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Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect. In preclinical and clinical models, however, tumor growth data are limited by the lower limit of detection (i.e., a measurable lesion) and confounding variables, such as tumor microenvironment, and immune responses may cause and mask deviations from exponential growth models. In this work, we present alternative growth models to investigate the presence of an Allee effect in cancer cells seeded at low cell densities in a controlled in vitro setting. We propose a stochastic modeling framework to disentangle expected deviations due to small population size stochastic effects from cooperative growth and use the moment approach for stochastic parameter estimation to calibrate the observed growth trajectories. We validate the framework on simulated data and apply this approach to longitudinal cell proliferation data of BT-474 luminal B breast cancer cells. We find that cell population growth kinetics are best described by a model structure that considers the Allee effect, in that the birth rate of tumor cells increases with cell number in the regime of small population size. This indicates a potentially critical role of cooperative behavior among tumor cells at low cell densities with relevance to early stage growth patterns of emerging and relapsed tumors. [ABSTRACT FROM AUTHOR]

While sequencing ancient DNA (aDNA) from archaeological material is now commonplace, very few attempts to sequence ancient transcriptomes have been made, even from typically stable deposition environments such as permafrost. This is presumably due to assumptions that RNA completely degrades relatively quickly, particularly when dealing with autolytic, nuclease-rich mammalian tissues. However, given the recent successes in sequencing ancient RNA (aRNA) from various sources including plants and animals, we suspect that these assumptions may be incorrect or exaggerated. To challenge the underlying dogma, we generated shotgun RNA data from sources that might normally be dismissed for such study. Here, we present aRNA data generated from two historical wolf skins, and permafrost-preserved liver tissue of a 14,300-year-old Pleistocene canid. Not only is the latter the oldest RNA ever to be sequenced, but it also shows evidence of biologically relevant tissue specificity and close similarity to equivalent data derived from modern-day control tissue. Other hallmarks of RNA sequencing (RNA-seq) data such as exon-exon junction presence and high endogenous ribosomal RNA (rRNA) content confirms our data’s authenticity. By performing independent technical library replicates using two high-throughput sequencing platforms, we show not only that aRNA can survive for extended periods in mammalian tissues but also that it has potential for tissue identification. aRNA also has possible further potential, such as identifying in vivo genome activity and adaptation, when sequenced using this technology. [ABSTRACT FROM AUTHOR]

Speciation genomic studies aim to interpret patterns of genome-wide variation in light of the processes that give rise to new species. However, interpreting the genomic “landscape” of speciation is difficult, because many evolutionary processes can impact levels of variation. Facilitated by the first chromosome-level assembly for the group, we use whole-genome sequencing and simulations to shed light on the processes that have shaped the genomic landscape during a radiation of monkeyflowers. After inferring the phylogenetic relationships among the 9 taxa in this radiation, we show that highly similar diversity (π) and differentiation (FST) landscapes have emerged across the group. Variation in these landscapes was strongly predicted by the local density of functional elements and the recombination rate, suggesting that the landscapes have been shaped by widespread natural selection. Using the varying divergence times between pairs of taxa, we show that the correlations between FST and genome features arose almost immediately after a population split and have become stronger over time. Simulations of genomic landscape evolution suggest that background selection (BGS; i.e., selection against deleterious mutations) alone is too subtle to generate the observed patterns, but scenarios that involve positive selection and genetic incompatibilities are plausible alternative explanations. Finally, tests for introgression among these taxa reveal widespread evidence of heterogeneous selection against gene flow during this radiation. Combined with previous evidence for adaptation in this system, we conclude that the correlation in FST among these taxa informs us about the processes contributing to adaptation and speciation during a rapid radiation. [ABSTRACT FROM AUTHOR]

Noncontact methods to measure animal activity and physiology are necessary to monitor undisturbed states such as hibernation. Although some noncontact measurement systems are commercially available, they are often incompatible with realistic habitats, which feature freely moving animals in small, cluttered environments. A growing market of single-board computers, microcontrollers, and inexpensive sensors has made it possible to assemble bespoke integrated sensor systems at significantly lower price points. Herein, we describe a custom-built nesting box imager (NBI) that uses a single-board computer (Raspberry Pi) with a passive infrared (IR) motion sensor, silicon charge-coupled device (CCD), and IR camera CCD to monitor the activity, surface body temperature, and respiratory rate of the meadow jumping mouse during hibernation cycles. The data are logged up to 12 samples per minute and postprocessed using custom Matlab scripts. The entire unit can be built at a price point below US$400, which will be drastically reduced as IR (thermal) arrays are integrated into more consumer electronics and become less expensive. [ABSTRACT FROM AUTHOR]

For many years, double-layer phospholipid membrane vesicles, released by most cells, were not considered to be of biological significance. This stance has dramatically changed with the recognition of extracellular vesicles (EVs) as carriers of biologically active molecules that can traffic to local or distant targets and execute defined biological functions. The dimensionality of the field has expanded with the appreciation of diverse types of EVs and the complexity of vesicle biogenesis, cargo loading, release pathways, targeting mechanisms, and vesicle processing. With the expanded interest in the field and the accelerated rate of publications on EV structure and function in diverse biomedical fields, it has become difficult to distinguish between well-established biological features of EV and the untested hypotheses or speculative assumptions that await experimental proof. With the growing interest despite the limited evidence, we sought in this essay to formulate a set of unsolved mysteries in the field, sort out established data from fascinating hypotheses, and formulate several challenging questions that must be answered for the field to advance. [ABSTRACT FROM AUTHOR]

The evidence that diel patterns of physiology and behaviour in mammals are governed by circadian ‘clocks’ is based almost entirely on studies of nocturnal rodents. The emergent circadian paradigm, however, neglects the roles of energy metabolism and alimentary function (feeding and digestion) as determinants of activity pattern. The temporal control of activity varies widely across taxa, and ungulates, microtine rodents, and insectivores provide examples in which circadian timekeeping is vestigial. The nocturnal rodent/human paradigm of circadian organisation is unhelpful when considering the broader manifestation of activity patterns in mammals. [ABSTRACT FROM AUTHOR]

In primates, both the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (dlPFC) are key regions of the frontoparietal cognitive control network. To study the role of the dACC and its communication with the dlPFC in cognitive control, we recorded local field potentials (LFPs) from the dlPFC before and during the reversible deactivation of the dACC, in macaque monkeys engaging in uncued switches between 2 stimulus-response rules, namely prosaccade and antisaccade. Cryogenic dACC deactivation impaired response accuracy during maintenance of—but not the initial switching to—the cognitively demanding antisaccade rule, which coincided with a reduction in task-related theta activity and the correct-error (C-E) difference in dlPFC beta-band power. During both rule switching and maintenance, dACC deactivation prolonged the animals’ reaction time and reduced task-related alpha power in the dlPFC. Our findings support a role of the dACC in prefrontal oscillatory activities that are involved the maintenance of a new, challenging task rule. [ABSTRACT FROM AUTHOR]

Hsp90 is a conserved molecular chaperone that assists in the folding and function of diverse cellular regulators, with a profound impact on biology, disease, and evolution. As a central hub of protein interaction networks, Hsp90 engages with hundreds of protein–protein interactions within eukaryotic cells. These interactions include client proteins, which physically interact with Hsp90 and depend on the chaperone for stability or function, as well as co-chaperones and partner proteins that modulate chaperone function. Currently, there are no methods to accurately predict Hsp90 interactors and there has been considerable network rewiring over evolutionary time, necessitating experimental approaches to define the Hsp90 network in the species of interest. This is a pressing challenge for fungal pathogens, for which Hsp90 is a key regulator of stress tolerance, drug resistance, and virulence traits. To address this challenge, we applied a novel biochemical fractionation and quantitative proteomic approach to examine alterations to the proteome upon perturbation of Hsp90 in a leading human fungal pathogen, Candida albicans. In parallel, we performed affinity purification coupled to mass spectrometry to define physical interacting partners for Hsp90 and the Hsp90 co-chaperones and identified 164 Hsp90-interacting proteins, including 111 that are specific to the pathogen. We performed the first analysis of the Hsp90 interactome upon antifungal drug stress and demonstrated that Hsp90 stabilizes processing body (P-body) and stress granule proteins that contribute to drug tolerance. We also describe novel roles for Hsp90 in regulating posttranslational modification of the Rvb1-Rvb2-Tah1-Pih1 (R2TP) complex and the formation of protein aggregates in response to thermal stress. This study provides a global view of the Hsp90 interactome in a fungal pathogen, demonstrates the dynamic role of Hsp90 in response to environmental perturbations, and highlights a novel connection between Hsp90 and the regulation of mRNA-associated protein granules. [ABSTRACT FROM AUTHOR]

The developmental pathway of the neural retina (NR) and retinal pigment epithelium (RPE) has been revealed by extensive research in mice. However, the molecular mechanisms underlying the development of the human NR and RPE, as well as the interactions between these two tissues, have not been well defined. Here, we analyzed 2,421 individual cells from human fetal NR and RPE using single-cell RNA sequencing (RNA-seq) technique and revealed the tightly regulated spatiotemporal gene expression network of human retinal cells. We identified major cell classes of human fetal retina and potential crucial transcription factors for each cell class. We dissected the dynamic expression patterns of visual cycle– and ligand-receptor interaction–related genes in the RPE and NR. Moreover, we provided a map of disease-related genes for human fetal retinal cells and highlighted the importance of retinal progenitor cells as potential targets of inherited retinal diseases. Our findings captured the key in vivo features of the development of the human NR and RPE and offered insightful clues for further functional studies. [ABSTRACT FROM AUTHOR]

From invertebrates to vertebrates, a wealth of species display transient sociality during their life cycle. Investigating the causes of dispersal in temporary associations is important to better understand population dynamics. It is also essential to identify possible mechanisms involved in the evolutionary transition from transient to stable sociality, which has been documented repeatedly across taxa and typically requires the suppression of dispersal. In many animals, the onset of dispersal during ontogeny coincides with a sharp decline in social tolerance, but the causal relationship still remains poorly understood. Spiders offer relevant models to explore this question, because the adults of the vast majority of species (>48,000) are solitary and aggressive, but juveniles of most (if not all) species are gregarious and display amicable behaviors. We deployed a combination of behavioral, chemical, and modelling approaches in spiderlings of a solitary species to investigate the mechanisms controlling the developmental switch leading to the decline of social cohesion and the loss of tolerance. We show that maturation causes an increase in mobility that is sufficient to elicit dispersal without requiring any change in social behaviors. Our results further demonstrate that social isolation following dispersal triggers aggressiveness in altering the processing of conspecifics’ cues. We thus provide strong evidence that aggression is a consequence, not a cause, of dispersal in spiderlings. Overall, this study highlights the need of extended social interactions to preserve tolerance, which opens new perspectives for understanding the routes to permanent sociality. [ABSTRACT FROM AUTHOR]

Citizen science is mainstream: millions of people contribute data to a growing array of citizen science projects annually, forming massive datasets that will drive research for years to come. Many citizen science projects implement a “leaderboard” framework, ranking the contributions based on number of records or species, encouraging further participation. But is every data point equally “valuable?” Citizen scientists collect data with distinct spatial and temporal biases, leading to unfortunate gaps and redundancies, which create statistical and informational problems for downstream analyses. Up to this point, the haphazard structure of the data has been seen as an unfortunate but unchangeable aspect of citizen science data. However, we argue here that this issue can actually be addressed: we provide a very simple, tractable framework that could be adapted by broadscale citizen science projects to allow citizen scientists to optimize the marginal value of their efforts, increasing the overall collective knowledge. [ABSTRACT FROM AUTHOR]

Spontaneous mutations are the source of new genetic variation and are thus central to the evolutionary process. In molecular evolution and quantitative genetics, the nature of genetic variation depends critically on the distribution of effects of mutations on fitness and other quantitative traits. Spontaneous mutation accumulation (MA) experiments have been the principal approach for investigating the overall rate of occurrence and cumulative effect of mutations but have not allowed the phenotypic effects of individual mutations to be studied directly. Here, we crossed MA lines of the green alga Chlamydomonas reinhardtii with its unmutated ancestral strain to create haploid recombinant lines, each carrying an average of 50% of the accumulated mutations in a large number of combinations. With the aid of the genome sequences of the MA lines, we inferred the genotypes of the mutations, assayed their growth rate as a measure of fitness, and inferred the distribution of fitness effects (DFE) using a Bayesian mixture model. We infer that the DFE is highly leptokurtic (L-shaped). Of mutations with absolute fitness effects exceeding 1%, about one-sixth increase fitness in the laboratory environment. The inferred distribution of effects for deleterious mutations is consistent with a strong role for nearly neutral evolution. Specifically, such a distribution predicts that nucleotide variation and genetic variation for quantitative traits will be insensitive to change in the effective population size. [ABSTRACT FROM AUTHOR]

Multispecies microbial communities often display “community functions” arising from interactions of member species. Interactions are often difficult to decipher, making it challenging to design communities with desired functions. Alternatively, similar to artificial selection for individuals in agriculture and industry, one could repeatedly choose communities with the highest community functions to reproduce by randomly partitioning each into multiple “Newborn” communities for the next cycle. However, previous efforts in selecting complex communities have generated mixed outcomes that are difficult to interpret. To understand how to effectively enact community selection, we simulated community selection to improve a community function that requires 2 species and imposes a fitness cost on one or both species. Our simulations predict that improvement could be easily stalled unless various aspects of selection were carefully considered. These aspects include promoting species coexistence, suppressing noncontributors, choosing additional communities besides the highest functioning ones to reproduce, and reducing stochastic fluctuations in the biomass of each member species in Newborn communities. These considerations can be addressed experimentally. When executed effectively, community selection is predicted to improve costly community function, and may even force species to evolve slow growth to achieve species coexistence. Our conclusions hold under various alternative model assumptions and are therefore applicable to a variety of communities. [ABSTRACT FROM AUTHOR]

The zebrafish Danio rerio is a powerful model system to study the genetics of development and disease. However, maintenance of zebrafish husbandry records is both time intensive and laborious, and a standardized way to manage and track the large amount of unique lines in a given laboratory or centralized facility has not been embraced by the field. Here, we present FishNET, an intuitive, open-source, relational database for managing data and information related to zebrafish husbandry and maintenance. By creating a “virtual facility,” FishNET enables users to remotely inspect the rooms, racks, tanks, and lines within a given facility. Importantly, FishNET scales from one laboratory to an entire facility with several laboratories to multiple facilities, generating a cohesive laboratory and community-based platform. Automated data entry eliminates confusion regarding line nomenclature and streamlines maintenance of individual lines, while flexible query forms allow researchers to retrieve database records based on user-defined criteria. FishNET also links associated embryonic and adult biological samples with data, such as genotyping results or confocal images, to enable robust and efficient colony management and storage of laboratory information. A shared calendar function with email notifications and automated reminders for line turnover, automated tank counts, and census reports promote communication with both end users and administrators. The expected benefits of FishNET are improved vivaria efficiency, increased quality control for experimental numbers, and flexible data reporting and retrieval. FishNET’s easy, intuitive record management and open-source, end-user–modifiable architecture provides an efficient solution to real-time zebrafish colony management for users throughout a facility and institution and, in some cases, across entire research hubs. [ABSTRACT FROM AUTHOR]

Almost all animals and plants are inhabited by diverse communities of microorganisms, the microbiota, thereby forming an integrated entity, the metaorganism. Natural selection should favor hosts that shape the community composition of these microbes to promote a beneficial host-microbe symbiosis. Indeed, animal hosts often pose selective environments, which only a subset of the environmentally available microbes are able to colonize. How these microbes assemble after colonization to form the complex microbiota is less clear. Neutral models are based on the assumption that the alternatives in microbiota community composition are selectively equivalent and thus entirely shaped by random population dynamics and dispersal. Here, we use the neutral model as a null hypothesis to assess microbiata composition in host organisms, which does not rely on invoking any adaptive processes underlying microbial community assembly. We show that the overall microbiota community structure from a wide range of host organisms, in particular including previously understudied invertebrates, is in many cases consistent with neutral expectations. Our approach allows to identify individual microbes that are deviating from the neutral expectation and are therefore interesting candidates for further study. Moreover, using simulated communities, we demonstrate that transient community states may play a role in the deviations from the neutral expectation. Our findings highlight that the consideration of neutral processes and temporal changes in community composition are critical for an in-depth understanding of microbiota-host interactions. [ABSTRACT FROM AUTHOR]

Investigation of marine mammal dive-by-dive blood distribution and oxygenation has been limited by a lack of noninvasive technology for use in freely diving animals. Here, we developed a noninvasive near-infrared spectroscopy (NIRS) device to measure relative changes in blood volume and haemoglobin oxygenation continuously in the blubber and brain of voluntarily diving harbour seals. Our results show that seals routinely exhibit preparatory peripheral vasoconstriction accompanied by increased cerebral blood volume approximately 15 s before submersion. These anticipatory adjustments confirm that blood redistribution in seals is under some degree of cognitive control that precedes the mammalian dive response. Seals also routinely increase cerebral oxygenation at a consistent time during each dive, despite a lack of access to ambient air. We suggest that this frequent and reproducible reoxygenation pattern, without access to ambient air, is underpinned by previously unrecognised changes in cerebral drainage. The ability to track blood volume and oxygenation in different tissues using NIRS will facilitate a more accurate understanding of physiological plasticity in diving animals in an increasingly disturbed and exploited environment. [ABSTRACT FROM AUTHOR]

Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively unexplored. Here, we report that αSacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αSun). We identify complex N-linked glycans as binding partners for αSacetyl and demonstrate that cellular internalization of αSacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αSacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αSacetyl. Importantly, our results are specific to αSacetyl because αSun does not demonstrate sensitivity for N-linked glycans in any of our assays. Our study identifies extracellular N-linked glycans—and the glycoprotein neurexin 1β specifically—as key modulators of neuronal uptake of αSacetyl, drawing attention to the potential therapeutic value of αSacetyl-glycan interactions. [ABSTRACT FROM AUTHOR]

Declarative memory encompasses representations of specific events as well as knowledge extracted by accumulation over multiple episodes. To investigate how these different sorts of memories are created, we developed a new behavioral task in rodents. The task consists of 3 distinct conditions (stable, overlapping, and random). Rodents are exposed to multiple sample trials, in which they explore objects in specific spatial arrangements, with object identity changing from trial to trial. In the stable condition, the locations are constant during all sample trials even though the objects themselves change; in the test trial, 1 object’s location is changed. In the random condition, object locations are presented in the sample phase without a specific spatial pattern. In the overlapping condition, 1 location is shared (overlapping) between all trials, while the other location changes during sample trials. We show that in the overlapping condition, instead of only remembering the last sample trial, rodents form a cumulative memory of the sample trials. Here, we could show that both mice and rats can accumulate information across multiple trials and express a long-term abstracted memory. [ABSTRACT FROM AUTHOR]

Infections with human herpesviruses are ubiquitous and a public health concern worldwide. Current treatments reduce the severity of some symptoms associated to herpetic infections but neither remove the viral reservoir from the infected host nor protect from the recurrent symptom outbreaks that characterise herpetic infections. The difficulty in therapeutically tackling these viral systems stems in part from their remarkably large proteomes and the complex networks of physical and functional associations that they tailor. This study presents our efforts to unravel the complexity of the interactome of herpes simplex virus type 1 (HSV1), the prototypical herpesvirus species. Inspired by our previous work, we present an improved and more integrative computational pipeline for the protein–protein interaction (PPI) network reconstruction in HSV1, together with a newly developed consensus clustering framework, which allowed us to extend the analysis beyond binary physical interactions and revealed a system-level layout of higher-order functional associations in the virion proteome. Additionally, the analysis provided new functional annotation for the currently undercharacterised protein in unique short region 10 (pUS10). In-depth bioinformatics sequence analysis unravelled structural features in pUS10 reminiscent of those observed in some capsid-associated proteins in tailed bacteriophages, with which herpesviruses are believed to share a common ancestry. Using immunoaffinity purification (IP)–mass spectrometry (MS), we obtained additional support for our bioinformatically predicted interaction between pUS10 and the inner tegument protein in unique long region 37 (pUL37), which binds cytosolic capsids, contributing to initial tegumentation and eventually virion maturation. In summary, this study unveils new, to our knowledge, insights at both the system and molecular levels that can help us better understand the complexity behind herpesvirus infections. [ABSTRACT FROM AUTHOR]

Plasmodium actins form very short filaments and have a noncanonical link between ATP hydrolysis and polymerization. Long filaments are detrimental to the parasites, but the structural factors constraining Plasmodium microfilament lengths have remained unknown. Using high-resolution crystallography, we show that magnesium binding causes a slight flattening of the Plasmodium actin I monomer, and subsequent phosphate release results in a more twisted conformation. Thus, the Mg-bound monomer is closer in conformation to filamentous (F) actin than the Ca form, and this likely facilitates polymerization. A coordinated potassium ion resides in the active site during hydrolysis and leaves together with the phosphate, a process governed by the position of the Arg178/Asp180-containing A loop. Asp180 interacts with either Lys270 or His74, depending on the protonation state of the histidine, while Arg178 links the inner and outer domains (ID and OD) of the actin protomer. Hence, the A loop acts as a switch between stable and unstable filament conformations, the latter leading to fragmentation. Our data provide a comprehensive model for polymerization, ATP hydrolysis and phosphate release, and fragmentation of parasite microfilaments. Similar mechanisms may well exist in canonical actins, although fragmentation is much less favorable due to several subtle sequence differences as well as the methylation of His73, which is absent on the corresponding His74 in Plasmodium actin I. [ABSTRACT FROM AUTHOR]

Hypervariable T cell receptors (TCRs) play a key role in adaptive immunity, recognizing a vast diversity of pathogen-derived antigens. Our ability to extract clinically relevant information from large high-throughput sequencing of TCR repertoires (RepSeq) data is limited, because little is known about TCR–disease associations. We present Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE), a statistical approach that identifies TCR sequences actively involved in current immune responses from a single RepSeq sample and apply it to repertoires of patients with a variety of disorders—patients with autoimmune disease (ankylosing spondylitis [AS]), under cancer immunotherapy, or subject to an acute infection (live yellow fever [YF] vaccine). We validate the method with independent assays. ALICE requires no longitudinal data collection nor large cohorts, and it is directly applicable to most RepSeq datasets. Its results facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design. [ABSTRACT FROM AUTHOR]

Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are “capsid binders” that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo–electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens. [ABSTRACT FROM AUTHOR]

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 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. [ABSTRACT FROM AUTHOR]

Aquatic ecosystems worldwide continue to experience unprecedented warming and ecological change. Warming increases metabolic rates of animals, plants, and microbes, accelerating their use of energy and materials, their population growth, and interaction rates. At a much larger biological scale, warming accelerates ecosystem-level processes, elevating fluxes of carbon and oxygen between biota and the atmosphere. Although these general effects of temperature at finer and broader biological scales are widely observed, they can lead to contradictory predictions for how warming affects the structure and function of ecological communities at the intermediate scale of biological organization. We experimentally tested the hypothesis that the presence of predators and their associated species interactions modify the temperature dependence of net ecosystem oxygen production and respiration. We tracked a series of independent freshwater ecosystems (370 L) over 9 weeks, and we found that at higher temperatures, cascading effects of predators on zooplankton prey and algae were stronger than at lower temperatures. When grazing was weak or absent, standing phytoplankton biomass declined by 85%–95% (<1-fold) over the temperature gradient (19–30 °C), and by 3-fold when grazers were present and lacked predators. These temperature-dependent species interactions and consequent community biomass shifts occurred without signs of species loss or community collapse, and only modestly affected the temperature dependence of net ecosystem oxygen fluxes. The exponential increases in net ecosystem oxygen production and consumption were relatively insensitive to differences in trophic interactions among ecosystems. Furthermore, monotonic declines in phytoplankton standing stock suggested no threshold effects of warming across systems. We conclude that local changes in community structure, including temperature-dependent trophic cascades, may be compatible with prevailing and predictable effects of temperature on ecosystem functions related to fundamental effects of temperature on metabolism. [ABSTRACT FROM AUTHOR]

The MooSciTIC project is a capacity-building initiative targeting West African research scientists and higher education teachers. The project aimed to improve the self-reliance of researchers and upgrade research practices by providing on-site summer schools on trans-disciplinary topics such as scientific writing, communication, and integrity. Here, we explain how this program was designed and implemented and share the positive responses from our trainees, hoping to inspire similar initiatives. [ABSTRACT FROM AUTHOR]

The origin and subsequent maintenance of sex and recombination are among the most elusive and controversial problems in evolutionary biology. Here, we propose a novel hypothesis, suggesting that sexual reproduction not only evolved to reduce the negative effects of the accumulation of deleterious mutations and processes associated with pathogen and/or parasite resistance but also to prevent invasion by transmissible selfish neoplastic cheater cells, henceforth referred to as transmissible cancer cells. Sexual reproduction permits systematic change of the multicellular organism's genotype and hence an enhanced detection of transmissible cancer cells by immune system. Given the omnipresence of oncogenic processes in multicellular organisms, together with the fact that transmissible cancer cells can have dramatic effects on their host fitness, our scenario suggests that the benefits of sex and concomitant recombination will be large and permanent, explaining why sexual reproduction is, despite its costs, the dominant mode of reproduction among eukaryotes. [ABSTRACT FROM AUTHOR]

Humans not only value extrinsic monetary rewards but also their own morality and their image in the eyes of others. Yet violating moral norms is frequent, especially when people know that they are not under scrutiny. When moral values and monetary payoffs are at odds, how does the brain weigh the benefits and costs of moral and monetary payoffs? Here, using a neurocomputational model of decision value (DV) and functional (f)MRI, we investigated whether different brain systems are engaged when deciding whether to earn money by contributing to a "bad cause" and when deciding whether to sacrifice money to contribute to a "good cause," both when such choices were made privately or in public. Although similar principles of DV computations were used to solve these dilemmas, they engaged 2 distinct valuation systems. When weighing monetary benefits and moral costs, people were willing to trade their moral values in exchange for money, an effect accompanied by DV computation engaging the anterior insula and the lateral prefrontal cortex (PFC). In contrast, weighing monetary costs against compliance with one's moral values engaged the ventral putamen. Moreover, regardless of the type of dilemma, a brain network including the anterior cingulate cortex (ACC), anterior insula, and the right temporoparietal junction (TJP) was more engaged in public than in private settings. Together, these findings identify how the brain processes three sources of motivation: extrinsic rewards, moral values, and concerns for image. [ABSTRACT FROM AUTHOR]

A morphospecies is defined as a taxonomic species based wholly on morphology, but often morphospecies consist of clusters of cryptic species that can be identified genetically or molecularly. The nature of the evolutionary novelty that accompanies speciation in a morphospecies is an intriguing question. Morphospecies are particularly common among ciliates, a group of unicellular eukaryotes that separates 2 kinds of nuclei—the silenced germline nucleus (micronucleus [MIC]) and the actively expressed somatic nucleus (macronucleus [MAC])—within a common cytoplasm. Because of their very similar morphologies, members of the Tetrahymena genus are considered a morphospecies. We explored the hidden genomic evolution within this genus by performing a comprehensive comparative analysis of the somatic genomes of 10 species and the germline genomes of 2 species of Tetrahymena. These species show high genetic divergence; phylogenomic analysis suggests that the genus originated about 300 million years ago (Mya). Seven universal protein domains are preferentially included among the species-specific (i.e., the youngest) Tetrahymena genes. In particular, leucine-rich repeat (LRR) genes make the largest contribution to the high level of genome divergence of the 10 species. LRR genes can be sorted into 3 different age groups. Parallel evolutionary trajectories have independently occurred among LRR genes in the different Tetrahymena species. Thousands of young LRR genes contain tandem arrays of exactly 90-bp exons. The introns separating these exons show a unique, extreme phase 2 bias, suggesting a clonal origin and successive expansions of 90-bp–exon LRR genes. Identifying LRR gene age groups allowed us to document a Tetrahymena intron length cycle. The youngest 90-bp exon LRR genes in T. thermophila are concentrated in pericentromeric and subtelomeric regions of the 5 micronuclear chromosomes, suggesting that these regions act as genome innovation centers. Copies of a Tetrahymena Long interspersed element (LINE)-like retrotransposon are very frequently found physically adjacent to 90-bp exon/intron repeat units of the youngest LRR genes. We propose that Tetrahymena species have used a massive exon-shuffling mechanism, involving unequal crossing over possibly in concert with retrotransposition, to create the unique 90-bp exon array LRR genes. [ABSTRACT FROM AUTHOR]

Outbreaks of emerging plant diseases and insect pests are increasing at an alarming rate threatening the food security needs of a booming world population. The role of plant pathologists in addressing these threats to plant health is critical. Here, we share our personal experience with the appearance in Bangladesh of a destructive new fungal disease called wheat blast and stress the importance of open-science platforms and crowdsourced community responses in tackling emerging plant diseases. Benefits of the open-science approach include recruitment of multidisciplinary experts, application of cutting-edge methods, and timely replication of data analyses to increase the robustness of the findings. Based on our experiences, we provide some general recommendations and practical guidance for responding to emerging plant diseases. [ABSTRACT FROM AUTHOR]

Sensory experience elicits complex activity patterns throughout the neocortex. Projections from the neocortex converge onto the medial temporal lobe (MTL), in which distributed neocortical firing patterns are distilled into sparse representations. The precise nature of these neuronal representations is still unknown. Here, we show that population activity patterns in the MTL are governed by high levels of semantic abstraction. We recorded human single-unit activity in the MTL (4,917 units, 25 patients) while subjects viewed 100 images grouped into 10 semantic categories of 10 exemplars each. High levels of semantic abstraction were indicated by representational similarity analyses (RSAs) of patterns elicited by individual stimuli. Moreover, pattern classifiers trained to decode semantic categories generalised successfully to unseen exemplars, and classifiers trained to decode exemplar identity more often confused exemplars of the same versus different categories. Semantic abstraction and generalisation may thus be key to efficiently distill the essence of an experience into sparse representations in the human MTL. Although semantic abstraction is efficient and may facilitate generalisation of knowledge to novel situations, it comes at the cost of a loss of detail and may be central to the generation of false memories. [ABSTRACT FROM AUTHOR]

Many animals can encode temporal intervals and use them to plan their actions, but only humans can flexibly extract a regular beat from complex patterns, such as musical rhythms. Beat-based timing is hypothesized to rely on the integration of sensory information with temporal information encoded in motor regions such as the medial premotor cortex (MPC), but how beat-based timing might be encoded in neuronal populations is mostly unknown. Gámez and colleagues show that the MPC encodes temporal information via a population code visible as circular trajectories in state space; these patterns may represent precursors to more-complex skills such as beat-based timing. [ABSTRACT FROM AUTHOR]

Evolutionary innovations are qualitatively novel traits that emerge through evolution and increase biodiversity. The genetic mechanisms of innovation remain poorly understood. A systems view of innovation requires the analysis of genotype networks—the vast networks of genetic variants that produce the same phenotype. Innovations can occur at the intersection of two different genotype networks. However, the experimental characterization of genotype networks has been hindered by the vast number of genetic variants that need to be functionally analyzed. Here, we use high-throughput sequencing to study the fitness landscape at the intersection of the genotype networks of two catalytic RNA molecules (ribozymes). We determined the ability of numerous neighboring RNA sequences to catalyze two different chemical reactions, and we use these data as a proxy for a genotype to fitness map where two functions come in close proximity. We find extensive functional overlap, and numerous genotypes can catalyze both functions. We demonstrate through evolutionary simulations that these numerous points of intersection facilitate the discovery of a new function. However, the rate of adaptation of the new function depends upon the local ruggedness around the starting location in the genotype network. As a consequence, one direction of adaptation is more rapid than the other. We find that periods of neutral evolution increase rates of adaptation to the new function by allowing populations to spread out in their genotype network. Our study reveals the properties of a fitness landscape where genotype networks intersect and the consequences for evolutionary innovations. Our results suggest that historic innovations in natural systems may have been facilitated by overlapping genotype networks. [ABSTRACT FROM AUTHOR]

The Drosophila wing was proposed to be a taste organ more than 35 years ago, but there has been remarkably little study of its role in chemoreception. We carry out a differential RNA-seq analysis of a row of sensilla on the anterior wing margin and find expression of many genes associated with pheromone and chemical perception. To ask whether these sensilla might receive pheromonal input, we devised a dye-transfer paradigm and found that large, hydrophobic molecules comparable to pheromones can be transferred from one fly to the wing margin of another. One gene, Ionotropic receptor (IR)52a, is coexpressed in neurons of these sensilla with fruitless, a marker of sexual circuitry; IR52a is also expressed in legs. Mutation of IR52a and optogenetic silencing of IR52a+ neurons decrease levels of male sexual behavior. Optogenetic activation of IR52a+ neurons induces males to show courtship toward other males and, remarkably, toward females of another species. Surprisingly, IR52a is also required in females for normal sexual behavior. Optogenetic activation of IR52a+ neurons in mated females induces copulation, which normally occurs at very low levels. Unlike other chemoreceptors that act in males to inhibit male–male interactions and promote male–female interactions, IR52a acts in both males and females, and can promote male–male as well as male–female interactions. Moreover, IR52a+ neurons can override the circuitry that normally suppresses sexual behavior toward unproductive targets. Circuit mapping and Ca2+ imaging using the trans-Tango system reveals second-order projections of IR52a+ neurons in the subesophageal zone (SEZ), some of which are sexually dimorphic. Optogenetic activation of IR52a+ neurons in the wing activates second-order projections in the SEZ. Taken together, this study provides a molecular description of the chemosensory sensilla of a greatly understudied taste organ and defines a gene that regulates the sexual circuitry of the fly. [ABSTRACT FROM AUTHOR]

Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix–loop–helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30–dependent manner, also demonstrated increased mortality with starvation–refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation–refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation–refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival. [ABSTRACT FROM AUTHOR]

Evidence is rapidly mounting that transposable element (TE) expression and replication may impact biology more widely than previously thought. This includes potential effects on normal physiology of somatic tissues and dysfunctional impacts in diseases associated with aging, such as cancer and neurodegeneration. Investigation of the biological impact of mobile elements in somatic cells will be greatly facilitated by the use of donor elements that are engineered to report de novo events in vivo. In multicellular organisms, reporter constructs demonstrating engineered long interspersed nuclear element (LINE-1; L1) mobilization have been in use for quite some time, and strategies similar to L1 retrotransposition reporter assays have been developed to report replication of Ty1 elements in yeast and mouse intracisternal A particle (IAP) long terminal repeat (LTR) retrotransposons in cultivated cells. We describe a novel approach termed cellular labeling of endogenous retrovirus replication (CLEVR), which reports replication of the gypsy element within specific cells in vivo in Drosophila. The gypsy-CLEVR reporter reveals gypsy replication both in cell culture and in individual neurons and glial cells of the aging adult fly. We also demonstrate that the gypsy-CLEVR replication rate is increased when the short interfering RNA (siRNA) silencing system is genetically disrupted. This CLEVR strategy makes use of universally conserved features of retroviruses and should be widely applicable to other LTR retrotransposons, endogenous retroviruses (ERVs), and exogenous retroviruses. [ABSTRACT FROM AUTHOR]

Rapid point-of-care resistance diagnostics (POC-RD) are a key tool in the fight against antibiotic resistance. By tailoring drug choice to infection genotype, doctors can improve treatment efficacy while limiting costs of inappropriate antibiotic prescription. Here, we combine epidemiological theory and data to assess the potential of resistance diagnostics (RD) innovations in a public health context, as a means to limit or even reverse selection for antibiotic resistance. POC-RD can be used to impose a nonbiological fitness cost on resistant strains by enabling diagnostic-informed treatment and targeted interventions that reduce resistant strains’ opportunities for transmission. We assess this diagnostic-imposed fitness cost in the context of a spectrum of bacterial population biologies and find that POC-RD have a greater potential against obligate pathogens than opportunistic pathogens already subject to selection under “bystander” antibiotic exposure during asymptomatic carriage (e.g., the pneumococcus). We close by generalizing the notion of RD-informed strategies to incorporate carriage surveillance information and illustrate that coupling transmission-control interventions to the discovery of resistant strains in carriage can potentially select against resistance in a broad range of opportunistic pathogens. [ABSTRACT FROM AUTHOR]

Centromeres are essential chromosomal regions that mediate kinetochore assembly and spindle attachments during cell division. Despite their functional conservation, centromeres are among the most rapidly evolving genomic regions and can shape karyotype evolution and speciation across taxa. Although significant progress has been made in identifying centromere-associated proteins, the highly repetitive centromeres of metazoans have been refractory to DNA sequencing and assembly, leaving large gaps in our understanding of their functional organization and evolution. Here, we identify the sequence composition and organization of the centromeres of Drosophila melanogaster by combining long-read sequencing, chromatin immunoprecipitation for the centromeric histone CENP-A, and high-resolution chromatin fiber imaging. Contrary to previous models that heralded satellite repeats as the major functional components, we demonstrate that functional centromeres form on islands of complex DNA sequences enriched in retroelements that are flanked by large arrays of satellite repeats. Each centromere displays distinct size and arrangement of its DNA elements but is similar in composition overall. We discover that a specific retroelement, G2/Jockey-3, is the most highly enriched sequence in CENP-A chromatin and is the only element shared among all centromeres. G2/Jockey-3 is also associated with CENP-A in the sister species D. simulans, revealing an unexpected conservation despite the reported turnover of centromeric satellite DNA. Our work reveals the DNA sequence identity of the active centromeres of a premier model organism and implicates retroelements as conserved features of centromeric DNA. [ABSTRACT FROM AUTHOR]

Malaria parasites possess the remarkable ability to maintain chronic infections that fail to elicit a protective immune response, characteristics that have stymied vaccine development and cause people living in endemic regions to remain at risk of malaria despite previous exposure to the disease. These traits stem from the tremendous antigenic diversity displayed by parasites circulating in the field. For Plasmodium falciparum, the most virulent of the human malaria parasites, this diversity is exemplified by the variant gene family called var, which encodes the major surface antigen displayed on infected red blood cells (RBCs). This gene family exhibits virtually limitless diversity when var gene repertoires from different parasite isolates are compared. Previous studies indicated that this remarkable genome plasticity results from extensive ectopic recombination between var genes during mitotic replication; however, the molecular mechanisms that direct this process to antigen-encoding loci while the rest of the genome remains relatively stable were not determined. Using targeted DNA double-strand breaks (DSBs) and long-read whole-genome sequencing, we show that a single break within an antigen-encoding region of the genome can result in a cascade of recombination events leading to the generation of multiple chimeric var genes, a process that can greatly accelerate the generation of diversity within this family. We also found that recombinations did not occur randomly, but rather high-probability, specific recombination products were observed repeatedly. These results provide a molecular basis for previously described structured rearrangements that drive diversification of this highly polymorphic gene family. [ABSTRACT FROM AUTHOR]

Intestinal intraepithelial lymphocytes (IELs) expressing CD8αα on αβ T cells (TCRαβ+CD8αα+ IELs) have suppressive capabilities in enterocolitis, but the mechanism that maintains homeostasis and cell number is not fully understood. Here, we demonstrated that the number of TCRαβ+CD8αα+ IELs was severely reduced in mice lacking recombination signal binding protein for immunoglobulin kappa J region (Rbpj) or Notch1 and Notch2 in T cells. Rbpj-deficient TCRαβ+CD8αα+ IELs expressed low levels of Atp8a2, which encodes a protein with flippase activity that regulates phospholipid asymmetry of plasma membrane such as flipping phosphatidylserine in the inner leaflet of plasma membrane. Rbpj-deficient TCRαβ+CD8αα+ IELs cannot maintain phosphatidylserine in the inner leaflet of the plasma membrane. Furthermore, depletion of intestinal macrophages restored TCRαβ+CD8αα+ IELs in Rbpj-deficient mice, suggesting that exposure of phosphatidylserine on the plasma membrane in Rbpj-deficient TCRαβ+CD8αα+ IELs acts as an “eat-me” signal. Together, these results revealed that Notch–Atp8a2 is a fundamental regulator for IELs and highlighted that membrane phospholipid asymmetry controlled by Notch-mediated flippase expression is a critical determinant in setting or balancing the number of TCRαβ+CD8αα+ IELs. [ABSTRACT FROM AUTHOR]

Schistosomes infect over 200 million people. The prodigious egg output of these parasites is the sole driver of pathology due to infection, yet our understanding of sexual reproduction by schistosomes is limited because normal egg production is not sustained for more than a few days in vitro. Here, we describe culture conditions that support schistosome sexual development and sustained egg production in vitro. Female schistosomes rely on continuous pairing with male worms to fuel the maturation of their reproductive organs. Exploiting these new culture conditions, we explore the process of male-stimulated female maturation and demonstrate that physical contact with a male worm, and not insemination, is sufficient to induce female development and the production of viable parthenogenetic haploid embryos. We further report the characterization of a nuclear receptor (NR), which we call Vitellogenic Factor 1 (VF1), that is essential for female sexual development following pairing with a male worm. Taken together, these results provide a platform to study the fascinating sexual biology of these parasites on a molecular level, illuminating new strategies to control schistosome egg production. [ABSTRACT FROM AUTHOR]

Lifelong infection of the gastric mucosa by Helicobacter pylori can lead to peptic ulcers and gastric cancer. However, how the bacteria maintain chronic colonization in the face of constant mucus and epithelial cell turnover in the stomach is unclear. Here, we present a new model of how H. pylori establish and persist in stomach, which involves the colonization of a specialized microenvironment, or microniche, deep in the gastric glands. Using quantitative three-dimensional (3D) confocal microscopy and passive CLARITY technique (PACT), which renders tissues optically transparent, we analyzed intact stomachs from mice infected with a mixture of isogenic, fluorescent H. pylori strains with unprecedented spatial resolution. We discovered that a small number of bacterial founders initially establish colonies deep in the gastric glands and then expand to colonize adjacent glands, forming clonal population islands that persist over time. Gland-associated populations do not intermix with free-swimming bacteria in the surface mucus, and they compete for space and prevent newcomers from establishing in the stomach. Furthermore, bacterial mutants deficient in gland colonization are outcompeted by wild-type (WT) bacteria. Finally, we found that host factors such as the age at infection and T-cell responses control bacterial density within the glands. Collectively, our results demonstrate that microniches in the gastric glands house a persistent H. pylori reservoir, which we propose replenishes the more transient bacterial populations in the superficial mucosa. [ABSTRACT FROM AUTHOR]

The movement towards open science is a consequence of seemingly pervasive failures to replicate previous research. This transition comes with great benefits but also significant challenges that are likely to affect those who carry out the research, usually early career researchers (ECRs). Here, we describe key benefits, including reputational gains, increased chances of publication, and a broader increase in the reliability of research. The increased chances of publication are supported by exploratory analyses indicating null findings are substantially more likely to be published via open registered reports in comparison to more conventional methods. These benefits are balanced by challenges that we have encountered and that involve increased costs in terms of flexibility, time, and issues with the current incentive structure, all of which seem to affect ECRs acutely. Although there are major obstacles to the early adoption of open science, overall open science practices should benefit both the ECR and improve the quality of research. We review 3 benefits and 3 challenges and provide suggestions from the perspective of ECRs for moving towards open science practices, which we believe scientists and institutions at all levels would do well to consider. [ABSTRACT FROM AUTHOR]

Perception likely results from the interplay between sensory information and top-down signals. In this electroencephalography (EEG) study, we utilised the hierarchical frequency tagging (HFT) method to examine how such integration is modulated by expectation and attention. Using intermodulation (IM) components as a measure of nonlinear signal integration, we show in three different experiments that both expectation and attention enhance integration between top-down and bottom-up signals. Based on a multispectral phase coherence (MSPC) measure, we present two direct physiological measures to demonstrate the distinct yet related mechanisms of expectation and attention, which would not have been possible using other amplitude-based measures. Our results link expectation to the modulation of descending signals and to the integration of top-down and bottom-up information at lower levels of the visual hierarchy. Meanwhile, the results link attention to the modulation of ascending signals and to the integration of information at higher levels of the visual hierarchy. These results are consistent with the predictive coding account of perception. [ABSTRACT FROM AUTHOR]

During the second World Summit of Human Gene Editing, Jiankui He presented the gene-editing project that led to the birth of two baby girls with man-made C-C chemokine receptor type 5 (CCR5) mutations. This extremely irresponsible behavior violated the ethical consensus of scientists all over the world. His presentation revealed a troubling lack not only of basic medical ethics but also of the requisite understanding of genetics and gene editing. Here, we review the rationale and design of his experiment along with the presented data, and provide our scientific criticism of this misconduct. [ABSTRACT FROM AUTHOR]

The need for replication of initial results has been rediscovered only recently in many fields of research. In preclinical biomedical research, it is common practice to conduct exact replications with the same sample sizes as those used in the initial experiments. Such replication attempts, however, have lower probability of replication than is generally appreciated. Indeed, in the common scenario of an effect just reaching statistical significance, the statistical power of the replication experiment assuming the same effect size is approximately 50%—in essence, a coin toss. Accordingly, we use the provocative analogy of “replicating” a neuroprotective drug animal study with a coin flip to highlight the need for larger sample sizes in replication experiments. Additionally, we provide detailed background for the probability of obtaining a significant p value in a replication experiment and discuss the variability of p values as well as pitfalls of simple binary significance testing in both initial preclinical experiments and replication studies with small sample sizes. We conclude that power analysis for determining the sample size for a replication study is obligatory within the currently dominant hypothesis testing framework. Moreover, publications should include effect size point estimates and corresponding measures of precision, e.g., confidence intervals, to allow readers to assess the magnitude and direction of reported effects and to potentially combine the results of initial and replication study later through Bayesian or meta-analytic approaches. [ABSTRACT FROM AUTHOR]

Our motor commands can be exquisitely timed according to the demands of the environment, and the ability to generate rhythms of different tempos is a hallmark of musical cognition. Yet, the neuronal underpinnings behind rhythmic tapping remain elusive. Here, we found that the activity of hundreds of primate medial premotor cortices (MPCs; pre-supplementary motor area [preSMA] and supplementary motor area [SMA]) neurons show a strong periodic pattern that becomes evident when their responses are projected into a state space using dimensionality reduction analysis. We show that different tapping tempos are encoded by circular trajectories that travelled at a constant speed but with different radii, and that this neuronal code is highly resilient to the number of participating neurons. Crucially, the changes in the amplitude of the oscillatory dynamics in neuronal state space are a signature of duration encoding during rhythmic timing, regardless of whether it is guided by an external metronome or is internally controlled and is not the result of repetitive motor commands. This dynamic state signal predicted the duration of the rhythmically produced intervals on a trial-by-trial basis. Furthermore, the increase in variability of the neural trajectories accounted for the scalar property, a hallmark feature of temporal processing across tasks and species. Finally, we found that the interval-dependent increments in the radius of periodic neural trajectories are the result of a larger number of neurons engaged in the production of longer intervals. Our results support the notion that rhythmic timing during tapping behaviors is encoded in the radial curvature of periodic MPC neural population trajectories. [ABSTRACT FROM AUTHOR]

To form a percept of the environment, the brain needs to solve the binding problem—inferring whether signals come from a common cause and are integrated or come from independent causes and are segregated. Behaviourally, humans solve this problem near-optimally as predicted by Bayesian causal inference; but the neural mechanisms remain unclear. Combining Bayesian modelling, electroencephalography (EEG), and multivariate decoding in an audiovisual spatial localisation task, we show that the brain accomplishes Bayesian causal inference by dynamically encoding multiple spatial estimates. Initially, auditory and visual signal locations are estimated independently; next, an estimate is formed that combines information from vision and audition. Yet, it is only from 200 ms onwards that the brain integrates audiovisual signals weighted by their bottom-up sensory reliabilities and top-down task relevance into spatial priority maps that guide behavioural responses. As predicted by Bayesian causal inference, these spatial priority maps take into account the brain’s uncertainty about the world’s causal structure and flexibly arbitrate between sensory integration and segregation. The dynamic evolution of perceptual estimates thus reflects the hierarchical nature of Bayesian causal inference, a statistical computation, which is crucial for effective interactions with the environment. [ABSTRACT FROM AUTHOR]

The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3− efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output. [ABSTRACT FROM AUTHOR]

In experimental evolution, scientists evolve organisms in the lab, typically by challenging them to new environmental conditions. How best to evolve a desired trait? Should the challenge be applied abruptly, gradually, periodically, sporadically? Should one apply chemical mutagenesis, and do strains with high innate mutation rate evolve faster? What are ideal population sizes of evolving populations? There are endless strategies, beyond those that can be exposed by individual labs. We therefore arranged a community challenge, Evolthon, in which students and scientists from different labs were asked to evolve Escherichia coli or Saccharomyces cerevisiae for an abiotic stress—low temperature. About 30 participants from around the world explored diverse environmental and genetic regimes of evolution. After a period of evolution in each lab, all strains of each species were competed with one another. In yeast, the most successful strategies were those that used mating, underscoring the importance of sex in evolution. In bacteria, the fittest strain used a strategy based on exploration of different mutation rates. Different strategies displayed variable levels of performance and stability across additional challenges and conditions. This study therefore uncovers principles of effective experimental evolutionary regimens and might prove useful also for biotechnological developments of new strains and for understanding natural strategies in evolutionary arms races between species. Evolthon constitutes a model for community-based scientific exploration that encourages creativity and cooperation. [ABSTRACT FROM AUTHOR]

Periodic patterning represents a fundamental process in tissue morphogenesis. In chicken dorsal skin, feather formation starts from the midline; then the morphogenetic wave propagates bilaterally, leaving a regular hexagonal array of feather germs. Yet, in vitro reconstitution showed feather germs appear simultaneously, leading to the hypothesis that the feather-forming wave results from the coupling of local Turing patterning processes with an unidentified global event. In this issue, Ho and colleagues showed such a global event in chicken feathers involves a spreading Ectodysplasin A (EDA) wave and Fibroblast Growth Factor 20 (FGF20)-cell aggregate-based mechanochemical coupling. In flightless birds, feather germs form periodically but without precise hexagonal patterning due to the lack of global wave. [ABSTRACT FROM AUTHOR]