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Science is increasingly done in large teams, making it more likely that papers will be written by several authors from different institutes, disciplines, and cultural backgrounds. A small number of “Ten simple rules” papers have been written on collaboration and on writing but not on combining the two. Collaborative writing with multiple authors has additional challenges, including varied levels of engagement of coauthors, provision of fair credit through authorship or acknowledgements, acceptance of a diversity of work styles, and the need for clear communication. Miscommunication, a lack of leadership, and inappropriate tools or writing approaches can lead to frustration, delay of publication, or even the termination of a project. To provide insight into collaborative writing, we use our experience from the Global Lake Ecological Observatory Network (GLEON) to frame 10 simple rules for collaboratively writing a multi-authored paper. We consider a collaborative multi-authored paper to have three or more people from at least two different institutions. A multi-authored paper can be a result of a single discrete research project or the outcome of a larger research program that includes other papers based on common data or methods. The writing of a multi-authored paper is embedded within a broader context of planning and collaboration among team members. Our recommended rules include elements of both the planning and writing of a paper, and they can be iterative, although we have listed them in numerical order. It will help to revisit the rules frequently throughout the writing process. With the 10 rules outlined below, we aim to provide a foundation for writing multi-authored papers and conducting exciting and influential science.

Author summary Conferences are great venues for disseminating algorithmic bioinformatics results, but they unfortunately do not offer an opportunity to make major revisions in the way that journals do. As a result, it is not possible for authors to fix mistakes that might be easily correctable but nevertheless can cause the paper to be rejected. As a reviewer, I wish that I had the opportunity to tell the authors, “Hey, you forgot to do this really important thing, without which it is hard to accept the paper, but if you could go back and fix it, you might have a great paper for the conference.” This lack of a back and forth can be especially problematic for first-time submitters or those from outside the field, e.g., biologists. In this article, I outline Ten Simple Rules to follow when writing an algorithmic bioinformatics conference paper to avoid having it rejected.

“There is no problem that a library card can't solve” according to author Eleanor Brown [1]. This advice is sound, probably for both life and science, but even the best tool (like the library) is most effective when accompanied by instructions and a basic understanding of how and when to use it. For many budding scientists, the first day in a new lab setting often involves a stack of papers, an email full of links to pertinent articles, or some promise of a richer understanding so long as one reads enough of the scientific literature. However, the purpose and approach to reading a scientific article is unlike that of reading a news story, novel, or even a textbook and can initially seem unapproachable. Having good habits for reading scientific literature is key to setting oneself up for success, identifying new research questions, and filling in the gaps in one’s current understanding; developing these good habits is the first crucial step. Advice typically centers around two main tips: read actively and read often. However, active reading, or reading with an intent to understand, is both a learned skill and a level of effort. Although there is no one best way to do this, we present 10 simple rules, relevant to novices and seasoned scientists alike, to teach our strategy for active reading based on our experience as readers and as mentors of undergraduate and graduate researchers, medical students, fellows, and early career faculty. Rules 1–5 are big picture recommendations. Rules 6–8 relate to philosophy of reading. Rules 9–10 guide the “now what?” questions one should ask after reading and how to integrate what was learned into one’s own science.

Papers describing software are an important part of computational fields of scientific research. These “software papers” are unique in a number of ways, and they require special consideration to improve their impact on the scientific community and their efficacy at conveying important information. Here, we discuss 10 specific rules for writing software papers, covering some of the different scenarios and publication types that might be encountered, and important questions from which all computational researchers would benefit by asking along the way., Author summary Computational researchers have a responsibility to ensure that the software they write stands up to the same scientific scrutiny as traditional research studies. These 10 simple rules make doing so easier by enhancing usability, reproducibility, transparency, and other crucial characteristics that aren’t taught in most computer science or research methods curricula.

Locusts are short horned grasshoppers that exhibit two behaviour types depending on their local population density. These are: solitarious, where they will actively avoid other locusts, and gregarious where they will seek them out. It is in this gregarious state that locusts can form massive and destructive flying swarms or plagues. However, these swarms are usually preceded by the aggregation of juvenile wingless locust nymphs. In this paper we attempt to understand how the distribution of food resources affect the group formation process. We do this by introducing a multi-population partial differential equation model that includes non-local locust interactions, local locust and food interactions, and gregarisation. Our results suggest that, food acts to increase the maximum density of locust groups, lowers the percentage of the population that needs to be gregarious for group formation, and decreases both the required density of locusts and time for group formation around an optimal food width. Finally, by looking at foraging efficiency within the numerical experiments we find that there exists a foraging advantage to being gregarious., Author summary Locusts are short horned grass hoppers that live in two diametrically opposed behavioural states. In the first, solitarious, they will actively avoid other locusts, whereas the second, gregarious, they will actively seek them out. It is in this gregarious state that locusts form the recognisable and destructive flying adult swarms. However, prior to swarm formation juvenile flightless locusts will form marching hopper bands and make their way from food source to food source. Predicting where these hopper bands might form is key to controlling locust outbreaks. Research has shown that changes in food distributions can affect the transition from solitarious to gregarious. In this paper we construct a mathematical model of locust-locust and locust-food interactions to investigate how food distributions affect the aggregation of juvenile locusts, termed groups, an important precursor to hopper bands. Our findings suggest that there is an optimal food distribution for group formation and that being gregarious increases a locusts ability to forage when food becomes more patchy.

Stochastic models of biomolecular reaction networks are commonly employed in systems and synthetic biology to study the effects of stochastic fluctuations emanating from reactions involving species with low copy-numbers. For such models, the Kolmogorov’s forward equation is called the chemical master equation (CME), and it is a fundamental system of linear ordinary differential equations (ODEs) that describes the evolution of the probability distribution of the random state-vector representing the copy-numbers of all the reacting species. The size of this system is given by the number of states that are accessible by the chemical system, and for most examples of interest this number is either very large or infinite. Moreover, approximations that reduce the size of the system by retaining only a finite number of important chemical states (e.g. those with non-negligible probability) result in high-dimensional ODE systems, even when the number of reacting species is small. Consequently, accurate numerical solution of the CME is very challenging, despite the linear nature of the underlying ODEs. One often resorts to estimating the solutions via computationally intensive stochastic simulations. The goal of the present paper is to develop a novel deep-learning approach for computing solution statistics of high-dimensional CMEs by reformulating the stochastic dynamics using Kolmogorov’s backward equation. The proposed method leverages superior approximation properties of Deep Neural Networks (DNNs) to reliably estimate expectations under the CME solution for several user-defined functions of the state-vector. This method is algorithmically based on reinforcement learning and it only requires a moderate number of stochastic simulations (in comparison to typical simulation-based approaches) to train the “policy function”. This allows not just the numerical approximation of various expectations for the CME solution but also of its sensitivities with respect to all the reaction network parameters (e.g. rate constants). We provide four examples to illustrate our methodology and provide several directions for future research., Author summary We develop a deep learning framework for estimating solutions of the chemical master equation (CME) that is fundamental to stochastic analysis of reaction networks. The CME is a system of ordinary differential equations that describes the time-evolution of the probability density of the random state-vector, and owing to an inherent curse of dimensionality, directly solving the CME is generally impractical with existing approaches. Moreover, the commonly employed simulation-based approaches for estimating CME solutions often require an exorbitant amount of computational time, even for moderately-sized networks. To counter these issues, we develop a deep reinforcement learning based method, called DeepCME, in this paper. DeepCME not only estimates function expectations based on the CME solution, but it also solves the more challenging problem of estimating their sensitivities with respect to all the model parameters. We illustrate our approach with four carefully chosen reaction network examples with varying sizes. Our results demonstrate that DeepCME reliably estimates the expectations of interest, along with all the parametric sensitivities, at a fraction of the computational cost of simulation-based estimators. We present many directions for future research and suggest further improvements to DeepCME that can greatly enhance its accuracy and applicability.

This paper describes a data-driven simulation study that explores the relative impact of several low-cost and practical non-pharmaceutical interventions on the spread of COVID-19 in an outpatient hospital dialysis unit. The interventions considered include: (i) voluntary self-isolation of healthcare personnel (HCPs) with symptoms; (ii) a program of active syndromic surveillance and compulsory isolation of HCPs; (iii) the use of masks or respirators by patients and HCPs; (iv) improved social distancing among HCPs; (v) increased physical separation of dialysis stations; and (vi) patient isolation combined with preemptive isolation of exposed HCPs. Our simulations show that under conditions that existed prior to the COVID-19 outbreak, extremely high rates of COVID-19 infection can result in a dialysis unit. In simulations under worst-case modeling assumptions, a combination of relatively inexpensive interventions such as requiring surgical masks for everyone, encouraging social distancing between healthcare professionals (HCPs), slightly increasing the physical distance between dialysis stations, and—once the first symptomatic patient is detected—isolating that patient, replacing the HCP having had the most exposure to that patient, and relatively short-term use of N95 respirators by other HCPs can lead to a substantial reduction in both the attack rate and the likelihood of any spread beyond patient zero. For example, in a scenario with R0 = 3.0, 60% presymptomatic viral shedding, and a dialysis patient being the infection source, the attack rate falls from 87.8% at baseline to 34.6% with this intervention bundle. Furthermore, the likelihood of having no additional infections increases from 6.2% at baseline to 32.4% with this intervention bundle., Author summary As we write this, the COVID-19 pandemic has essentially taken over the world, with more than 20 million cases spread over 216 countries. A big concern for policy makers all across the world has been the impact of COVID-19 on healthcare systems and whether these systems can cope with the enormous strain placed on them by COVID-19. In this paper, we consider the spread of COVID-19 in a specific healthcare setting: the outpatient dialysis unit. Hemodialysis patients are extremely vulnerable to infections in large part due to multiple immune-system deficiencies associated with renal failure and hemodialysis. Hemodialysis facilities also increase the risk of COVID-19 transmission because each patient is in frequent, close contact with other patients and healthcare personnel. Thus, a dialysis unit can be seen as a microcosm for the worst-case impacts of COVID-19 in a healthcare setting. In this manuscript, we show via high-fidelity modeling and simulations that under pessimistic modeling assumptions, there is a combination of relatively simple, inexpensive, and practical non-pharmaceutical interventions that can substantially lower the impact of COVID-19 in the dialysis unit. Our simulations are based on fine-grained healthcare personnel movement data that we make available for other modelers to use.

The cerebral vasculature has a complex and hierarchical network, ranging from vessels of a few millimeters to superficial cortical vessels with diameters of a few hundred micrometers, and to the microvasculature (arteriole/venule) and capillary beds in the cortex. In standard imaging techniques, it is difficult to segment all vessels in the network, especially in the case of the human brain. This study proposes a hybrid modeling approach that determines these networks by explicitly segmenting the large vessels from medical images and employing a novel vascular generation algorithm. The framework enables vasculatures to be generated at coarse and fine scales for individual arteries and veins with vascular subregions, following the personalized anatomy of the brain and macroscale vasculatures. In this study, the vascular structures of superficial cortical (pial) vessels before they penetrate the cortex are modeled as a mesoscale vasculature. The validity of the present approach is demonstrated through comparisons with partially observed data from existing measurements of the vessel distributions on the brain surface, pathway fractal features, and vascular territories of the major cerebral arteries. Additionally, this validation provides some biological insights: (i) vascular pathways may form to ensure a reasonable supply of blood to the local surface area; (ii) fractal features of vascular pathways are not sensitive to overall and local brain geometries; and (iii) whole pathways connecting the upstream and downstream entire-scale cerebral circulation are highly dependent on the local curvature of the cerebral sulci., Author summary Cerebral autoregulation in the complex vascular networks of the brain is an amazing achievement. We believe that numerical analysis of the cerebral blood circulation using an anatomically precise vascular model provides a powerful tool for evaluating the direct relationships between local- and global-scale blood flows. However, there is a lack of information about the overall vascular pathways in the human brain, preventing a monolithic model of the human cerebrovasculature from being established. This paper presents a multiscale model of human cerebrovasculature based on a hybrid approach that uses image-based geometries and a newly developed mathematical algorithm. One important argument of this paper is the validity of the cerebrovasculature represented in the model, which reflects anatomical features of major cerebral vasculatures and brain shape, and has strong similarities with available data for human superficial cortical vessels. Investigations of the reconstructed model allow us to derive some biological insights and associated hypotheses for the cerebral vasculature. The authors believe the present cerebrovascular model can be applied to numerical simulations of the entire-scale cerebral blood flow.

High-throughput data such as metabolomics, genomics, transcriptomics, and proteomics have become familiar data types within the “-omics” family. For this work, we focus on subsets that interact with one another and represent these “pathways” as graphs. Observed pathways often have disjoint components, i.e., nodes or sets of nodes (metabolites, etc.) not connected to any other within the pathway, which notably lessens testing power. In this paper we propose the Pathway Integrated Regression-based Kernel Association Test (PaIRKAT), a new kernel machine regression method for incorporating known pathway information into the semi-parametric kernel regression framework. This work extends previous kernel machine approaches. This paper also contributes an application of a graph kernel regularization method for overcoming disconnected pathways. By incorporating a regularized or “smoothed” graph into a score test, PaIRKAT can provide more powerful tests for associations between biological pathways and phenotypes of interest and will be helpful in identifying novel pathways for targeted clinical research. We evaluate this method through several simulation studies and an application to real metabolomics data from the COPDGene study. Our simulation studies illustrate the robustness of this method to incorrect and incomplete pathway knowledge, and the real data analysis shows meaningful improvements of testing power in pathways. PaIRKAT was developed for application to metabolomic pathway data, but the techniques are easily generalizable to other data sources with a graph-like structure., Author summary PaIRKAT is a tool for improving testing power on high dimensional data by including graph topography in the kernel machine regression setting. Studies on high-dimensional data can struggle to include the complex relationships between variables. The semi-parametric kernel machine regression model is a powerful tool for capturing these types of relationships. They provide a framework for testing for relationships between outcomes of interest and high dimensional data such as metabolomic, genomic, or proteomic pathways. Our paper proposes a kernel machine method for including known biological connections between high dimensional variables by representing them as edges of ‘graphs’ or ‘networks.’ It is common for nodes (e.g., metabolites) to be disconnected from all others within the graph, which leads to meaningful decreases in testing power when graph information is ignored. We include a graph regularization or ‘smoothing’ approach for managing this issue. We demonstrate the benefits of this approach through simulation studies and an application to the metabolomic data from the COPDGene study.

Read-depths (RDs) are frequently used in identifying structural variants (SVs) from sequencing data. For existing RD-based SV callers, it is difficult for them to determine breakpoints in single-nucleotide resolution due to the noisiness of RD data and the bin-based calculation. In this paper, we propose to use the deep segmentation model UNet to learn base-wise RD patterns surrounding breakpoints of known SVs. We integrate model predictions with an RD-based SV caller to enhance breakpoints in single-nucleotide resolution. We show that UNet can be trained with a small amount of data and can be applied both in-sample and cross-sample. An enhancement pipeline named RDBKE significantly increases the number of SVs with more precise breakpoints on simulated and real data. The source code of RDBKE is freely available at https://github.com/yaozhong/deepIntraSV., Author summary In this paper, we used the deep segmentation model UNet to alleviate the bin size limitation of RD-based SV callers. UNet was initially proposed for image data. Here, we demonstrated that the UNet model could also be applied for one-dimensional genomic data. We formalized the breakpoint prediction as a segmentation task and inferred breakpoints in single-nucleotide resolution from predicted label marks. Through a set of experiments on both simulated and real WGS data, we demonstrated that the UNet model could be trained with a small amount of data, and an enhancement pipeline called RDBKE significantly increased the number of SVs with more precise breakpoints.

[EN] Myriad risk factors-including uncontrolled hypertension, aging, and diverse genetic mutations-contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing. Author summary Aneurysms are local dilatations of the arterial wall that are responsible for significant disability and death. Detailed analyses of clinical data continue to provide insight into the natural history of these potentially lethal conditions, with myriad risk factors-including uncontrolled hypertension, aging, and diverse genetic mutations-contributing to their development and enlargement. Yet, because of the co-existence of these risk factors in most cases, it has been difficult to isolate individual effects or to understand how they act in combination. In this paper, we use a computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing factors both in isolation and in combination as well as with superimposed hypertension and aging. The present study recovers many findings from mouse models but with new and important observations that promise to guide in vivo and ex vivo studies as we seek to understand and eventually better treat these complex, multi-factorial lesions, with data-informed patient-specific computations eventually the way forward., This work was supported, in part, by grants from the US NIH (P01 HL134605, U01 HL142518, and R01 HL146723) to JDH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

During these days of global emergency for the COVID-19 disease outbreak, there is an urgency to share reliable information able to help worldwide life scientists to get better insights and make sense of the large amount of data currently available. In this study we used the results presented in [1] to perform two different Systems Biology analyses on the HCoV-host interactome. In the first one, we reconstructed the interactome of the HCoV-host proteins, integrating it with highly reliable miRNA and drug interactions information. We then added the IL-6 gene, identified in recent publications [2] as heavily involved in the COVID-19 progression and, interestingly, we identified several interactions with the reconstructed interactome. In the second analysis, we performed a Gene Ontology and a Pathways enrichment analysis on the full set of the HCoV-host interactome proteins and on the ones belonging to a significantly dense cluster of interacting proteins identified in the first analysis. Results of the two analyses provide a compact but comprehensive glance on some of the current state-of-the-art regulations, GO, and pathways involved in the HCoV-host interactome, and that could support all scientists currently focusing on SARS-CoV-2 research., Author summary In this paper we provide data about the HCoV-host interactome that can be extracted from the integration of several public available databases. We used the initial interactome published by Zhou et al. and analyzed if there are already known and validated interactions. We also looked into possible known miRNAs and drugs interactions to suggest possible biomarker candidates and treatment options. We also performed a Gene Ontology and a Pathways enrichment analysis to understand which are the pathways most likely involved in the proteins targeted by SARS-CoV-2. This paper not only provides a set of validated and reliable data that could help researchers in their fight against the COVID-19 disease outbreak, but also demonstrates how Systems Biology can be effectively used to quickly gather preliminary but still significant data without resorting only to expensive lab experiments.

Humans are able to track multiple objects at any given time in their daily activities—for example, we can drive a car while monitoring obstacles, pedestrians, and other vehicles. Several past studies have examined how humans track targets simultaneously and what underlying behavioral and neural mechanisms they use. At the same time, computer-vision researchers have proposed different algorithms to track multiple targets automatically. These algorithms are useful for video surveillance, team-sport analysis, video analysis, video summarization, and human–computer interaction. Although there are several efficient biologically inspired algorithms in artificial intelligence, the human multiple-target tracking (MTT) ability is rarely imitated in computer-vision algorithms. In this paper, we review MTT studies in neuroscience and biologically inspired MTT methods in computer vision and discuss the ways in which they can be seen as complementary., Author summary Multiple-target tracking (MTT) is a challenging task vital for both a human’s daily life and for many artificial intelligent systems, such as those used for urban traffic control. Neuroscientists are interested in discovering the underlying neural mechanisms that successfully exploit cognitive resources, e.g., spatial attention or memory, during MTT. Computer-vision specialists aim to develop powerful MTT algorithms based on advanced models or data-driven computational methods. In this paper, we review MTT studies from both communities and discuss how findings from cognitive studies can inspire developers to construct higher performing MTT algorithms. Moreover, some directions have been proposed through which MTT algorithms could raise new questions in the cognitive science domain, and answering them can shed light on neural processes underlying MTT.

Analyzing the rhythm of animals’ acoustic signals is of interest to a growing number of researchers: evolutionary biologists want to disentangle how these structures evolved and what patterns can be found, and ecologists and conservation biologists aim to discriminate cryptic species on the basis of parameters of acoustic signals such as temporal structures. Temporal structures are also relevant for research on vocal production learning, a part of which is for the animal to learn a temporal structure. These structures, in other words, these rhythms, are the topic of this paper. How can they be investigated in a meaningful, comparable and universal way? Several approaches exist. Here we used five methods to compare their suitability and interpretability for different questions and datasets and test how they support the reproducibility of results and bypass biases. Three very different datasets with regards to recording situation, length and context were analyzed: two social vocalizations of Neotropical bats (multisyllabic, medium long isolation calls of Saccopteryx bilineata, and monosyllabic, very short isolation calls of Carollia perspicillata) and click trains of sperm whales, Physeter macrocephalus. Techniques to be compared included Fourier analysis with a newly developed goodness-of-fit value, a generate-and-test approach where data was overlaid with varying artificial beats, and the analysis of inter-onset-intervals and calculations of a normalized Pairwise Variability Index (nPVI). We discuss the advantages and disadvantages of the methods and we also show suggestions on how to best visualize rhythm analysis results. Furthermore, we developed a decision tree that will enable researchers to select a suitable and comparable method on the basis of their data., Author summary In the analysis of animal communication more and more interest is shown in rhythm of animal communication and what information this might convey. In this paper, we establish a workflow to analyze the temporal structure–namely the rhythm–of any particular animals’acoustic signal with methods that are applicable for a wide range of signals and results that are easily comparable and interpretable. This workflow will enhance the understanding of rhythmicality in animals’ acoustic signals as well as facilitate comparison between species. Methods we conducted ranged from simple distributional and visual analysis to higher mathematics such as Fourier analysis. All analyses rely on Inter-Onset-Intervals, the duration between the beginning of one element and the next. We used different datasets from two neotropical bat species as well as from the sperm whale. With this selection, we cover very short sequences with only few elements up to sequences of around 200 elements, multisyllabic and monosyllabic sequences and social communication as well as sounds used for orientation and foraging.

In bacteria functionally related genes comprising metabolic pathways and protein complexes are frequently encoded in operons and are widely conserved across phylogenetically diverse species. The evolution of these operon-encoded processes is affected by diverse mechanisms such as gene duplication, loss, rearrangement, and horizontal transfer. These mechanisms can result in functional diversification, increasing the potential evolution of novel biological pathways, and enabling pre-existing pathways to adapt to the requirements of particular environments. Despite the fundamental importance that these mechanisms play in bacterial environmental adaptation, a systematic approach for studying the evolution of operon organization is lacking. Herein, we present a novel method to study the evolution of operons based on phylogenetic clustering of operon-encoded protein families and genomic-proximity network visualizations of operon architectures. We applied this approach to study the evolution of the synthase dependent exopolysaccharide (EPS) biosynthetic systems: cellulose, acetylated cellulose, poly-β-1,6-N-acetyl-D-glucosamine (PNAG), Pel, and alginate. These polymers have important roles in biofilm formation, antibiotic tolerance, and as virulence factors in opportunistic pathogens. Our approach revealed the complex evolutionary landscape of EPS machineries, and enabled operons to be classified into evolutionarily distinct lineages. Cellulose operons show phyla-specific operon lineages resulting from gene loss, rearrangement, and the acquisition of accessory loci, and the occurrence of whole-operon duplications arising through horizonal gene transfer. Our evolution-based classification also distinguishes between PNAG production from Gram-negative and Gram-positive bacteria on the basis of structural and functional evolution of the acetylation modification domains shared by PgaB and IcaB loci, respectively. We also predict several pel-like operon lineages in Gram-positive bacteria and demonstrate in our companion paper (Whitfield et al PLoS Pathogens, in press) that Bacillus cereus produces a Pel-dependent biofilm that is regulated by cyclic-3’,5’-dimeric guanosine monophosphate (c-di-GMP)., Author summary In bacterial genomes, biological processes are frequently encoded by neighbouring co-transcribed genes, termed operons. In addition, operon-associated genes often belong to distinct evolutionary families with diverse biological functions. Studying the evolution of bacterial operons provides valuable insight into understanding the biological significance of genes involved in environmental adaptation. To date, no systematic approach has been devised to examine both the complex evolutionary relationships of operon encoded genes and the evolution of operon organization as a whole. To address this challenge, we developed an integrative method to study operon evolution by combining phylogenetic tree based clustering and genomic-context networks. We applied this method to perform the first systematic survey of all known synthase-dependent exopolysaccharide biosynthetic machineries, demonstrating the generalizability of our approach for operons of diverse size, protein family composition, and species distribution. Our method identified distinct biofilm operon clades across phylogenetically diverse bacteria, that result from gene rearrangement, duplication, loss, fusion, and horizontal gene transfer. We found different evolutionary trajectories for Gram-negative and Gram-positive PNAG biofilm production machineries, and in a companion paper (Whitfield et al PLoS Pathogens, in press) present experimental validation that the Pel polysaccharide is produced by a Gram-positive bacterium.

We describe Orbit Image Analysis, an open-source whole slide image analysis tool. The tool consists of a generic tile-processing engine which allows the execution of various image analysis algorithms provided by either Orbit itself or from other open-source platforms using a tile-based map-reduce execution framework. Orbit Image Analysis is capable of sophisticated whole slide imaging analyses due to several key features. First, Orbit has machine-learning capabilities. This deep learning segmentation can be integrated with complex object detection for analysis of intricate tissues. In addition, Orbit can run locally as standalone or connect to the open-source image server OMERO. Another important characteristic is its scale-out functionality, using the Apache Spark framework for distributed computing. In this paper, we describe the use of Orbit in three different real-world applications: quantification of idiopathic lung fibrosis, nerve fibre density quantification, and glomeruli detection in the kidney., Author summary Whole slide images (WSI) are digital scans of samples, e.g. tissue sections. It is very convenient to view samples in this digital form, and with the increasing computation power it can also be used for quantification. These images are often too large to be analysed with standard tools. To overcome this issue, we created on open-source tool called Orbit Image Analysis which divides the images into smaller parts and allows the analysis of it with either embedded algorithms or the integration of existing tools. It also provides mechanisms to process huge amounts of images in distributed computing environments, such as clusters or cloud infrastructures. In this paper we describe the Orbit system and demonstrate its application based on three real-word use-cases.

Integrative clustering is used to identify groups of samples by jointly analysing multiple datasets describing the same set of biological samples, such as gene expression, copy number, methylation etc. Most existing algorithms for integrative clustering assume that there is a shared consistent set of clusters across all datasets, and most of the data samples follow this structure. However in practice, the structure across heterogeneous datasets can be more varied, with clusters being joined in some datasets and separated in others. In this paper, we present a probabilistic clustering method to identify groups across datasets that do not share the same cluster structure. The proposed algorithm, Clusternomics, identifies groups of samples that share their global behaviour across heterogeneous datasets. The algorithm models clusters on the level of individual datasets, while also extracting global structure that arises from the local cluster assignments. Clusters on both the local and the global level are modelled using a hierarchical Dirichlet mixture model to identify structure on both levels. We evaluated the model both on simulated and on real-world datasets. The simulated data exemplifies datasets with varying degrees of common structure. In such a setting Clusternomics outperforms existing algorithms for integrative and consensus clustering. In a real-world application, we used the algorithm for cancer subtyping, identifying subtypes of cancer from heterogeneous datasets. We applied the algorithm to TCGA breast cancer dataset, integrating gene expression, miRNA expression, DNA methylation and proteomics. The algorithm extracted clinically meaningful clusters with significantly different survival probabilities. We also evaluated the algorithm on lung and kidney cancer TCGA datasets with high dimensionality, again showing clinically significant results and scalability of the algorithm., Author summary Integrative clustering is the task of identifying groups of samples by combining information from several datasets. An example of this task is cancer subtyping, where we cluster tumour samples based on several datasets, such as gene expression, proteomics and others. Most existing algorithms assume that all such datasets share a similar cluster structure, with samples outside these clusters treated as noise. The structure can, however, be much more heterogeneous: some meaningful clusters may appear only in some datasets. In the paper, we introduce the Clusternomics algorithm that identifies groups of samples across heterogeneous datasets. It models both cluster structure of individual datasets, and the global structure that appears as a combination of local structures. The algorithm uses probabilistic modelling to identify the groups and share information across the local and global levels. We evaluated the algorithm on both simulated and real world datasets, where the algorithm found clinically significant clusters with different survival outcomes.

The ability to produce timely and accurate flu forecasts in the United States can significantly impact public health. Augmenting forecasts with internet data has shown promise for improving forecast accuracy and timeliness in controlled settings, but results in practice are less convincing, as models augmented with internet data have not consistently outperformed models without internet data. In this paper, we perform a controlled experiment, taking into account data backfill, to improve clarity on the benefits and limitations of augmenting an already good flu forecasting model with internet-based nowcasts. Our results show that a good flu forecasting model can benefit from the augmentation of internet-based nowcasts in practice for all considered public health-relevant forecasting targets. The degree of forecast improvement due to nowcasting, however, is uneven across forecasting targets, with short-term forecasting targets seeing the largest improvements and seasonal targets such as the peak timing and intensity seeing relatively marginal improvements. The uneven forecasting improvements across targets hold even when “perfect” nowcasts are used. These findings suggest that further improvements to flu forecasting, particularly seasonal targets, will need to derive from other, non-nowcasting approaches., Author summary It has been demonstrated in retrospective settings that flu forecasting can be improved by augmenting forecasting models with internet-based nowcasts (i.e., one-week-ahead forecasts generated with internet data). The improvement of internet-assisted forecasting models, however, has not translated to overall improvement in flu forecasting of public health-relevant targets. This is partially due to the relatively simple forecasting models that nowcasts are augmenting and partially because nowcasts do not directly inform all public health-relevant targets, such as the start, the peak timing, and the peak intensity of the flu season (i.e., seasonal targets). This paper conducts an experiment to provide clarity on the benefits and limitations of augmenting flu forecasting models with internet-based nowcasts in practice. We show that 1) nowcasts can improve flu forecasting across all geographic regions, flu seasons, and public health-relevant targets, including seasonal targets, and 2) the benefits of nowcasting are uneven, as even in the perfect nowcasting setting, only marginal improvements to forecasts of seasonal targets are possible relative to short-term forecasts. This is because nowcasts provide direct information about short-term targets but only indirect information about seasonal targets. This paper supports previous findings that nowcasts can improve flu forecasting but clarifies the limitations of those improvements, both in terms of magnitude of possible improvement as well as which targets can be improved. The continued advancement of flu forecasting hinges on the development of model improvements separate from nowcasting.

Learning the reliability of different sources of rewards is critical for making optimal choices. However, despite the existence of detailed theory describing how the expected reward is learned in the basal ganglia, it is not known how reward uncertainty is estimated in these circuits. This paper presents a class of models that encode both the mean reward and the spread of the rewards, the former in the difference between the synaptic weights of D1 and D2 neurons, and the latter in their sum. In the models, the tendency to seek (or avoid) options with variable reward can be controlled by increasing (or decreasing) the tonic level of dopamine. The models are consistent with the physiology of and synaptic plasticity in the basal ganglia, they explain the effects of dopaminergic manipulations on choices involving risks, and they make multiple experimental predictions., Author Summary To maximize their chances for survival, animals need to base their decisions not only on the average consequences of chosen actions, but also on the variability of the rewards resulting from these actions. For example, when an animal’s food reserves are depleted, it should prefer to forage in an area where food is guaranteed over an area where the amount of food is higher on average but variable, thus avoiding the risk of starvation. To implement such policies, animals need to be able to learn about variability of rewards resulting from taking different actions. This paper proposes how such learning may be implemented in a circuit of subcortical nuclei called the basal ganglia. It also suggests how the information about reward uncertainty can be used during decision making, so that animals can make choices that not only maximize expected rewards but also minimize risks.

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 (http://mflux.org) 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., Author Summary Metabolic information is important for disease treatment, bioprocess optimization, environmental remediation, biogeochemical cycle regulation, and our understanding of life’s origin and evolution. 13C-MFA can quantify microbial physiology at the level of metabolic reaction rates. To speed up microbial characterizations and fluxomic studies, we hypothesize that genetic and environmental factors generate specific fluxome patterns that can be recognized by machine learning. Aided by constraint programming and quadratic optimization, our platform based on machine learning (ML) can predict meaningful metabolic information about bacterial species in their environments. Further, it can offer constraints to improve the accuracy of flux balance analysis. This study infers that the bacterial metabolic network has a certain degree of rigidity in allocating carbon fluxes, and different microbial species may share common regulatory strategies for balancing carbon and energy metabolisms. As a proof of concept, we demonstrate that the use of data-driven artificial intelligence (AI) approaches, e.g., ML, may assist mechanistic based models to elucidate the topology of microbial fluxomes.

There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance., Author summary Time-varying connectivity attempts to quantify the fluctuating covariance relationship between two or more regions through time. In recent years, it has become popular to do this with fMRI neuroimaging data. There have been many methods proposed to quantify time-varying connectivity, but very few attempts to systematically compare them. In this paper, we present tvc_benchmarker, which is a python package that consists of four simulations. The parameters of the data are justified on fMRI signal properties. Five different methods are evaluated in this paper, but other researchers can use tvc_benchmarker to evaluate their methodologies and their results can be submitted to be included in future reports. Methods are evaluated on their ability to track a fluctuating covariance parameter between time series. Of the evaluated methods, the jackknife correlation method performed the best at tracking a fluctuating covariance parameter in these four simulations.

As science becomes increasingly interdisciplinary, we are expected to acquire both breadth of knowledge and depth of expertise. In bioinformatics, this is especially true. Keeping up to date with major techniques across multiple specialisations can be daunting, but you need not face it alone. A journal club is an excellent way to take in the scientific literature, keep up with developments in your field, and hone your communication and analytical skills. In general, a journal club is a group of people who meet regularly to discuss one or more scientific papers. The structure of such a club can vary. In the more traditional format, an individual studies a paper and then presents it to the group, usually in the form of PowerPoint slides, with time for questions. In some institutions, the journal club is for students only, designed to fulfill the requirements of a course or postgraduate program; attendance is obligatory, the scope of the literature is narrow, and the format is prescribed. The preparation of slides and a lecture may be required. Other kinds of journal clubs are just lab meetings in disguise, with the usual lab head and group members in attendance and one member nominated to present the paper. A formal style often fits well within an established academic structure—but what if your discipline is emerging? Consider the field of bioinformatics. Expertise may be spread across departments and institutions, and there may not be an obvious place or critical mass in any one lab for a traditional journal club. Research students, “pet bioinformaticians,” [1] and those interested in bioinformatics from adjoining fields all need a place to gather. We are pleased to offer an alternative structure to address this situation—an informal journal club, designed to bring together a diversity of backgrounds and career stages to discuss bioinformatics while building a network of like-minded peers. Additional benefits of such a journal club may include friendship and breakfast (see Rule 2)! We thoroughly recommend it to anyone who asks (as well as those who don’t). While this advice is drawn from our experiences in the Parkville Bioinformatics Journal Club, it is applicable to developing informal journal clubs of all disciplines. The advice contained in these rules will also help those who want to spice up their existing formal format. So don’t be a “lonely bioinformatician”[1], create a journal club! Follow these Ten Simple Rules to find out how.

The sleep onset process (SOP) is a dynamic process correlated with a multitude of behavioral and physiological markers. A principled analysis of the SOP can serve as a foundation for answering questions of fundamental importance in basic neuroscience and sleep medicine. Unfortunately, current methods for analyzing the SOP fail to account for the overwhelming evidence that the wake/sleep transition is governed by continuous, dynamic physiological processes. Instead, current practices coarsely discretize sleep both in terms of state, where it is viewed as a binary (wake or sleep) process, and in time, where it is viewed as a single time point derived from subjectively scored stages in 30-second epochs, effectively eliminating SOP dynamics from the analysis. These methods also fail to integrate information from both behavioral and physiological data. It is thus imperative to resolve the mismatch between the physiological evidence and analysis methodologies. In this paper, we develop a statistically and physiologically principled dynamic framework and empirical SOP model, combining simultaneously-recorded physiological measurements with behavioral data from a novel breathing task requiring no arousing external sensory stimuli. We fit the model using data from healthy subjects, and estimate the instantaneous probability that a subject is awake during the SOP. The model successfully tracked physiological and behavioral dynamics for individual nights, and significantly outperformed the instantaneous transition models implicit in clinical definitions of sleep onset. Our framework also provides a principled means for cross-subject data alignment as a function of wake probability, allowing us to characterize and compare SOP dynamics across different populations. This analysis enabled us to quantitatively compare the EEG of subjects showing reduced alpha power with the remaining subjects at identical response probabilities. Thus, by incorporating both physiological and behavioral dynamics into our model framework, the dynamics of our analyses can finally match those observed during the SOP., Author Summary How can we tell when someone has fallen asleep? Understanding the way we fall asleep is an important problem in sleep medicine, since sleep disorders can disrupt the process of falling asleep. In the case of insomnia, subjects may fall asleep too slowly, whereas during sleep deprivation or narcolepsy, subjects fall asleep too quickly. Current methods for tracking the wake/sleep transition are time-consuming, subjective, and simplify the sleep onset process in a way that severely limits the accuracy, power, and scope of any resulting clinical metrics. In this paper, we describe a new physiologically principled method that dynamically combines information from brainwaves, muscle activity, and a novel minimally-disruptive behavioral task, to automatically create a continuous dynamic characterization of a person's state of wakefulness. We apply this method to a cohort of healthy subjects, successfully tracking the changes in wakefulness as the subjects fall asleep. This analysis reveals and statistically quantifies a subset of subjects who still respond to behavioral stimuli even though their brain would appear to be asleep by clinical measures. By developing an automated tool to precisely track the wake/sleep transition, we can better characterize and diagnose sleep disorders, and more precisely measure the effect of sleep medications.

The study of microbial communities and their interactions has attracted the interest of the scientific community, because of their potential for applications in biotechnology, ecology and medicine. The complexity of interspecies interactions, which are key for the macroscopic behavior of microbial communities, cannot be studied easily experimentally. For this reason, the modeling of microbial communities has begun to leverage the knowledge of established constraint-based methods, which have long been used for studying and analyzing the microbial metabolism of individual species based on genome-scale metabolic reconstructions of microorganisms. A main problem of genome-scale metabolic reconstructions is that they usually contain metabolic gaps due to genome misannotations and unknown enzyme functions. This problem is traditionally solved by using gap-filling algorithms that add biochemical reactions from external databases to the metabolic reconstruction, in order to restore model growth. However, gap-filling algorithms could evolve by taking into account metabolic interactions among species that coexist in microbial communities. In this work, a gap-filling method that resolves metabolic gaps at the community level was developed. The efficacy of the algorithm was tested by analyzing its ability to resolve metabolic gaps on a synthetic community of auxotrophic Escherichia coli strains. Subsequently, the algorithm was applied to resolve metabolic gaps and predict metabolic interactions in a community of Bifidobacterium adolescentis and Faecalibacterium prausnitzii, two species present in the human gut microbiota, and in an experimentally studied community of Dehalobacter and Bacteroidales species of the ACT-3 community. The community gap-filling method can facilitate the improvement of metabolic models and the identification of metabolic interactions that are difficult to identify experimentally in microbial communities., Author summary Microbes are the most abundant form of life on earth and they are almost never found in isolation as they live in close association with one another and with other organisms. The metabolic capacity of individual microbial species dictates their ways of interacting with other species as well as with their environment. The metabolic interactions among microorganisms has been recognised as the driving force for the properties of microbial communities. For this reason, understanding the effect of microbial metabolism on interspecies metabolic interactions is essential for the study of microbial communities. This study can benefit from metabolic modeling and the insights offered by constraint-based methods which have been developed for interrogating metabolic models. In this paper, we present an algorithm that predicts cooperative and competitive metabolic interactions between species while it resolves metabolic gaps in their metabolic models in a computationally efficient way. We use our community gap-filling algorithm to study microbial communities with interesting environmental and health-related applications.

Because local field potentials (LFPs) arise from multiple sources in different spatial locations, they do not easily reveal coordinated activity across neural populations on a trial-to-trial basis. As we show here, however, once disparate source signals are decoupled, their trial-to-trial fluctuations become more accessible, and cross-population correlations become more apparent. To decouple sources we introduce a general framework for estimation of current source densities (CSDs). In this framework, the set of LFPs result from noise being added to the transform of the CSD by a biophysical forward model, while the CSD is considered to be the sum of a zero-mean, stationary, spatiotemporal Gaussian process, having fast and slow components, and a mean function, which is the sum of multiple time-varying functions distributed across space, each varying across trials. We derived biophysical forward models relevant to the data we analyzed. In simulation studies this approach improved identification of source signals compared to existing CSD estimation methods. Using data recorded from primate auditory cortex, we analyzed trial-to-trial fluctuations in both steady-state and task-evoked signals. We found cortical layer-specific phase coupling between two probes and showed that the same analysis applied directly to LFPs did not recover these patterns. We also found task-evoked CSDs to be correlated across probes, at specific cortical depths. Using data from Neuropixels probes in mouse visual areas, we again found evidence for depth-specific phase coupling of primary visual cortex and lateromedial area based on the CSDs., Author summary To better understand information processing in the brain, it is important to identify situations in which neural activity is coordinated across populations of neurons, including those in distinct layers of the cortex. Bulk population activity results in voltage changes across extracellular electrodes, but in raw form such voltage recordings can be hard to analyze and interpret. In this paper, we develop a novel framework for locating the sources of currents that produce the measured voltages, and decomposing those currents into interpretable components. We use this flexible framework to develop statistical methods of analysis, and we show that our methodology can be more effective than existing techniques for current source localization. We apply the method to extracellular recordings in two contexts: primate auditory cortex in response to tone stimuli, and mouse visual cortex in response to visual stimuli. In both cases, we get results that are useful for understanding cross-population activity while being difficult or impossible to obtain using the raw voltage signals. We thereby demonstrate the broad utility of our approach for identifying coordinated neural activity based on extracellular voltage recordings.

The cost of sequencing the genome is dropping at a much faster rate compared to assembling and finishing the genome. The use of lightly sampled genomes (genome-skims) could be transformative for genomic ecology, and results using k-mers have shown the advantage of this approach in identification and phylogenetic placement of eukaryotic species. Here, we revisit the basic question of estimating genomic parameters such as genome length, coverage, and repeat structure, focusing specifically on estimating the k-mer repeat spectrum. We show using a mix of theoretical and empirical analysis that there are fundamental limitations to estimating the k-mer spectra due to ill-conditioned systems, and that has implications for other genomic parameters. We get around this problem using a novel constrained optimization approach (Spline Linear Programming), where the constraints are learned empirically. On reads simulated at 1X coverage from 66 genomes, our method, REPeat SPECTra Estimation (RESPECT), had 2.2% error in length estimation compared to 27% error previously achieved. In shotgun sequenced read samples with contaminants, RESPECT length estimates had median error 4%, in contrast to other methods that had median error 80%. Together, the results suggest that low-pass genomic sequencing can yield reliable estimates of the length and repeat content of the genome. The RESPECT software will be publicly available at https://urldefense.proofpoint.com/v2/url?u=https-3A__github.com_shahab-2Dsarmashghi_RESPECT.git&d=DwIGAw&c=-35OiAkTchMrZOngvJPOeA&r=ZozViWvD1E8PorCkfwYKYQMVKFoEcqLFm4Tg49XnPcA&m=f-xS8GMHKckknkc7Xpp8FJYw_ltUwz5frOw1a5pJ81EpdTOK8xhbYmrN4ZxniM96&s=717o8hLR1JmHFpRPSWG6xdUQTikyUjicjkipjFsKG4w&e=., Author summary The cost of sequencing the genome is dropping at a much faster rate compared to assembling and finishing the genome. The use of lightly sampled genomes (genome skims) could be transformative for genomic ecology. Analyzing genome skims, mostly based on statistics of small oligomers, remains challenging, but recent results have shown the advantage of this approach for the identification and phylogenetic placement of eukaryotic species. In this paper, we present a method, RESPECT, to estimate genomic properties such as genome length and repetitiveness from low-coverage genome skims. We trained RESPECT using assembled genomes and tested it on low-coverage simulated and real reads. Benchmarking results reveal that RESPECT has excellent accuracy in estimating the genome length compared to other methods, and can provide critical information regarding the repeat structure of the genome.

Slow-wave sleep cortical brain activity, conformed by slow-oscillations and sleep spindles, plays a key role in memory consolidation. The increase of the power of the slow-wave events, obtained by auditory sensory stimulation, positively correlates with memory consolidation performance. However, little is known about the experimental protocol maximizing this effect, which could be induced by the power of slow-oscillation, the number of sleep spindles, or the timing of both events’ co-occurrence. Using a mean-field model of thalamocortical activity, we studied the effect of several stimulation protocols, varying the pulse shape, duration, amplitude, and frequency, as well as a target-phase using a closed-loop approach. We evaluated the effect of these parameters on slow-oscillations (SO) and sleep-spindles (SP), considering: (i) the power at the frequency bands of interest, (ii) the number of SO and SP, (iii) co-occurrences between SO and SP, and (iv) synchronization of SP with the up-peak of the SO. The first three targets are maximized using a decreasing ramp pulse with a pulse duration of 50 ms. Also, we observed a reduction in the number of SO when increasing the stimulus energy by rising its amplitude. To assess the target-phase parameter, we applied closed-loop stimulation at 0°, 45°, and 90° of the phase of the narrow-band filtered ongoing activity, at 0.85 Hz as central frequency. The 0° stimulation produces better results in the power and number of SO and SP than the rhythmic or random stimulation. On the other hand, stimulating at 45° or 90° change the timing distribution of spindles centers but with fewer co-occurrences than rhythmic and 0° phase. Finally, we propose the application of closed-loop stimulation at the rising zero-cross point using pulses with a decreasing ramp shape and 50 ms of duration for future experimental work., Author summary During the non-REM (NREM) phase of sleep, events that are known as slow oscillations (SO) and spindles (SP) can be detected by EEG. These events have been associated with the consolidation of declarative memories and learning. Thus, there is an ongoing interest in promoting them during sleep by non-invasive manipulations such as sensory stimulation. In this paper, we used a computational model of brain activity that generates SO and SP, to investigate which type of sensory stimulus –shape, amplitude, duration, periodicity– would be optimal for increasing the events’ frequency and their co-occurrence. We found that a decreasing ramp of 50 ms duration is the most effective. The effectiveness increases when the stimulus pulse is delivered in a closed-loop configuration triggering the pulse at a target phase of the ongoing SO activity. A desirable secondary effect is to promote SPs at the rising phase of the SO oscillation.

Motivation Protein structure prediction has been greatly improved by deep learning, but most efforts are devoted to template-free modeling. But very few deep learning methods are developed for TBM (template-based modeling), a popular technique for protein structure prediction. TBM has been studied extensively in the past, but its accuracy is not satisfactory when highly similar templates are not available. Results This paper presents a new method NDThreader (New Deep-learning Threader) to address the challenges of TBM. NDThreader first employs DRNF (deep convolutional residual neural fields), which is an integration of deep ResNet (convolutional residue neural networks) and CRF (conditional random fields), to align a query protein to templates without using any distance information. Then NDThreader uses ADMM (alternating direction method of multipliers) and DRNF to further improve sequence-template alignments by making use of predicted distance potential. Finally, NDThreader builds 3D models from a sequence-template alignment by feeding it and sequence coevolution information into a deep ResNet to predict inter-atom distance distribution, which is then fed into PyRosetta for 3D model construction. Our experimental results show that NDThreader greatly outperforms existing methods such as CNFpred, HHpred, DeepThreader and CEthreader. NDThreader was blindly tested in CASP14 as a part of RaptorX server, which obtained the best average GDT score among all CASP14 servers on the 58 TBM targets., Author summary TBM (template-based modeling) is a popular method for protein structure prediction. However, existing methods cannot generate good models when the protein under prediction does not have very similar templates in Protein Data Bank (PDB). Recently significant progress has been made on template-free protein structure prediction by deep learning, but very few deep learning methods were developed for TBM. To further improve TBM for protein structure prediction, we present a new deep learning method that greatly outperforms existing ones in identifying the best templates, generating sequence-template alignment and constructing 3D models from alignments. Blindly tested in CASP14, our server obtained the best average model quality score on the 58 TBM targets among all the CASP14-participating servers, which confirms that our method is effective for TBM.

Eukaryotic genome sequencing and de novo assembly, once the exclusive domain of well-funded international consortia, have become increasingly affordable, thus fitting the budgets of individual research groups. Third-generation long-read DNA sequencing technologies are increasingly used, providing extensive genomic toolkits that were once reserved for a few select model organisms. Generating high-quality genome assemblies and annotations for many aquatic species still presents significant challenges due to their large genome sizes, complexity, and high chromosome numbers. Indeed, selecting the most appropriate sequencing and software platforms and annotation pipelines for a new genome project can be daunting because tools often only work in limited contexts. In genomics, generating a high-quality genome assembly/annotation has become an indispensable tool for better understanding the biology of any species. Herein, we state 12 steps to help researchers get started in genome projects by presenting guidelines that are broadly applicable (to any species), sustainable over time, and cover all aspects of genome assembly and annotation projects from start to finish. We review some commonly used approaches, including practical methods to extract high-quality DNA and choices for the best sequencing platforms and library preparations. In addition, we discuss the range of potential bioinformatics pipelines, including structural and functional annotations (e.g., transposable elements and repetitive sequences). This paper also includes information on how to build a wide community for a genome project, the importance of data management, and how to make the data and results Findable, Accessible, Interoperable, and Reusable (FAIR) by submitting them to a public repository and sharing them with the research community.

Single-cell Hi-C (scHi-C) sequencing technologies allow us to investigate three-dimensional chromatin organization at the single-cell level. However, we still need computational tools to deal with the sparsity of the contact maps from single cells and embed single cells in a lower-dimensional Euclidean space. This embedding helps us understand relationships between the cells in different dimensions, such as cell-cycle dynamics and cell differentiation. We present an open-source computational toolbox, scHiCTools, for analyzing single-cell Hi-C data comprehensively and efficiently. The toolbox provides two methods for screening single cells, three common methods for smoothing scHi-C data, three efficient methods for calculating the pairwise similarity of cells, three methods for embedding single cells, three methods for clustering cells, and a build-in function to visualize the cells embedding in a two-dimensional or three-dimensional plot. scHiCTools, written in Python3, is compatible with different platforms, including Linux, macOS, and Windows., Author summary Single-cell Hi-C contact maps describe the numbers of interactions among genomic loci across the entire genome, and provide researchers 3D chromatin organization in each cell. There are growing demands for an easy and fast way to analyze and visualize single-cell Hi-C data, and analyzing single-cell Hi-C data exposes several inherent data analysis challenges. To move beyond existing computational tools and methods to analyze and visualize single-cell Hi-C data, we present a software package, scHiCTools, which is implemented in Python. The software package provides researchers a collection of methods to investigate the cell-to-cell similarity based on their 3D chromatin organization, cluster cells into groups accordingly, and visualize cells in two-dimensional or three-dimensional scatter plots. In this paper, we provide an overview of scHiCTools’ structure and capabilities. We then apply scHiCTools to several single-cell Hi-C datasets to benchmark the performance of the methods provided in our toolbox, and present some plots generated using the software package.

Since the seminal 1961 paper of Monod and Jacob, mathematical models of biomolecular circuits have guided our understanding of cell regulation. Model-based exploration of the functional capabilities of any given circuit requires systematic mapping of multidimensional spaces of model parameters. Despite significant advances in computational dynamical systems approaches, this analysis remains a nontrivial task. Here, we use a nonlinear system of ordinary differential equations to model oocyte selection in Drosophila, a robust symmetry-breaking event that relies on autoregulatory localization of oocyte-specification factors. By applying an algorithmic approach that implements symbolic computation and topological methods, we enumerate all phase portraits of stable steady states in the limit when nonlinear regulatory interactions become discrete switches. Leveraging this initial exact partitioning and further using numerical exploration, we locate parameter regions that are dense in purely asymmetric steady states when the nonlinearities are not infinitely sharp, enabling systematic identification of parameter regions that correspond to robust oocyte selection. This framework can be generalized to map the full parameter spaces in a broad class of models involving biological switches., Author summary Identification of qualitatively different regimes in models of biomolecular switches is essential for understanding dynamics of complex biological processes, including symmetry breaking in cells and cell networks. We demonstrate how topological methods, symbolic computation, and numerical simulations can be combined for systematic mapping of symmetry-broken states in a mathematical model of oocyte specification in Drosophila, a leading experimental system of animal oogenesis. Our algorithmic framework reveals global connectedness of parameter domains corresponding to robust oocyte specification and enables systematic navigation through multidimensional parameter spaces in a large class of biomolecular switches.

The origin of life involved complicated evolutionary processes. Computer modeling is a promising way to reveal relevant mechanisms. However, due to the limitation of our knowledge on prebiotic chemistry, it is usually difficult to justify parameter-setting for the modeling. Thus, typically, the studies were conducted in a reverse way: the parameter-space was explored to find those parameter values “supporting” a hypothetical scene (that is, leaving the parameter-justification a later job when sufficient knowledge is available). Exploring the parameter-space manually is an arduous job (especially when the modeling becomes complicated) and additionally, difficult to characterize as regular “Methods” in a paper. Here we show that a machine-learning-like approach may be adopted, automatically optimizing the parameters. With this efficient parameter-exploring approach, the evolutionary modeling on the origin of life would become much more powerful. In particular, based on this, it is expected that more near-reality (complex) models could be introduced, and thereby theoretical research would be more tightly associated with experimental investigation in this field–hopefully leading to significant steps forward in respect to our understanding on the origin of life., Author summary People have long been interested in the evolutionary processes through which life on our planet could have arisen from a non-life background. However, it seems that experimental studies in this field are proceeding slowly, perhaps owing to the complication of such processes. In the meantime, computer modeling has shown its potential to disclose the evolutionary mechanisms involved. Now a major difficulty of the computer modeling work is to justify the parameter-setting–on account of our limited knowledge on prebiotic chemistry and environments. Thus, people tend to explore the parameter space to seek parameter values in favor of the hypothetic scene and leave the parameter-justification a later job when sufficient knowledge is available. To date, the parameter-exploration is usually conducted manually (in many cases by trial and error), thus arduous and unpredictable. Inspired by the algorithm of machine-learning, we designed an automatic approach of parameter-exploration. The results showed that the approach is quite effective–that is, “good” parameter-sets in favor of hypothetic scenes in the origin of life can be found automatically. It is expected that such a machine-learning-like method would greatly enhance the efficiency of our evolutionary modeling studies on the origin of life in future.

Respiratory syncytial virus (RSV) infection results in millions of hospitalizations and thousands of deaths each year. Variations in the adaptive and innate immune response appear to be associated with RSV severity. To investigate the host response to RSV infection in infants, we performed a systems-level study of RSV pathophysiology, incorporating high-throughput measurements of the peripheral innate and adaptive immune systems and the airway epithelium and microbiota. We implemented a novel multi-omic data integration method based on multilayered principal component analysis, penalized regression, and feature weight back-propagation, which enabled us to identify cellular pathways associated with RSV severity. In both airway and immune cells, we found an association between RSV severity and activation of pathways controlling Th17 and acute phase response signaling, as well as inhibition of B cell receptor signaling. Dysregulation of both the humoral and mucosal response to RSV may play a critical role in determining illness severity., Author summary This paper presents a novel approach to understanding the localized molecular responses to respiratory syncytial virus (RSV) and the system-level correlates of clinical outcomes. To do this, we developed a novel statistical method able to integrate high dimensional molecular data characterizing the host airway microbota and immune and nasal gene expression. We show that this integrative approach facilitates superior performance in estimating clinical outcome as opposed to any single data type. Using this approach, we identified both cell type-specific and shared biomarkers and regulatory pathways associated with RSV severity. Specifically, we identified an association between RSV severity, activation of pathways controlling Th17, and inhibition of B cell receptor signaling, which were present in both the site of infection airway and in peripheral immune cells. These results can guide future efforts to identify biomarkers for identifying or predicting illness severity following infant RSV infection. They may also be useful as biomarkers to inform the efficacy of future interventions (e.g., therapies) or preventative measures to suppress the rate of severe disease (e.g., vaccines).

Variants of the susceptible-infected-removed (SIR) model of Kermack & McKendrick (1927) enjoy wide application in epidemiology, offering simple yet powerful inferential and predictive tools in the study of diverse infectious diseases across human, animal and plant populations. Direct transmission models (DTM) are a subset of these that treat the processes of disease transmission as comprising a series of discrete instantaneous events. Infections transmitted indirectly by persistent environmental pathogens, however, are examples where a DTM description might fail and are perhaps better described by models that comprise explicit environmental transmission routes, so-called environmental transmission models (ETM). In this paper we discuss the stochastic susceptible-exposed-infected-removed (SEIR) DTM and susceptible-exposed-infected-removed-pathogen (SEIR-P) ETM and we show that the former is the timescale separation limit of the latter, with ETM host-disease dynamics increasingly resembling those of a DTM when the pathogen’s characteristic timescale is shortened, relative to that of the host population. Using graphical posterior predictive checks (GPPC), we investigate the validity of the SEIR model when fitted to simulated SEIR-P host infection and removal times. Such analyses demonstrate how, in many cases, the SEIR model is robust to departure from direct transmission. Finally, we present a case study of white spot disease (WSD) in penaeid shrimp with rates of environmental transmission and pathogen decay (SEIR-P model parameters) estimated using published results of experiments. Using SEIR and SEIR-P simulations of a hypothetical WSD outbreak management scenario, we demonstrate how relative shortening of the pathogen timescale comes about in practice. With atttempts to remove diseased shrimp from the population every 24h, we see SEIR and SEIR-P model outputs closely conincide. However, when removals are 6-hourly, the two models’ mean outputs diverge, with distinct predictions of outbreak size and duration., Author summary Mathematical models of the spread and progression of communicable disease in populations are important tools in efforts to prevent and control outbreaks. A common class of disease models assume that infection is transmitted directly from infectious to susceptible individuals when they are in close proximity—so called direct transmission models. These are used widely and have proven invaluable as simplified descriptions of a wide array of infectious diseases in diverse populations. However, many pathogens spread through indirect, environmental routes of transmission, for example via contact with contaminated water sources in the case of cholera, or inhalation of infectious airborne droplets for respiratory infections, such as Covid-19. We show that direct transmission models work well for such pathogens with short environmental lifetimes and where hosts shed pathogens into the environment at high rates. This means that we do not require information about environmental pathogen levels to understand the behaviour of outbreaks caused by these pathogens. When shedding rates are also low, e.g., with macroparasitic infections, or when variable environmental factors play a role in transmissibility, then explicit modelling of both the pathogen and environmental transmission will provide a more accurate picture than a direct transmission approximation.

Estimating the latent dynamics underlying biological processes is a central problem in computational biology. State-space models with Gaussian statistics are widely used for estimation of such latent dynamics and have been successfully utilized in the analysis of biological data. Gaussian statistics, however, fail to capture several key features of the dynamics of biological processes (e.g., brain dynamics) such as abrupt state changes and exogenous processes that affect the states in a structured fashion. Although Gaussian mixture process noise models have been considered as an alternative to capture such effects, data-driven inference of their parameters is not well-established in the literature. The objective of this paper is to develop efficient algorithms for inferring the parameters of a general class of Gaussian mixture process noise models from noisy and limited observations, and to utilize them in extracting the neural dynamics that underlie auditory processing from magnetoencephalography (MEG) data in a cocktail party setting. We develop an algorithm based on Expectation-Maximization to estimate the process noise parameters from state-space observations. We apply our algorithm to simulated and experimentally-recorded MEG data from auditory experiments in the cocktail party paradigm to estimate the underlying dynamic Temporal Response Functions (TRFs). Our simulation results show that the richer representation of the process noise as a Gaussian mixture significantly improves state estimation and capturing the heterogeneity of the TRF dynamics. Application to MEG data reveals improvements over existing TRF estimation techniques, and provides a reliable alternative to current approaches for probing neural dynamics in a cocktail party scenario, as well as attention decoding in emerging applications such as smart hearing aids. Our proposed methodology provides a framework for efficient inference of Gaussian mixture process noise models, with application to a wide range of biological data with underlying heterogeneous and latent dynamics., Author summary While Gaussian statistics are widely-used in analyzing biological data, they are not able to fully capture the observed heterogeneity and abrupt changes in the dynamics that govern the underlying biological processes. A notable example of such a process is the ability of the human brain to focus attention on one speaker among many in a cocktail party and switch attention to any other at will. We propose a signal processing methodology to extract the dynamics of such switching processes from noisy biological data in a robust and computationally efficient manner, and apply them to experimentally-recoded magnetoencephalography data from the human brain under cocktail party settings. Our results provide new insight on the heterogeneous neural dynamics that govern auditory attention switching. While our proposed methodology can be readily used as a reliable alternative to existing approaches in studying auditory processing in the human brain, it is suitable to be applied to a wide range of biological data with underlying heterogeneous dynamics.

The development of mechanistic models of biological systems is a central part of Systems Biology. One major challenge in developing these models is the accurate inference of model parameters. In recent years, nested sampling methods have gained increased attention in the Systems Biology community due to the fact that they are parallelizable and provide error estimates with no additional computations. One drawback that severely limits the usability of these methods, however, is that they require the likelihood function to be available, and thus cannot be applied to systems with intractable likelihoods, such as stochastic models. Here we present a likelihood-free nested sampling method for parameter inference which overcomes these drawbacks. This method gives an unbiased estimator of the Bayesian evidence as well as samples from the posterior. We derive a lower bound on the estimators variance which we use to formulate a novel termination criterion for nested sampling. The presented method enables not only the reliable inference of the posterior of parameters for stochastic systems of a size and complexity that is challenging for traditional methods, but it also provides an estimate of the obtained variance. We illustrate our approach by applying it to several realistically sized models with simulated data as well as recently published biological data. We also compare our developed method with the two most popular other likeliood-free approaches: pMCMC and ABC-SMC. The C++ code of the proposed methods, together with test data, is available at the github web page https://github.com/Mijan/LFNS_paper., Author summary The behaviour of mathematical models of biochemical reactions is governed by model parameters encoding for various reaction rates, molecule concentrations and other biochemical quantities. As the general purpose of these models is to reproduce and predict the true biological response to different stimuli, the inference of these parameters, given experimental observations, is a crucial part of Systems Biology. While plenty of methods have been published for the inference of model parameters, most of them require the availability of the likelihood function and thus cannot be applied to models that do not allow for the computation of the likelihood. Further, most established methods do not provide an estimate of the variance of the obtained estimator. In this paper, we present a novel inference method that accurately approximates the posterior distribution of parameters and does not require the evaluation of the likelihood function. Our method is based on the nested sampling algorithm and approximates the likelihood with a particle filter. We show that the resulting posterior estimates are unbiased and provide a way to estimate not just the posterior distribution, but also an error estimate of the final estimator. We illustrate our method on several stochastic models with simulated data as well as one model of transcription with real biological data.

The spatial distribution of visual items allows us to infer the presence of latent causes in the world. For instance, a spatial cluster of ants allows us to infer the presence of a common food source. However, optimal inference requires the integration of a computationally intractable number of world states in real world situations. For example, optimal inference about whether a common cause exists based on N spatially distributed visual items requires marginalizing over both the location of the latent cause and 2N possible affiliation patterns (where each item may be affiliated or non-affiliated with the latent cause). How might the brain approximate this inference? We show that subject behaviour deviates qualitatively from Bayes-optimal, in particular showing an unexpected positive effect of N (the number of visual items) on the false-alarm rate. We propose several “point-estimating” observer models that fit subject behaviour better than the Bayesian model. They each avoid a costly computational marginalization over at least one of the variables of the generative model by “committing” to a point estimate of at least one of the two generative model variables. These findings suggest that the brain may implement partially committal variants of Bayesian models when detecting latent causes based on complex real world data., Author summary Perceptual systems are designed to make sense of fragmented sensory data by inferring common, latent causes. Seeing a cluster of insects might allow us to infer the presence of a common food source, whereas the same number of insects scattered over a larger area of land might not evoke the same suspicions. The ability to reliably make this inference based on statistical information about the environment is surprisingly non-trivial: making the best possible inference requires making full use of the probabilistic information provided by the sensory data, which would require considering a combinatorially explosive number of hypothetical world states. In this paper, we test human subjects on their ability to perform a causal detection task: subjects are asked to judge whether an underlying cause of clustering is present or absent, based on the spatial distribution of those items. We show that subjects do not reason optimally on this task, and that particular computational short cuts (“committing” to certain world states over others, rather than representing them all) might underlie perceptual decision-making in these causal detection schemes.

There has been a spate of interest in association networks in biological and medical research, for example, genetic interaction networks. In this paper, we propose a novel method, the extended joint hub graphical lasso (EDOHA), to estimate multiple related interaction networks for high dimensional omics data across multiple distinct classes. To be specific, we construct a convex penalized log likelihood optimization problem and solve it with an alternating direction method of multipliers (ADMM) algorithm. The proposed method can also be adapted to estimate interaction networks for high dimensional compositional data such as microbial interaction networks. The performance of the proposed method in the simulated studies shows that EDOHA has remarkable advantages in recognizing class-specific hubs than the existing comparable methods. We also present three applications of real datasets. Biological interpretations of our results confirm those of previous studies and offer a more comprehensive understanding of the underlying mechanism in disease., Author summary Reconstruction of multiple association networks from high dimensional omics data is an important topic, especially in biology. Previous studies focused on estimating different networks and detecting common hubs among all classes. Integration of information over different classes of data while allowing the difference in the hub nodes is also biologically plausible. Therefore, we propose a method, EDOHA, to jointly construct multiple interaction networks with the capacity in finding different hub networks for each class of data. Simulation studies show better performance over conventional methods. The method has been demonstrated in three real-world data.

To facilitate the development of large-scale transcriptional regulatory networks (TRNs) that may enable in-silico analyses of disease mechanisms, a reliable catalogue of experimentally verified direct transcriptional regulatory interactions (DTRIs) is needed for training and validation. There has been a long history of using low-throughput experiments to validate single DTRIs. Therefore, we reason that a reliable set of DTRIs could be produced by curating the published literature for such evidence. In our survey of previous curation efforts, we identified the lack of details about the quantity and the types of experimental evidence to be a major gap, despite the theoretical importance of such details for the identification of bona fide DTRIs. We developed a curation protocol to inspect the published literature for support of DTRIs at the experiment level, focusing on genes important to the development of the mammalian nervous system. We sought to record three types of low-throughput experiments: Transcription factor (TF) perturbation, TF-DNA binding, and TF-reporter assays. Using this protocol, we examined a total of 1,310 papers to assemble a collection of 1,499 unique DTRIs, involving 251 TFs and 825 target genes, many of which were not reported in any other DTRI resource. The majority of DTRIs (965; 64%) were supported by two or more types of experimental evidence and 27% were supported by all three. Of the DTRIs with all three types of evidence, 170 had been tested using primary tissues or cells and 44 had been tested directly in the central nervous system. We used our resource to document research biases among reports towards a small number of well-studied TFs. To demonstrate a use case for this resource, we compared our curation to a previously published high-throughput perturbation screen and found significant enrichment of the curated targets among genes differentially expressed in the developing brain in response to Pax6 deletion. This study demonstrates a proof-of-concept for the assembly of a high resolution DTRI resource to support the development of large-scale TRNs., Author summary The capacity to computationally reconstruct gene regulatory networks using large-scale biological data is currently limited by the absence of a high confidence set of one-to-one regulatory interactions. Given the lengthy history of using small scale experimental assays to investigate individual interactions, we reason that a reliable collection of gene regulatory interactions could be compiled by systematically inspecting the published literature. To this end, we developed a curation protocol to examine and record evidence of regulatory interactions at the individual experiment level. Focusing on the area of brain development, we applied our pipeline to 1,310 publications. We identified 3,601 individual experiments, providing detailed information about 1,499 regulatory interactions. Many of these interactions have verified activity specifically in the embryonic brain. By capturing reports of regulatory interactions at this level of detail, we equip the users with more granular information than other similar resources, enabling more informed assessments of reliability.

8 pages.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, A recent paper published in PLOS Computational Biology [1] introduces the Scaling Invariance Method (SIM) for analysing structural local identifiability and observability. These two properties define mathematically the possibility of determining the values of the parameters (identifiability) and states (observability) of a dynamic model by observing its output. In this note we warn that SIM considers scaling symmetries as the only possible cause of non-identifiability and non-observability. We show that other types of symmetries can cause the same problems without being detected by SIM, and that in those cases the method may lead one to conclude that the model is identifiable and observable when it is actually not, AFV has received funding from a Ramón y Cajal Fellowship (RYC-2019-027537-I) and from the Spanish Ministry of Science, Innovation and Universities and the European Union FEDER under project grant SYNBIOCONTROL (DPI2017-82896-C2-2-R). GM was funded by the CSIC intramural project grant MOEBIUS (PIE 202070E062)

A current strategy for obtaining haplotype information from several individuals involves short-read sequencing of pooled amplicons, where fragments from each individual is identified by a unique DNA barcode. In this paper, we report a new method to recover the phylogeny of haplotypes from short-read sequences obtained using pooled amplicons from a mixture of individuals, without barcoding. The method, AFPhyloMix, accepts an alignment of the mixture of reads against a reference sequence, obtains the single-nucleotide-polymorphisms (SNP) patterns along the alignment, and constructs the phylogenetic tree according to the SNP patterns. AFPhyloMix adopts a Bayesian inference model to estimate the phylogeny of the haplotypes and their relative abundances, given that the number of haplotypes is known. In our simulations, AFPhyloMix achieved at least 80% accuracy at recovering the phylogenies and relative abundances of the constituent haplotypes, for mixtures with up to 15 haplotypes. AFPhyloMix also worked well on a real data set of kangaroo mitochondrial DNA sequences., Author summary In evolutionary studies, it is customary to obtain homologous sequences from different individuals in a population or a species to construct a phylogeny. Frequently, sequences from different individuals will be identical; we refer to a set of identical sequences as a haplotype. If short-read sequencing technologies are used to obtain sequences from many individuals, the sequence from each individual is tagged with a unique barcode, and a mixed sample of tagged sequences is subsequently sequenced. The tagged sequences can be identified using the appropriate bioinformatics tools, for further downstream analyses. We have developed a novel method, AFPhyloMix, to reconstruct the phylogeny of a mixed sample of homologous sequences, and the relative abundance of different haplotypes, from different individuals without the need for barcoding. AFPhyloMix aligns the short reads obtained to a reference alignment, and identifies the variable sites along the alignment. On the basis of the patterns of nucleotide frequencies at these and neighbouring sites, AFPhyloMix uses a Bayesian inference model to compute the phylogenetic tree and the haplotype relative abundances. Our results show that AFPhyloMix works well on both the simulated data set and the real data set.

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America., Author summary Mathematical models have played an important role in helping countries around the world decide how to best tackle the COVID-19 pandemic. In this paper, we describe a COVID-19 model, called Covasim (COVID-19 Agent-based Simulator), that we developed to help answer these questions. Covasim can be tailored to the local context by using detailed data on the population (such as the population age distribution and number of contacts between people) and the epidemic (such as diagnosed cases and reported deaths). While Covasim can be used to explore theoretical research questions or to make projections, its main purpose is to evaluate the effect of different interventions on the epidemic. These interventions include physical interventions (mobility restrictions and masks), diagnostic interventions (testing, contact tracing, and quarantine), and pharmaceutical interventions (vaccination). Covasim is open-source, written in Python, and comes with extensive documentation, tutorials, and a webapp to ensure it can be used as easily and broadly as possible. In partnership with local stakeholders, Covasim has been used to answer policy and research questions in more than a dozen countries, including India, the United States, Vietnam, and Australia.

Increased availability of epidemiological data, novel digital data streams, and the rise of powerful machine learning approaches have generated a surge of research activity on real-time epidemic forecast systems. In this paper, we propose the use of a novel data source, namely retail market data to improve seasonal influenza forecasting. Specifically, we consider supermarket retail data as a proxy signal for influenza, through the identification of sentinel baskets, i.e., products bought together by a population of selected customers. We develop a nowcasting and forecasting framework that provides estimates for influenza incidence in Italy up to 4 weeks ahead. We make use of the Support Vector Regression (SVR) model to produce the predictions of seasonal flu incidence. Our predictions outperform both a baseline autoregressive model and a second baseline based on product purchases. The results show quantitatively the value of incorporating retail market data in forecasting models, acting as a proxy that can be used for the real-time analysis of epidemics., Comment: 17 pages, 2 figures, 4 tables (1 in appendix), 1 algorithm, submitted to PLOS Computational Biology

Information processing can leave distinct footprints on the statistics of neural spiking. For example, efficient coding minimizes the statistical dependencies on the spiking history, while temporal integration of information may require the maintenance of information over different timescales. To investigate these footprints, we developed a novel approach to quantify history dependence within the spiking of a single neuron, using the mutual information between the entire past and current spiking. This measure captures how much past information is necessary to predict current spiking. In contrast, classical time-lagged measures of temporal dependence like the autocorrelation capture how long—potentially redundant—past information can still be read out. Strikingly, we find for model neurons that our method disentangles the strength and timescale of history dependence, whereas the two are mixed in classical approaches. When applying the method to experimental data, which are necessarily of limited size, a reliable estimation of mutual information is only possible for a coarse temporal binning of past spiking, a so-called past embedding. To still account for the vastly different spiking statistics and potentially long history dependence of living neurons, we developed an embedding-optimization approach that does not only vary the number and size, but also an exponential stretching of past bins. For extra-cellular spike recordings, we found that the strength and timescale of history dependence indeed can vary independently across experimental preparations. While hippocampus indicated strong and long history dependence, in visual cortex it was weak and short, while in vitro the history dependence was strong but short. This work enables an information-theoretic characterization of history dependence in recorded spike trains, which captures a footprint of information processing that is beyond time-lagged measures of temporal dependence. To facilitate the application of the method, we provide practical guidelines and a toolbox., Author summary Even with exciting advances in recording techniques of neural spiking activity, experiments only provide a comparably short glimpse into the activity of only a tiny subset of all neurons. How can we learn from these experiments about the organization of information processing in the brain? To that end, we exploit that different properties of information processing leave distinct footprints on the firing statistics of individual spiking neurons. In our work, we focus on a particular statistical footprint: We quantify how much a single neuron’s spiking depends on its own preceding activity, which we call history dependence. By quantifying history dependence in neural spike recordings, one can, in turn, infer some of the properties of information processing. Because recording lengths are limited in practice, a direct estimation of history dependence from experiments is challenging. The embedding optimization approach that we present in this paper aims at extracting a maximum of history dependence within the limits set by a reliable estimation. The approach is highly adaptive and thereby enables a meaningful comparison of history dependence between neurons with vastly different spiking statistics, which we exemplify on a diversity of spike recordings. In conjunction with recent, highly parallel spike recording techniques, the approach could yield valuable insights on how hierarchical processing is organized in the brain.

Next-generation sequencing (NGS) is a powerful tool for massive detection of DNA sequence variants such as single nucleotide polymorphisms (SNPs), multi-nucleotide polymorphisms (MNPs) and insertions/deletions (indels). For routine screening of numerous samples, these variants are often converted into cleaved amplified polymorphic sequence (CAPS) markers which are based on the presence versus absence of restriction sites within PCR products. Current computational tools for SNP to CAPS conversion are limited and usually infeasible to use for large datasets as those generated with NGS. Moreover, there is no available tool for massive conversion of MNPs and indels into CAPS markers. Here, we present VCF2CAPS–a new software for identification of restriction endonucleases that recognize SNP/MNP/indel-containing sequences from NGS experiments. Additionally, the program contains filtration utilities not available in other SNP to CAPS converters–selection of markers with a single polymorphic cut site within a user-specified sequence length, and selection of markers that differentiate up to three user-defined groups of individuals from the analyzed population. Performance of VCF2CAPS was tested on a thoroughly analyzed dataset from a genotyping-by-sequencing (GBS) experiment. A selection of CAPS markers picked by the program was subjected to experimental verification. CAPS markers, also referred to as PCR-RFLPs, belong to basic tools exploited in plant, animal and human genetics. Our new software–VCF2CAPS–fills the gap in the current inventory of genetic software by high-throughput CAPS marker design from next-generation sequencing (NGS) data. The program should be of interest to geneticists involved in molecular diagnostics. In this paper we show a successful exemplary application of VCF2CAPS and we believe that its usefulness is guaranteed by the growing availability of NGS services.

[Abstract] Brain networks exhibit very variable and dynamical functional connectivity and flexible configurations of information exchange despite their overall fixed structure. Brain oscillations are hypothesized to underlie time-dependent functional connectivity by periodically changing the excitability of neural populations. In this paper, we investigate the role of the connection delay and the detuning between the natural frequencies of neural populations in the transmission of signals. Based on numerical simulations and analytical arguments, we show that the amount of information transfer between two oscillating neural populations could be determined by their connection delay and the mismatch in their oscillation frequencies. Our results highlight the role of the collective phase response curve of the oscillating neural populations for the efficacy of signal transmission and the quality of the information transfer in brain networks., [Author summary] Collective dynamics in brain networks are characterized by a coordinated activity of their constituent neurons that lead to brain oscillations. Many evidences highlight the role that brain oscillations play in signal transmission, the control of the effective communication between brain areas, and the integration of information processed by different specialized regions. Oscillations periodically modulate the excitability of neurons and determine the response of those areas receiving the signals. Based on the communication through coherence (CTC) theory, the adjustment of the phase difference between local oscillations of connected areas can specify the timing of exchanged signals and therefore, the efficacy of the communication channels. In this respect, an important factor is the delay in the transmission of signals from one region to another that affects the phase difference and timing, and consequently the impact of the signals. Despite this delay plays an essential role in CTC theory, its role has been mostly overlooked in previous studies. In this manuscript, we concentrate on the role that the connection delay and the oscillation frequency of the populations play in the signal transmission, and consequently in the effective connectivity, between two brain areas. Through extensive numerical simulations, as well as analytical results with reduced models, we show that these parameters have two essential impacts on the effective connectivity of neural networks: First, that the populations advancing in phase to others do not necessarily play the role of the information source; and second, that the amount and direction of information transfer dependents on the oscillation frequency of the populations., The work of AP, IF and CM was partially supported by the Spanish State Research Agency, through the Severo Ochoa and Maria de Maeztu Program for Centers and Units of Excellence in R&D (MDM-2017-0711) and the MINECO (Spain) through project TEC2016-80063-C3 (AEI/FEDER, UE). IF and CM acknowledge support from the Ministerio de Ciencia e Innovación through projects PID2019-111537GB-C21/AEI/10.13039/501100011033 and PID2019-111537GB-C22/AEI/10.13039/501100011033, respectively.

Translation elongation is regulated by a series of complicated mechanisms in both prokaryotes and eukaryotes. Although recent advance in ribosome profiling techniques has enabled one to capture the genome-wide ribosome footprints along transcripts at codon resolution, the regulatory codes of elongation dynamics are still not fully understood. Most of the existing computational approaches for modeling translation elongation from ribosome profiling data mainly focus on local contextual patterns, while ignoring the continuity of the elongation process and relations between ribosome densities of remote codons. Modeling the translation elongation process in full-length coding sequence (CDS) level has not been studied to the best of our knowledge. In this paper, we developed a deep learning based approach with a multi-input and multi-output framework, named RiboMIMO, for modeling the ribosome density distributions of full-length mRNA CDS regions. Through considering the underlying correlations in translation efficiency among neighboring and remote codons and extracting hidden features from the input full-length coding sequence, RiboMIMO can greatly outperform the state-of-the-art baseline approaches and accurately predict the ribosome density distributions along the whole mRNA CDS regions. In addition, RiboMIMO explores the contributions of individual input codons to the predictions of output ribosome densities, which thus can help reveal important biological factors influencing the translation elongation process. The analyses, based on our interpretable metric named codon impact score, not only identified several patterns consistent with the previously-published literatures, but also for the first time (to the best of our knowledge) revealed that the codons located at a long distance from the ribosomal A site may also have an association on the translation elongation rate. This finding of long-range impact on translation elongation velocity may shed new light on the regulatory mechanisms of protein synthesis. Overall, these results indicated that RiboMIMO can provide a useful tool for studying the regulation of translation elongation in the range of full-length CDS., Author summary Translation elongation is a process in which amino acids are linked into proteins by ribosomes in cells. Translation elongation rates along the mRNAs are not constant, and are regulated by a series of mechanisms, such as codon rarity and mRNA stability. In this study, we modeled the translation elongation process at a full-length coding sequence level and developed a deep learning based approach to predict the translation elongation rates from mRNA sequences, through extracting the regulatory codes of elongation rates from the contextual sequences. The analyses, based on our interpretable metric named codon impact score, for the first time (to the best of our knowledge), revealed that in addition to the neighboring codons of the ribosomal A sites, the remote codons may also have an important impact on the translation elongation rates. This new finding may stimulate additional experiments and shed light on the regulatory mechanisms of protein synthesis.

The high-resolution and mass accuracy of Fourier transform mass spectrometry (FT-MS) has made it an increasingly popular technique for discerning the composition of soil, plant and aquatic samples containing complex mixtures of proteins, carbohydrates, lipids, lignins, hydrocarbons, phytochemicals and other compounds. Thus, there is a growing demand for informatics tools to analyze FT-MS data that will aid investigators seeking to understand the availability of carbon compounds to biotic and abiotic oxidation and to compare fundamental chemical properties of complex samples across groups. We present ftmsRanalysis, an R package which provides an extensive collection of data formatting and processing, filtering, visualization, and sample and group comparison functionalities. The package provides a suite of plotting methods and enables expedient, flexible and interactive visualization of complex datasets through functions which link to a powerful and interactive visualization user interface, Trelliscope. Example analysis using FT-MS data from a soil microbiology study demonstrates the core functionality of the package and highlights the capabilities for producing interactive visualizations., Author summary High-resolution mass spectrometry instruments provide a mechanism for researchers to better understand the fundamental chemical composition of materials such as soil, plants, petroleum, and beverages. The large and complex data generated by analysis of these materials has led to a growing demand for software tools to aid researchers in processing, analyzing, and creating informative visualizations of these data. To move beyond existing software tools designed for specific purposes and visualizations of data from an individual sample, we present a software package, ftmsRanalysis, that provides researchers with a large collection of methods for streamlining the downstream processing high-resolution mass spectrometry data. ftmsRanalysis provides methods to compute useful chemical properties, filter data, define groups of samples, statistically compare sample groups, and make visualizations for many samples simultaneously. In this paper, we give an overview of ftmsRanalysis’ general structure and capabilities. We then apply ftmsRanalysis to a soil microbiology dataset and present some of the results and visualizations generated by using the software package.

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., Author summary Circadian clocks are endogenous pacemakers that generate gene expression oscillations with a period of approximately 24h. They enable an organism to anticipate daily changes in light and temperature and allow to align physiological properties to the most beneficial time around the solar day. The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian pacemaker in mammals that coordinates peripheral clocks throughout the body and even encodes seasons. Gene expression oscillations of circadian clock genes in this master pacemaker have been shown to dissociate after perturbations of the system such as light pulses and jet-lag. The underlying mechanism remains unknown. We show that this dissociation may occur even within a single cell of the pacemaker. Data-driven mathematical modeling suggests that the dissociation relies upon a weak interaction between interlocked gene-regulatory feedback loops. Differential responses of these feedback loops to light perturbations is consistent with the concept of morning and evening oscillators.

As sequencing prices drop, genomic data accumulates-seemingly at a steadily increasing pace. Most genomic data potentially have value beyond the initial purpose-but only if shared with the scientific community. This, of course, is often easier said than done. Some of the challenges in sharing genomic data include data volume (raw file sizes and number of files), complexities, formats, nomenclatures, metadata descriptions, and the choice of a repository. In this paper, we describe 10 quick tips for sharing open genomic data.