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Visual selective attention acts as a filter on perceptual information, facilitating learning and inference about important events in an agent's environment. A role for visual attention in reward-based decisions has previously been demonstrated, but it remains unclear how visual attention is recruited during aversive learning, particularly when learning about multiple stimuli concurrently. This question is of particular importance in psychopathology, where enhanced attention to threat is a putative feature of pathological anxiety. Using an aversive reversal learning task that required subjects to learn, and exploit, predictions about multiple stimuli, we show that the allocation of visual attention is influenced significantly by aversive value but not by uncertainty. Moreover, this relationship is bidirectional in that attention biases value updates for attended stimuli, resulting in heightened value estimates. Our findings have implications for understanding biased attention in psychopathology and support a role for learning in the expression of threat-related attentional biases in anxiety. [ABSTRACT FROM AUTHOR]

Guanylate binding proteins (GBPs) belong to the dynamin-related superfamily and exhibit various functions in the fight against infections. The functions of the human guanylate binding protein 1 (hGBP1) are tightly coupled to GTP hydrolysis and dimerization. Despite known crystal structures of the hGBP1 monomer and GTPase domain dimer, little is known about the dynamics of hGBP1. To gain a mechanistic understanding of hGBP1, we performed sub-millisecond multi-resolution molecular dynamics simulations of both the hGBP1 monomer and dimer. We found that hGBP1 is a highly flexible protein that undergoes a hinge motion similar to the movements observed for other dynamin-like proteins. Another large-scale motion was observed for the C-terminal helix α13, providing a molecular view for the α13–α13 distances previously reported for the hGBP1 dimer. Most of the loops of the GTPase domain were found to be flexible, revealing why GTP binding is needed for hGBP1 dimerization to occur. [ABSTRACT FROM AUTHOR]

Deficits in the ankle plantarflexor muscles, such as weakness and contracture, occur commonly in conditions such as cerebral palsy, stroke, muscular dystrophy, Charcot-Marie-Tooth disease, and sarcopenia. While these deficits likely contribute to observed gait pathologies, determining cause-effect relationships is difficult due to the often co-occurring biomechanical and neural deficits. To elucidate the effects of weakness and contracture, we systematically introduced isolated deficits into a musculoskeletal model and generated simulations of walking to predict gait adaptations due to these deficits. We trained a planar model containing 9 degrees of freedom and 18 musculotendon actuators to walk using a custom optimization framework through which we imposed simple objectives, such as minimizing cost of transport while avoiding falling and injury, and maintaining head stability. We first generated gaits at prescribed speeds between 0.50 m/s and 2.00 m/s that reproduced experimentally observed kinematic, kinetic, and metabolic trends for walking. We then generated a gait at self-selected walking speed; quantitative comparisons between our simulation and experimental data for joint angles, joint moments, and ground reaction forces showed root-mean-squared errors of less than 1.6 standard deviations and normalized cross-correlations above 0.8 except for knee joint moment trajectories. Finally, we applied mild, moderate, and severe levels of muscle weakness or contracture to either the soleus (SOL) or gastrocnemius (GAS) or both of these major plantarflexors (PF) and retrained the model to walk at a self-selected speed. The model was robust to all deficits, finding a stable gait in all cases. Severe PF weakness caused the model to adopt a slower, "heel-walking" gait. Severe contracture of only SOL or both PF yielded similar results: the model adopted a "toe-walking" gait with excessive hip and knee flexion during stance. These results highlight how plantarflexor weakness and contracture may contribute to observed gait patterns. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the “line of equistimulation;” this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study. [ABSTRACT FROM AUTHOR]

Given the association of disturbances in non-esterified fatty acid (NEFA) metabolism with the development of Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, computational models of glucose-insulin dynamics have been extended to account for the interplay with NEFA. In this study, we use arteriovenous measurement across the subcutaneous adipose tissue during a mixed meal challenge test to evaluate the performance and underlying assumptions of three existing models of adipose tissue metabolism and construct a new, refined model of adipose tissue metabolism. Our model introduces new terms, explicitly accounting for the conversion of glucose to glyceraldehye-3-phosphate, the postprandial influx of glycerol into the adipose tissue, and several physiologically relevant delays in insulin signalling in order to better describe the measured adipose tissues fluxes. We then applied our refined model to human adipose tissue flux data collected before and after a diet intervention as part of the Yoyo study, to quantify the effects of caloric restriction on postprandial adipose tissue metabolism. Significant increases were observed in the model parameters describing the rate of uptake and release of both glycerol and NEFA. Additionally, decreases in the model’s delay in insulin signalling parameters indicates there is an improvement in adipose tissue insulin sensitivity following caloric restriction. [ABSTRACT FROM AUTHOR]

Seasonal influenza is a sometimes surprisingly impactful disease, causing thousands of deaths per year along with much additional morbidity. Timely knowledge of the outbreak state is valuable for managing an effective response. The current state of the art is to gather this knowledge using in-person patient contact. While accurate, this is time-consuming and expensive. This has motivated inquiry into new approaches using internet activity traces, based on the theory that lay observations of health status lead to informative features in internet data. These approaches risk being deceived by activity traces having a coincidental, rather than informative, relationship to disease incidence; to our knowledge, this risk has not yet been quantitatively explored. We evaluated both simulated and real activity traces of varying deceptiveness for influenza incidence estimation using linear regression. We found that deceptiveness knowledge does reduce error in such estimates, that it may help automatically-selected features perform as well or better than features that require human curation, and that a semantic distance measure derived from the Wikipedia article category tree serves as a useful proxy for deceptiveness. This suggests that disease incidence estimation models should incorporate not only data about how internet features map to incidence but also additional data to estimate feature deceptiveness. By doing so, we may gain one more step along the path to accurate, reliable disease incidence estimation using internet data. This capability would improve public health by decreasing the cost and increasing the timeliness of such estimates. [ABSTRACT FROM AUTHOR]

Achieving global food security for the estimated 9 billion people by 2050 is a major scientific challenge. Crop productivity is fundamentally restricted by the rate of fixation of atmospheric carbon. The dedicated enzyme, RubisCO, has a low turnover and poor specificity for CO2. This limitation of C3 photosynthesis (the basic carbon-assimilation pathway present in all plants) is alleviated in some lineages by use of carbon-concentrating-mechanisms, such as the C4 cycle—a biochemical pump that concentrates CO2 near RubisCO increasing assimilation efficacy. Most crops use only C3 photosynthesis, so one promising research strategy to boost their productivity focuses on introducing a C4 cycle. The simplest proposal is to use the cycle to concentrate CO2 inside individual chloroplasts. The photosynthetic efficiency would then depend on the leakage of CO2 out of a chloroplast. We examine this proposal with a 3D spatial model of carbon and oxygen diffusion and C4 photosynthetic biochemistry inside a typical C3-plant mesophyll cell geometry. We find that the cost-efficiency of C4 photosynthesis depends on the gas permeability of the chloroplast envelope, the C4 pathway having higher quantum efficiency than C3 for permeabilities below 300 μm/s. However, at higher permeabilities the C4 pathway still provides a substantial boost to carbon assimilation with only a moderate decrease in efficiency. The gains would be capped by the ability of chloroplasts to harvest light, but even under realistic light regimes a 100% boost to carbon assimilation is possible. This could be achieved in conjunction with lower investment in chloroplasts if their cell surface coverage is also reduced. Incorporation of this C4 cycle into C3 crops could thus promote higher growth rates and better drought resistance in dry, high-sunlight climates. [ABSTRACT FROM AUTHOR]

Characterization of Human Endogenous Retrovirus (HERV) expression within the transcriptomic landscape using RNA-seq is complicated by uncertainty in fragment assignment because of sequence similarity. We present Telescope, a computational software tool that provides accurate estimation of transposable element expression (retrotranscriptome) resolved to specific genomic locations. Telescope directly addresses uncertainty in fragment assignment by reassigning ambiguously mapped fragments to the most probable source transcript as determined within a Bayesian statistical model. We demonstrate the utility of our approach through single locus analysis of HERV expression in 13 ENCODE cell types. When examined at this resolution, we find that the magnitude and breadth of the retrotranscriptome can be vastly different among cell types. Furthermore, our approach is robust to differences in sequencing technology, and demonstrates that the retrotranscriptome has potential to be used for cell type identification. We compared our tool with other approaches for quantifying TE expression, and found that Telescope has the greatest resolution, as it estimates expression at specific TE insertions rather than at the TE subfamily level. Telescope performs highly accurate quantification of the retrotranscriptomic landscape in RNA-seq experiments, revealing a differential complexity in the transposable element biology of complex systems not previously observed. Telescope is available at . [ABSTRACT FROM AUTHOR]

Cancer driver genes, i.e., oncogenes and tumor suppressor genes, are involved in the acquisition of important functions in tumors, providing a selective growth advantage, allowing uncontrolled proliferation and avoiding apoptosis. It is therefore important to identify these driver genes, both for the fundamental understanding of cancer and to help finding new therapeutic targets or biomarkers. Although the most frequently mutated driver genes have been identified, it is believed that many more remain to be discovered, particularly for driver genes specific to some cancer types. In this paper, we propose a new computational method called LOTUS to predict new driver genes. LOTUS is a machine-learning based approach which allows to integrate various types of data in a versatile manner, including information about gene mutations and protein-protein interactions. In addition, LOTUS can predict cancer driver genes in a pan-cancer setting as well as for specific cancer types, using a multitask learning strategy to share information across cancer types. We empirically show that LOTUS outperforms five other state-of-the-art driver gene prediction methods, both in terms of intrinsic consistency and prediction accuracy, and provide predictions of new cancer genes across many cancer types. [ABSTRACT FROM AUTHOR]

Although information theoretic approaches have been used extensively in the analysis of the neural code, they have yet to be used to describe how information is accumulated in time while sensory systems are categorizing dynamic sensory stimuli such as speech sounds or visual objects. Here, we present a novel method to estimate the cumulative information for stimuli or categories. We further define a time-varying categorical information index that, by comparing the information obtained for stimuli versus categories of these same stimuli, quantifies invariant neural representations. We use these methods to investigate the dynamic properties of avian cortical auditory neurons recorded in zebra finches that were listening to a large set of call stimuli sampled from the complete vocal repertoire of this species. We found that the time-varying rates carry 5 times more information than the mean firing rates even in the first 100 ms. We also found that cumulative information has slow time constants (100–600 ms) relative to the typical integration time of single neurons, reflecting the fact that the behaviorally informative features of auditory objects are time-varying sound patterns. When we correlated firing rates and information values, we found that average information correlates with average firing rate but that higher-rates found at the onset response yielded similar information values as the lower-rates found in the sustained response: the onset and sustained response of avian cortical auditory neurons provide similar levels of independent information about call identity and call-type. Finally, our information measures allowed us to rigorously define categorical neurons; these categorical neurons show a high degree of invariance for vocalizations within a call-type. Peak invariance is found around 150 ms after stimulus onset. Surprisingly, call-type invariant neurons were found in both primary and secondary avian auditory areas. [ABSTRACT FROM AUTHOR]

Recently available cancer sequencing data have revealed a complex view of the cancer genome containing a multitude of mutations, including drivers responsible for cancer progression and neutral passengers. Measuring selection in cancer and distinguishing drivers from passengers have important implications for development of novel treatment strategies. It has recently been argued that a third of cancers are evolving neutrally, as their mutational frequency spectrum follows a 1/f power law expected from neutral evolution in a particular intermediate frequency range. We study a stochastic model of cancer evolution and derive a formula for the probability distribution of the cancer cell frequency of a subclonal driver, demonstrating that driver frequency is biased towards 0 and 1. We show that it is difficult to capture a driver mutation at an intermediate frequency, and thus the calling of neutrality due to a lack of such driver will significantly overestimate the number of neutrally evolving tumors. Our approach provides precise quantification of the validity of the 1/f statistic across the entire range of all relevant parameter values. We also show that our conclusions remain valid for non-exponential models: spatial 3d model and sigmoidal growth, relevant for early- and late stages of cancer growth. [ABSTRACT FROM AUTHOR]

Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase. To explain cell decision making downstream of death receptor activation, we developed a semi-stochastic model of DISC/RIPoptosome formation. The model is a hybrid of a direct Gillespie stochastic simulation algorithm for slow assembly of the RIPoptosome and a deterministic model of downstream caspase activation. The model explains how alterations in the level of death receptor-ligand complexes, their clustering properties and intrinsic molecular fluctuations in RIPoptosome assembly drive heterogeneous dynamics of Caspase-8 activation. The model highlights how kinetic proofreading leads to heterogeneous cell responses and results in fractional cell killing at low levels of receptor stimulation. It reveals that the noise in Caspase-8 activation—exclusively caused by the stochastic molecular assembly of the DISC/RIPoptosome platform—has a key function in extrinsic apoptotic stimuli recognition. [ABSTRACT FROM AUTHOR]

Biological network figures are ubiquitous in the biology and medical literature. On the one hand, a good network figure can quickly provide information about the nature and degree of interactions between items and enable inferences about the reason for those interactions. On the other hand, good network figures are difficult to create. In this paper, we outline 10 simple rules for creating biological network figures for communication, from choosing layouts, to applying color or other channels to show attributes, to the use of layering and separation. These rules are accompanied by illustrative examples. We also provide a concise set of references and additional resources for each rule. [ABSTRACT FROM AUTHOR]

The co-evolutionary dynamics of competing populations can be strongly affected by frequency-dependent selection and spatial population structure. As co-evolving populations grow into a spatial domain, their initial spatial arrangement and their growth rate differences are important factors that determine the long-term outcome. We here model producer and free-rider co-evolution in the context of a diffusive public good (PG) that is produced by the producers at a cost but evokes local concentration-dependent growth benefits to all. The benefit of the PG can be non-linearly dependent on public good concentration. We consider the spatial growth dynamics of producers and free-riders in one, two and three dimensions by modeling producer cell, free-rider cell and public good densities in space, driven by the processes of birth, death and diffusion (cell movement and public good distribution). Typically, one population goes extinct, but the time-scale of this process varies with initial conditions and the growth rate functions. We establish that spatial variation is transient regardless of dimensionality, and that structured initial conditions lead to increasing times to get close to an extinction state, called ε-extinction time. Further, we find that uncorrelated initial spatial structures do not influence this ε-extinction time in comparison to a corresponding well-mixed (non-spatial) system. In order to estimate the ε-extinction time of either free-riders or producers we derive a slow manifold solution. For invading populations, i.e. for populations that are initially highly segregated, we observe a traveling wave, whose speed can be calculated. Our results provide quantitative predictions for the transient spatial dynamics of cooperative traits under pressure of extinction. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons (DAs) of the rodent substantia nigra pars compacta (SNc) display varied electrophysiological properties in vitro. Despite this, projection patterns and functional inputs from DAs to other structures are conserved, so in vivo delivery of consistent, well-timed dopamine modulation to downstream circuits must be coordinated. Here we show robust coordination by linear parameter controllers, discovered through powerful mathematical analyses of data and models, and from which consistent control of DA subthreshold oscillations (STOs) and spontaneous firing emerges. These units of control represent coordinated intracellular variables, sufficient to regulate complex cellular properties with radical simplicity. Using an evolutionary algorithm and dimensionality reduction, we discovered metaparameters, which when regressed against STO features, revealed a 2-dimensional control plane for the neuron’s 22-dimensional parameter space that fully maps the natural range of DA subthreshold electrophysiology. This plane provided a basis for spiking currents to reproduce a large range of the naturally occurring spontaneous firing characteristics of SNc DAs. From it we easily produced a unique population of models, derived using unbiased parameter search, that show good generalization to channel blockade and compensatory intracellular mechanisms. From this population of models, we then discovered low-dimensional controllers for regulating spontaneous firing properties, and gain insight into how currents active in different voltage regimes interact to produce the emergent activity of SNc DAs. Our methods therefore reveal simple regulators of neuronal function lurking in the complexity of combined ion channel dynamics. [ABSTRACT FROM AUTHOR]

Yellow fever is a vector-borne disease endemic in tropical regions of Africa, where 90% of the global burden occurs, and Latin America. It is notoriously under-reported with uncertainty arising from a complex transmission cycle including a sylvatic reservoir and non-specific symptom set. Resulting estimates of burden, particularly in Africa, are highly uncertain. We examine two established models of yellow fever transmission within a Bayesian model averaging framework in order to assess the relative evidence for each model’s assumptions and to highlight possible data gaps. Our models assume contrasting scenarios of the yellow fever transmission cycle in Africa. The first takes the force of infection in each province to be static across the observation period; this is synonymous with a constant infection pressure from the sylvatic reservoir. The second model assumes the majority of transmission results from the urban cycle; in this case, the force of infection is dynamic and defined through a fixed value of R0 in each province. Both models are coupled to a generalised linear model of yellow fever occurrence which uses environmental covariates to allow us to estimate transmission intensity in areas where data is sparse. We compare these contrasting descriptions of transmission through a Bayesian framework and trans-dimensional Markov chain Monte Carlo sampling in order to assess each model’s evidence given the range of uncertainty in parameter values. The resulting estimates allow us to produce Bayesian model averaged predictions of yellow fever burden across the African endemic region. We find strong support for the static force of infection model which suggests a higher proportion of yellow fever transmission occurs as a result of infection from an external source such as the sylvatic reservoir. However, the model comparison highlights key data gaps in serological surveys across the African endemic region. As such, conclusions concerning the most prevalent transmission routes for yellow fever will be limited by the sparsity of data which is particularly evident in the areas with highest predicted transmission intensity. Our model and estimation approach provides a robust framework for model comparison and predicting yellow fever burden in Africa. However, key data gaps increase uncertainty surrounding estimates of model parameters and evidence. As more mathematical models are developed to address new research questions, it is increasingly important to compare them with established modelling approaches to highlight uncertainty in structures and data. [ABSTRACT FROM AUTHOR]

G-quadruplexes (G4) are secondary structures formed by guanine-rich nucleic acid sequences and shown to exist in living cells where they participate in regulation of gene expression and chromosome maintenance. G-quadruplexes with solvent-exposed guanine tetrads show the tendency to associate together through cofacial stacking, which may be important for packaging of G4-forming sequences and allows for the design of higher-order G4 DNA structures. To understand the molecular driving forces for G4 association, here, we study the binding interaction between two parallel-stranded G-quadruplexes using all-atom molecular dynamics simulations. The predicted dimerization free energies show that direct binding through the 5’-G-tetrads is the most preferred of all possible end-to-end stacking orientations, consistently with all available experimental data. Decomposition of dimerization enthalpies in combination with simulations at varying ionic strength further indicate that the observed orientational preferences arise from a fine balance between the electrostatic repulsion of the sugar-phosphate backbones and favorable counterion binding at the dimeric interface. We also demonstrate how these molecular-scale findings can be used to devise means of controlling G4 dimerization equilibrium, e.g., by altering salt concentration and using G4-targeted ligands. [ABSTRACT FROM AUTHOR]

Cells interacting through an extracellular matrix (ECM) exhibit emergent behaviors resulting from collective intercellular interaction. In wound healing and tissue development, characteristic compaction of ECM gel is induced by multiple cells that generate tensions in the ECM fibers and coordinate their actions with other cells. Computational prediction of collective cell-ECM interaction based on first principles is highly complex especially as the number of cells increase. Here, we introduce a computationally-efficient method for predicting nonlinear behaviors of multiple cells interacting mechanically through a 3-D ECM fiber network. The key enabling technique is superposition of single cell computational models to predict multicellular behaviors. While cell-ECM interactions are highly nonlinear, they can be linearized accurately with a unique method, termed Dual-Faceted Linearization. This method recasts the original nonlinear dynamics in an augmented space where the system behaves more linearly. The independent state variables are augmented by combining auxiliary variables that inform nonlinear elements involved in the system. This computational method involves a) expressing the original nonlinear state equations with two sets of linear dynamic equations b) reducing the order of the augmented linear system via principal component analysis and c) superposing individual single cell-ECM dynamics to predict collective behaviors of multiple cells. The method is computationally efficient compared to original nonlinear dynamic simulation and accurate compared to traditional Taylor expansion linearization. Furthermore, we reproduce reported experimental results of multi-cell induced ECM compaction. [ABSTRACT FROM AUTHOR]

A fundamental challenge in neuroscience is to understand what structure in the world is represented in spatially distributed patterns of neural activity from multiple single-trial measurements. This is often accomplished by learning a simple, linear transformations between neural features and features of the sensory stimuli or motor task. While successful in some early sensory processing areas, linear mappings are unlikely to be ideal tools for elucidating nonlinear, hierarchical representations of higher-order brain areas during complex tasks, such as the production of speech by humans. Here, we apply deep networks to predict produced speech syllables from a dataset of high gamma cortical surface electric potentials recorded from human sensorimotor cortex. We find that deep networks had higher decoding prediction accuracy compared to baseline models. Having established that deep networks extract more task relevant information from neural data sets relative to linear models (i.e., higher predictive accuracy), we next sought to demonstrate their utility as a data analysis tool for neuroscience. We first show that deep network’s confusions revealed hierarchical latent structure in the neural data, which recapitulated the underlying articulatory nature of speech motor control. We next broadened the frequency features beyond high-gamma and identified a novel high-gamma-to-beta coupling during speech production. Finally, we used deep networks to compare task-relevant information in different neural frequency bands, and found that the high-gamma band contains the vast majority of information relevant for the speech prediction task, with little-to-no additional contribution from lower-frequency amplitudes. Together, these results demonstrate the utility of deep networks as a data analysis tool for basic and applied neuroscience. [ABSTRACT FROM AUTHOR]

Prophylactic interventions such as vaccine allocation are some of the most effective public health policy planning tools. The supply of vaccines, however, is limited and an important challenge is to optimally allocate the vaccines to minimize epidemic impact. This resource allocation question (which we refer to as VID) has multiple dimensions: when, where, to whom, etc. Most of the existing literature in this topic deals with the latter (to whom), proposing policies that prioritize individuals by age and disease risk. However, since seasonal influenza spread has a typical spatial trend, and due to the temporal constraints enforced by the availability schedule, the when and where problems become equally, if not more, relevant. In this paper, we study the VID problem in the context of seasonal influenza spread in the United States. We develop a national scale metapopulation model for influenza that integrates both short and long distance human mobility, along with realistic data on vaccine uptake. We also design GA, a greedy algorithm for allocating the vaccine supply at the state level under temporal constraints and show that such a strategy improves over the current baseline of pro-rata allocation, and the improvement is more pronounced for higher vaccine efficacy and moderate flu season intensity. Further, the resulting strategy resembles a ring vaccination applied spatiallyacross the US. [ABSTRACT FROM AUTHOR]

According to the Centers for Disease Control and Prevention (CDC), one in twenty five hospital patients are infected with at least one healthcare acquired infection (HAI) on any given day. Early detection of possible HAI outbreaks help practitioners implement countermeasures before the infection spreads extensively. Here, we develop an efficient data and model driven method to detect outbreaks with high accuracy. We leverage mechanistic modeling of C. difficile infection, a major HAI disease, to simulate its spread in a hospital wing and design efficient near-optimal algorithms to select people and locations to monitor using an optimization formulation. Results show that our strategy detects up to 95% of “future” C. difficile outbreaks. We design our method by incorporating specific hospital practices (like swabbing for infections) as well. As a result, our method outperforms state-of-the-art algorithms for outbreak detection. Finally, a qualitative study of our result shows that the people and locations we select to monitor as sensors are intuitive and meaningful. [ABSTRACT FROM AUTHOR]

Many models of classical conditioning fail to describe important phenomena, notably the rapid return of fear after extinction. To address this shortfall, evidence converged on the idea that learning agents rely on latent-state inferences, i.e. an ability to index disparate associations from cues to rewards (or penalties) and infer which index (i.e. latent state) is presently active. Our goal was to develop a model of latent-state inferences that uses latent states to predict rewards from cues efficiently and that can describe behavior in a diverse set of experiments. The resulting model combines a Rescorla-Wagner rule, for which updates to associations are proportional to prediction error, with an approximate Bayesian rule, for which beliefs in latent states are proportional to prior beliefs and an approximate likelihood based on current associations. In simulation, we demonstrate the model’s ability to reproduce learning effects both famously explained and not explained by the Rescorla-Wagner model, including rapid return of fear after extinction, the Hall-Pearce effect, partial reinforcement extinction effect, backwards blocking, and memory modification. Lastly, we derive our model as an online algorithm to maximum likelihood estimation, demonstrating it is an efficient approach to outcome prediction. Establishing such a framework is a key step towards quantifying normative and pathological ranges of latent-state inferences in various contexts. [ABSTRACT FROM AUTHOR]

Even in the steady-state, the number of biomolecules in living cells fluctuates dynamically, and the frequency spectrum of this chemical fluctuation carries valuable information about the dynamics of the reactions creating these biomolecules. Recent advances in single-cell techniques enable direct monitoring of the time-traces of the protein number in each cell; however, it is not yet clear how the stochastic dynamics of these time-traces is related to the reaction mechanism and dynamics. Here, we derive a rigorous relation between the frequency-spectrum of the product number fluctuation and the reaction mechanism and dynamics, starting from a generalized master equation. This relation enables us to analyze the time-traces of the protein number and extract information about dynamics of mRNA number and transcriptional regulation, which cannot be directly observed by current experimental techniques. We demonstrate our frequency spectrum analysis of protein number fluctuation, using the gene network model of luciferase expression under the control of the Bmal 1a promoter in mouse fibroblast cells. We also discuss how the dynamic heterogeneity of transcription and translation rates affects the frequency-spectra of the mRNA and protein number. [ABSTRACT FROM AUTHOR]

Cooperation is ubiquitous across all levels of biological systems ranging from microbial communities to human societies. It, however, seemingly contradicts the evolutionary theory, since cooperators are exploited by free-riders and thus are disfavored by natural selection. Many studies based on evolutionary game theory have tried to solve the puzzle and figure out the reason why cooperation exists and how it emerges. Network reciprocity is one of the mechanisms to promote cooperation, where nodes refer to individuals and links refer to social relationships. The spatial arrangement of mutant individuals, which refers to the clustering of mutants, plays a key role in network reciprocity. Besides, many other mechanisms supporting cooperation suggest that the clustering of mutants plays an important role in the expansion of mutants. However, the clustering of mutants and the game dynamics are typically coupled. It is still unclear how the clustering of mutants alone alters the evolutionary dynamics. To this end, we employ a minimal model with frequency independent fitness on a circle. It disentangles the clustering of mutants from game dynamics. The distance between two mutants on the circle is adopted as a natural indicator for the clustering of mutants or assortment. We find that the assortment is an amplifier of the selection for the connected mutants compared with the separated ones. Nevertheless, as mutants are separated, the more dispersed mutants are, the greater the chance of invasion is. It gives rise to the non-monotonic effect of clustering, which is counterintuitive. On the other hand, we find that less assortative mutants speed up fixation. Our model shows that the clustering of mutants plays a non-trivial role in fixation, which has emerged even if the game interaction is absent. [ABSTRACT FROM AUTHOR]

A variety of simple models has been proposed to understand the collective motion of animals. These models can be insightful but may lack important elements necessary to predict the motion of each individual in the collective. Adding more detail increases predictability but can make models too complex to be insightful. Here we report that deep attention networks can obtain a model of collective behavior that is simultaneously predictive and insightful thanks to an organization in modules. When using simulated trajectories, the model recovers the ground-truth interaction rule used to generate them, as well as the number of interacting neighbours. For experimental trajectories of large groups of 60-100 zebrafish, Danio rerio, the model obtains that interactions between pairs can approximately be described as repulsive, attractive or as alignment, but only when moving slowly. At high velocities, interactions correspond only to alignment or alignment mixed with repulsion at close distances. The model also shows that each zebrafish decides where to move by aggregating information from the group as a weighted average over neighbours. Weights are higher for neighbours that are close, in a collision path or moving faster in frontal and lateral locations. The network also extracts that the number of interacting individuals is dynamical and typically in the range 8–22, with 1–10 more important ones. Our results suggest that each animal decides by dynamically selecting information from the collective. [ABSTRACT FROM AUTHOR]

A key question in ecology is the relative impact of internal nonlinear dynamics and external perturbations on the long-term trajectories of natural systems. Measles has been analyzed extensively as a paradigm for consumer-resource dynamics due to the oscillatory nature of the host-pathogen life cycle, the abundance of rich data to test theory, and public health relevance. The dynamics of measles in London, in particular, has acted as a prototypical test bed for such analysis using incidence data from the pre-vaccination era (1944–1967). However, during this timeframe there were few external large-scale perturbations, limiting an assessment of the relative impact of internal and extra demographic perturbations to the host population. Here, we extended the previous London analyses to include nearly a century of data that also contains four major demographic changes: the First and Second World Wars, the 1918 influenza pandemic, and the start of a measles mass vaccination program. By combining mortality and incidence data using particle filtering methods, we show that a simple stochastic epidemic model, with minimal historical specifications, can capture the nearly 100 years of dynamics including changes caused by each of the major perturbations. We show that the majority of dynamic changes are explainable by the internal nonlinear dynamics of the system, tuned by demographic changes. In addition, the 1918 influenza pandemic and World War II acted as extra perturbations to this basic epidemic oscillator. Our analysis underlines that long-term ecological and epidemiological dynamics can follow very simple rules, even in a non-stationary population subject to significant perturbations and major secular changes. [ABSTRACT FROM AUTHOR]

Stochastic mechanistic epidemiological models largely contribute to better understand pathogen emergence and spread, and assess control strategies at various scales (from within-host to transnational scale). However, developing realistic models which involve multi-disciplinary knowledge integration faces three major challenges in predictive epidemiology: lack of readability once translated into simulation code, low reproducibility and reusability, and long development time compared to outbreak time scale. We introduce here EMULSION, an artificial intelligence-based software intended to address those issues and help modellers focus on model design rather than programming. EMULSION defines a domain-specific language to make all components of an epidemiological model (structure, processes, parameters…) explicit as a structured text file. This file is readable by scientists from other fields (epidemiologists, biologists, economists), who can contribute to validate or revise assumptions at any stage of model development. It is then automatically processed by EMULSION generic simulation engine, preventing any discrepancy between model description and implementation. The modelling language and simulation architecture both rely on the combination of advanced artificial intelligence methods (knowledge representation and multi-level agent-based simulation), allowing several modelling paradigms (from compartment- to individual-based models) at several scales (up to metapopulation). The flexibility of EMULSION and its capability to support iterative modelling are illustrated here through examples of progressive complexity, including late revisions of core model assumptions. EMULSION is also currently used to model the spread of several diseases in real pathosystems. EMULSION provides a command-line tool for checking models, producing model diagrams, running simulations, and plotting outputs. Written in Python 3, EMULSION runs on Linux, MacOS, and Windows. It is released under Apache-2.0 license. A comprehensive documentation with installation instructions, a tutorial and many examples are available from: . [ABSTRACT FROM AUTHOR]

The scientific method has been guiding biological research for a long time. It not only prescribes the order and types of activities that give a scientific study validity and a stamp of approval but also has substantially shaped how we collectively think about the endeavor of investigating nature. The advent of high-throughput data generation, data mining, and advanced computational modeling has thrown the formerly undisputed, monolithic status of the scientific method into turmoil. On the one hand, the new approaches are clearly successful and expect the same acceptance as the traditional methods, but on the other hand, they replace much of the hypothesis-driven reasoning with inductive argumentation, which philosophers of science consider problematic. Intrigued by the enormous wealth of data and the power of machine learning, some scientists have even argued that significant correlations within datasets could make the entire quest for causation obsolete. Many of these issues have been passionately debated during the past two decades, often with scant agreement. It is proffered here that hypothesis-driven, data-mining–inspired, and “allochthonous” knowledge acquisition, based on mathematical and computational models, are vectors spanning a 3D space of an expanded scientific method. The combination of methods within this space will most certainly shape our thinking about nature, with implications for experimental design, peer review and funding, sharing of result, education, medical diagnostics, and even questions of litigation. [ABSTRACT FROM AUTHOR]

In many brain areas, sensory responses are heavily modulated by factors including attentional state, context, reward history, motor preparation, learned associations, and other cognitive variables. Modelling the effect of these modulatory factors on sensory responses has proven challenging, mostly due to the time-varying and nonlinear nature of the underlying computations. Here we present a computational model capable of capturing and dissociating multiple time-varying modulatory effects on neuronal responses on the order of milliseconds. The model’s performance is tested on extrastriate perisaccadic visual responses in nonhuman primates. Visual neurons respond to stimuli presented around the time of saccades differently than during fixation. These perisaccadic changes include sensitivity to the stimuli presented at locations outside the neuron’s receptive field, which suggests a contribution of multiple sources to perisaccadic response generation. Current computational approaches cannot quantitatively characterize the contribution of each modulatory source in response generation, mainly due to the very short timescale on which the saccade takes place. In this study, we use a high spatiotemporal resolution experimental paradigm along with a novel extension of the generalized linear model framework (GLM), termed the sparse-variable GLM, to allow for time-varying model parameters representing the temporal evolution of the system with a resolution on the order of milliseconds. We used this model framework to precisely map the temporal evolution of the spatiotemporal receptive field of visual neurons in the middle temporal area during the execution of a saccade. Moreover, an extended model based on a factorization of the sparse-variable GLM allowed us to disassociate and quantify the contribution of individual sources to the perisaccadic response. Our results show that our novel framework can precisely capture the changes in sensitivity of neurons around the time of saccades, and provide a general framework to quantitatively track the role of multiple modulatory sources over time. [ABSTRACT FROM AUTHOR]

Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this “presumably transient” dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock. [ABSTRACT FROM AUTHOR]

We performed a mathematical analysis of the dynamic control loops regulating the vasomotor tone of vascular smooth muscle, blood volume, and mean arterial pressure, which involve the arginine vasopressin (AVP) system, the atrial natriuretic peptide system (ANP), and the renin-angiotensin-aldosterone system (RAAS). Our loop analysis of the AVP-ANP-RAAS system revealed the concurrent presence of two different regulatory mechanisms, which perform the same qualitative function: one affects blood pressure by regulating vasoconstriction, the other by regulating blood volume. Both the systems are candidate oscillators consisting of the negative-feedback loop of a monotone system: they admit a single equilibrium that can either be stable or give rise to oscillatory instability. Also a subsystem, which includes ANP and AVP stimulation of vascular smooth muscle cells, turns out to be a candidate oscillator composed of a monotone system with multiple negative feedback loops, and we show that its oscillatory potential is higher when the delays along all feedback loops are comparable. Our results give insight into the physiological mechanisms ruling long-term homeostasis of blood hydraulic parameters, which operate based on dynamical loops of interactions. [ABSTRACT FROM AUTHOR]

Phylogenetic networks generalize phylogenetic trees by allowing the modelization of events of reticulate evolution. Among the different kinds of phylogenetic networks that have been proposed in the literature, the subclass of binary tree-child networks is one of the most studied ones. However, very little is known about the combinatorial structure of these networks. In this paper we address the problem of generating all possible binary tree-child (BTC) networks with a given number of leaves in an efficient way via reduction/augmentation operations that extend and generalize analogous operations for phylogenetic trees, and are biologically relevant. Since our solution is recursive, this also provides us with a recurrence relation giving an upper bound on the number of such networks. We also show how the operations introduced in this paper can be employed to extend the evolutive history of a set of sequences, represented by a BTC network, to include a new sequence. An implementation in python of the algorithms described in this paper, along with some computational experiments, can be downloaded from . [ABSTRACT FROM AUTHOR]

Higher-order genomic architecture varies according to cell type and changes dramatically during differentiation. One of the remarkable examples of spatial genomic reorganization is the rod photoreceptor cell differentiation in nocturnal mammals. The inverted nuclear architecture found in adult mouse rod cells is formed through the reorganization of the conventional architecture during terminal differentiation. However, the mechanisms underlying these changes remain largely unknown. Here, we found that the dynamic deformation of nuclei via actomyosin-mediated contractility contributes to chromocenter clustering and promotes genomic architecture reorganization during differentiation by conducting an in cellulo experiment coupled with phase-field modeling. Similar patterns of dynamic deformation of the nucleus and a concomitant migration of the nuclear content were also observed in rod cells derived from the developing mouse retina. These results indicate that the common phenomenon of dynamic nuclear deformation, which accompanies dynamic cell behavior, can be a universal mechanism for spatiotemporal genomic reorganization. [ABSTRACT FROM AUTHOR]

T cells use their T-cell receptors (TCRs) to scan other cells for antigenic peptides presented by MHC molecules (pMHC). If a TCR encounters a pMHC, it can trigger a signalling pathway that could lead to the activation of the T cell and the initiation of an immune response. It is currently not clear how the binding of pMHC to the TCR initiates signalling within the T cell. One hypothesis is that conformational changes in the TCR lead to further downstream signalling. Here we investigate four different TCRs in their free state as well as in their pMHC bound state using large scale molecular simulations totalling 26 000 ns. We find that the dynamical features within TCRs differ significantly between unbound TCR and TCR/pMHC simulations. However, apart from expected results such as reduced solvent accessibility and flexibility of the interface residues, these features are not conserved among different TCR types. The presence of a pMHC alone is not sufficient to cause cross-TCR-conserved dynamical features within a TCR. Our results argue against models of TCR triggering involving conserved allosteric conformational changes. [ABSTRACT FROM AUTHOR]

In various fields, statistical models of interest are analytically intractable and inference is usually performed using a simulation-based method. However elegant these methods are, they are often painstakingly slow and convergence is difficult to assess. As a result, statistical inference is greatly hampered by computational constraints. However, for a given statistical model, different users, even with different data, are likely to perform similar computations. Computations done by one user are potentially useful for other users with different data sets. We propose a pooling of resources across researchers to capitalize on this. More specifically, we preemptively chart out the entire space of possible model outcomes in a prepaid database. Using advanced interpolation techniques, any individual estimation problem can now be solved on the spot. The prepaid method can easily accommodate different priors as well as constraints on the parameters. We created prepaid databases for three challenging models and demonstrate how they can be distributed through an online parameter estimation service. Our method outperforms state-of-the-art estimation techniques in both speed (with a 23,000 to 100,000-fold speed up) and accuracy, and is able to handle previously quasi inestimable models. [ABSTRACT FROM AUTHOR]

Understanding the optimization objectives that shape shoot architectures remains a critical problem in plant biology. Here, we performed 3D scanning of 152 Arabidopsis shoot architectures, including wildtype and 10 mutant strains, and we uncovered a design principle that describes how architectures make trade-offs between competing objectives. First, we used graph-theoretic analysis to show that Arabidopsis shoot architectures strike a Pareto optimal that can be captured as maximizing performance in transporting nutrients and minimizing costs in building the architecture. Second, we identify small sets of genes that can be mutated to shift the weight prioritizing one objective over the other. Third, we show that this prioritization weight feature is significantly less variable across replicates of the same genotype compared to other common plant traits (e.g., number of rosette leaves, total volume occupied). This suggests that this feature is a robust descriptor of a genotype, and that local variability in structure may be compensated for globally in a homeostatic manner. Overall, our work provides a framework to understand optimization trade-offs made by shoot architectures and provides evidence that these trade-offs can be modified genetically, which may aid plant breeding and selection efforts. [ABSTRACT FROM AUTHOR]

Kinetic models of metabolic networks offer the promise of quantitative phenotype prediction. The mechanistic characterization of enzyme catalyzed reactions allows for tracing the effect of perturbations in metabolite concentrations and reaction fluxes in response to genetic and environmental perturbation that are beyond the scope of stoichiometric models. In this study, we develop a two-step computational pipeline for the rapid parameterization of kinetic models of metabolic networks using a curated metabolic model and available 13C-labeling distributions under multiple genetic and environmental perturbations. The first step involves the elucidation of all intracellular fluxes in a core model of E. coli containing 74 reactions and 61 metabolites using 13C-Metabolic Flux Analysis (13C-MFA). Here, fluxes corresponding to the mid-exponential growth phase are elucidated for seven single gene deletion mutants from upper glycolysis, pentose phosphate pathway and the Entner-Doudoroff pathway. The computed flux ranges are then used to parameterize the same (i.e., k-ecoli74) core kinetic model for E. coli with 55 substrate-level regulations using the newly developed K-FIT parameterization algorithm. The K-FIT algorithm employs a combination of equation decomposition and iterative solution techniques to evaluate steady-state fluxes in response to genetic perturbations. k-ecoli74 predicted 86% of flux values for strains used during fitting within a single standard deviation of 13C-MFA estimated values. By performing both tasks using the same network, errors associated with lack of congruity between the two networks are avoided, allowing for seamless integration of data with model building. Product yield predictions and comparison with previously developed kinetic models indicate shifts in flux ranges and the presence or absence of mutant strains delivering flux towards pathways of interest from training data significantly impact predictive capabilities. Using this workflow, the impact of completeness of fluxomic datasets and the importance of specific genetic perturbations on uncertainties in kinetic parameter estimation are evaluated. [ABSTRACT FROM AUTHOR]

Value-based decision-making involves trading off the cost associated with an action against its expected reward. Research has shown that both physical and mental effort constitute such subjective costs, biasing choices away from effortful actions, and discounting the value of obtained rewards. Facing conflicts between competing action alternatives is considered aversive, as recruiting cognitive control to overcome conflict is effortful. Moreover, engaging control to proactively suppress irrelevant information that could conflict with task-relevant information would presumably also be cognitively costly. Yet, it remains unclear whether the cognitive control demands involved in preventing and resolving conflict also constitute costs in value-based decisions. The present study investigated this question by embedding irrelevant distractors (flanker arrows) within a reversal-learning task, with intermixed free and instructed trials. Results showed that participants learned to adapt their free choices to maximize rewards, but were nevertheless biased to follow the suggestions of irrelevant distractors. Thus, the perceived cost of investing cognitive control to suppress an external suggestion could sometimes trump internal value representations. By adapting computational models of reinforcement learning, we assessed the influence of conflict at both the decision and learning stages. Modelling the decision showed that free choices were more biased when participants were less sure about which action was more rewarding. This supports the hypothesis that the costs linked to conflict management were traded off against expected rewards. During the learning phase, we found that learning rates were reduced in instructed, relative to free, choices. Learning rates were further reduced by conflict between an instruction and subjective action values, whereas learning was not robustly influenced by conflict between one’s actions and external distractors. Our results show that the subjective cognitive control costs linked to conflict factor into value-based decision-making, and highlight that different types of conflict may have different effects on learning about action outcomes. [ABSTRACT FROM AUTHOR]

State-space and action representations form the building blocks of decision-making processes in the brain; states map external cues to the current situation of the agent whereas actions provide the set of motor commands from which the agent can choose to achieve specific goals. Although these factors differ across environments, it is currently unknown whether or how accurately state and action representations are acquired by the agent because previous experiments have typically provided this information a priori through instruction or pre-training. Here we studied how state and action representations adapt to reflect the structure of the world when such a priori knowledge is not available. We used a sequential decision-making task in rats in which they were required to pass through multiple states before reaching the goal, and for which the number of states and how they map onto external cues were unknown a priori. We found that, early in training, animals selected actions as if the task was not sequential and outcomes were the immediate consequence of the most proximal action. During the course of training, however, rats recovered the true structure of the environment and made decisions based on the expanded state-space, reflecting the multiple stages of the task. Similarly, we found that the set of actions expanded with training, although the emergence of new action sequences was sensitive to the experimental parameters and specifics of the training procedure. We conclude that the profile of choices shows a gradual shift from simple representations to more complex structures compatible with the structure of the world. [ABSTRACT FROM AUTHOR]

Predicting RNA-binding protein (RBP) specificity is important for understanding gene expression regulation and RNA-mediated enzymatic processes. It is widely believed that RBP binding specificity is determined by both the sequence and structural contexts of RNAs. Existing approaches, including traditional machine learning algorithms and more recently, deep learning models, have been extensively applied to integrate RNA sequence and its predicted or experimental RNA structural probabilities for improving the accuracy of RBP binding prediction. Such models were trained mostly on the large-scale in vitro datasets, such as the RNAcompete dataset. However, in RNAcompete, most synthetic RNAs are unstructured, which makes machine learning methods not effectively extract RBP-binding structural preferences. Furthermore, RNA structure may be variable or multi-modal according to both theoretical and experimental evidence. In this work, we propose ThermoNet, a thermodynamic prediction model by integrating a new sequence-embedding convolutional neural network model over a thermodynamic ensemble of RNA secondary structures. First, the sequence-embedding convolutional neural network generalizes the existing k-mer based methods by jointly learning convolutional filters and k-mer embeddings to represent RNA sequence contexts. Second, the thermodynamic average of deep-learning predictions is able to explore structural variability and improves the prediction, especially for the structured RNAs. Extensive experiments demonstrate that our method significantly outperforms existing approaches, including RCK, DeepBind and several other recent state-of-the-art methods for predictions on both in vitro and in vivo data. The implementation of ThermoNet is available at . [ABSTRACT FROM AUTHOR]

How muscles are used is a key to understanding the internal driving of fish swimming. However, the underlying mechanisms of some features of the muscle activation patterns and their differential appearance in different species are still obscure. In this study, we explain the muscle activation patterns by using 3D computational fluid dynamics models coupled to the motion of fish with prescribed deformation and examining the torque and power required along the fish body with two primary swimming modes. We find that the torque required by the hydrodynamic forces and body inertia exhibits a wave pattern that travels faster than the curvature wave in both anguilliform and carangiform swimmers, which can explain the traveling wave speeds of the muscle activations. Notably, intermittent negative power (i.e., power delivered by the fluid to the body) on the posterior part, along with a timely transfer of torque and energy by tendons, explains the decrease in the duration of muscle activation towards the tail. The torque contribution from the body elasticity further clarifies the wave speed increase or the reverse of the wave direction of the muscle activation on the posterior part of a carangiform swimmer. For anguilliform swimmers, the absence of the aforementioned changes in the muscle activation on the posterior part is consistent with our torque prediction and the absence of long tendons from experimental observations. These results provide novel insights into the functions of muscles and tendons as an integral part of the internal driving system, especially from an energy perspective, and they highlight the differences in the internal driving systems between the two primary swimming modes. [ABSTRACT FROM AUTHOR]

We present a new computational model of speech motor control: the Feedback-Aware Control of Tasks in Speech or FACTS model. FACTS employs a hierarchical state feedback control architecture to control simulated vocal tract and produce intelligible speech. The model includes higher-level control of speech tasks and lower-level control of speech articulators. The task controller is modeled as a dynamical system governing the creation of desired constrictions in the vocal tract, after Task Dynamics. Both the task and articulatory controllers rely on an internal estimate of the current state of the vocal tract to generate motor commands. This estimate is derived, based on efference copy of applied controls, from a forward model that predicts both the next vocal tract state as well as expected auditory and somatosensory feedback. A comparison between predicted feedback and actual feedback is then used to update the internal state prediction. FACTS is able to qualitatively replicate many characteristics of the human speech system: the model is robust to noise in both the sensory and motor pathways, is relatively unaffected by a loss of auditory feedback but is more significantly impacted by the loss of somatosensory feedback, and responds appropriately to externally-imposed alterations of auditory and somatosensory feedback. The model also replicates previously hypothesized trade-offs between reliance on auditory and somatosensory feedback and shows for the first time how this relationship may be mediated by acuity in each sensory domain. These results have important implications for our understanding of the speech motor control system in humans. [ABSTRACT FROM AUTHOR]

Prediction of antibiotic resistance phenotypes from whole genome sequencing data by machine learning methods has been proposed as a promising platform for the development of sequence-based diagnostics. However, there has been no systematic evaluation of factors that may influence performance of such models, how they might apply to and vary across clinical populations, and what the implications might be in the clinical setting. Here, we performed a meta-analysis of seven large Neisseria gonorrhoeae datasets, as well as Klebsiella pneumoniae and Acinetobacter baumannii datasets, with whole genome sequence data and antibiotic susceptibility phenotypes using set covering machine classification, random forest classification, and random forest regression models to predict resistance phenotypes from genotype. We demonstrate how model performance varies by drug, dataset, resistance metric, and species, reflecting the complexities of generating clinically relevant conclusions from machine learning-derived models. Our findings underscore the importance of incorporating relevant biological and epidemiological knowledge into model design and assessment and suggest that doing so can inform tailored modeling for individual drugs, pathogens, and clinical populations. We further suggest that continued comprehensive sampling and incorporation of up-to-date whole genome sequence data, resistance phenotypes, and treatment outcome data into model training will be crucial to the clinical utility and sustainability of machine learning-based molecular diagnostics. [ABSTRACT FROM AUTHOR]

Proteases are multifunctional, promiscuous enzymes that degrade proteins as well as peptides and drive important processes in health and disease. Current technology has enabled the construction of libraries of peptide substrates that detect protease activity, which provides valuable biological information. An ideal library would be orthogonal, such that each protease only hydrolyzes one unique substrate, however this is impractical due to off-target promiscuity (i.e., one protease targets multiple different substrates). Therefore, when a library of probes is exposed to a cocktail of proteases, each protease activates multiple probes, producing a convoluted signature. Computational methods for parsing these signatures to estimate individual protease activities primarily use an extensive collection of all possible protease-substrate combinations, which require impractical amounts of training data when expanding to search for more candidate substrates. Here we provide a computational method for estimating protease activities efficiently by reducing the number of substrates and clustering proteases with similar cleavage activities into families. We envision that this method will be used to extract meaningful diagnostic information from biological samples. [ABSTRACT FROM AUTHOR]

Pathway analysis is widely used to gain mechanistic insights from high-throughput omics data. However, most existing methods do not consider signal integration represented by pathway topology, resulting in enrichment of convergent pathways when downstream genes are modulated. Incorporation of signal flow and integration in pathway analysis could rank the pathways based on modulation in key regulatory genes. This implementation can be facilitated for large-scale data by discrete state network modeling due to simplicity in parameterization. Here, we model cellular heterogeneity using discrete state dynamics and measure pathway activities in cross-sectional data. We introduce a new algorithm, Boolean Omics Network Invariant-Time Analysis (BONITA), for signal propagation, signal integration, and pathway analysis. Our signal propagation approach models heterogeneity in transcriptomic data as arising from intercellular heterogeneity rather than intracellular stochasticity, and propagates binary signals repeatedly across networks. Logic rules defining signal integration are inferred by genetic algorithm and are refined by local search. The rules determine the impact of each node in a pathway, which is used to score the probability of the pathway’s modulation by chance. We have comprehensively tested BONITA for application to transcriptomics data from translational studies. Comparison with state-of-the-art pathway analysis methods shows that BONITA has higher sensitivity at lower levels source node modulation and similar sensitivity at higher levels of source node modulation. Application of BONITA pathway analysis to previously validated RNA-sequencing studies identifies additional relevant pathways in in-vitro human cell line experiments and in-vivo infant studies. Additionally, BONITA successfully detected modulation of disease specific pathways when comparing relevant RNA-sequencing data with healthy controls. Most interestingly, the two highest impact score nodes identified by BONITA included known drug targets. Thus, BONITA is a powerful approach to prioritize not only pathways but also specific mechanistic role of genes compared to existing methods. BONITA is available at: . [ABSTRACT FROM AUTHOR]

Across diverse biological systems—ranging from neural networks to intracellular signaling and genetic regulatory networks—the information about changes in the environment is frequently encoded in the full temporal dynamics of the network nodes. A pressing data-analysis challenge has thus been to efficiently estimate the amount of information that these dynamics convey from experimental data. Here we develop and evaluate decoding-based estimation methods to lower bound the mutual information about a finite set of inputs, encoded in single-cell high-dimensional time series data. For biological reaction networks governed by the chemical Master equation, we derive model-based information approximations and analytical upper bounds, against which we benchmark our proposed model-free decoding estimators. In contrast to the frequently-used k-nearest-neighbor estimator, decoding-based estimators robustly extract a large fraction of the available information from high-dimensional trajectories with a realistic number of data samples. We apply these estimators to previously published data on Erk and Ca2+ signaling in mammalian cells and to yeast stress-response, and find that substantial amount of information about environmental state can be encoded by non-trivial response statistics even in stationary signals. We argue that these single-cell, decoding-based information estimates, rather than the commonly-used tests for significant differences between selected population response statistics, provide a proper and unbiased measure for the performance of biological signaling networks. [ABSTRACT FROM AUTHOR]

In-silico identification of potential target genes for disease is an essential aspect of drug target discovery. Recent studies suggest that successful targets can be found through by leveraging genetic, genomic and protein interaction information. Here, we systematically tested the ability of 12 varied algorithms, based on network propagation, to identify genes that have been targeted by any drug, on gene-disease data from 22 common non-cancerous diseases in OpenTargets. We considered two biological networks, six performance metrics and compared two types of input gene-disease association scores. The impact of the design factors in performance was quantified through additive explanatory models. Standard cross-validation led to over-optimistic performance estimates due to the presence of protein complexes. In order to obtain realistic estimates, we introduced two novel protein complex-aware cross-validation schemes. When seeding biological networks with known drug targets, machine learning and diffusion-based methods found around 2-4 true targets within the top 20 suggestions. Seeding the networks with genes associated to disease by genetics decreased performance below 1 true hit on average. The use of a larger network, although noisier, improved overall performance. We conclude that diffusion-based prioritisers and machine learning applied to diffusion-based features are suited for drug discovery in practice and improve over simpler neighbour-voting methods. We also demonstrate the large impact of choosing an adequate validation strategy and the definition of seed disease genes. [ABSTRACT FROM AUTHOR]

Thirteen tubulin protofilaments, made of αβ-tubulin heterodimers, interact laterally to produce cytoskeletal microtubules. Microtubules exhibit the striking property of dynamic instability, manifested in their intermittent growth and shrinkage at both ends. This behavior is key to many cellular processes, such as cell division, migration, maintenance of cell shape, etc. Although assembly and disassembly of microtubules is known to be linked to hydrolysis of a guanosine triphosphate molecule in the pocket of β-tubulin, detailed mechanistic understanding of corresponding conformational changes is still lacking. Here we take advantage of the recent generation of in-microtubule structures of tubulin to examine the properties of protofilaments, which serve as important microtubule assembly and disassembly intermediates. We find that initially straight tubulin protofilaments, relax to similar non-radially curved and slightly twisted conformations. Our analysis further suggests that guanosine triphosphate hydrolysis primarily affects the flexibility and conformation of the inter-dimer interface, without a strong impact on the shape or flexibility of αβ-heterodimer. Inter-dimer interfaces are significantly more flexible compared to intra-dimer interfaces. We argue that such a difference in flexibility could be key for distinct stability of the plus and minus microtubule ends. The higher flexibility of the inter-dimer interface may have implications for development of pulling force by curving tubulin protofilaments during microtubule disassembly, a process of major importance for chromosome motions in mitosis. [ABSTRACT FROM AUTHOR]

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equation the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term “well-balanced bifurcations”. Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 μm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply. [ABSTRACT FROM AUTHOR]

Single-cell RNA-sequencing (scRNA-seq) provides new opportunities to gain a mechanistic understanding of many biological processes. Current approaches for single cell clustering are often sensitive to the input parameters and have difficulty dealing with cell types with different densities. Here, we present Panoramic View (PanoView), an iterative method integrated with a novel density-based clustering, Ordering Local Maximum by Convex hull (OLMC), that uses a heuristic approach to estimate the required parameters based on the input data structures. In each iteration, PanoView will identify the most confident cell clusters and repeat the clustering with the remaining cells in a new PCA space. Without adjusting any parameter in PanoView, we demonstrated that PanoView was able to detect major and rare cell types simultaneously and outperformed other existing methods in both simulated datasets and published single-cell RNA-sequencing datasets. Finally, we conducted scRNA-Seq analysis of embryonic mouse hypothalamus, and PanoView was able to reveal known cell types and several rare cell subpopulations. [ABSTRACT FROM AUTHOR]