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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]

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]

Accurately predicting and testing the types of Pulmonary arterial hypertension (PAH) of each patient using cost-effective microarray-based expression data and machine learning algorithms could greatly help either identifying the most targeting medicine or adopting other therapeutic measures that could correct/restore defective genetic signaling at the early stage. Furthermore, the prediction model construction processes can also help identifying highly informative genes controlling PAH, leading to enhanced understanding of the disease etiology and molecular pathways. In this study, we used several different gene filtering methods based on microarray expression data obtained from a high-quality patient PAH dataset. Following that, we proposed a novel feature selection and refinement algorithm in conjunction with well-known machine learning methods to identify a small set of highly informative genes. Results indicated that clusters of small-expression genes could be extremely informative at predicting and differentiating different forms of PAH. Additionally, our proposed novel feature refinement algorithm could lead to significant enhancement in model performance. To summarize, integrated with state-of-the-art machine learning and novel feature refining algorithms, the most accurate models could provide near-perfect classification accuracies using very few (close to ten) low-expression genes. [ABSTRACT FROM AUTHOR]

The article offers information on the challenging scientific problems faced by humanity. Topics discussed include information on the efforts to empower Africans to join the global neuroscience community; discussions on the BRAIN initiative in the U.S. and the Human Brain Project in Europe; and the information on the limiting factor for computational neuroscience development in Africa.

Omic data analysis is steadily growing as a driver of basic and applied molecular biology research. Core to the interpretation of complex and heterogeneous biological phenotypes are computational approaches in the fields of statistics and machine learning. In parallel, constraint-based metabolic modeling has established itself as the main tool to investigate large-scale relationships between genotype, phenotype, and environment. The development and application of these methodological frameworks have occurred independently for the most part, whereas the potential of their integration for biological, biomedical, and biotechnological research is less known. Here, we describe how machine learning and constraint-based modeling can be combined, reviewing recent works at the intersection of both domains and discussing the mathematical and practical aspects involved. We overlap systematic classifications from both frameworks, making them accessible to nonexperts. Finally, we delineate potential future scenarios, propose new joint theoretical frameworks, and suggest concrete points of investigation for this joint subfield. A multiview approach merging experimental and knowledge-driven omic data through machine learning methods can incorporate key mechanistic information in an otherwise biologically-agnostic learning process. [ABSTRACT FROM AUTHOR]

The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons. [ABSTRACT FROM AUTHOR]

Based on morphology it is often challenging to distinguish between the many different soft tissue sarcoma subtypes. Moreover, outcome of disease is highly variable even between patients with the same disease. Machine learning on transcriptome sequencing data could be a valuable new tool to understand differences between and within entities. Here we used machine learning analysis to identify novel diagnostic and prognostic markers and therapeutic targets for soft tissue sarcomas. Gene expression data was used from the Cancer Genome Atlas, the Genotype-Tissue Expression data and the French Sarcoma Group. We identified three groups of tumors that overlap in their molecular profile as seen with unsupervised t-Distributed Stochastic Neighbor Embedding clustering and a deep neural network. The three groups corresponded to subtypes that are morphologically overlapping. Using a random forest algorithm, we identified novel diagnostic markers for soft tissue sarcoma that distinguished between synovial sarcoma and MPNST, and that we validated using qRT-PCR in an independent series. Next, we identified prognostic genes that are strong predictors of disease outcome when used in a k-nearest neighbor algorithm. The prognostic genes were further validated in expression data from the French Sarcoma Group. One of these, HMMR, was validated in an independent series of leiomyosarcomas using immunohistochemistry on tissue micro array as a prognostic gene for disease-free interval. Furthermore, reconstruction of regulatory networks combined with data from the Connectivity Map showed, amongst others, that HDAC inhibitors could be a potential effective therapy for multiple soft tissue sarcoma subtypes. A viability assay with two HDAC inhibitors confirmed that both leiomyosarcoma and synovial sarcoma are sensitive to HDAC inhibition. In this study we identified novel diagnostic markers, prognostic markers and therapeutic leads from multiple soft tissue sarcoma gene expression datasets. Thus, machine learning algorithms are powerful new tools to improve our understanding of rare tumor entities. [ABSTRACT FROM AUTHOR]

Place cells in the mammalian hippocampus signal self-location with sparse spatially stable firing fields. Based on observation of place cell activity it is possible to accurately decode an animal’s location. The precision of this decoding sets a lower bound for the amount of information that the hippocampal population conveys about the location of the animal. In this work we use a novel recurrent neural network (RNN) decoder to infer the location of freely moving rats from single unit hippocampal recordings. RNNs are biologically plausible models of neural circuits that learn to incorporate relevant temporal context without the need to make complicated assumptions about the use of prior information to predict the current state. When decoding animal position from spike counts in 1D and 2D-environments, we show that the RNN consistently outperforms a standard Bayesian approach with either flat priors or with memory. In addition, we also conducted a set of sensitivity analysis on the RNN decoder to determine which neurons and sections of firing fields were the most influential. We found that the application of RNNs to neural data allowed flexible integration of temporal context, yielding improved accuracy relative to the more commonly used Bayesian approaches and opens new avenues for exploration of the neural code. [ABSTRACT FROM AUTHOR]

The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for inference of disease-associated human differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human biology from mouse datasets. We found that semi-supervised training of a neural network identified significantly more true human biological associations than interpreting mouse experiments directly. Evaluating the experimental design of mouse experiments where our model was most successful revealed principles of experimental design that may improve translational performance. Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches, combining mouse and human data for biological inference, provide the most accurate assessment of human in vivo disease processes. Finally, we proffer a delineation of four categories of model system-to-human “Translation Problems” defined by the resolution and coverage of the datasets available for molecular insight translation and suggest that the task of translating insights from model systems to human disease contexts may be better accomplished by a combination of translation-minded experimental design and computational approaches. [ABSTRACT FROM AUTHOR]

Although a standard reinforcement learning model can capture many aspects of reward-seeking behaviors, it may not be practical for modeling human natural behaviors because of the richness of dynamic environments and limitations in cognitive resources. We propose a modular reinforcement learning model that addresses these factors. Based on this model, a modular inverse reinforcement learning algorithm is developed to estimate both the rewards and discount factors from human behavioral data, which allows predictions of human navigation behaviors in virtual reality with high accuracy across different subjects and with different tasks. Complex human navigation trajectories in novel environments can be reproduced by an artificial agent that is based on the modular model. This model provides a strategy for estimating the subjective value of actions and how they influence sensory-motor decisions in natural behavior. [ABSTRACT FROM AUTHOR]

The article focuses on the need for accurate and timely influenza forecasting for deploying effective public health measures. Topics discussed include data preprocessing and modeling considerations of forecasting algorithms; surveillance methods used by different agencies and the U.S. Outpatient Influenza-like Illness Surveillance Network; and no uniformity between surveillance data collection practices.

Isolation profoundly influences social behavior in all animals. In humans, isolation has serious effects on health and disease. Drosophila melanogaster is a powerful model to study small-scale, temporally-transient social behavior. However, longer-term analysis of large groups of flies is hampered by the lack of effective and reliable tools. We built a new imaging arena and improved the existing tracking algorithm to reliably follow a large number of flies simultaneously. Next, based on the automatic classification of touch and graph-based social network analysis, we designed an algorithm to quantify changes in the social network in response to prior social isolation. We observed that isolation significantly and swiftly enhanced individual and local social network parameters depicting near-neighbor relationships. We explored the genome-wide molecular correlates of these behavioral changes and found that whereas behavior changed throughout the six days of isolation, gene expression alterations occurred largely on day one. These changes occurred mostly in metabolic genes, and we verified the metabolic changes by showing an increase of lipid content in isolated flies. In summary, we describe a highly reliable tracking and analysis pipeline for large groups of flies that we use to unravel the behavioral, molecular and physiological impact of isolation on social network dynamics in Drosophila. [ABSTRACT FROM AUTHOR]

Manually curating biomedical knowledge from publications is necessary to build a knowledge based service that provides highly precise and organized information to users. The process of retrieving relevant publications for curation, which is also known as document triage, is usually carried out by querying and reading articles in PubMed. However, this query-based method often obtains unsatisfactory precision and recall on the retrieved results, and it is difficult to manually generate optimal queries. To address this, we propose a machine-learning assisted triage method. We collect previously curated publications from two databases UniProtKB/Swiss-Prot and the NHGRI-EBI GWAS Catalog, and used them as a gold-standard dataset for training deep learning models based on convolutional neural networks. We then use the trained models to classify and rank new publications for curation. For evaluation, we apply our method to the real-world manual curation process of UniProtKB/Swiss-Prot and the GWAS Catalog. We demonstrate that our machine-assisted triage method outperforms the current query-based triage methods, improves efficiency, and enriches curated content. Our method achieves a precision 1.81 and 2.99 times higher than that obtained by the current query-based triage methods of UniProtKB/Swiss-Prot and the GWAS Catalog, respectively, without compromising recall. In fact, our method retrieves many additional relevant publications that the query-based method of UniProtKB/Swiss-Prot could not find. As these results show, our machine learning-based method can make the triage process more efficient and is being implemented in production so that human curators can focus on more challenging tasks to improve the quality of knowledge bases. [ABSTRACT FROM AUTHOR]

The accuracy of machine learning tasks critically depends on high quality ground truth data. Therefore, in many cases, producing good ground truth data typically involves trained professionals; however, this can be costly in time, effort, and money. Here we explore the use of crowdsourcing to generate a large number of training data of good quality. We explore an image analysis task involving the segmentation of corn tassels from images taken in a field setting. We investigate the accuracy, speed and other quality metrics when this task is performed by students for academic credit, Amazon MTurk workers, and Master Amazon MTurk workers. We conclude that the Amazon MTurk and Master Mturk workers perform significantly better than the for-credit students, but with no significant difference between the two MTurk worker types. Furthermore, the quality of the segmentation produced by Amazon MTurk workers rivals that of an expert worker. We provide best practices to assess the quality of ground truth data, and to compare data quality produced by different sources. We conclude that properly managed crowdsourcing can be used to establish large volumes of viable ground truth data at a low cost and high quality, especially in the context of high throughput plant phenotyping. We also provide several metrics for assessing the quality of the generated datasets. [ABSTRACT FROM AUTHOR]

We use reinforcement learning to train an agent for computational RNA design: given a target secondary structure, design a sequence that folds to that structure in silico. Our agent uses a novel graph convolutional architecture allowing a single model to be applied to arbitrary target structures of any length. After training it on randomly generated targets, we test it on the Eterna100 benchmark and find it outperforms all previous algorithms. Analysis of its solutions shows it has successfully learned some advanced strategies identified by players of the game Eterna, allowing it to solve some very difficult structures. On the other hand, it has failed to learn other strategies, possibly because they were not required for the targets in the training set. This suggests the possibility that future improvements to the training protocol may yield further gains in performance. [ABSTRACT FROM AUTHOR]

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience. [ABSTRACT FROM AUTHOR]

Mounting evidence suggests that glycans, rather than merely serving as a “shield”, contribute critically to antigenicity of the HIV envelope (Env) glycoprotein, representing critical antigenic determinants for many broadly neutralizing antibodies (bNAbs). While many studies have focused on defining the role of individual glycans or groups of proximal glycans in bNAb binding, little is known about the effects of changes in the overall glycan landscape in modulating antibody access and Env antigenicity. Here we developed a systems glycobiology approach to reverse engineer the complexity of HIV glycan heterogeneity to guide antigenicity-based de novo glycoprotein design. bNAb binding was assessed against a panel of 94 recombinant gp120 monomers exhibiting defined glycan site occupancies. Using a Bayesian machine learning algorithm, bNAb-specific glycan footprints were identified and used to design antigens that selectively alter bNAb antigenicity as a proof-of concept. Our approach provides a new design strategy to predictively modulate antigenicity via the alteration of glycan topography, thereby focusing the humoral immune response on sites of viral vulnerability for HIV. [ABSTRACT FROM AUTHOR]

Understanding how neurons cooperate to integrate sensory inputs and guide behavior is a fundamental problem in neuroscience. A large body of methods have been developed to study neuronal firing at the single cell and population levels, generally seeking interpretability as well as predictivity. However, these methods are usually confronted with the lack of ground-truth necessary to validate the approach. Here, using neuronal data from the head-direction (HD) system, we present evidence demonstrating how gradient boosted trees, a non-linear and supervised Machine Learning tool, can learn the relationship between behavioral parameters and neuronal responses with high accuracy by optimizing the information rate. Interestingly, and unlike other classes of Machine Learning methods, the intrinsic structure of the trees can be interpreted in relation to behavior (e.g. to recover the tuning curves) or to study how neurons cooperate with their peers in the network. We show how the method, unlike linear analysis, reveals that the coordination in thalamo-cortical circuits is qualitatively the same during wakefulness and sleep, indicating a brain-state independent feed-forward circuit. Machine Learning tools thus open new avenues for benchmarking model-based characterization of spike trains. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders affecting about 1% of the world population. For patients with focal seizures that cannot be treated with antiepileptic drugs, the common treatment is a surgical procedure for removal of the seizure onset zone (SOZ). In this work we introduce an algorithm for automatic localization of the seizure onset zone (SOZ) in epileptic patients based on electrocorticography (ECoG) recordings. The proposed algorithm builds upon the hypothesis that the abnormal excessive (or synchronous) neuronal activity in the brain leading to seizures starts in the SOZ and then spreads to other areas in the brain. Thus, when this abnormal activity starts, signals recorded at electrodes close to the SOZ should have a relatively large causal influence on the rest of the recorded signals. The SOZ localization is executed in two steps. First, the algorithm represents the set of electrodes using a directed graph in which nodes correspond to recording electrodes and the edges’ weights quantify the pair-wise causal influence between the recorded signals. Then, the algorithm infers the SOZ from the estimated graph using a variant of the PageRank algorithm followed by a novel post-processing phase. Inference results for 19 patients show a close match between the SOZ inferred by the proposed approach and the SOZ estimated by expert neurologists (success rate of 17 out of 19). [ABSTRACT FROM AUTHOR]

This work introduces a number of algebraic topology approaches, including multi-component persistent homology, multi-level persistent homology, and electrostatic persistence for the representation, characterization, and description of small molecules and biomolecular complexes. In contrast to the conventional persistent homology, multi-component persistent homology retains critical chemical and biological information during the topological simplification of biomolecular geometric complexity. Multi-level persistent homology enables a tailored topological description of inter- and/or intra-molecular interactions of interest. Electrostatic persistence incorporates partial charge information into topological invariants. These topological methods are paired with Wasserstein distance to characterize similarities between molecules and are further integrated with a variety of machine learning algorithms, including k-nearest neighbors, ensemble of trees, and deep convolutional neural networks, to manifest their descriptive and predictive powers for protein-ligand binding analysis and virtual screening of small molecules. Extensive numerical experiments involving more than 4,414 protein-ligand complexes from the PDBBind database (a non-redundant collection of PDBBind refined sets 2007, 2013, 2015, and 2016) and 128,374 ligand-target and decoy-target pairs in the DUD database are performed to test respectively the scoring power and the discriminatory power of the proposed topological learning strategies. It is demonstrated that the present topological learning outperforms other existing methods in protein-ligand binding affinity prediction and ligand-decoy discrimination. [ABSTRACT FROM AUTHOR]

Survival analysis represents an important outcome measure in clinical research and clinical trials; further, survival ranking may offer additional advantages in clinical trials. In this study, we developed a non-parametric ranking-based technique to transform patients' survival data into a linear space of hazard ranks. The transformation enables the utilization of machine learning base-learners including Gaussian process regression, Lasso, and random forest on survival data. The method was submitted to the DREAM Amyotrophic Lateral Sclerosis (ALS) Stratification Challenge. Ranked first place, the model gave more accurate ranking predictions on the PRO-ACT ALS dataset in comparison to Cox proportional hazard model. By utilizing right-censored data in its training process, the method demonstrated its state-of-the-art predictive power in ALS survival ranking. Its feature selection identified multiple important factors, some of which conflicts with previous studies. [ABSTRACT FROM AUTHOR]

The adaptation of the CRISPR-Cas9 system as a genome editing technique has generated much excitement in recent years owing to its ability to manipulate targeted genes and genomic regions that are complementary to a programmed single guide RNA (sgRNA). However, the efficacy of a specific sgRNA is not uniquely defined by exact sequence homology to the target site, thus unintended off-targets might additionally be cleaved. Current methods for sgRNA design are mainly concerned with predicting off-targets for a given sgRNA using basic sequence features and employ elementary rules for ranking possible sgRNAs. Here, we introduce CRISTA (CRISPR Target Assessment), a novel algorithm within the machine learning framework that determines the propensity of a genomic site to be cleaved by a given sgRNA. We show that the predictions made with CRISTA are more accurate than other available methodologies. We further demonstrate that the occurrence of bulges is not a rare phenomenon and should be accounted for in the prediction process. Beyond predicting cleavage efficiencies, the learning process provides inferences regarding patterns that underlie the mechanism of action of the CRISPR-Cas9 system. We discover that attributes that describe the spatial structure and rigidity of the entire genomic site as well as those surrounding the PAM region are a major component of the prediction capabilities. [ABSTRACT FROM AUTHOR]

Although deep learning approaches have had tremendous success in image, video and audio processing, computer vision, and speech recognition, their applications to three-dimensional (3D) biomolecular structural data sets have been hindered by the geometric and biological complexity. To address this problem we introduce the element-specific persistent homology (ESPH) method. ESPH represents 3D complex geometry by one-dimensional (1D) topological invariants and retains important biological information via a multichannel image-like representation. This representation reveals hidden structure-function relationships in biomolecules. We further integrate ESPH and deep convolutional neural networks to construct a multichannel topological neural network (TopologyNet) for the predictions of protein-ligand binding affinities and protein stability changes upon mutation. To overcome the deep learning limitations from small and noisy training sets, we propose a multi-task multichannel topological convolutional neural network (MM-TCNN). We demonstrate that TopologyNet outperforms the latest methods in the prediction of protein-ligand binding affinities, mutation induced globular protein folding free energy changes, and mutation induced membrane protein folding free energy changes. Availability: weilab.math.msu.edu/TDL/ [ABSTRACT FROM AUTHOR]

Various types of biological knowledge describe networks of interactions among elementary entities. For example, transcriptional regulatory networks consist of interactions among proteins and genes. Current knowledge about the exact structure of such networks is highly incomplete, and laboratory experiments that manipulate the entities involved are conducted to test hypotheses about these networks. In recent years, various automated approaches to experiment selection have been proposed. Many of these approaches can be characterized as active machine learning algorithms. Active learning is an iterative process in which a model is learned from data, hypotheses are generated from the model to propose informative experiments, and the experiments yield new data that is used to update the model. This review describes the various models, experiment selection strategies, validation techniques, and successful applications described in the literature; highlights common themes and notable distinctions among methods; and identifies likely directions of future research and open problems in the area. [ABSTRACT FROM AUTHOR]

Insects that feed by ingesting plant and animal fluids cause devastating damage to humans, livestock, and agriculture worldwide, primarily by transmitting pathogens of plants and animals. The feeding processes required for successful pathogen transmission by sucking insects can be recorded by monitoring voltage changes across an insect-food source feeding circuit. The output from such monitoring has traditionally been examined manually, a slow and onerous process. We taught a computer program to automatically classify previously described insect feeding patterns involved in transmission of the pathogen causing citrus greening disease. We also show how such analysis contributes to discovery of previously unrecognized feeding states and can be used to characterize plant resistance mechanisms. This advance greatly reduces the time and effort required to analyze insect feeding, and should facilitate developing, screening, and testing of novel intervention strategies to disrupt pathogen transmission affecting agriculture, livestock and human health. [ABSTRACT FROM AUTHOR]

The rapid advancement of technology in genomics and targeted genetic manipulation has made comparative biology an increasingly prominent strategy to model human disease processes. Predicting orthology relationships between species is a vital component of comparative biology. Dozens of strategies for predicting orthologs have been developed using combinations of gene and protein sequence, phylogenetic history, and functional interaction with progressively increasing accuracy. A relatively new class of orthology prediction strategies combines aspects of multiple methods into meta-tools, resulting in improved prediction performance. Here we present WORMHOLE, a novel ortholog prediction meta-tool that applies machine learning to integrate 17 distinct ortholog prediction algorithms to identify novel least diverged orthologs (LDOs) between 6 eukaryotic species—humans, mice, zebrafish, fruit flies, nematodes, and budding yeast. Machine learning allows WORMHOLE to intelligently incorporate predictions from a wide-spectrum of strategies in order to form aggregate predictions of LDOs with high confidence. In this study we demonstrate the performance of WORMHOLE across each combination of query and target species. We show that WORMHOLE is particularly adept at improving LDO prediction performance between distantly related species, expanding the pool of LDOs while maintaining low evolutionary distance and a high level of functional relatedness between genes in LDO pairs. We present extensive validation, including cross-validated prediction of PANTHER LDOs and evaluation of evolutionary divergence and functional similarity, and discuss future applications of machine learning in ortholog prediction. A WORMHOLE web tool has been developed and is available at . [ABSTRACT FROM AUTHOR]

Neuroprosthetic brain-computer interfaces function via an algorithm which decodes neural activity of the user into movements of an end effector, such as a cursor or robotic arm. In practice, the decoder is often learned by updating its parameters while the user performs a task. When the user’s intention is not directly observable, recent methods have demonstrated value in training the decoder against a surrogate for the user’s intended movement. Here we show that training a decoder in this way is a novel variant of an imitation learning problem, where an oracle or expert is employed for supervised training in lieu of direct observations, which are not available. Specifically, we describe how a generic imitation learning meta-algorithm, dataset aggregation (DA), can be adapted to train a generic brain-computer interface. By deriving existing learning algorithms for brain-computer interfaces in this framework, we provide a novel analysis of regret (an important metric of learning efficacy) for brain-computer interfaces. This analysis allows us to characterize the space of algorithmic variants and bounds on their regret rates. Existing approaches for decoder learning have been performed in the cursor control setting, but the available design principles for these decoders are such that it has been impossible to scale them to naturalistic settings. Leveraging our findings, we then offer an algorithm that combines imitation learning with optimal control, which should allow for training of arbitrary effectors for which optimal control can generate goal-oriented control. We demonstrate this novel and general BCI algorithm with simulated neuroprosthetic control of a 26 degree-of-freedom model of an arm, a sophisticated and realistic end effector. [ABSTRACT FROM AUTHOR]

Sub-cellular localisation of proteins is an essential post-translational regulatory mechanism that can be assayed using high-throughput mass spectrometry (MS). These MS-based spatial proteomics experiments enable us to pinpoint the sub-cellular distribution of thousands of proteins in a specific system under controlled conditions. Recent advances in high-throughput MS methods have yielded a plethora of experimental spatial proteomics data for the cell biology community. Yet, there are many third-party data sources, such as immunofluorescence microscopy or protein annotations and sequences, which represent a rich and vast source of complementary information. We present a unique transfer learning classification framework that utilises a nearest-neighbour or support vector machine system, to integrate heterogeneous data sources to considerably improve on the quantity and quality of sub-cellular protein assignment. We demonstrate the utility of our algorithms through evaluation of five experimental datasets, from four different species in conjunction with four different auxiliary data sources to classify proteins to tens of sub-cellular compartments with high generalisation accuracy. We further apply the method to an experiment on pluripotent mouse embryonic stem cells to classify a set of previously unknown proteins, and validate our findings against a recent high resolution map of the mouse stem cell proteome. The methodology is distributed as part of the open-source Bioconductor suite for spatial proteomics data analysis. [ABSTRACT FROM AUTHOR]

13C metabolic flux analysis (13C-MFA) has been widely used to measure in vivo enzyme reaction rates (i.e., metabolic flux) in microorganisms. Mining the relationship between environmental and genetic factors and metabolic fluxes hidden in existing fluxomic data will lead to predictive models that can significantly accelerate flux quantification. In this paper, we present a web-based platform MFlux () that predicts the bacterial central metabolism via machine learning, leveraging data from approximately 100 13C-MFA papers on heterotrophic bacterial metabolisms. Three machine learning methods, namely Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), and Decision Tree, were employed to study the sophisticated relationship between influential factors and metabolic fluxes. We performed a grid search of the best parameter set for each algorithm and verified their performance through 10-fold cross validations. SVM yields the highest accuracy among all three algorithms. Further, we employed quadratic programming to adjust flux profiles to satisfy stoichiometric constraints. Multiple case studies have shown that MFlux can reasonably predict fluxomes as a function of bacterial species, substrate types, growth rate, oxygen conditions, and cultivation methods. Due to the interest of studying model organism under particular carbon sources, bias of fluxome in the dataset may limit the applicability of machine learning models. This problem can be resolved after more papers on 13C-MFA are published for non-model species. [ABSTRACT FROM AUTHOR]

A new approach for the segregation of monaural sound mixtures is presented based on the principle of temporal coherence and using auditory cortical representations. Temporal coherence is the notion that perceived sources emit coherently modulated features that evoke highly-coincident neural response patterns. By clustering the feature channels with coincident responses and reconstructing their input, one may segregate the underlying source from the simultaneously interfering signals that are uncorrelated with it. The proposed algorithm requires no prior information or training on the sources. It can, however, gracefully incorporate cognitive functions and influences such as memories of a target source or attention to a specific set of its attributes so as to segregate it from its background. Aside from its unusual structure and computational innovations, the proposed model provides testable hypotheses of the physiological mechanisms of this ubiquitous and remarkable perceptual ability, and of its psychophysical manifestations in navigating complex sensory environments. [ABSTRACT FROM AUTHOR]

Given sufficient large protein families, and using a global statistical inference approach, it is possible to obtain sufficient accuracy in protein residue contact predictions to predict the structure of many proteins. However, these approaches do not consider the fact that the contacts in a protein are neither randomly, nor independently distributed, but actually follow precise rules governed by the structure of the protein and thus are interdependent. Here, we present PconsC2, a novel method that uses a deep learning approach to identify protein-like contact patterns to improve contact predictions. A substantial enhancement can be seen for all contacts independently on the number of aligned sequences, residue separation or secondary structure type, but is largest for β-sheet containing proteins. In addition to being superior to earlier methods based on statistical inferences, in comparison to state of the art methods using machine learning, PconsC2 is superior for families with more than 100 effective sequence homologs. The improved contact prediction enables improved structure prediction. [ABSTRACT FROM AUTHOR]

The article offers information on Dr. Serafim Batzoglou, the inaugural winner of International Society for Computational Biology (ISCB) Innovator Award in 2016.