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There is increasing scrutiny around how science is communicated to the public. For instance, a Twitter account @justsaysinmice (with 70.4K followers in January 2021) was created to call attention to news headlines that omit that mice, not humans, are the ones for whom the study findings apply. This is the case of many headlines reporting on Alzheimer disease (AD) research. AD is characterized by a degeneration of the human brain, loss of cognition, and behavioral changes, for which no treatment is available. Around 200 rodent models have been developed to study AD, even though AD is an exclusively human condition that does not occur naturally in other species and appears impervious to reproduction in artificial animal models, an information not always disclosed. It is not known what prompts writers of news stories to either omit or acknowledge, in the story’s headlines, that the study was done in mice and not in humans. Here, we raised the hypothesis that how science is reported by scientists plays a role on the news reporting. To test this hypothesis, we investigated whether an association exists between articles’ titles and news’ headlines regarding the omission, or not, of mice. To this end, we analyzed a sample of 623 open-access scientific papers indexed in PubMed in 2018 and 2019 that used mice either as models or as the biological source for experimental studies in AD research. We found a significant association (p < 0.01) between articles’ titles and news stories’ headlines, revealing that when authors omit the species in the paper’s title, writers of news stories tend to follow suit. We also found that papers not mentioning mice in their titles are more newsworthy and significantly more tweeted than papers that do. Our study shows that science reporting may affect media reporting and asks for changes in the way we report about findings obtained with animal models used to study human diseases., This study reveals that when scientists omit from the papers’ title that research findings were obtained using mice, as opposed to humans, the media tend to replicate the trend by omitting the use of mice from the news stories headlines that report on these papers, thereby perpetuating the misleading omission.

Developing new software tools for analysis of large-scale biological data is a key component of advancing modern biomedical research. Scientific reproduction of published findings requires running computational tools on data generated by such studies, yet little attention is presently allocated to the installability and archival stability of computational software tools. Scientific journals require data and code sharing, but none currently require authors to guarantee the continuing functionality of newly published tools. We have estimated the archival stability of computational biology software tools by performing an empirical analysis of the internet presence for 36,702 omics software resources published from 2005 to 2017. We found that almost 28% of all resources are currently not accessible through uniform resource locators (URLs) published in the paper they first appeared in. Among the 98 software tools selected for our installability test, 51% were deemed “easy to install,” and 28% of the tools failed to be installed at all because of problems in the implementation. Moreover, for papers introducing new software, we found that the number of citations significantly increased when authors provided an easy installation process. We propose for incorporation into journal policy several practical solutions for increasing the widespread installability and archival stability of published bioinformatics software., Developing new software tools for analysis of large-scale biological data involves numerous unique challenges; this Perspective article surveys more than 36,000 software resources, concluding that a rigorous standardized approach is needed to ensure the installability and archival stability of software tools prior to their publication.

In the scientific literature, spin refers to reporting practices that distort the interpretation of results and mislead readers so that results are viewed in a more favourable light. The presence of spin in biomedical research can negatively impact the development of further studies, clinical practice, and health policies. This systematic review aims to explore the nature and prevalence of spin in the biomedical literature. We searched MEDLINE, PreMEDLINE, Embase, Scopus, and hand searched reference lists for all reports that included the measurement of spin in the biomedical literature for at least 1 outcome. Two independent coders extracted data on the characteristics of reports and their included studies and all spin-related outcomes. Results were grouped inductively into themes by spin-related outcome and are presented as a narrative synthesis. We used meta-analyses to analyse the association of spin with industry sponsorship of research. We included 35 reports, which investigated spin in clinical trials, observational studies, diagnostic accuracy studies, systematic reviews, and meta-analyses. The nature of spin varied according to study design. The highest (but also greatest) variability in the prevalence of spin was present in trials. Some of the common practices used to spin results included detracting from statistically nonsignificant results and inappropriately using causal language. Source of funding was hypothesised by a few authors to be a factor associated with spin; however, results were inconclusive, possibly due to the heterogeneity of the included papers. Further research is needed to assess the impact of spin on readers’ decision-making. Editors and peer reviewers should be familiar with the prevalence and manifestations of spin in their area of research in order to ensure accurate interpretation and dissemination of research., Author summary In the scientific literature, spin refers to reporting practices that distort the interpretation of results and mislead readers so that results are viewed in a more favourable light. The presence of spin in biomedical research can negatively impact the development of further studies, clinical practice, and health policies. We conducted a systematic review to explore the nature and prevalence of spin in the biomedical literature. We included 35 reports, which investigated spin in clinical trials, observational studies, diagnostic accuracy studies, systematic reviews, and meta-analyses. The nature of spin varied according to study design. The highest (but also greatest) variability in the prevalence of spin was present in trials. Some of the common practices used to spin results included detracting from statistically nonsignificant results and inappropriately using causal language. Source of funding was hypothesised by a few authors to be a factor associated with spin; however, results were inconclusive, possibly due to the heterogeneity of the included papers. Further research is needed to assess the impact of spin on readers’ decision-making. Editors and peer reviewers should be familiar with the prevalence and manifestations of spin in their area of research in order to ensure accurate interpretation and dissemination of research.

Architectural changes at the cellular and organism level are integral and necessary to successful development and growth. During mammalian preimplantation development, cells reduce in size and the architecture of the embryo changes significantly. Such changes must be coordinated correctly to ensure continued development of the embryo and, ultimately, a successful pregnancy. However, the nature of such transformations is poorly defined during mammalian preimplantation development. In order to quantitatively describe changes in cell environment and organism architecture, we designed Internal Versus External Neighbourhood (IVEN). IVEN is a user-interactive, open-source pipeline that classifies cells into different populations based on their position and quantifies the number of neighbours of every cell within a dataset in a 3D environment. Through IVEN-driven analyses, we show how transformations in cell environment, defined here as changes in cell neighbourhood, are related to changes in embryo geometry and major developmental events during preimplantation mammalian development. Moreover, we demonstrate that modulation of the FGF pathway alters spatial relations of inner cells and neighbourhood distributions, leading to overall changes in embryo architecture. In conjunction with IVEN-driven analyses, we uncover differences in the dynamic of cell size changes over the preimplantation period and determine that cells within the mammalian embryo initiate growth phase only at the time of implantation., This paper presents IVEN (Internal Versus External Neighbourhood), a new user-interactive tool for the quantitative description of cell environment and organismal architecture, and uses it to reveal how changes in embryo architecture relate to changes in cell neighbourhood, identifying nuanced effects of FGF treatment on embryo morphology.

Have you ever sought to use metagenomic DNA sequences reported in scientific publications? Were you successful? Here, we reveal that metagenomes from no fewer than 20% of the papers found in our literature search, published between 2016 and 2019, were not deposited in a repository or were simply inaccessible. The proportion of inaccessible data within the literature has been increasing year-on-year. Noncompliance with Open Data is best predicted by the scientific discipline of the journal. The number of citations, journal type (e.g., Open Access or subscription journals), and publisher are not good predictors of data accessibility. However, many publications in high–impact factor journals do display a higher likelihood of accessible metagenomic data sets. Twenty-first century science demands compliance with the ethical standard of data sharing of metagenomes and DNA sequence data more broadly. Data accessibility must become one of the routine and mandatory components of manuscript submissions—a requirement that should be applicable across the increasing number of disciplines using metagenomics. Compliance must be ensured and reinforced by funders, publishers, editors, reviewers, and, ultimately, the authors., Have you ever sought to use metagenomic DNA sequences reported in scientific publications? Were you successful? This Essay reveals that every fifth published metagenome is not available to science, and asks whether data accessibility should be considered a mandatory component of manuscript submission.

Predicting individual mental traits and behavioral dispositions from brain imaging data through machine-learning approaches is becoming a rapidly evolving field in neuroscience. Beyond scientific and clinical applications, such approaches also hold the potential to gain substantial influence in fields such as human resource management, education, or criminal law. Although several challenges render real-life applications of such tools difficult, future conflicts of individual, economic, and public interests are preprogrammed, given the prospect of improved personalized predictions across many domains. In this Perspective paper, we thus argue for the need to engage in a discussion on the ethical, legal, and societal implications of the emergent possibilities for brain-based predictions and outline some of the aspects for this discourse., Advances in machine learning on neuroimaging data have opened up the possibility of objectively predicting individual traits like intelligence, personality, or clinical risks from brain scans. This Perspective article discusses the methodological and ethical challenges arising from these advances.

Transient receptor potential (TRP) proteins form Ca2+-permeable, nonselective cation channels, but their role in neuronal Ca2+ homeostasis is elusive. In the present paper, we show that TRPC channels potently regulate synaptic plasticity by changing the presynaptic Ca2+-homeostasis of hippocampal neurons. Specifically, loss of TRPC1/C4/C5 channels decreases basal-evoked secretion, reduces the pool size of readily releasable vesicles, and accelerates synaptic depression during high-frequency stimulation (HFS). In contrast, primary TRPC5 channel-expressing neurons, identified by a novel TRPC5–τ-green fluorescent protein (τGFP) knockin mouse line, show strong short-term enhancement (STE) of synaptic signaling during HFS, indicating a key role of TRPC5 in short-term plasticity. Lentiviral expression of either TRPC1 or TRPC5 turns classic synaptic depression of wild-type neurons into STE, demonstrating that TRPCs are instrumental in regulating synaptic plasticity. Presynaptic Ca2+ imaging shows that TRPC activity strongly boosts synaptic Ca2+ dynamics, showing that TRPC channels provide an additional presynaptic Ca2+ entry pathway, which efficiently regulates synaptic strength and plasticity., Transient receptor potential (TRP) proteins can form non-selective cation channels, but their role in synaptic transmission is poorly understood. This study shows that calcium-permeable TRPC channels provide an additional calcium entry pathway at presynaptic sites and are efficient regulators of synaptic strength and plasticity.

The centrifuge is an essential tool for many aspects of research and medical diagnostics. However, conventional centrifuges are often inaccessible outside of standard laboratory settings, such as remote field sites, because they require a constant external power source and can be prohibitively costly in resource-limited settings and Science, technology, engineering, and mathematics (STEM)-focused programs. Here we present the 3D-Fuge, a 3D-printed hand-powered centrifuge, as a novel alternative to standard benchtop centrifuges. Based on the design principles of a paper-based centrifuge, this 3D-printed instrument increases the volume capacity to 2 mL and can reach hand-powered centrifugation speeds up to 6,000 rpm. The 3D-Fuge devices presented here are capable of centrifugation of a wide variety of different solutions such as spinning down samples for biomarker applications and performing nucleotide extractions as part of a portable molecular lab setup. We introduce the design and proof-of-principle trials that demonstrate the utility of low-cost 3D-printed centrifuges for use in remote field biology and educational settings., This Community Page article describes a low-cost 3D-printed centrifuge to enable sequencing in remote field conditions and lowering the barrier to synthetic biology research in high schools to broaden participation in hands-on STEM.

In a growing plant root, the inner vascular system is sealed off by an epithelium, the endodermis. The space between all of the cells in the endodermal layer is filled with an impermeable mass called the Casparian strip, which closes the spaces between cells in the endodermal layer. The role of the Casparian strip has been proposed to prevent backflow of water and nutrients into the soil, but as mutant plants lacking the Casparian strip only have weak phenotypes, the view that it serves an essential function in plants has been challenged. In an accompanying paper, it is shown that loss of the Casparian strip impacts the ability of the plant to take up ammonium and allocate it to the shoots., What is the function of the Casparian strip, a plant structure first described in 1865? This Primer explores the implications of a new study which reports that loss of the Casparian strip in root endodermis affects the ability of the plant to take up ammonium and allocate it to the shoots.

Phenomics has the potential to facilitate significant advances in biology but requires the development of high-throughput technologies capable of generating and analysing high-dimensional data. There are significant challenges associated with building such technologies, not least those required for investigating dynamic processes such as embryonic development, during which high rates of temporal, spatial, and functional change are inherently difficult to capture. Here, we present EmbryoPhenomics, an accessible high-throughput platform for phenomics in aquatic embryos comprising an Open-source Video Microscope (OpenVIM) that produces high-resolution videos of multiple embryos under tightly controlled environmental conditions. These videos are then analysed by the Python package Embryo Computer Vision (EmbryoCV), which extracts phenomic data for morphological, physiological, behavioural, and proxy traits during the process of embryonic development. We demonstrate the broad-scale applicability of EmbryoPhenomics in a series of experiments assessing chronic, acute, and multistressor responses to environmental change (temperature and salinity) in >30 million images of >600 embryos of two species with markedly different patterns of development—the pond snail Radix balthica and the marine amphipod Orchestia gammarellus. The challenge of phenomics is significant but so too are the rewards, and it is particularly relevant to the urgent task of assessing complex organismal responses to current rates of environmental change. EmbryoPhenomics can acquire and process data capturing functional, temporal, and spatial responses in the earliest, most dynamic life stages and is potentially game changing for those interested in studying development and phenomics more widely., EmbryoPhenomics is an open-source technology platform for high-throughput phenome screening of aquatic embryos. This paper demonstrates its application in experiments assessing the sensitivity of aquatic embryos to environmental stress, consisting of more than 600 embryos and more than 30 million images., Author summary Phenomics is the collection of high-dimensional phenotypic data on an organism-wide scale, and it requires high-throughput technologies. However, a lack of technologies for efficiently visualising and measuring whole-organism responses to different environments represents a serious challenge for biologists. This challenge is most apparent when studying complex responses, such as those occurring during the dynamic period of embryonic development, when the phenotype changes markedly through time. Here, we present EmbryoPhenomics (www.embryophenomics.org), a new open-source technological platform comprising high-throughput bioimaging hardware that produces high-resolution video of multiple, developing embryos maintained under controlled environmental conditions and software for automatically quantifying embryo responses from these videos. We demonstrate the broad applicability of EmbryoPhenomics using four experiments assessing responses to global change (elevated temperature and salinity) in which we generate data for more than 600 embryos produced from video comprising more than 30 million images. EmbryoPhenomics was used to capture functional, temporal, and spatial change in morphological, physiological, and behavioural responses in the earliest, most dynamic life stages and addresses a serious bottleneck in biology. Such capabilities are urgently required, particularly within the context of assessing the response of embryos to the current unprecedented rates of global environmental change.

Access to analytical code is essential for transparent and reproducible research. We review the state of code availability in ecology using a random sample of 346 nonmolecular articles published between 2015 and 2019 under mandatory or encouraged code-sharing policies. Our results call for urgent action to increase code availability: only 27% of eligible articles were accompanied by code. In contrast, data were available for 79% of eligible articles, highlighting that code availability is an important limiting factor for computational reproducibility in ecology. Although the percentage of ecological journals with mandatory or encouraged code-sharing policies has increased considerably, from 15% in 2015 to 75% in 2020, our results show that code-sharing policies are not adhered to by most authors. We hope these results will encourage journals, institutions, funding agencies, and researchers to address this alarming situation., Publication of the analytical code underlying a scientific study is increasingly expected or even mandated by journals, allowing others to reproduce the results. However, a survey of more than 300 recently published ecology papers finds the majority have no code publicly available, handicapping efforts to improve scientific transparency.

In Europe, responsible research and innovation (RRI) has emerged as a science policy measure that demands the early integration of a broad range of social actors and perspectives into research and development (R&D). More collaboration of the social sciences and humanities (SSH) with science and engineering appears within this policy framework as a crucial element that will enable better technological development. However, RRI is new to both natural scientists and SSH scholars, and interdisciplinary collaborations are challenging for many reasons. In this paper, we discuss these challenges while suggesting that what RRI can be in a particular project is not a given but remains an empirical question. Natural scientists and SSH scholars need to coresearch RRI in an experimental mode. © 2018 Delgado, Åm. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

After 40 years, the 1976 US Toxic Substances Control Act (TSCA) was revised under the Frank R. Lautenberg Chemical Safety for the 21st Century Act. Its original goals of protecting the public from hazardous chemicals were hindered by complex and cumbersome administrative burdens, data limitations, vulnerabilities in risk assessments, and recurring corporate lawsuits. As a result, countless chemicals were entered into commercial use without toxicological information. Few chemicals of the many identified as potential public health threats were regulated or banned. This paper explores the factors that have worked against a comprehensive and rational policy for regulating toxic chemicals and discusses whether the TSCA revisions offer greater public protection against existing and new chemicals.

Individuals chronically infected with HIV-1 harbor complex viral populations within their bloodstreams. Recently, it has come to light that when these people infect others, the new infection is typically established by only one or a small number of virions from within this complex viral swarm. An important goal is to characterize the biological properties of HIV-1 virions that seed and exist early in new human infections because these are potentially the only viruses against which a prophylactic HIV-1 vaccine would need to elicit protection. This includes understanding how the Envelope (Env) protein of these virions interacts with the T-cell receptor CD4, which supports attachment and entry of HIV-1 into target cells. We examined early HIV-1 isolates for their ability to infect cells via the CD4 receptor of 15 different primate species. Primates were the original source of HIV-1 and now serve as valuable animal models for studying HIV-1. We find that most primary isolates of HIV-1 from the blood, including early isolates, are highly selective and enter cells through some primate CD4 receptor orthologs but not others. This phenotype is remarkably consistent, regardless of route of transmission, viral subtype, or time of isolation post infection. We show that the weak CD4 binding affinity of blood-derived HIV-1 isolates is what makes them sensitive to the small sequence differences in CD4 from one primate species to the next. To substantiate this, we engineered an early HIV-1 Env to have high, medium, or low binding affinity to CD4, and we show that it loses the ability to enter cells via the CD4 receptor of many primate species as the binding affinity gets weaker. Based on the phenotype of selective use of primate CD4, we find that weak CD4 binding appears to be a nearly universal property of HIV-1 circulating in the bloodstream. Therefore, weak binding to CD4 must be a selected and important property in the biology of HIV-1 in the body. We identify six primate species that encode CD4 receptors that fully support the entry of early HIV-1 isolates despite their low binding affinity for CD4. These findings will help inform long-standing efforts to model HIV-1 transmission and early disease in primates., The current animal model for HIV, the macaque, encodes a CD4 receptor that is non-permissive for HIV entry. This paper reveals that six primate species encode CD4 receptors compatible with HIV infection, potentially making them powerful tools for the study of HIV biology. Furthermore, weak CD4 binding is a nearly constant, and apparently selected, property of HIV circulating in the human bloodstream.

Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies—F4, F6, F7, and F9—are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 μM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development., Structures of hepatitis A virus in complex with five neutralizing antibodies reveal a single conserved antigenic site and pinpoint key structure-activity correlates, allowing in silico screening to identify a potent candidate inhibitor drug, golvatinib., Author summary Hepatitis A virus (HAV) is a unique, hepatotropic human picornavirus that infects approximately 1.5 million people annually and continues to cause mortality despite a successful vaccine. There are no licensed therapeutic drugs to date. Better knowledge of HAV antigenic features and neutralizing mechanisms will facilitate the development of HAV-targeting antiviral drugs. In this study, we report 4 potent HAV-specific neutralizing monoclonal antibodies (NAbs), together with our previous reported R10, that efficiently inhibit HAV infection by blocking attachment to the host cell. All 5 epitopes are located within the same patch and are highly conserved across 6 genotypes of human HAV, which suggests a single antigenic site for HAV, highlighting a prime target for structure-based drug design. Analysis of complexes with the 5 NAbs with varying neutralizing activities pinpointed key structure-activity correlates. By using a robust in silico docking method, one promising inhibitor named golvatinib was successfully identified from the DrugBank Database. In vitro assays confirmed its ability to block viral infection and revealed its neutralizing mechanism. Our approach could be useful in the design of effective drugs for picornavirus infections.

Data, including information generated from them by processing and analysis, are an asset with measurable value. The assets that biological research funding produces are the data generated, the information derived from these data, and, ultimately, the discoveries and knowledge these lead to. From the time when Henry Oldenburg published the first scientific journal in 1665 (Proceedings of the Royal Society) to the founding of the United States National Library of Medicine in 1879 to the present, there has been a sustained drive to improve how researchers can record and discover what is known. Researchers' experimental work builds upon years and (collectively) billions of dollars' worth of earlier work. Today, researchers are generating data at ever-faster rates because of advances in instrumentation and technology, coupled with decreases in production costs. Unfortunately, the ability of researchers to manage and disseminate their results has not kept pace, so their work cannot achieve its maximal impact. Strides have recently been made, but more awareness is needed of the essential role that biological data resources, including biocuration, play in maintaining and linking this ever-growing flood of data and information. The aim of this paper is to describe the nature of data as an asset, the role biocurators play in increasing its value, and consistent, practical means to measure effectiveness that can guide planning and justify costs in biological research information resources' development and management.

A centipede with a wooden leg, of course. Laying aside for the moment the issue of whether any centipede does have 100 legs, this childish joke is an indicator of the special place that these creepy-crawliest of arthropods occupy in our collective psyche. Here's another one—a 150-year-old poem called the Centipede's Dilemma, usually attributed to Katherine Craster: “A centipede was happy—quite!/Until a toad in fun/Said, ‘Pray, which leg moves after which?’/This raised her doubts to such a pitch,/She fell exhausted in the ditch/Not knowing how to run.” This poem in turn gave its name to the Centipede Syndrome—the phenomenon whereby concentrating on a normally unconscious task compromises our ability to perform it. The arthropods are one of Earth's real success stories—there are more species of arthropod than in any other animal phylum, but our knowledge of the genomic basis of arthropod biology is massively skewed towards insects. The phylum Arthropoda is conventionally subdivided into five subphyla, four of which are still with us. The hexapods (insects and their kin) scored the first arthropod genome sequence—that of the lab workhorse Drosophila melanogaster, published back in 2000—followed by many other insect genomes since. The chelicerates (spiders, scorpions, horseshoe crabs, etc.) and crustaceans (shrimps, crabs, barnacles, etc.) had to wait 11 more years for the publication of the sequences of Tetranychus urticae (red spider mite) and Daphnia pulex (water flea), respectively. Trilobites haven't been seen for a while now, so this just leaves the myriapods as the only extant arthropod subphylum with no sequenced genome. The myriapods comprise two major classes—the largely vegetarian millipedes and the rather viciously carnivorous centipedes—plus two relatively insignificant ones (the tiny, stubby pauropods and the translucent symphylans). Myriapods arose more than 400 million years ago (and possibly as far back as the Cambrian), probably as an independent land invasion from the insects (they're all terrestrial). The most obvious shared trait of the subphylum is the large number of near-identical segments, most bearing one or two pairs of legs. There are now at least 13,000 recognized myriapod species across the world; about a quarter of these are centipedes: predators with 30–400 legs, venom-injecting pincers on their heads, simple eyes, and a predilection for skulking. As well as the intriguing biology of the myriapods themselves, there are other reasons to be interested in their genomes. The myriapods are the presumed sister-group of the crustaceans and insects—creatures of enormous importance to us, whether as food, pests, pollinators, disease vectors, or biological models. This means that myriapod genomes could present a unique opportunity to reconstruct the common ancestor of this group of subphyla, which together form the “mandibulates.” An international consortium of researchers from 52 different institutions now publish in PLOS Biology the sequence of the genome of Strigamia maritima, a Northern European beach bum centipede that is easily collected in the wild, has been the model myriapod for developmental studies, and has a conveniently modest-sized genome (Figure 1). There are some downsides to the choice of this species, in that S. maritima is atypical in not having eyes and springing from its egg with the full adult complement of segments, but otherwise it seems a fine choice for our first glimpse of a myriapod genome. Figure 1 Strigamia maritima, whose genome sequence has just been revealed. At an estimated 290 megabases, the genome is about one-tenth the size of ours, and the authors describe about two-thirds of this, the remaining third being too highly repetitive. They also re-sequenced four individuals to capture some of the genetic variation that's present in the wild. The authors were able to identify about 15,000 genes (we have more than 20,000), distributed across one pair of very large chromosomes and seven pairs of tiny ones, including X and Y sex chromosomes. The arrangement of the genes is relatively conservative, resembling that of genomes from other animal phyla, and much less scrambled than are the genomes of some model arthropods such as flies. Together with some of the more conservative insect genomes (silk moth, red flour beetle) and that of the crustacean water flea, this will help fill in our picture of the ancestral mandibulate from which this massive diversity sprung. Having laid out the basic properties of the genome, the authors take us on a whistle-stop tour of interesting links between the gene complement of the centipede's genome and features of its biology. These include the structure of the Hox gene cluster (a major orchestrator of body plans in other animals), the elements of the centipede's immune system, endocrine system, and major developmental pathways, and a hint that some genes are actively modified by methylation, presumably to regulate them. Many of these are just variations on a theme, but I'll focus on a few nuggets that speak more directly to the evolutionary history of S. maritima. One sense that needs to develop substantially when an animal lineage takes the first steps out of water and onto dry land is the sense of smell. Vertebrates, insects, and myriapods have made this career choice independently, and it's already known that the first two groups of animals have reached different solutions to the problem of detecting chemicals in air. The current study now shows that despite belonging to the same phylum as insects, myriapods have gone down a third route, olfaction-wise. Instead of having the large repertoire of odorant receptors and odorant-binding proteins that insect genomes have, the centipede genome contains expanded sets of two other protein families—gustatory receptors and ionotropic receptors. The authors infer that when the great granddaddy of all myriapods needed to sniff the Cambrian air, it's these protein families that stepped up to provide the instrumentation. The paper reveals further evidence of the intriguing tendency of evolution to have more than one way to skin a cat—in insects, a single gene called Dscam uses massively alternative splicing to generate a dizzyingly diverse array of cell-surface proteins (approximately 150,000) that underlie the complexity of the nervous and immune systems. The centipede appears to achieve the same end, but by using up to a hundred Dscam-like genes, each with the potential to undergo a more modest degree of alternative splicing. S. maritima is a member of the Geophilimorph order of centipedes, all of which are blind underground-dwellers. Correspondingly, the authors find no evidence in its genome for any recognised way of sensing light—no obvious photoreceptors, and no components of the circadian clock. To check whether this is a general feature of centipedes or merely a characteristic of this subterranean group, the authors check transcripts from the house centipede Scutigera coleoptrata. This animal has genes encoding proteins needed for light detection and circadian behaviour, suggesting that this wholesale loss is a geophilimorph-specific sacrifice, dispensing with genes that have no role to play in the underworld. The description of the S. maritima genome surely heralds a new era in myriapod biology, but in the interim some of you will still be wondering whether any centipede lives up to the eponymous leg number. The answer, barring accidents or prostheses, is apparently no, as all centipedes have odd numbers of leg-bearing segments. Gratifyingly, however, S. maritima comes very close—although their segment numbers vary somewhat, I count 94 legs on the animal pictured here, and animals with 98 legs are common. Chipman AD, Ferrier DEK, Brena C, Qu J, Hughes DST, et al. (2014) The First Myriapod Genome Sequence Reveals Conservative Arthropod Gene Content and Genome Organisation in the Centipede Strigamia maritima . doi:10.1371/journal.pbio.1002005

A study of the bacterium Caulobacter crescentus reveals an SOS-independent DNA damage response pathway that acts via a novel cell division inhibitor, DidA, to suppress septum synthesis., Cells must coordinate DNA replication with cell division, especially during episodes of DNA damage. The paradigm for cell division control following DNA damage in bacteria involves the SOS response where cleavage of the transcriptional repressor LexA induces a division inhibitor. However, in Caulobacter crescentus, cells lacking the primary SOS-regulated inhibitor, sidA, can often still delay division post-damage. Here we identify didA, a second cell division inhibitor that is induced by DNA damage, but in an SOS-independent manner. Together, DidA and SidA inhibit division, such that cells lacking both inhibitors divide prematurely following DNA damage, with lethal consequences. We show that DidA does not disrupt assembly of the division machinery and instead binds the essential division protein FtsN to block cytokinesis. Intriguingly, mutations in FtsW and FtsI, which drive the synthesis of septal cell wall material, can suppress the activity of both SidA and DidA, likely by causing the FtsW/I/N complex to hyperactively initiate cell division. Finally, we identify a transcription factor, DriD, that drives the SOS-independent transcription of didA following DNA damage., Author Summary Cells have evolved sophisticated mechanisms for repairing their DNA and maintaining genome integrity. A critical aspect of the repair process is an arrest of cell cycle progression, thereby ensuring that cell division is not attempted before the genome has been repaired and fully duplicated. Our paper explores the molecular mechanisms that underlie the inhibition of cell division following DNA damage in the bacterium Caulobacter crescentus. For most bacteria, the primary, and only mechanism previously described involves the SOS response, in which DNA damage induces cleavage of the transcriptional repressor LexA, driving induction of a battery of genes that includes an inhibitor of cell division (sulA in E. coli and sidA in Caulobacter). Here, we report that Caulobacter cells have a second, SOS-independent damage response pathway that induces another division inhibitor, didA, which works together with sidA to block cell division following DNA damage. We also identify the damage-sensitive transcription factor responsible for inducing DidA. Finally, our study demonstrates that DidA and SidA inhibit cell division in an atypical manner. Many division inhibitors in bacteria appear to inhibit the protein FtsZ, which forms a ring at the site of cell division. DidA and SidA, however, target a trio of proteins, FtsW/I/N, that help synthesize the new cell wall that will separate the daughter cells (the septum). In sum, our work expands our understanding of how bacterial cells respond to DNA damage and the mechanisms by which they regulate cell division.

Eukaryotic protein kinases regulate most cellular functions by phosphorylating targeted protein substrates through a highly conserved catalytic core. In the active state, the catalytic core oscillates between open, intermediate, and closed conformations. Currently, the intramolecular interactions that regulate the active state mechanics are not well understood. Here, using cAMP-dependent protein kinase as a representative model coupled with biochemical, biophysical, and computational techniques, we define a set of highly conserved electrostatic and hydrophobic interactions working harmoniously to regulate these mechanics. These include the previously identified salt bridge between a lysine from the β3-strand and a glutamate from the αC-helix as well as an electrostatic interaction between the phosphorylated activation loop and αC-helix and an ensemble of hydrophobic residues of the Regulatory spine and Shell. Moreover, for over three decades it was thought that the highly conserved β3-lysine was essential for phosphoryl transfer, but our findings show that the β3-lysine is not required for phosphoryl transfer but is essential for the active state mechanics., Author Summary Eukaryotic protein kinases (EPKs) regulate over a third of the human proteome by transferring the γ-phosphate from adenosine triphosphate (ATP) to a protein substrate in a process known as protein phosphorylation. Biochemical and biophysical studies have shown that EPKs undergo multiconformational rearrangements in which the catalytic core is oscillating between open, intermediate, and closed conformations when active. Presently, the intramolecular interactions that regulate this dynamic process are not well understood. In this paper, we show how a set of conserved electrostatic and hydrophobic interactions harmoniously regulate the active state mechanics. The electrostatic interactions involve the highly conserved salt bridge between the lysine from subdomain-II and glutamate from subdomain-III as well as an interaction between the activation loop and αC-helix. The hydrophobic interactions include the nonlinear motifs known as the Regulatory spine and Shell that traverse both lobes of the catalytic core. Furthermore, our findings show that the highly conserved “catalytic lysine” is not directly required for phosphoryl transfer but rather serves as a hub that aligns and positions the dynamic core elements required for catalysis.

Positive-strand RNA viruses build extensive membranous replication compartments to support replication and protect the virus from antiviral responses by the host. These viruses require host factors and various lipids to form viral replication complexes (VRCs). The VRCs built by Tomato bushy stunt virus (TBSV) are enriched with phosphatidylethanolamine (PE) through a previously unknown pathway. To unravel the mechanism of PE enrichment within the TBSV replication compartment, in this paper, the authors demonstrate that TBSV co-opts the guanosine triphosphate (GTP)-bound active form of the endosomal Rab5 small GTPase via direct interaction with the viral replication protein. Deletion of Rab5 orthologs in a yeast model host or expression of dominant negative mutants of plant Rab5 greatly decreases TBSV replication and prevents the redistribution of PE to the sites of viral replication. We also show that enrichment of PE in the viral replication compartment is assisted by actin filaments. Interestingly, the closely related Carnation Italian ringspot virus, which replicates on the boundary membrane of mitochondria, uses a similar strategy to the peroxisomal TBSV to hijack the Rab5-positive endosomes into the viral replication compartments. Altogether, usurping the GTP-Rab5–positive endosomes allows TBSV to build a PE-enriched viral replication compartment, which is needed to support peak-level replication. Thus, the Rab family of small GTPases includes critical host factors assisting VRC assembly and genesis of the viral replication compartment., Author Summary Plants, animals, and humans are threatened by positive-stranded RNA viruses, which are one of the major groups of intracellular pathogens. To support robust virus replication, these viruses subvert intracellular membranes and co-opt host proteins into virus-induced replication compartments. Tomato bushy stunt virus (TBSV) is a model virus used in yeast to dissect the roles of lipids and proteins in virus replication. In this work, the authors show that one of the two TBSV replication proteins interacts with the guanosine triphosphate (GTP)-bound Rab5 small GTPase, which allows the virus to take advantage of phosphatidylethanolamine (PE)-rich endosomes to build viral replication compartments consisting of peroxisomes. Peak level of TBSV replication depends on the co-opted abundant PE-rich Rab5-positive membranes in plants, too.

The One Health initiative is a global effort fostering interdisciplinary collaborations to address challenges in human, animal, and environmental health. While One Health has received considerable press, its benefits remain unclear because its effects have not been quantitatively described. We systematically surveyed the published literature and used social network analysis to measure interdisciplinarity in One Health studies constructing dynamic pathogen transmission models. The number of publications fulfilling our search criteria increased by 14.6% per year, which is faster than growth rates for life sciences as a whole and for most biology subdisciplines. Surveyed publications clustered into three communities: one used by ecologists, one used by veterinarians, and a third diverse-authorship community used by population biologists, mathematicians, epidemiologists, and experts in human health. Overlap between these communities increased through time in terms of author number, diversity of co-author affiliations, and diversity of citations. However, communities continue to differ in the systems studied, questions asked, and methods employed. While the infectious disease research community has made significant progress toward integrating its participating disciplines, some segregation—especially along the veterinary/ecological research interface—remains., "One Health" is a global initiative fostering interdisciplinary collaborations to address health challenges. Although an empirical analysis of published disease models shows a rapid growth in cross-disciplinary "One Health" collaborations, the continued segregation of medical, veterinary, and ecological communities poses an ongoing challenge., Author Summary A cohesive reaction to emerging threats requires the efficient dissemination of knowledge and methodologies across multiple disciplinary boundaries. A “One Health” approach has been advocated to facilitate cross-disciplinary communication and research in responding to challenges in human, animal, and environmental health. We empirically describe collaboration networks surrounding one aspect of this One Health initiative: infectious disease transmission models. A systematic literature review and social network analysis showed that dynamic disease modelling grew faster than most biological and natural science disciplines over the last 25 y, yet the field remains somewhat compartmentalized. Many researchers contribute to a broad, cross-disciplinary group of journals, but publications from veterinarians and ecologists remain segregated into relatively discrete communities. While the veterinary and ecological communities regularly reference the broad, cross-disciplinary group, they only rarely cite each other; furthermore, the highest-tiered medical journals contributed very few papers to our search. Therefore, our results are somewhat mixed: while One Health may have precipitated a great deal of research interest in infectious disease, it has not fully overcome the barriers that segregate its contributing disciplines.

Autophagy is the mechanism by which cellular material is delivered to lysosomes and degraded. This process has become a major focus of biological and biomedical research with thousands of papers published each year and rapidly growing appreciation that autophagy affects many normal and pathological processes. However, as we learn more about this evolutionarily ancient process, we are discovering that autophagy's effects may work for both the good and the bad of an organism. Here, I discuss some of these context-dependent findings and how, as we make sense of them, we can try to apply our knowledge for practical purposes.

Once there were ten identical monkeys. Their father made them draw lots and gave the winner a long bamboo pole. Each day the monkey with the pole whacks coconuts out of a tree, his brothers catch them and shell them, and they all feed off the proceeds. The monkey carrying the pole finds it quite hard and is normally very tired by the end of the day; over the years, he wonders whether it's worth the hassle. But one day there's an almighty flood. The monkey with the pole is lagging behind as usual and watches his nine brothers drown in the distance. When the flood abates, he walks on, finds a mate, and eventually passes the pole on to one of his ten identical children. Bacterial populations grow rapidly and asexually, generating millions of genetically identical progeny. Traditionally, it has been assumed that if these bugs are placed in a uniform environment, then they'll behave identically—nature and nurture are invariant, so there is neither motivation nor mechanism for diversity. Increasingly, however, we're appreciating that there are many intrinsic advantages to diversity, and nature can readily exploit this by using stochastic mechanisms to program populations of organisms to vary despite genetic and environmental uniformity. As with the monkeys, however, there are several ways in which it can pay to be different. One obvious way in which diversity of phenotype can yield dividends is by allowing specialization: “division of labor.” The unpleasant human pathogen Salmonella Typhimurium is one bug that's already known to do this; a small proportion of a genetically identical horde of invading bacteria express high levels of virulence factors called ttss-1, while the majority produce only low levels. The ttss-1 genes encode Type III Secretory System 1, a large and complex molecular “hypodermic needle” that allows the high-expressing “T+” bugs to inject the host cells full of effector proteins. These proteins in turn manipulate the host cells in a range of ways that favor proliferation by the T+ bacteria's more numerous low ttss-1-expressing “T−” brethren, thereby promoting virulence. A paper just published in PLOS Biology by Markus Arnoldini, Martin Ackermann, and colleagues adds a biologically intriguing and potentially clinically important twist to this touching tale of cooperation in Salmonella. They start from the observation that the T+ subpopulation seems to grow more slowly, and the authors check this in detail using an elegant high-throughput single-cell method based on time-lapse movies of a microfluidic system and bacteria containing a fluorescent reporter of ttss-1 expression (Figure 1). Slow growth is often associated with tolerance of antibiotics, however, so the authors ask the direct question of whether the T+ cells are better able to survive the ravages of a dose of ciprofloxacin. They were, and the authors then confirm that survival depends on the ability to turn on ttss-1 and does not involve the emergence of drug resistance by mutation. The T+ bugs were also more tolerant to kanamycin, a structurally and functionally unrelated antibiotic, and even survived high, clinically relevant doses of both drugs. Figure 1 Bugs in tubes. A 13-hour time-lapse montage of images from the microfluidics device used for this study. The bottom of each tube is closed so that as bugs divide they move up the tube and are shed at the top. The blue bar in the middle indicates normal ... The assumption was that the costly expression of abundant protein (in this case, ttss-1) caused slow growth, and slow growth caused tolerance. The authors tested this mechanistic chain by artificially slowing the growth of bugs that couldn't express ttss-1 and by gratuitously expressing high levels of an arbitrary protein, LacZ. Both experiments made bugs more tolerant to antibiotics. Like the monkey's pole, ttss-1 expression is therefore the agent both of a continuing cooperative behavior (virulence) and a burdensome bet hedge that pays off (tolerance) when disaster strikes. A potentially alarming consequence of this is that treating an infection with antibiotics might inadvertently select for virulence by preferentially culling nonvirulent (T−) cells. To examine whether this is possible, the authors set up a competition between normal Salmonella (which can switch stochastically between T+ and T− states) and a genetically avirulent one which is always T−. In the absence of antibiotic, the unburdened avirulent bugs win, but if antibiotic is present, the hedged bet pays off, and the switchers take over. The study therefore shows that two fundamental drivers of cellular heterogeneity—division-of-labor and bet hedging—can be intricately intertwined by the sharing of a common agent. The authors wonder whether this entanglement means that bet hedging might serve to prevent cheater mutants (those which can't switch to a T+ phenotype but freeload off those that can) from subverting the division-of-labor system. Crucially, when the heterogeneous traits involved are drug tolerance and virulence, then unfortunate clinical consequences may arise from the peculiar confluence of two facts—that expression of virulence proteins is expensive enough to slow cellular growth and that slow cellular growth helps bacteria to weather the presence of antibiotics. Clearly we need a better understanding of this unforeseen potential downside of antibiotic treatment; we don't want to select for killers when we aim to cure. Arnoldini M, Vizcarra IA, Pena-Miller R, Stocker N, Diard M, et al. (2014) Bistable Expression of Virulence Genes in Salmonella Leads to the Formation of an Antibiotic-Tolerant Subpopulation. doi:10.1371/journal.pbio.1001928

Reproductive competition often continues long after copulation ends. This article reviews the field and introduces a new paper showing that nematode sperm can directly harm the female germ line., Intense reproductive competition often continues long after animals finish mating. In many species, sperm from one male compete with those from others to find and fertilize oocytes. Since this competition occurs inside the female reproductive tract, she often influences the outcome through physical or chemical factors, leading to cryptic female choice. Finally, traits that help males compete with each other are sometimes harmful to females, and female countermeasures may thwart the interests of males, which can lead to an arms race between the sexes known as sexually antagonistic coevolution. New studies from Caenorhabditis nematodes suggest that males compete with each other by producing sperm that migrate aggressively and that these sperm may be more likely to win access to oocytes. However, one byproduct of this competition appears to be an increased probability that these sperm will go astray, invading the ovary, prematurely activating oocytes, and sometimes crossing basement membranes and leaving the gonad altogether. These harmful effects are sometimes observed in crosses between animals of the same species but are most easily detected in interspecies crosses, leading to dramatically lowered fitness, presumably because the competitiveness of the sperm and the associated female countermeasures are not precisely matched. This mismatch is most obvious in crosses involving individuals from androdioecious species (which have both hermaphrodites and males), as predicted by the lower levels of sperm competition these species experience. These results suggest a striking example of sexually antagonistic coevolution and dramatically expand the value of nematodes as a laboratory system for studying postcopulatory interactions.