order to ensure the robustness of the model. The performance of the deterioration prediction model developed is then validated through a comparison with a state-of-art stochastic model in contrast to real hospital datasets, and the results obtained from the developed model significantly outperformed the long-established Weibull distribution-based deterioration prediction methodology with mean absolute errors of 1.405 and 9.852, respectively. Therefore, the developed model is expected to assist decision-makers in creating more efficient maintenance programs as well as more data-driven capital renewal plans.

Description: The harmonic closeness centrality measure associates, to each node of a graph, the average of the inverse of its distances from all the other nodes (by assuming that unreachable nodes are at infinite distance). This notion has been adapted to temporal graphs (that is, graphs in which edges can appear and disappear during time) and in this paper we address the question of finding the top-k nodes for this metric. Computing the temporal closeness for one node can be done in O(m) time, where m is the number of temporal edges. Therefore computing exactly the closeness for all nodes, in order to find the ones with top closeness, would require O(nm) time, where n is the number of nodes. This time complexity is intractable for large temporal graphs. Instead, we show how this measure can be efficiently approximated by using a “backward” temporal breadth-first search algorithm and a classical sampling technique. Our experimental results show that the approximation is excellent for nodes with high closeness, allowing us to detect them in practice in a fraction of the time needed for computing the exact closeness of all nodes. We validate our approach with an extensive set of experiments.

Description: High order convective Cahn-Hilliard type equations describe the faceting of a growing surface, or the dynamics of phase transitions in ternary oil-water-surfactant systems. In this paper, we prove the well-posedness of the classical solutions for the Cauchy problem, associated with this equation.

Description: We consider a rather general problem of nonparametric estimation of an uncountable set of probability density functions (p.d.f.’s) of the form: f ( x ; r ) , where r is a non-random real variable and ranges from R 1 to R 2 . We put emphasis on the algorithmic aspects of this problem, since they are crucial for exploratory analysis of big data that are needed for the estimation. A specialized learning algorithm, based on the 2D FFT, is proposed and tested on observations that allow for estimate p.d.f.’s of a jet engine temperatures as a function of its rotation speed. We also derive theoretical results concerning the convergence of the estimation procedure that contains hints on selecting parameters of the estimation algorithm.

Description: We report the design of a Spiking Neural Network (SNN) edge detector with biologically inspired neurons that has a conceptual similarity with both Hodgkin-Huxley (HH) model neurons and Leaky Integrate-and-Fire (LIF) neurons. The computation of the membrane potential, which is used to determine the occurrence or absence of spike events, at each time step, is carried out by using the analytical solution to a simplified version of the HH neuron model. We find that the SNN based edge detector detects more edge pixels in images than those obtained by a Sobel edge detector. We designed a pipeline for image classification with a low-exposure frame simulation layer, SNN edge detection layers as pre-processing layers and a Convolutional Neural Network (CNN) as a classification module. We tested this pipeline for the task of classification with the Digits dataset, which is available in MATLAB. We find that the SNN based edge detection layer increases the image classification accuracy at lower exposure times, that is, for 1 〈 t 〈 T /4, where t is the number of milliseconds in a simulated exposure frame and T is the total exposure time, with reference to a Sobel edge or Canny edge detection layer in the pipeline. These results pave the way for developing novel cognitive neuromorphic computing architectures for millisecond timescale detection and object classification applications using event or spike cameras.

Description: Microscopic crowd simulation can help to enhance the safety of pedestrians in situations that range from museum visits to music festivals. To obtain a useful prediction, the input parameters must be chosen carefully. In many cases, a lack of knowledge or limited measurement accuracy add uncertainty to the input. In addition, for meaningful parameter studies, we first need to identify the most influential parameters of our parametric computer models. The field of uncertainty quantification offers standardized and fully automatized methods that we believe to be beneficial for pedestrian dynamics. In addition, many methods come at a comparatively low cost, even for computationally expensive problems. This allows for their application to larger scenarios. We aim to identify and adapt fitting methods to microscopic crowd simulation in order to explore their potential in pedestrian dynamics. In this work, we first perform a variance-based sensitivity analysis using Sobol’ indices and then crosscheck the results by a derivative-based measure, the activity scores. We apply both methods to a typical scenario in crowd simulation, a bottleneck. Because constrictions can lead to high crowd densities and delays in evacuations, several experiments and simulation studies have been conducted for this setting. We show qualitative agreement between the results of both methods. Additionally, we identify a one-dimensional subspace in the input parameter space and discuss its impact on the simulation. Moreover, we analyze and interpret the sensitivity indices with respect to the bottleneck scenario.

Description: Standard (Lomb-Scargle, likelihood, etc.) procedures for power-spectrum analysis provide convenient estimates of the significance of any peak in a power spectrum, based—typically—on the assumption that the measurements being analyzed have a normal (i.e., Gaussian) distribution. However, the measurement sequence provided by a real experiment or a real observational program may not meet this requirement. The RONO (rank-order normalization) procedure generates a proxy distribution that retains the rank-order of the original measurements but has a strictly normal distribution. The proxy distribution may then be analyzed by standard power-spectrum analysis. We show by an example that the resulting power spectrum may prove to be quite close to the power spectrum obtained from the original data by a standard procedure, even if the distribution of the original measurements is far from normal. Such a comparison would tend to validate the original analysis.

Description: Toward strong demand for very high-speed I/O for processors, physical performance growth of hardware I/O speed was drastically increased in this decade. However, the recent Big Data applications still demand the larger I/O bandwidth and the lower latency for the speed. Because the current I/O performance does not improve so drastically, it is the time to consider another way to increase it. To overcome this challenge, we focus on lossless data compression technology to decrease the amount of data itself in the data communication path. The recent Big Data applications treat data stream that flows continuously and never allow stalling processing due to the high speed. Therefore, an elegant hardware-based data compression technology is demanded. This paper proposes a novel lossless data compression, called ASE coding. It encodes streaming data by applying the entropy coding approach. ASE coding instantly assigns the fewest bits to the corresponding compressed data according to the number of occupied entries in a look-up table. This paper describes the detailed mechanism of ASE coding. Furthermore, the paper demonstrates performance evaluations to promise that ASE coding adaptively shrinks streaming data and also works on a small amount of hardware resources without stalling or buffering any part of data stream.

Description: Text annotation is the process of identifying the sense of a textual segment within a given context to a corresponding entity on a concept ontology. As the bag of words paradigm’s limitations become increasingly discernible in modern applications, several information retrieval and artificial intelligence tasks are shifting to semantic representations for addressing the inherent natural language polysemy and homonymy challenges. With extensive application in a broad range of scientific fields, such as digital marketing, bioinformatics, chemical engineering, neuroscience, and social sciences, community detection has attracted great scientific interest. Focusing on linguistics, by aiming to identify groups of densely interconnected subgroups of semantic ontologies, community detection application has proven beneficial in terms of disambiguation improvement and ontology enhancement. In this paper we introduce a novel distributed supervised knowledge-based methodology employing community detection algorithms for text annotation with Wikipedia Entities, establishing the unprecedented concept of community Coherence as a metric for local contextual coherence compatibility. Our experimental evaluation revealed that deeper inference of relatedness and local entity community coherence in the Wikipedia graph bears substantial improvements overall via a focus on accuracy amelioration of less common annotations. The proposed methodology is propitious for wider adoption, attaining robust disambiguation performance.

Description: Geomechanical modelling of the processes associated to the exploitation of subsurface resources, such as land subsidence or triggered/induced seismicity, is a common practice of major interest. The prediction reliability depends on different sources of uncertainty, such as the parameterization of the constitutive model characterizing the deep rock behaviour. In this study, we focus on a Sobol’-based sensitivity analysis and uncertainty reduction via assimilation of land deformations. A synthetic test case application on a deep hydrocarbon reservoir is considered, where land settlements are predicted with the aid of a 3-D Finite Element (FE) model. Data assimilation is performed via the Ensemble Smoother (ES) technique and its variation in the form of Multiple Data Assimilation (ES-MDA). However, the ES convergence is guaranteed with a large number of Monte Carlo (MC) simulations, that may be computationally infeasible in large scale and complex systems. For this reason, a surrogate model based on the generalized Polynomial Chaos Expansion (gPCE) is proposed as an approximation of the forward problem. This approach allows to efficiently compute the Sobol’ indices for the sensitivity analysis and greatly reduce the computational cost of the original ES and MDA formulations, also enhancing the accuracy of the overall prediction process.

Description: Clustering is an unsupervised machine learning technique with many practical applications that has gathered extensive research interest. Aside from deterministic or probabilistic techniques, fuzzy C-means clustering (FCM) is also a common clustering technique. Since the advent of the FCM method, many improvements have been made to increase clustering efficiency. These improvements focus on adjusting the membership representation of elements in the clusters, or on fuzzifying and defuzzifying techniques, as well as the distance function between elements. This study proposes a novel fuzzy clustering algorithm using multiple different fuzzification coefficients depending on the characteristics of each data sample. The proposed fuzzy clustering method has similar calculation steps to FCM with some modifications. The formulas are derived to ensure convergence. The main contribution of this approach is the utilization of multiple fuzzification coefficients as opposed to only one coefficient in the original FCM algorithm. The new algorithm is then evaluated with experiments on several common datasets and the results show that the proposed algorithm is more efficient compared to the original FCM as well as other clustering methods.

Description: Business processes evolve over time to adapt to changing business environments. This requires continuous monitoring of business processes to gain insights into whether they conform to the intended design or deviate from it. The situation when a business process changes while being analysed is denoted as Concept Drift. Its analysis is concerned with studying how a business process changes, in terms of detecting and localising changes and studying the effects of the latter. Concept drift analysis is crucial to enable early detection and management of changes, that is, whether to promote a change to become part of an improved process, or to reject the change and make decisions to mitigate its effects. Despite its importance, there exists no comprehensive framework for analysing concept drift types, affected process perspectives, and granularity levels of a business process. This article proposes the CONcept Drift Analysis in Process Mining (CONDA-PM) framework describing phases and requirements of a concept drift analysis approach. CONDA-PM was derived from a Systematic Literature Review (SLR) of current approaches analysing concept drift. We apply the CONDA-PM framework on current approaches to concept drift analysis and evaluate their maturity. Applying CONDA-PM framework highlights areas where research is needed to complement existing efforts.

Description: Let P be a set of n points in R d , k ≥ 1 be an integer and ε ∈ ( 0 , 1 ) be a constant. An ε-coreset is a subset C ⊆ P with appropriate non-negative weights (scalars), that approximates any given set Q ⊆ R d of k centers. That is, the sum of squared distances over every point in P to its closest point in Q is the same, up to a factor of 1 ± ε to the weighted sum of C to the same k centers. If the coreset is small, we can solve problems such as k-means clustering or its variants (e.g., discrete k-means, where the centers are restricted to be in P, or other restricted zones) on the small coreset to get faster provable approximations. Moreover, it is known that such coreset support streaming, dynamic and distributed data using the classic merge-reduce trees. The fact that the coreset is a subset implies that it preserves the sparsity of the data. However, existing such coresets are randomized and their size has at least linear dependency on the dimension d. We suggest the first such coreset of size independent of d. This is also the first deterministic coreset construction whose resulting size is not exponential in d. Extensive experimental results and benchmarks are provided on public datasets, including the first coreset of the English Wikipedia using Amazon’s cloud.

Description: We examine a distributed detection problem in a wireless sensor network, where sensor nodes collaborate to detect a Gaussian signal with an unknown change of power, i.e., a scale parameter. Due to power/bandwidth constraints, we consider the case where each sensor quantizes its observation into a binary digit. The binary data are then transmitted through error-prone wireless links to a fusion center, where a generalized likelihood ratio test (GLRT) detector is employed to perform a global decision. We study the design of a binary quantizer based on an asymptotic analysis of the GLRT. Interestingly, the quantization threshold of the quantizer is independent of the unknown scale parameter. Numerical results are included to illustrate the performance of the proposed quantizer and GLRT in binary symmetric channels (BSCs).

Description: More and more hybrid electric vehicles are driven since they offer such advantages as energy savings and better active safety performance. Hybrid vehicles have two or more power driving systems and frequently switch working condition, so controlling stability is very important. In this work, a two-stage Kalman algorithm method is used to fuse data in hybrid vehicle stability testing. First, the RT3102 navigation system and Dewetron system are introduced. Second, a modeling of data fusion is proposed based on the Kalman filter. Then, this modeling is simulated and tested on a sample vehicle, using Carsim and Simulink software to test the results. The results showed the merits of this modeling.

Description: Currently deep learning has made great breakthroughs in visual and speech processing, mainly because it draws lessons from the hierarchical mode that brain deals with images and speech. In the field of NLP, a topic model is one of the important ways for modeling documents. Topic models are built on a generative model that clearly does not match the way humans write. In this paper, we propose Event Model, which is unsupervised and based on the language processing mechanism of neurolinguistics, to model documents. In Event Model, documents are descriptions of concrete or abstract events seen, heard, or sensed by people and words are objects in the events. Event Model has two stages: word learning and dimensionality reduction. Word learning is to learn semantics of words based on deep learning. Dimensionality reduction is the process that representing a document as a low dimensional vector by a linear mode that is completely different from topic models. Event Model achieves state-of-the-art results on document retrieval tasks.

Description: by Eliseo Ferrante, Ali Emre Turgut, Edgar Duéñez-Guzmán, Marco Dorigo, Tom Wenseleers Division of labor is ubiquitous in biological systems, as evidenced by various forms of complex task specialization observed in both animal societies and multicellular organisms. Although clearly adaptive, the way in which division of labor first evolved remains enigmatic, as it requires the simultaneous co-occurrence of several complex traits to achieve the required degree of coordination. Recently, evolutionary swarm robotics has emerged as an excellent test bed to study the evolution of coordinated group-level behavior. Here we use this framework for the first time to study the evolutionary origin of behavioral task specialization among groups of identical robots. The scenario we study involves an advanced form of division of labor, common in insect societies and known as “task partitioning”, whereby two sets of tasks have to be carried out in sequence by different individuals. Our results show that task partitioning is favored whenever the environment has features that, when exploited, reduce switching costs and increase the net efficiency of the group, and that an optimal mix of task specialists is achieved most readily when the behavioral repertoires aimed at carrying out the different subtasks are available as pre-adapted building blocks. Nevertheless, we also show for the first time that self-organized task specialization could be evolved entirely from scratch, starting only from basic, low-level behavioral primitives, using a nature-inspired evolutionary method known as Grammatical Evolution. Remarkably, division of labor was achieved merely by selecting on overall group performance, and without providing any prior information on how the global object retrieval task was best divided into smaller subtasks. We discuss the potential of our method for engineering adaptively behaving robot swarms and interpret our results in relation to the likely path that nature took to evolve complex sociality and task specialization.

Description: by Patrícia Santos-Oliveira, António Correia, Tiago Rodrigues, Teresa M Ribeiro-Rodrigues, Paulo Matafome, Juan Carlos Rodríguez-Manzaneque, Raquel Seiça, Henrique Girão, Rui D. M. Travasso Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.

Description: by Sayed-Rzgar Hosseini, Aditya Barve, Andreas Wagner All biological evolution takes place in a space of possible genotypes and their phenotypes. The structure of this space defines the evolutionary potential and limitations of an evolving system. Metabolism is one of the most ancient and fundamental evolving systems, sustaining life by extracting energy from extracellular nutrients. Here we study metabolism’s potential for innovation by analyzing an exhaustive genotype-phenotype map for a space of 10 15 metabolisms that encodes all possible subsets of 51 reactions in central carbon metabolism. Using flux balance analysis, we predict the viability of these metabolisms on 10 different carbon sources which give rise to 1024 potential metabolic phenotypes. Although viable metabolisms with any one phenotype comprise a tiny fraction of genotype space, their absolute numbers exceed 10 9 for some phenotypes. Metabolisms with any one phenotype typically form a single network of genotypes that extends far or all the way through metabolic genotype space, where any two genotypes can be reached from each other through a series of single reaction changes. The minimal distance of genotype networks associated with different phenotypes is small, such that one can reach metabolisms with novel phenotypes – viable on new carbon sources – through one or few genotypic changes. Exceptions to these principles exist for those metabolisms whose complexity (number of reactions) is close to the minimum needed for viability. Increasing metabolic complexity enhances the potential for both evolutionary conservation and evolutionary innovation.

Description: by Pengxing Cao, Ada W. C. Yan, Jane M. Heffernan, Stephen Petrie, Robert G. Moss, Louise A. Carolan, Teagan A. Guarnaccia, Anne Kelso, Ian G. Barr, Jodie McVernon, Karen L. Laurie, James M. McCaw Influenza is an infectious disease that primarily attacks the respiratory system. Innate immunity provides both a very early defense to influenza virus invasion and an effective control of viral growth. Previous modelling studies of virus–innate immune response interactions have focused on infection with a single virus and, while improving our understanding of viral and immune dynamics, have been unable to effectively evaluate the relative feasibility of different hypothesised mechanisms of antiviral immunity. In recent experiments, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. These results imply that virus-induced early immune responses may be responsible for the observed viral hierarchy. Here we introduce and analyse a family of within-host models of re-infection viral kinetics which allow for different viruses to stimulate the innate immune response to different degrees. The proposed models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their abilities to reproduce the re-exposure data. Our results show that 1) a model with viral control mediated solely by a virus-resistant state, as commonly considered in the literature, is not able to reproduce the observed viral hierarchy; 2) the synchronised and desynchronised behaviour of consecutive virus infections is highly dependent upon the interval between primary virus and challenge virus exposures and is consistent with virus-dependent stimulation of the innate immune response. Our study provides the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza and its role in viral control.

Description: by Paul M. Harrison, Laurent Badel, Mark J. Wall, Magnus J. E. Richardson Models of neocortical networks are increasingly including the diversity of excitatory and inhibitory neuronal classes. Significant variability in cellular properties are also seen within a nominal neuronal class and this heterogeneity can be expected to influence the population response and information processing in networks. Recent studies have examined the population and network effects of variability in a particular neuronal parameter with some plausibly chosen distribution. However, the empirical variability and covariance seen across multiple parameters are rarely included, partly due to the lack of data on parameter correlations in forms convenient for model construction. To addess this we quantify the heterogeneity within and between the neocortical pyramidal-cell classes in layers 2/3, 4, and the slender-tufted and thick-tufted pyramidal cells of layer 5 using a combination of intracellular recordings, single-neuron modelling and statistical analyses. From the response to both square-pulse and naturalistic fluctuating stimuli, we examined the class-dependent variance and covariance of electrophysiological parameters and identify the role of the h current in generating parameter correlations. A byproduct of the dynamic I-V method we employed is the straightforward extraction of reduced neuron models from experiment. Empirically these models took the refractory exponential integrate-and-fire form and provide an accurate fit to the perisomatic voltage responses of the diverse pyramidal-cell populations when the class-dependent statistics of the model parameters were respected. By quantifying the parameter statistics we obtained an algorithm which generates populations of model neurons, for each of the four pyramidal-cell classes, that adhere to experimentally observed marginal distributions and parameter correlations. As well as providing this tool, which we hope will be of use for exploring the effects of heterogeneity in neocortical networks, we also provide the code for the dynamic I-V method and make the full electrophysiological data set available.

Description: Community detection in a complex network is an important problem of much interest in recent years. In general, a community detection algorithm chooses an objective function and captures the communities of the network by optimizing the objective function, and then, one uses various heuristics to solve the optimization problem to extract the interesting communities for the user. In this article, we demonstrate the procedure to transform a graph into points of a metric space and develop the methods of community detection with the help of a metric defined for a pair of points. We have also studied and analyzed the community structure of the network therein. The results obtained with our approach are very competitive with most of the well-known algorithms in the literature, and this is justified over the large collection of datasets. On the other hand, it can be observed that time taken by our algorithm is quite less compared to other methods and justifies the theoretical findings.

Description: by Ariel Afek, Hila Cohen, Shiran Barber-Zucker, Raluca Gordân, David B. Lukatsky Recent genome-wide experiments in different eukaryotic genomes provide an unprecedented view of transcription factor (TF) binding locations and of nucleosome occupancy. These experiments revealed that a large fraction of TF binding events occur in regions where only a small number of specific TF binding sites (TFBSs) have been detected. Furthermore, in vitro protein-DNA binding measurements performed for hundreds of TFs indicate that TFs are bound with wide range of affinities to different DNA sequences that lack known consensus motifs. These observations have thus challenged the classical picture of specific protein-DNA binding and strongly suggest the existence of additional recognition mechanisms that affect protein-DNA binding preferences. We have previously demonstrated that repetitive DNA sequence elements characterized by certain symmetries statistically affect protein-DNA binding preferences. We call this binding mechanism nonconsensus protein-DNA binding in order to emphasize the point that specific consensus TFBSs do not contribute to this effect. In this paper, using the simple statistical mechanics model developed previously, we calculate the nonconsensus protein-DNA binding free energy for the entire C . elegans and D . melanogaster genomes. Using the available chromatin immunoprecipitation followed by sequencing (ChIP-seq) results on TF-DNA binding preferences for ~100 TFs, we show that DNA sequences characterized by low predicted free energy of nonconsensus binding have statistically higher experimental TF occupancy and lower nucleosome occupancy than sequences characterized by high free energy of nonconsensus binding. This is in agreement with our previous analysis performed for the yeast genome. We suggest therefore that nonconsensus protein-DNA binding assists the formation of nucleosome-free regions, as TFs outcompete nucleosomes at genomic locations with enhanced nonconsensus binding. In addition, here we perform a new, large-scale analysis using in vitro TF-DNA preferences obtained from the universal protein binding microarrays (PBM) for ~90 eukaryotic TFs belonging to 22 different DNA-binding domain types. As a result of this new analysis, we conclude that nonconsensus protein-DNA binding is a widespread phenomenon that significantly affects protein-DNA binding preferences and need not require the presence of consensus (specific) TFBSs in order to achieve genome-wide TF-DNA binding specificity.

Description: A three-step iterative method with fifth-order convergence as a new modification of Newton’s method was presented. This method is for finding multiple roots of nonlinear equation with unknown multiplicity m whose multiplicity m is the highest multiplicity. Its order of convergence is analyzed and proved. Results for some numerical examples show the efficiency of the new method.

Description: by The PLOS Computational Biology Staff

Description: by James Tamerius, Cécile Viboud, Jeffrey Shaman, Gerardo Chowell While a relationship between environmental forcing and influenza transmission has been established in inter-pandemic seasons, the drivers of pandemic influenza remain debated. In particular, school effects may predominate in pandemic seasons marked by an atypical concentration of cases among children. For the 2009 A/H1N1 pandemic, Mexico is a particularly interesting case study due to its broad geographic extent encompassing temperate and tropical regions, well-documented regional variation in the occurrence of pandemic outbreaks, and coincidence of several school breaks during the pandemic period. Here we fit a series of transmission models to daily laboratory-confirmed influenza data in 32 Mexican states using MCMC approaches, considering a meta-population framework or the absence of spatial coupling between states. We use these models to explore the effect of environmental, school–related and travel factors on the generation of spatially-heterogeneous pandemic waves. We find that the spatial structure of the pandemic is best understood by the interplay between regional differences in specific humidity (explaining the occurrence of pandemic activity towards the end of the school term in late May-June 2009 in more humid southeastern states), school vacations (preventing influenza transmission during July-August in all states), and regional differences in residual susceptibility (resulting in large outbreaks in early fall 2009 in central and northern Mexico that had yet to experience fully-developed outbreaks). Our results are in line with the concept that very high levels of specific humidity, as present during summer in southeastern Mexico, favor influenza transmission, and that school cycles are a strong determinant of pandemic wave timing.

Description: by Alireza Alemi, Carlo Baldassi, Nicolas Brunel, Riccardo Zecchina Understanding the theoretical foundations of how memories are encoded and retrieved in neural populations is a central challenge in neuroscience. A popular theoretical scenario for modeling memory function is the attractor neural network scenario, whose prototype is the Hopfield model. The model simplicity and the locality of the synaptic update rules come at the cost of a poor storage capacity, compared with the capacity achieved with perceptron learning algorithms. Here, by transforming the perceptron learning rule, we present an online learning rule for a recurrent neural network that achieves near-maximal storage capacity without an explicit supervisory error signal, relying only upon locally accessible information. The fully-connected network consists of excitatory binary neurons with plastic recurrent connections and non-plastic inhibitory feedback stabilizing the network dynamics; the memory patterns to be memorized are presented online as strong afferent currents, producing a bimodal distribution for the neuron synaptic inputs. Synapses corresponding to active inputs are modified as a function of the value of the local fields with respect to three thresholds. Above the highest threshold, and below the lowest threshold, no plasticity occurs. In between these two thresholds, potentiation/depression occurs when the local field is above/below an intermediate threshold. We simulated and analyzed a network of binary neurons implementing this rule and measured its storage capacity for different sizes of the basins of attraction. The storage capacity obtained through numerical simulations is shown to be close to the value predicted by analytical calculations. We also measured the dependence of capacity on the strength of external inputs. Finally, we quantified the statistics of the resulting synaptic connectivity matrix, and found that both the fraction of zero weight synapses and the degree of symmetry of the weight matrix increase with the number of stored patterns.

Description: by Sander Land, Steven A. Niederer Biophysical models of cardiac tension development provide a succinct representation of our understanding of force generation in the heart. The link between protein kinetics and interactions that gives rise to high cooperativity is not yet fully explained from experiments or previous biophysical models. We propose a biophysical ODE-based representation of cross-bridge (XB), tropomyosin and troponin within a contractile regulatory unit (RU) to investigate the mechanisms behind cooperative activation, as well as the role of cooperativity in dynamic tension generation across different species. The model includes cooperative interactions between regulatory units (RU-RU), between crossbridges (XB-XB), as well more complex interactions between crossbridges and regulatory units (XB-RU interactions). For the steady-state force-calcium relationship, our framework predicts that: (1) XB-RU effects are key in shifting the half-activation value of the force-calcium relationship towards lower [Ca 2+ ], but have only small effects on cooperativity. (2) XB-XB effects approximately double the duty ratio of myosin, but do not significantly affect cooperativity. (3) RU-RU effects derived from the long-range action of tropomyosin are a major factor in cooperative activation, with each additional unblocked RU increasing the rate of additional RU’s unblocking. (4) Myosin affinity for short (1–4 RU) unblocked stretches of actin of is very low, and the resulting suppression of force at low [Ca 2+ ] is a major contributor in the biphasic force-calcium relationship. We also reproduce isometric tension development across mouse, rat and human at physiological temperature and pacing rate, and conclude that species differences require only changes in myosin affinity and troponin I/troponin C affinity. Furthermore, we show that the calcium dependence of the rate of tension redevelopment k tr is explained by transient blocking of RU’s by a temporary decrease in XB-RU effects.

Description: by Jonas Paulsen, Odin Gramstad, Philippe Collas The three-dimensional (3D) structure of the genome is important for orchestration of gene expression and cell differentiation. While mapping genomes in 3D has for a long time been elusive, recent adaptations of high-throughput sequencing to chromosome conformation capture (3C) techniques, allows for genome-wide structural characterization for the first time. However, reconstruction of "consensus" 3D genomes from 3C-based data is a challenging problem, since the data are aggregated over millions of cells. Recent single-cell adaptations to the 3C-technique, however, allow for non-aggregated structural assessment of genome structure, but data suffer from sparse and noisy interaction sampling. We present a manifold based optimization (MBO) approach for the reconstruction of 3D genome structure from chromosomal contact data. We show that MBO is able to reconstruct 3D structures based on the chromosomal contacts, imposing fewer structural violations than comparable methods. Additionally, MBO is suitable for efficient high-throughput reconstruction of large systems, such as entire genomes, allowing for comparative studies of genomic structure across cell-lines and different species.

Description: by Hiroo Kenzaki, Shoji Takada Nucleosomes, basic units of chromatin, are known to show spontaneous DNA unwrapping dynamics that are crucial for transcriptional activation, but its structural details are yet to be elucidated. Here, employing a coarse-grained molecular model that captures residue-level structural details up to histone tails, we simulated equilibrium fluctuations and forced unwrapping of single nucleosomes at various conditions. The equilibrium simulations showed spontaneous unwrapping from outer DNA and subsequent rewrapping dynamics, which are in good agreement with experiments. We found several distinct partially unwrapped states of nucleosomes, as well as reversible transitions among these states. At a low salt concentration, histone tails tend to sit in the concave cleft between the histone octamer and DNA, tightening the nucleosome. At a higher salt concentration, the tails tend to bound to the outer side of DNA or be expanded outwards, which led to higher degree of unwrapping. Of the four types of histone tails, H3 and H2B tail dynamics are markedly correlated with partial unwrapping of DNA, and, moreover, their contributions were distinct. Acetylation in histone tails was simply mimicked by changing their charges, which enhanced the unwrapping, especially markedly for H3 and H2B tails.

Description: by Sebastian Bitzer, Jelle Bruineberg, Stefan J. Kiebel Even for simple perceptual decisions, the mechanisms that the brain employs are still under debate. Although current consensus states that the brain accumulates evidence extracted from noisy sensory information, open questions remain about how this simple model relates to other perceptual phenomena such as flexibility in decisions, decision-dependent modulation of sensory gain, or confidence about a decision. We propose a novel approach of how perceptual decisions are made by combining two influential formalisms into a new model. Specifically, we embed an attractor model of decision making into a probabilistic framework that models decision making as Bayesian inference. We show that the new model can explain decision making behaviour by fitting it to experimental data. In addition, the new model combines for the first time three important features: First, the model can update decisions in response to switches in the underlying stimulus. Second, the probabilistic formulation accounts for top-down effects that may explain recent experimental findings of decision-related gain modulation of sensory neurons. Finally, the model computes an explicit measure of confidence which we relate to recent experimental evidence for confidence computations in perceptual decision tasks.

Description: by Malachi Griffith, Jason R. Walker, Nicholas C. Spies, Benjamin J. Ainscough, Obi L. Griffith Massively parallel RNA sequencing (RNA-seq) has rapidly become the assay of choice for interrogating RNA transcript abundance and diversity. This article provides a detailed introduction to fundamental RNA-seq molecular biology and informatics concepts. We make available open-access RNA-seq tutorials that cover cloud computing, tool installation, relevant file formats, reference genomes, transcriptome annotations, quality-control strategies, expression, differential expression, and alternative splicing analysis methods. These tutorials and additional training resources are accompanied by complete analysis pipelines and test datasets made available without encumbrance at www.rnaseq.wiki.

Description: by Arjun Bharioke, Dmitri B. Chklovskii Neurons must faithfully encode signals that can vary over many orders of magnitude despite having only limited dynamic ranges. For a correlated signal, this dynamic range constraint can be relieved by subtracting away components of the signal that can be predicted from the past, a strategy known as predictive coding, that relies on learning the input statistics. However, the statistics of input natural signals can also vary over very short time scales e.g., following saccades across a visual scene. To maintain a reduced transmission cost to signals with rapidly varying statistics, neuronal circuits implementing predictive coding must also rapidly adapt their properties. Experimentally, in different sensory modalities, sensory neurons have shown such adaptations within 100 ms of an input change. Here, we show first that linear neurons connected in a feedback inhibitory circuit can implement predictive coding. We then show that adding a rectification nonlinearity to such a feedback inhibitory circuit allows it to automatically adapt and approximate the performance of an optimal linear predictive coding network, over a wide range of inputs, while keeping its underlying temporal and synaptic properties unchanged. We demonstrate that the resulting changes to the linearized temporal filters of this nonlinear network match the fast adaptations observed experimentally in different sensory modalities, in different vertebrate species. Therefore, the nonlinear feedback inhibitory network can provide automatic adaptation to fast varying signals, maintaining the dynamic range necessary for accurate neuronal transmission of natural inputs.

Description: by Murat Alp, Vipan K. Parihar, Charles L. Limoli, Francis A. Cucinotta In this work, a stochastic computational model of microscopic energy deposition events is used to study for the first time damage to irradiated neuronal cells of the mouse hippocampus. An extensive library of radiation tracks for different particle types is created to score energy deposition in small voxels and volume segments describing a neuron’s morphology that later are sampled for given particle fluence or dose. Methods included the construction of in silico mouse hippocampal granule cells from neuromorpho.org with spine and filopodia segments stochastically distributed along the dendritic branches. The model is tested with high-energy 56 Fe, 12 C, and 1 H particles and electrons. Results indicate that the tree-like structure of the neuronal morphology and the microscopic dose deposition of distinct particles may lead to different outcomes when cellular injury is assessed, leading to differences in structural damage for the same absorbed dose. The significance of the microscopic dose in neuron components is to introduce specific local and global modes of cellular injury that likely contribute to spine, filopodia, and dendrite pruning, impacting cognition and possibly the collapse of the neuron. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components. Going forward, this work can directly support the development of biophysical models of the modifications of spine and dendritic morphology observed after low dose charged particle irradiation by providing accurate descriptions of the underlying physical insults to complex neuron structures at the nano-meter scale.

Description: by Brinda Vallat, Carlos Madrid-Aliste, Andras Fiser Predicting the three-dimensional structure of proteins from their amino acid sequences remains a challenging problem in molecular biology. While the current structural coverage of proteins is almost exclusively provided by template-based techniques, the modeling of the rest of the protein sequences increasingly require template-free methods. However, template-free modeling methods are much less reliable and are usually applicable for smaller proteins, leaving much space for improvement. We present here a novel computational method that uses a library of supersecondary structure fragments, known as Smotifs, to model protein structures. The library of Smotifs has saturated over time, providing a theoretical foundation for efficient modeling. The method relies on weak sequence signals from remotely related protein structures to create a library of Smotif fragments specific to the target protein sequence. This Smotif library is exploited in a fragment assembly protocol to sample decoys, which are assessed by a composite scoring function. Since the Smotif fragments are larger in size compared to the ones used in other fragment-based methods, the proposed modeling algorithm, SmotifTF, can employ an exhaustive sampling during decoy assembly. SmotifTF successfully predicts the overall fold of the target proteins in about 50% of the test cases and performs competitively when compared to other state of the art prediction methods, especially when sequence signal to remote homologs is diminishing. Smotif-based modeling is complementary to current prediction methods and provides a promising direction in addressing the structure prediction problem, especially when targeting larger proteins for modeling.

Description: In this paper, we present three improvements to a three-point third order variant of Newton’s method derived from the Simpson rule. The first one is a fifth order method using the same number of functional evaluations as the third order method, the second one is a four-point 10th order method and the last one is a five-point 20th order method. In terms of computational point of view, our methods require four evaluations (one function and three first derivatives) to get fifth order, five evaluations (two functions and three derivatives) to get 10th order and six evaluations (three functions and three derivatives) to get 20th order. Hence, these methods have efficiency indexes of 1.495, 1.585 and 1.648, respectively which are better than the efficiency index of 1.316 of the third order method. We test the methods through some numerical experiments which show that the 20th order method is very efficient.

Description: by Po-Wei Chen, Luis L. Fonseca, Yusuf A. Hannun, Eberhard O. Voit The article demonstrates that computational modeling has the capacity to convert metabolic snapshots, taken sequentially over time, into a description of cellular, dynamic strategies. The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress. Using time dependent metabolic concentration data, we use a combination of mathematical modeling, reverse engineering, and optimization to infer dynamic changes in enzyme activities within the sphingolipid pathway. The details of the sphingolipid responses to heat stress are important, because they guide some of the longer-term alterations in gene expression, with which the cells adapt to the increased temperature. The analysis indicates that all enzyme activities in the system are affected and that the shapes of the time trends in activities depend on the fatty-acyl CoA chain lengths of the different ceramide species in the system.

Description: Robust small target detection of low signal-to-noise ratio (SNR) is very important in infrared search and track applications for self-defense or attacks. Due to the complex background, current algorithms have some unsolved issues with false alarm rate. In order to reduce the false alarm rate, an infrared small target detection algorithm based on saliency detection and support vector machine was proposed. Firstly, we detect salient regions that may contain targets with phase spectrum Fourier transform (PFT) approach. Then, target recognition was performed in the salient regions. Experimental results show the proposed algorithm has ideal robustness and efficiency for real infrared small target detection applications.

Description: In dynamic propagation environments, beamforming algorithms may suffer from strong interference, steering vector mismatches, a low convergence speed and a high computational complexity. Reduced-rank signal processing techniques provide a way to address the problems mentioned above. This paper presents a low-complexity robust data-dependent dimensionality reduction based on an iterative optimization with steering vector perturbation (IOVP) algorithm for reduced-rank beamforming and steering vector estimation. The proposed robust optimization procedure jointly adjusts the parameters of a rank reduction matrix and an adaptive beamformer. The optimized rank reduction matrix projects the received signal vector onto a subspace with lower dimension. The beamformer/steering vector optimization is then performed in a reduced dimension subspace. We devise efficient stochastic gradient and recursive least-squares algorithms for implementing the proposed robust IOVP design. The proposed robust IOVP beamforming algorithms result in a faster convergence speed and an improved performance. Simulation results show that the proposed IOVP algorithms outperform some existing full-rank and reduced-rank algorithms with a comparable complexity.

Description: Recently, wireless sensor networks (WSNs) have drawn great interest due to their outstanding monitoring and management potential in medical, environmental and industrial applications. Most of the applications that employ WSNs demand all of the sensor nodes to run on a common time scale, a requirement that highlights the importance of clock synchronization. The clock synchronization problem in WSNs is inherently related to parameter estimation. The accuracy of clock synchronization algorithms depends essentially on the statistical properties of the parameter estimation algorithms. Recently, studies dedicated to the estimation of synchronization parameters, such as clock offset and skew, have begun to emerge in the literature. The aim of this article is to provide an overview of the state-of-the-art clock synchronization algorithms for WSNs from a statistical signal processing point of view. This article focuses on describing the key features of the class of clock synchronization algorithms that exploit the traditional two-way message (signal) exchange mechanism. Upon introducing the two-way message exchange mechanism, the main clock offset estimation algorithms for pairwise synchronization of sensor nodes are first reviewed, and their performance is compared. The class of fully-distributed clock offset estimation algorithms for network-wide synchronization is then surveyed. The paper concludes with a list of open research problems pertaining to clock synchronization of WSNs.

Description: by Pengyi Yang, Xiaofeng Zheng, Vivek Jayaswal, Guang Hu, Jean Yee Hwa Yang, Raja Jothi Cell signaling underlies transcription/epigenetic control of a vast majority of cell-fate decisions. A key goal in cell signaling studies is to identify the set of kinases that underlie key signaling events. In a typical phosphoproteomics study, phosphorylation sites (substrates) of active kinases are quantified proteome-wide. By analyzing the activities of phosphorylation sites over a time-course, the temporal dynamics of signaling cascades can be elucidated. Since many substrates of a given kinase have similar temporal kinetics, clustering phosphorylation sites into distinctive clusters can facilitate identification of their respective kinases. Here we present a knowledge-based CLUster Evaluation (CLUE) approach for identifying the most informative partitioning of a given temporal phosphoproteomics data. Our approach utilizes prior knowledge, annotated kinase-substrate relationships mined from literature and curated databases, to first generate biologically meaningful partitioning of the phosphorylation sites and then determine key kinases associated with each cluster. We demonstrate the utility of the proposed approach on two time-series phosphoproteomics datasets and identify key kinases associated with human embryonic stem cell differentiation and insulin signaling pathway. The proposed approach will be a valuable resource in the identification and characterizing of signaling networks from phosphoproteomics data.

Description: by Deborah A. Striegel, Manami Hara, Vipul Periwal Pancreatic islets of Langerhans consist of endocrine cells, primarily α, β and δ cells, which secrete glucagon, insulin, and somatostatin, respectively, to regulate plasma glucose. β cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Due to the central functional significance of this local connectivity in the placement of β cells in an islet, it is important to characterize it quantitatively. However, quantification of the seemingly stochastic cytoarchitecture of β cells in an islet requires mathematical methods that can capture topological connectivity in the entire β-cell population in an islet. Graph theory provides such a framework. Using large-scale imaging data for thousands of islets containing hundreds of thousands of cells in human organ donor pancreata, we show that quantitative graph characteristics differ between control and type 2 diabetic islets. Further insight into the processes that shape and maintain this architecture is obtained by formulating a stochastic theory of β-cell rearrangement in whole islets, just as the normal equilibrium distribution of the Ornstein-Uhlenbeck process can be viewed as the result of the interplay between a random walk and a linear restoring force. Requiring that rearrangements maintain the observed quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that β-cell rearrangement is dependent on its connectivity in order to maintain an optimal cluster size in both normal and T2D islets.

Description: by Ghanim Ullah, Yina Wei, Markus A Dahlem, Martin Wechselberger, Steven J Schiff Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states.

Description: by John R. Houser, Craig Barnhart, Daniel R. Boutz, Sean M. Carroll, Aurko Dasgupta, Joshua K. Michener, Brittany D. Needham, Ophelia Papoulas, Viswanadham Sridhara, Dariya K. Sydykova, Christopher J. Marx, M. Stephen Trent, Jeffrey E. Barrick, Edward M. Marcotte, Claus O. Wilke How do bacteria regulate their cellular physiology in response to starvation? Here, we present a detailed characterization of Escherichia coli growth and starvation over a time-course lasting two weeks. We have measured multiple cellular components, including RNA and proteins at deep genomic coverage, as well as lipid modifications and flux through central metabolism. Our study focuses on the physiological response of E . coli in stationary phase as a result of being starved for glucose, not on the genetic adaptation of E . coli to utilize alternative nutrients. In our analysis, we have taken advantage of the temporal correlations within and among RNA and protein abundances to identify systematic trends in gene regulation. Specifically, we have developed a general computational strategy for classifying expression-profile time courses into distinct categories in an unbiased manner. We have also developed, from dynamic models of gene expression, a framework to characterize protein degradation patterns based on the observed temporal relationships between mRNA and protein abundances. By comparing and contrasting our transcriptomic and proteomic data, we have identified several broad physiological trends in the E . coli starvation response. Strikingly, mRNAs are widely down-regulated in response to glucose starvation, presumably as a strategy for reducing new protein synthesis. By contrast, protein abundances display more varied responses. The abundances of many proteins involved in energy-intensive processes mirror the corresponding mRNA profiles while proteins involved in nutrient metabolism remain abundant even though their corresponding mRNAs are down-regulated.

Description: by Shaun S. Sanders, Dale D. O. Martin, Stefanie L. Butland, Mathieu Lavallée-Adam, Diego Calzolari, Chris Kay, John R. Yates, Michael R. Hayden Palmitoylation involves the reversible posttranslational addition of palmitate to cysteines and promotes membrane binding and subcellular localization. Recent advancements in the detection and identification of palmitoylated proteins have led to multiple palmitoylation proteomics studies but these datasets are contained within large supplemental tables, making downstream analysis and data mining time-consuming and difficult. Consequently, we curated the data from 15 palmitoylation proteomics studies into one compendium containing 1,838 genes encoding palmitoylated proteins; representing approximately 10% of the genome. Enrichment analysis revealed highly significant enrichments for Gene Ontology biological processes, pathway maps, and process networks related to the nervous system. Strikingly, 41% of synaptic genes encode a palmitoylated protein in the compendium. The top disease associations included cancers and diseases and disorders of the nervous system, with Schizophrenia, HD, and pancreatic ductal carcinoma among the top five, suggesting that aberrant palmitoylation may play a pivotal role in the balance of cell death and survival. This compendium provides a much-needed resource for cell biologists and the palmitoylation field, providing new perspectives for cancer and neurodegeneration.

Description: by Liat Rockah-Shmuel, Ágnes Tóth-Petróczy, Dan S. Tawfik Systematic mappings of the effects of protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins are tolerant to most amino acid substitutions, including substitutions in positions that are highly conserved in nature. To obtain a more realistic distribution of the effects of protein mutations, we applied a laboratory drift comprising 17 rounds of random mutagenesis and selection of M.HaeIII, a DNA methyltransferase. During this drift, multiple mutations gradually accumulated. Deep sequencing of the drifted gene ensembles allowed determination of the relative effects of all possible single nucleotide mutations. Despite being averaged across many different genetic backgrounds, about 67% of all nonsynonymous, missense mutations were evidently deleterious, and an additional 16% were likely to be deleterious. In the early generations, the frequency of most deleterious mutations remained high. However, by the 17th generation, their frequency was consistently reduced, and those remaining were accepted alongside compensatory mutations. The tolerance to mutations measured in this laboratory drift correlated with sequence exchanges seen in M.HaeIII’s natural orthologs. The biophysical constraints dictating purging in nature and in this laboratory drift also seemed to overlap. Our experiment therefore provides an improved method for measuring the effects of protein mutations that more closely replicates the natural evolutionary forces, and thereby a more realistic view of the mutational space of proteins.

Description: by Shuai Yuan, H. Richard Johnston, Guosheng Zhang, Yun Li, Yi-Juan Hu, Zhaohui S. Qin With rapid decline of the sequencing cost, researchers today rush to embrace whole genome sequencing (WGS), or whole exome sequencing (WES) approach as the next powerful tool for relating genetic variants to human diseases and phenotypes. A fundamental step in analyzing WGS and WES data is mapping short sequencing reads back to the reference genome. This is an important issue because incorrectly mapped reads affect the downstream variant discovery, genotype calling and association analysis. Although many read mapping algorithms have been developed, the majority of them uses the universal reference genome and do not take sequence variants into consideration. Given that genetic variants are ubiquitous, it is highly desirable if they can be factored into the read mapping procedure. In this work, we developed a novel strategy that utilizes genotypes obtained a priori to customize the universal haploid reference genome into a personalized diploid reference genome. The new strategy is implemented in a program named RefEditor. When applying RefEditor to real data, we achieved encouraging improvements in read mapping, variant discovery and genotype calling. Compared to standard approaches, RefEditor can significantly increase genotype calling consistency (from 43% to 61% at 4X coverage; from 82% to 92% at 20X coverage) and reduce Mendelian inconsistency across various sequencing depths. Because many WGS and WES studies are conducted on cohorts that have been genotyped using array-based genotyping platforms previously or concurrently, we believe the proposed strategy will be of high value in practice, which can also be applied to the scenario where multiple NGS experiments are conducted on the same cohort. The RefEditor sources are available at https://github.com/superyuan/refeditor.

Description: by Alexey A. Gritsenko, Marc Hulsman, Marcel J. T. Reinders, Dick de Ridder Translation of RNA to protein is a core process for any living organism. While for some steps of this process the effect on protein production is understood, a holistic understanding of translation still remains elusive. In silico modelling is a promising approach for elucidating the process of protein synthesis. Although a number of computational models of the process have been proposed, their application is limited by the assumptions they make. Ribosome profiling (RP), a relatively new sequencing-based technique capable of recording snapshots of the locations of actively translating ribosomes, is a promising source of information for deriving unbiased data-driven translation models. However, quantitative analysis of RP data is challenging due to high measurement variance and the inability to discriminate between the number of ribosomes measured on a gene and their speed of translation. We propose a solution in the form of a novel multi-scale interpretation of RP data that allows for deriving models with translation dynamics extracted from the snapshots. We demonstrate the usefulness of this approach by simultaneously determining for the first time per-codon translation elongation and per-gene translation initiation rates of Saccharomyces cerevisiae from RP data for two versions of the Totally Asymmetric Exclusion Process (TASEP) model of translation. We do this in an unbiased fashion, by fitting the models using only RP data with a novel optimization scheme based on Monte Carlo simulation to keep the problem tractable. The fitted models match the data significantly better than existing models and their predictions show better agreement with several independent protein abundance datasets than existing models. Results additionally indicate that the tRNA pool adaptation hypothesis is incomplete, with evidence suggesting that tRNA post-transcriptional modifications and codon context may play a role in determining codon elongation rates.

Description: by Santiago Schnell

Description: by Alexander Ullrich, Mathias A. Böhme, Johannes Schöneberg, Harald Depner, Stephan J. Sigrist, Frank Noé Synaptic vesicle fusion is mediated by SNARE proteins forming in between synaptic vesicle (v-SNARE) and plasma membrane (t-SNARE), one of which is Syntaxin-1A. Although exocytosis mainly occurs at active zones, Syntaxin-1A appears to cover the entire neuronal membrane. By using STED super-resolution light microscopy and image analysis of Drosophila neuro-muscular junctions, we show that Syntaxin-1A clusters are more abundant and have an increased size at active zones. A computational particle-based model of syntaxin cluster formation and dynamics is developed. The model is parametrized to reproduce Syntaxin cluster-size distributions found by STED analysis, and successfully reproduces existing FRAP results. The model shows that the neuronal membrane is adjusted in a way to strike a balance between having most syntaxins stored in large clusters, while still keeping a mobile fraction of syntaxins free or in small clusters that can efficiently search the membrane or be traded between clusters. This balance is subtle and can be shifted toward almost no clustering and almost complete clustering by modifying the syntaxin interaction energy on the order of only 1 k B T. This capability appears to be exploited at active zones. The larger active-zone syntaxin clusters are more stable and provide regions of high docking and fusion capability, whereas the smaller clusters outside may serve as flexible reserve pool or sites of spontaneous ectopic release.

Description: by Stephan Köhler, Friederike Schmid, Giovanni Settanni Fibrinogen is a serum multi-chain protein which, when activated, aggregates to form fibrin, one of the main components of a blood clot. Fibrinolysis controls blood clot dissolution through the action of the enzyme plasmin, which cleaves fibrin at specific locations. Although the main biochemical factors involved in fibrin formation and lysis have been identified, a clear mechanistic picture of how these processes take place is not available yet. This picture would be instrumental, for example, for the design of improved thrombolytic or anti-haemorrhagic strategies, as well as, materials with improved biocompatibility. Here, we present extensive molecular dynamics simulations of fibrinogen which reveal large bending motions centered at a hinge point in the coiled-coil regions of the molecule. This feature, likely conserved across vertebrates according to our analysis, suggests an explanation for the mechanism of exposure to lysis of the plasmin cleavage sites on fibrinogen coiled-coil region. It also explains the conformational variability of fibrinogen observed during its adsorption on inorganic surfaces and it is supposed to play a major role in the determination of the hydrodynamic properties of fibrinogen. In addition the simulations suggest how the dynamics of the D region of fibrinogen may contribute to the allosteric regulation of the blood coagulation cascade through a dynamic coupling between the a- and b-holes, important for fibrin polymerization, and the integrin binding site P1.

Description: by Sergei Maslov, Kim Sneppen Populations of species in ecosystems are often constrained by availability of resources within their environment. In effect this means that a growth of one population, needs to be balanced by comparable reduction in populations of others. In neutral models of biodiversity all populations are assumed to change incrementally due to stochastic births and deaths of individuals. Here we propose and model another redistribution mechanism driven by abrupt and severe reduction in size of the population of a single species freeing up resources for the remaining ones. This mechanism may be relevant e.g. for communities of bacteria, with strain-specific collapses caused e.g. by invading bacteriophages, or for other ecosystems where infectious diseases play an important role. The emergent dynamics of our system is characterized by cyclic ‘‘diversity waves’’ triggered by collapses of globally dominating populations. The population diversity peaks at the beginning of each wave and exponentially decreases afterwards. Species abundances have bimodal time-aggregated distribution with the lower peak formed by populations of recently collapsed or newly introduced species while the upper peak - species that has not yet collapsed in the current wave. In most waves both upper and lower peaks are composed of several smaller peaks. This self-organized hierarchical peak structure has a long-term memory transmitted across several waves. It gives rise to a scale-free tail of the time-aggregated population distribution with a universal exponent of 1.7. We show that diversity wave dynamics is robust with respect to variations in the rules of our model such as diffusion between multiple environments, species-specific growth and extinction rates, and bet-hedging strategies.

Description: In this paper we investigate some parallel variants of Broyden’s method and, for the basic variant, we present its convergence properties. The main result is that the behavior of the considered parallel Broyden’s variants is comparable with the classical parallel Newton method, and significantly better than the parallel Cimmino method, both for linear and nonlinear cases. The considered variants are also compared with two more recently proposed parallel Broyden’s method. Some numerical experiments are presented to illustrate the advantages and limits of the proposed algorithms.

Description: by Hannah Edwards, Charlotte M. Deane Several protein structure classification schemes exist that partition the protein universe into structural units called folds. Yet these schemes do not discuss how these units sit relative to each other in a global structure space. In this paper we construct networks that describe such global relationships between folds in the form of structural bridges. We generate these networks using four different structural alignment methods across multiple score thresholds. The networks constructed using the different methods remain a similar distance apart regardless of the probability threshold defining a structural bridge. This suggests that at least some structural bridges are method specific and that any attempt to build a picture of structural space should not be reliant on a single structural superposition method. Despite these differences all representations agree on an organisation of fold space into five principal community structures: all- α , all- β sandwiches, all- β barrels, α / β and α + β . We project estimated fold ages onto the networks and find that not only are the pairings of unconnected folds associated with higher age differences than bridged folds, but this difference increases with the number of networks displaying an edge. We also examine different centrality measures for folds within the networks and how these relate to fold age. While these measures interpret the central core of fold space in varied ways they all identify the disposition of ancestral folds to fall within this core and that of the more recently evolved structures to provide the peripheral landscape. These findings suggest that evolutionary information is encoded along these structural bridges. Finally, we identify four highly central pivotal folds representing dominant topological features which act as key attractors within our landscapes.

Description: by Ayal Lavi, Omri Perez, Uri Ashery Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level.

Description: by Michael A. Cerullo

Description: by Jasmine Foo, Lin L Liu, Kevin Leder, Markus Riester, Yoh Iwasa, Christoph Lengauer, Franziska Michor The traditional view of cancer as a genetic disease that can successfully be treated with drugs targeting mutant onco-proteins has motivated whole-genome sequencing efforts in many human cancer types. However, only a subset of mutations found within the genomic landscape of cancer is likely to provide a fitness advantage to the cell. Distinguishing such “driver” mutations from innocuous “passenger” events is critical for prioritizing the validation of candidate mutations in disease-relevant models. We design a novel statistical index, called the Hitchhiking Index, which reflects the probability that any observed candidate gene is a passenger alteration, given the frequency of alterations in a cross-sectional cancer sample set, and apply it to a mutational data set in colorectal cancer. Our methodology is based upon a population dynamics model of mutation accumulation and selection in colorectal tissue prior to cancer initiation as well as during tumorigenesis. This methodology can be used to aid in the prioritization of candidate mutations for functional validation and contributes to the process of drug discovery.

Description: by Héctor García Martín, Vinay Satish Kumar, Daniel Weaver, Amit Ghosh, Victor Chubukov, Aindrila Mukhopadhyay, Adam Arkin, Jay D. Keasling Current limitations in quantitatively predicting biological behavior hinder our efforts to engineer biological systems to produce biofuels and other desired chemicals. Here, we present a new method for calculating metabolic fluxes, key targets in metabolic engineering, that incorporates data from 13 C labeling experiments and genome-scale models. The data from 13 C labeling experiments provide strong flux constraints that eliminate the need to assume an evolutionary optimization principle such as the growth rate optimization assumption used in Flux Balance Analysis (FBA). This effective constraining is achieved by making the simple but biologically relevant assumption that flux flows from core to peripheral metabolism and does not flow back. The new method is significantly more robust than FBA with respect to errors in genome-scale model reconstruction. Furthermore, it can provide a comprehensive picture of metabolite balancing and predictions for unmeasured extracellular fluxes as constrained by 13 C labeling data. A comparison shows that the results of this new method are similar to those found through 13 C Metabolic Flux Analysis ( 13 C MFA) for central carbon metabolism but, additionally, it provides flux estimates for peripheral metabolism. The extra validation gained by matching 48 relative labeling measurements is used to identify where and why several existing COnstraint Based Reconstruction and Analysis (COBRA) flux prediction algorithms fail. We demonstrate how to use this knowledge to refine these methods and improve their predictive capabilities. This method provides a reliable base upon which to improve the design of biological systems.

Description: by Julia C. Quindlen, Victor K. Lai, Victor H. Barocas Cutaneous mechanoreceptors transduce different tactile stimuli into neural signals that produce distinct sensations of touch. The Pacinian corpuscle (PC), a cutaneous mechanoreceptor located deep within the dermis of the skin, detects high frequency vibrations that occur within its large receptive field. The PC is comprised of lamellae that surround the nerve fiber at its core. We hypothesized that a layered, anisotropic structure, embedded deep within the skin, would produce the nonlinear strain transmission and low spatial sensitivity characteristic of the PC. A multiscale finite-element model was used to model the equilibrium response of the PC to indentation. The first simulation considered an isolated PC with fiber networks aligned with the PC’s surface. The PC was subjected to a 10 μm indentation by a 250 μm diameter indenter. The multiscale model captured the nonlinear strain transmission through the PC, predicting decreased compressive strain with proximity to the receptor’s core, as seen experimentally by others. The second set of simulations considered a single PC embedded epidermally (shallow) or dermally (deep) to model the PC’s location within the skin. The embedded models were subjected to 10 μm indentations at a series of locations on the surface of the skin. Strain along the long axis of the PC was calculated after indentation to simulate stretch along the nerve fiber at the center of the PC. Receptive fields for the epidermis and dermis models were constructed by mapping the long-axis strain after indentation at each point on the surface of the skin mesh. The dermis model resulted in a larger receptive field, as the calculated strain showed less indenter location dependence than in the epidermis model.

Description: by Vipin Narang, Muhamad Azfar Ramli, Amit Singhal, Pavanish Kumar, Gennaro de Libero, Michael Poidinger, Christopher Monterola Human gene regulatory networks (GRN) can be difficult to interpret due to a tangle of edges interconnecting thousands of genes. We constructed a general human GRN from extensive transcription factor and microRNA target data obtained from public databases. In a subnetwork of this GRN that is active during estrogen stimulation of MCF-7 breast cancer cells, we benchmarked automated algorithms for identifying core regulatory genes (transcription factors and microRNAs). Among these algorithms, we identified K-core decomposition, pagerank and betweenness centrality algorithms as the most effective for discovering core regulatory genes in the network evaluated based on previously known roles of these genes in MCF-7 biology as well as in their ability to explain the up or down expression status of up to 70% of the remaining genes. Finally, we validated the use of K-core algorithm for organizing the GRN in an easier to interpret layered hierarchy where more influential regulatory genes percolate towards the inner layers. The integrated human gene and miRNA network and software used in this study are provided as supplementary materials (S1 Data) accompanying this manuscript.

Description: by Jianfei Hu, Johnathan Neiswinger, Jin Zhang, Heng Zhu, Jiang Qian Scaffold proteins play a crucial role in facilitating signal transduction in eukaryotes by bringing together multiple signaling components. In this study, we performed a systematic analysis of scaffold proteins in signal transduction by integrating protein-protein interaction and kinase-substrate relationship networks. We predicted 212 scaffold proteins that are involved in 605 distinct signaling pathways. The computational prediction was validated using a protein microarray-based approach. The predicted scaffold proteins showed several interesting characteristics, as we expected from the functionality of scaffold proteins. We found that the scaffold proteins are likely to interact with each other, which is consistent with previous finding that scaffold proteins tend to form homodimers and heterodimers. Interestingly, a single scaffold protein can be involved in multiple signaling pathways by interacting with other scaffold protein partners. Furthermore, we propose two possible regulatory mechanisms by which the activity of scaffold proteins is coordinated with their associated pathways through phosphorylation process.

Description: by Vassilios Christopoulos, Paul R. Schrater Decisions involve two fundamental problems, selecting goals and generating actions to pursue those goals. While simple decisions involve choosing a goal and pursuing it, humans evolved to survive in hostile dynamic environments where goal availability and value can change with time and previous actions, entangling goal decisions with action selection. Recent studies suggest the brain generates concurrent action-plans for competing goals, using online information to bias the competition until a single goal is pursued. This creates a challenging problem of integrating information across diverse types, including both the dynamic value of the goal and the costs of action. We model the computations underlying dynamic decision-making with disparate value types, using the probability of getting the highest pay-off with the least effort as a common currency that supports goal competition. This framework predicts many aspects of decision behavior that have eluded a common explanation.

Description: by Chakravarthy Marella, Andrew E. Torda, Dominik Schwudke A lipidome is the set of lipids in a given organism, cell or cell compartment and this set reflects the organism’s synthetic pathways and interactions with its environment. Recently, lipidomes of biological model organisms and cell lines were published and the number of functional studies of lipids is increasing. In this study we propose a homology metric that can quantify systematic differences in the composition of a lipidome. Algorithms were developed to 1. consistently convert lipids structure into SMILES, 2. determine structural similarity between molecular species and 3. describe a lipidome in a chemical space model. We tested lipid structure conversion and structure similarity metrics, in detail, using sets of isomeric ceramide molecules and chemically related phosphatidylinositols. Template-based SMILES showed the best properties for representing lipid-specific structural diversity. We also show that sequence analysis algorithms are best suited to calculate distances between such template-based SMILES and we adjudged the Levenshtein distance as best choice for quantifying structural changes. When all lipid molecules of the LIPIDMAPS structure database were mapped in chemical space, they automatically formed clusters corresponding to conventional chemical families. Accordingly, we mapped a pair of lipidomes into the same chemical space and determined the degree of overlap by calculating the Hausdorff distance. We named this metric the ‘Lipidome jUXtaposition (LUX) score’. First, we tested this approach for estimating the lipidome similarity on four yeast strains with known genetic alteration in fatty acid synthesis. We show that the LUX score reflects the genetic relationship and growth temperature better than conventional methods although the score is based solely on lipid structures. Next, we applied this metric to high-throughput data of larval tissue lipidomes of Drosophila. This showed that the LUX score is sufficient to cluster tissues and determine the impact of nutritional changes in an unbiased manner, despite the limited information on the underlying structural diversity of each lipidome. This study is the first effort to define a lipidome homology metric based on structures that will enrich functional association of lipids in a similar manner to measures used in genetics. Finally, we discuss the significance of the LUX score to perform comparative lipidome studies across species borders.

Description: by Noah Ollikainen, René M. de Jong, Tanja Kortemme Interactions between small molecules and proteins play critical roles in regulating and facilitating diverse biological functions, yet our ability to accurately re-engineer the specificity of these interactions using computational approaches has been limited. One main difficulty, in addition to inaccuracies in energy functions, is the exquisite sensitivity of protein–ligand interactions to subtle conformational changes, coupled with the computational problem of sampling the large conformational search space of degrees of freedom of ligands, amino acid side chains, and the protein backbone. Here, we describe two benchmarks for evaluating the accuracy of computational approaches for re-engineering protein-ligand interactions: (i) prediction of enzyme specificity altering mutations and (ii) prediction of sequence tolerance in ligand binding sites. After finding that current state-of-the-art “fixed backbone” design methods perform poorly on these tests, we develop a new “coupled moves” design method in the program Rosetta that couples changes to protein sequence with alterations in both protein side-chain and protein backbone conformations, and allows for changes in ligand rigid-body and torsion degrees of freedom. We show significantly increased accuracy in both predicting ligand specificity altering mutations and binding site sequences. These methodological improvements should be useful for many applications of protein – ligand design. The approach also provides insights into the role of subtle conformational adjustments that enable functional changes not only in engineering applications but also in natural protein evolution.

Description: by Pete Riley, Michal Ben-Nun, Jon A. Linker, Angelia A. Cost, Jose L. Sanchez, Dylan George, David P. Bacon, Steven Riley The potential rapid availability of large-scale clinical episode data during the next influenza pandemic suggests an opportunity for increasing the speed with which novel respiratory pathogens can be characterized. Key intervention decisions will be determined by both the transmissibility of the novel strain (measured by the basic reproductive number R 0 ) and its individual-level severity. The 2009 pandemic illustrated that estimating individual-level severity, as described by the proportion p C of infections that result in clinical cases, can remain uncertain for a prolonged period of time. Here, we use 50 distinct US military populations during 2009 as a retrospective cohort to test the hypothesis that real-time encounter data combined with disease dynamic models can be used to bridge this uncertainty gap. Effectively, we estimated the total number of infections in multiple early-affected communities using the model and divided that number by the known number of clinical cases. Joint estimates of severity and transmissibility clustered within a relatively small region of parameter space, with 40 of the 50 populations bounded by: p C , 0.0133–0.150 and R 0 , 1.09–2.16. These fits were obtained despite widely varying incidence profiles: some with spring waves, some with fall waves and some with both. To illustrate the benefit of specific pairing of rapidly available data and infectious disease models, we simulated a future moderate pandemic strain with p C approximately ×10 that of 2009; the results demonstrating that even before the peak had passed in the first affected population, R 0 and p C could be well estimated. This study provides a clear reference in this two-dimensional space against which future novel respiratory pathogens can be rapidly assessed and compared with previous pandemics.

Description: The sign least mean square with reweighted L1-norm constraint (SLMS-RL1) algorithm is an attractive sparse channel estimation method among Gaussian mixture model (GMM) based algorithms for use in impulsive noise environments. The channel sparsity can be exploited by SLMS-RL1 algorithm based on appropriate reweighted factor, which is one of key parameters to adjust the sparse constraint for SLMS-RL1 algorithm. However, to the best of the authors’ knowledge, a reweighted factor selection scheme has not been developed. This paper proposes a Monte-Carlo (MC) based reweighted factor selection method to further strengthen the performance of SLMS-RL1 algorithm. To validate the performance of SLMS-RL1 using the proposed reweighted factor, simulations results are provided to demonstrate that convergence speed can be reduced by increasing the channel sparsity, while the steady-state MSE performance only slightly changes with different GMM impulsive-noise strengths.

Description: by Gang Li, Karen E. Ross, Cecilia N. Arighi, Yifan Peng, Cathy H. Wu, K. Vijay-Shanker MicroRNAs (miRNAs) regulate a wide range of cellular and developmental processes through gene expression suppression or mRNA degradation. Experimentally validated miRNA gene targets are often reported in the literature. In this paper, we describe miRTex, a text mining system that extracts miRNA-target relations, as well as miRNA-gene and gene-miRNA regulation relations. The system achieves good precision and recall when evaluated on a literature corpus of 150 abstracts with F-scores close to 0.90 on the three different types of relations. We conducted full-scale text mining using miRTex to process all the Medline abstracts and all the full-length articles in the PubMed Central Open Access Subset. The results for all the Medline abstracts are stored in a database for interactive query and file download via the website at http://proteininformationresource.org/mirtex. Using miRTex, we identified genes potentially regulated by miRNAs in Triple Negative Breast Cancer, as well as miRNA-gene relations that, in conjunction with kinase-substrate relations, regulate the response to abiotic stress in Arabidopsis thaliana . These two use cases demonstrate the usefulness of miRTex text mining in the analysis of miRNA-regulated biological processes.

Description: by Greg Jensen, Fabian Muñoz, Yelda Alkan, Vincent P. Ferrera, Herbert S. Terrace Transitive inference (the ability to infer that B 〉 D given that B 〉 C and C 〉 D ) is a widespread characteristic of serial learning, observed in dozens of species. Despite these robust behavioral effects, reinforcement learning models reliant on reward prediction error or associative strength routinely fail to perform these inferences. We propose an algorithm called betasort , inspired by cognitive processes, which performs transitive inference at low computational cost. This is accomplished by (1) representing stimulus positions along a unit span using beta distributions, (2) treating positive and negative feedback asymmetrically, and (3) updating the position of every stimulus during every trial, whether that stimulus was visible or not. Performance was compared for rhesus macaques, humans, and the betasort algorithm, as well as Q -learning, an established reward-prediction error (RPE) model. Of these, only Q -learning failed to respond above chance during critical test trials. Betasort’s success (when compared to RPE models) and its computational efficiency (when compared to full Markov decision process implementations) suggests that the study of reinforcement learning in organisms will be best served by a feature-driven approach to comparing formal models.

Description: by Alberto Romagnoni, Jérôme Ribot, Daniel Bennequin, Jonathan Touboul The layout of sensory brain areas is thought to subtend perception. The principles shaping these architectures and their role in information processing are still poorly understood. We investigate mathematically and computationally the representation of orientation and spatial frequency in cat primary visual cortex. We prove that two natural principles, local exhaustivity and parsimony of representation, would constrain the orientation and spatial frequency maps to display a very specific pinwheel-dipole singularity. This is particularly interesting since recent experimental evidences show a dipolar structures of the spatial frequency map co-localized with pinwheels in cat. These structures have important properties on information processing capabilities. In particular, we show using a computational model of visual information processing that this architecture allows a trade-off in the local detection of orientation and spatial frequency, but this property occurs for spatial frequency selectivity sharper than reported in the literature. We validated this sharpening on high-resolution optical imaging experimental data. These results shed new light on the principles at play in the emergence of functional architecture of cortical maps, as well as their potential role in processing information.

Description: by Kimberly Glass, Michelle Girvan The Gene Ontology (GO) provides biologists with a controlled terminology that describes how genes are associated with functions and how functional terms are related to one another. These term-term relationships encode how scientists conceive the organization of biological functions, and they take the form of a directed acyclic graph (DAG). Here, we propose that the network structure of gene-term annotations made using GO can be employed to establish an alternative approach for grouping functional terms that captures intrinsic functional relationships that are not evident in the hierarchical structure established in the GO DAG. Instead of relying on an externally defined organization for biological functions, our approach connects biological functions together if they are performed by the same genes, as indicated in a compendium of gene annotation data from numerous different sources. We show that grouping terms by this alternate scheme provides a new framework with which to describe and predict the functions of experimentally identified sets of genes.

Description: by Robert P. Jenkins, Anja Hanisch, Cristian Soza-Ried, Erik Sahai, Julian Lewis The somite segmentation clock is a robust oscillator used to generate regularly-sized segments during early vertebrate embryogenesis. It has been proposed that the clocks of neighbouring cells are synchronised via inter-cellular Notch signalling, in order to overcome the effects of noisy gene expression. When Notch-dependent communication between cells fails, the clocks of individual cells operate erratically and lose synchrony over a period of about 5 to 8 segmentation clock cycles (2–3 hours in the zebrafish). Here, we quantitatively investigate the effects of stochasticity on cell synchrony, using mathematical modelling, to investigate the likely source of such noise. We find that variations in the transcription, translation and degradation rate of key Notch signalling regulators do not explain the in vivo kinetics of desynchronisation. Rather, the analysis predicts that clock desynchronisation, in the absence of Notch signalling, is due to the stochastic dissociation of Her1/7 repressor proteins from the oscillating her1/7 autorepressed target genes. Using in situ hybridisation to visualise sites of active her1 transcription, we measure an average delay of approximately three minutes between the times of activation of the two her1 alleles in a cell. Our model shows that such a delay is sufficient to explain the in vivo rate of clock desynchronisation in Notch pathway mutant embryos and also that Notch-mediated synchronisation is sufficient to overcome this stochastic variation. This suggests that the stochastic nature of repressor/DNA dissociation is the major source of noise in the segmentation clock.

Description: by Maciej Jan Ejsmond, Jacek Radwan Major Histocompatibility Complex (MHC) genes code for proteins involved in the incitation of the adaptive immune response in vertebrates, which is achieved through binding oligopeptides (antigens) of pathogenic origin. Across vertebrate species, substitutions of amino acids at sites responsible for the specificity of antigen binding (ABS) are positively selected. This is attributed to pathogen-driven balancing selection, which is also thought to maintain the high polymorphism of MHC genes, and to cause the sharing of allelic lineages between species. However, the nature of this selection remains controversial. We used individual-based computer simulations to investigate the roles of two phenomena capable of maintaining MHC polymorphism: heterozygote advantage and host-pathogen arms race (Red Queen process). Our simulations revealed that levels of MHC polymorphism were high and driven mostly by the Red Queen process at a high pathogen mutation rate, but were low and driven mostly by heterozygote advantage when the pathogen mutation rate was low. We found that novel mutations at ABSs are strongly favored by the Red Queen process, but not by heterozygote advantage, regardless of the pathogen mutation rate. However, while the strong advantage of novel alleles increased the allele turnover rate, under a high pathogen mutation rate, allelic lineages persisted for a comparable length of time under Red Queen and under heterozygote advantage. Thus, when pathogens evolve quickly, the Red Queen is capable of explaining both positive selection and long coalescence times, but the tension between the novel allele advantage and persistence of alleles deserves further investigation.