title: Altered basal lipid metabolism underlies the functional impairment of naive CD8+ T cells in elderly humans

abstract:
BackgroundAging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear.

MethodsBiochemical and functional properties of naive CD8+ T cells were characterized and compared between middle aged and older individuals.

FindingsWe identified an age-related link between altered basal lipid metabolism in naive CD8+ T cells and their impaired responsiveness to stimulation, characterized by low proliferative potential and susceptibility to apoptosis. Reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, improved the functional capabilities of naive CD8+ T cells in elderly subjects.

InterpretationInterventions that favor lipid catabolism may find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens or tumors.

FundingA full list of the funding sources is detailed in the Acknowledgment section of the manuscript.

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSOld subjects are highly susceptible to infections and tumors and usually present with low responses to vaccine. This is mainly due to the age-related loss of primary immune resources, i.e. a quantitative decline of naive CD8+ T cells. Nonetheless, few studies have also underlined, within this cell subset, qualitative defects in elderly subjects.

Added value of this studyConsidering the well-demonstrated link between nutrient usage and lymphocyte functions, we characterized the bioenergetics features of old naive CD8+ T cells. Our data show an age-dependent altered basal metabolism in this cell subset, mostly at the levels of fatty acids and mitochondrial functions. These alterations were associated with functional defects which were partially reverted through the use of lipid-lowering strategies.

Implications of all the available evidenceThis study highlights the potential role of an altered cellular lipid metabolism in immunosenescence, providing clues to understand the epidemiological profile of emerging infections or tumors and to develop preventive and therapeutic strategies based on metabolic manipulation.


title: Sequence dependence of biomolecular phase separation

abstract: Cells are home to a wide variety of biomolecular condensates - phase-separated droplets that lack a membrane. In addition to nonspecific interactions, phase separation depends on specific binding motifs between constituent molecules. Nevertheless, few rules have been established on how these specific, heterotypic interactions drive phase separation. Using lattice-polymer simulations and mean-field theory, we show that the sequence of binding motifs strongly affects a polymers ability to phase separate, influencing both phase boundaries and condensate properties (e.g. viscosity and polymer diffusion). We find that sequences with large blocks of a single motif typically form more inter-polymer bonds which promote phase separation. Notably, the sequence of binding motifs influences phase separation primarily by determining the conformational entropy of self-bonding by single polymers. This contrasts with systems where the molecular architecture primarily affects the energy of the dense phase, providing a new entropy-based mechanism for the biological control of phase separation.

category: biophysics


title: Performance of a phylogenetic independent contrast method and an improved pairwise comparison under different scenarios of trait evolution after speciation and duplication

abstract:
O_LIDespite the importance of gene function to evolutionary biology, the applicability of comparative methods to gene function is poorly known. A specific case which has crystalized methodological questions is the "ortholog conjecture", the hypothesis that function evolves faster after duplication (i.e., in paralogs), and conversely is conserved between orthologs. Since the mode of functional evolution after duplication is not well known, we investigate under which reasonable evolutionary scenarios phylogenetic independent contrasts or pairwise comparisons can recover a putative signal of different functional evolution between orthologs and paralogs.
C_LIO_LIWe investigate three different simulation models, which represent reasonable but simplified hypotheses about the evolution of a gene function trait. These are time dependent trait acceleration, correlated changes in rates of both sequence and trait evolution, and asymmetric trait jump. For each model we tested phylogenetic independent contrasts and an improved pairwise comparison method which accounts for interactions between events and node age.
C_LIO_LIBoth approaches lose power to detect the trend of functional evolution when the functional trait accelerates for a long time following duplication for trees with many duplications, with better power of phylogenetic contrasts under intermediate scenarios. Concomitant increase in evolutionary rates of sequence and of trait after duplication can lead to both an incorrect rejection of the null under null simulations of trait evolution, and a false rejection of the ortholog conjecture under ortholog conjecture simulations, by phylogenetic independent contrasts. Improved pairwise comparisons are robust to this bias. Both approaches perform equally well under rapid shifts in traits.
C_LIO_LIConsidering our ignorance of gene function evolution, and the potential for bias under simple models, we recommend methodological pluralism in studying gene family evolution. Functional phylogenomics is complex and results supported by only one method should be treated with caution.
C_LI

category: evolutionary biology


title: Rapid behavioural response of urban birds to COVID-19 lockdown

abstract: Biodiversity is threatened by the growth of urban areas. However, it is still poorly understood how animals can cope with and adapt to these rapid and dramatic transformations of natural environments. The COVID-19 pandemic provides us with a unique opportunity to unveil the mechanisms involved in this process. Lockdown measures imposed in most countries are causing an unprecedented reduction of human activities giving us an experimental setting to assess the effects of our lifestyle on biodiversity. We studied the birds response to the population lockdown by using more than 126,000 bird records collected by a citizen science project in north eastern Spain. We compared the occurrence and detectability of birds during the spring 2020 lockdown with baseline data from previous years in the same urban areas and dates. We found that birds did not increase their probability of occurrence in urban areas during the lockdown, refuting the hypothesis that nature has recovered its space in human emptied urban areas. However, we found an increase in bird detectability, especially during early morning, suggesting a rapid change in the birds daily routines in response to quieter and less crowded cities. In conclusion, urban birds showed high behavioural plasticity to rapidly adjust to novel environmental conditions, as those imposed by the COVID-19.

category: ecology


title: Adaptive and maladaptive expression plasticity underlying herbicide resistance in an agricultural weed.

abstract:
Plastic phenotypic responses to environmental change are common, yet we lack a clear understanding of the fitness consequences of these plastic responses. Here, we use the evolution of herbicide resistance in the common morning glory (Ipomoea purpurea) as a model for understanding the relative importance of adaptive and maladaptive gene expression responses to herbicide. Specifically, we compare leaf gene expression changes caused by herbicide to the expression changes that evolve in response to artificial selection for herbicide resistance. We identify a number of genes that show plastic and evolved responses to herbicide and find that for the majority of genes with both plastic and evolved responses, plastic responses appear to be adaptive. We also find that selection for herbicide response increases gene expression plasticity. Overall, these results show the importance of adaptive plasticity for herbicide resistance in a common weed and that expression changes in response to strong environmental change can be adaptive.

Impact statementPredicting whether and how organisms will adapt to environmental change is a crucial goal. However, this goal can be complicated because environmental change can alter traits, in a process called plasticity. The extent and fitness consequences of plasticity will have important effects on the adaptive process. In this study, we use adaptation to herbicide in the agricultural weed, the common morning glory, as a model for understanding the extent and fitness consequences of plasticity in gene expression. We find evidence that gene expression plasticity is adaptive in the presence of herbicide, suggesting that understanding plasticity is crucial for understanding how organisms adapt to new environments.


title: The Origin of Conductive-Pulse Sensing Inside a Nanopore and the Role of Electro-Hydrodynamics

abstract: Nanopore sensing is nearly synonymous with resistive pulse sensing due to the characteristic reduction of ionic flux during molecular occupancy of a pore, particularly at high salt concentrations. However, conductive pulses are widely reported at low salt conditions wherein electroosmotic flow can be quite significant. Aside from transporting molecules like DNA, we investigated whether electroosmotic flow has other potential impacts on sensing attributes such current enhancements due to the analyte molecule. The overwhelming majority of literature reports counterions as the dominant mechanism of conductive events (a moleculecentric theory for conductive events). Conductive events are not well understood due to the complex interplay between (charged) nanopore walls, DNA grooves, ion mobility, and counterion clouds. Yet, the prevailing consensus of counterions being introduced into the pore by the molecule does not fit well with a growing number of experiments including the fact that proteins can generate conductive events despite having a heterogeneous surface charge. Herein, we demonstrate theory and experiments underpinning the translocation mechanism (i.e., electroosmosis or electrophoresis), pulse direction (i.e., conductive or resistive) and shape (e.g., monophasic or biphasic) through fine control of chemical, physical, and electronic parameters. Results from these studies predict strong electroosmosis plays a role in driving DNA events and generating conductive events due to polarization effects (i.e. a pore-centric theory). We believe these findings will stimulate a useful discussion on the nature of conductive events and their impact on molecular sensing in nanoscale pores.


title: Processing of novel food reveal payoff and rank-biased social learning in a wild primate

abstract: Social learning - learning from others - is the basis for behavioural traditions. Different social learning strategies (SLS), where individuals biasedly learn behaviours based on their content or who demonstrates them, may increase an individuals fitness and generate behavioural traditions. While SLS have been mostly studied in isolation, their interaction and the interplay between individual and social learning is less understood. We performed a field-based open diffusion experiment in a wild primate. We provided two groups of vervet monkeys with a novel food, unshelled peanuts, and documented how three different peanut opening techniques spread within the groups. We analysed data using hierarchical Bayesian dynamic learning models that explore the integration of multiple SLS with individual learning. We i) report evidence of social learning compared to strictly individual learning, ii) show that vervets preferentially socially learn the technique that yields the highest observed payoff and iii) also bias attention toward individuals of higher rank. This shows that behavioural preferences can arise when individuals integrate social information about the efficiency of a behaviour alongside cues related to the rank of a demonstrator. When these preferences converge to the same behaviour in a group, they may result in stable behavioural traditions.

category: animal behavior and cognition


title: Slit2 is necessary for optic axon organization in the zebrafish ventral midline

abstract: Slit-Robo signaling has been implicated in regulating several steps of retinal ganglion cell axon guidance, with a central role assigned to Slit2. We report here the phenotypical characterization of a CRISPR-Cas9-generated zebrafish null mutant for this gene, along with a detailed analysis of its expression pattern by WM-FISH. All evident defects in the optic axons in slit2-/- mutants were detected outside the retina, coincident with the major sites of expression at the ventral forebrain, around the developing optic nerve and anterior to the optic chiasm/proximal tract. Anterograde axon tracing experiments in zygotic and maternal-zygotic mutants, as well as morphants, showed the occurrence of axon sorting defects, which appeared mild at the optic nerve level, but more severe in the optic chiasm and the proximal tract. A remarkable sorting defect was the usual splitting of one of the optic nerves in two branches that surrounded the contralateral nerve at the chiasm. Although all axons eventually crossed the midline, the retinotopic order appeared lost at the proximal optic tract, to eventually correct distally. Time-lapse analysis demonstrated the sporadic occurrence of axon misrouting at the chiasm level, which could be responsible for the sorting errors. Our results support previous evidence of a channeling role for Slit molecules in retinal ganglion cell axons at the optic nerve, in addition to a function in the segregation of axons coming from each nerve and from different retinal regions at the medio-ventral area of the forebrain.

category: developmental biology


title: FisB relies on homo-oligomerization and lipid-binding to catalyze membrane fission in bacteria

abstract: Little is known about mechanisms of membrane fission in bacteria despite their requirement for cytokinesis. The only known dedicated membrane fission machinery in bacteria, FisB, is expressed during sporulation in Bacillus subtilis and is required to release the developing spore into the mother cell cytoplasm. Here we characterized the requirements for FisB-mediated membrane fission. FisB forms mobile clusters of [~]12 molecules that give way to an immobile cluster at the engulfment pole containing [~]40 proteins at the time of membrane fission. Analysis of FisB mutants revealed that binding to acidic lipids and homo-oligomerization are both critical for targeting FisB to the engulfment pole and membrane fission. Experiments using artificial membranes and filamentous cells suggest FisB does not have an intrinsic ability to sense or induce membrane curvature but can bridge membranes. Finally, modeling suggests homo-oligomerization and trans interactions with membranes are sufficient to explain FisB accumulation at the membrane neck that connects the engulfment membrane to the rest of the mother cell membrane during late stages of engulfment. Together, our results show that FisB is a robust and unusual membrane fission protein that relies on homo-oligomerization, lipid-binding and the unique membrane topology generated during engulfment for localization and membrane scission, but surprisingly, not on lipid microdomains, negative-curvature lipids, or curvature-sensing.


title: Apoptosis is not conserved in plants as revealed by critical examination of a model for plant apoptosis-like cell death

abstract:
BackgroundAnimals and plants diverged over one billion years ago and evolved unique mechanisms for many cellular processes, including cell death. One of the most well-studied cell-death programmes in animals, apoptosis, involves gradual cell dismantling and engulfment of cellular fragments, apoptotic bodies, through phagocytosis. However, rigid cell walls prevent plant cell fragmentation and thus apoptosis is not applicable for executing cell death in plants. Furthermore, plants are devoid of the key components of apoptotic machinery, including phagocytosis as well as caspases and Bcl-2 family proteins. Nevertheless, the concept of plant "apoptosis-like programmed cell death" (AL-PCD) is widespread. This is largely due to superficial morphological resemblances between plant cell death and apoptosis; in particular between protoplast shrinkage in plant cells killed by various stimuli and animal cell volume decrease preceding fragmentation into apoptotic bodies.

ResultsHere, we provide a comprehensive spatio-temporal analysis of cytological and biochemical events occurring in plant cells subjected to heat shock at 40-55{degrees}C and 85{degrees}C, the experimental conditions typically used to trigger AL-PCD and necrotic cell death, respectively. We show that cell death under both conditions was not accompanied by membrane blebbing or formation of apoptotic bodies, as would be expected during apoptosis. Instead, we observed instant and irreversible permeabilization of the plasma membrane and ATP depletion. These processes did not depend on mitochondrial functionality or the presence of Ca2+ and could not be prevented by an inhibitor of ferroptosis. We further reveal that the lack of protoplast shrinkage at 85{degrees}C, the only striking morphological difference between cell deaths induced by 40-55{degrees}C or 85{degrees}C heat shock, is a consequence of the fixative effect of the high temperature on intracellular contents.

ConclusionsWe conclude that heat shock-induced cell death is an energy-independent process best matching definition of necrosis. Although the initial steps of this necrotic cell death could be genetically regulated, classifying it as apoptosis or AL-PCD is a terminological misnomer. Our work supports the viewpoint that apoptosis is not conserved across animal and plant kingdoms and demonstrates the importance of focusing on plant-specific aspects of cell death pathways.

category: plant biology


title: Adaptation to recent outcomes attenuates the lasting effect of initial experience on risky decisions

abstract: Both primarily and recently encountered information have been shown to influence experience-based risky decision making. The primacy effect predicts that initial experience will influence later choices even if outcome probabilities change and reward is ultimately more or less sparse than primarily experienced. However, it has not been investigated whether extended initial experience would induce a more profound primacy effect upon risky choices than brief experience. Therefore, the present study tested in two experiments whether young adults adjusted their risk-taking behavior in the Balloon Analogue Risk task after an unsignaled and unexpected change point. The change point separated early "good luck" or "bad luck" trials from subsequent ones. While mostly positive (more reward) or mostly negative (no reward) events characterized the early trials, subsequent trials were unbiased. In Experiment 1, the change point occurred after one-sixth or one-third of the trials (brief vs. extended experience) without intermittence, whereas in Experiment 2, it occurred between separate task phases. In Experiment 1, if negative events characterized the early trials, after the change point, risk-taking behavior increased as compared with the early trials. Conversely, if positive events characterized the early trials, risk-taking behavior decreased after the change point. Although the adjustment of risk-taking behavior occurred due to integrating recent experiences, the impact of initial experience was simultaneously observed. The length of initial experience did not reliably influence the adjustment of behavior. In Experiment 2, participants became more prone to take risks as the task progressed, indicating that the impact of initial experience could be overcome. Altogether, we suggest that initial beliefs about outcome probabilities can be updated by recent experiences to adapt to the continuously changing decision environment.

category: neuroscience


title: Evolution of the canonical sex chromosomes of the guppy and its relatives

abstract: The sex chromosomes of the guppy, Poecilia reticulata, and its close relatives are of particular interest: they are much younger than the highly degenerate sex chromosomes of model systems such as mammals and Drosophila melanogaster, and they carry many of the genes responsible for the males dramatic coloration. Over the last decade, several studies have analyzed these sex chromosomes using a variety of approaches including sequencing genomes and transcriptomes, cytology, and linkage mapping. Conflicting conclusions have emerged, in particular concerning the history of the sex chromosomes and the evolution of suppressed recombination between the X and Y. Here we address these controversies by reviewing the evidence and reanalyzing data. We find no support for a nonrecombining sex determining region (SDR) or evolutionary strata in P. reticulata. Further, we find that the evidence most strongly support the hypothesis that the SDRs of P. picta and P. wingei evolved independently after those lineages diverged. We identify possible causes of conflicting results in previous studies and suggest best practices going forward.

category: genomics


title: Whole Genome Variation of Transposable Element Insertions in a Maize Diversity Panel

abstract: Intact transposable elements (TEs) account for 65% of the maize genome and can impact gene function and regulation. Although TEs comprise the majority of the maize genome and affect important phenotypes, genome wide patterns of TE polymorphisms in maize have only been studied in a handful of maize genotypes, due to the challenging nature of assessing highly repetitive sequences. We implemented a method to use short read sequencing data from 509 diverse inbred lines to classify the presence/absence of 445,418 non-redundant TEs that were previously annotated in four genome assemblies including B73, Mo17, PH207, and W22. Different orders of TEs (i.e. LTRs, Helitrons, TIRs) had different frequency distributions within the population. LTRs with lower LTR similarity were generally more frequent in the population than LTRs with higher LTR similarity, though high frequency insertions with very high LTR similarity were observed. LTR similarity and frequency estimates of nested elements and the outer elements in which they insert revealed that most nesting events occurred very near the timing of the outer element insertion. TEs within genes were at higher frequency than those that were outside of genes and this is particularly true for those not inserted into introns. Many TE insertional polymorphisms observed in this population were tagged by SNP markers. However, there were also 19.9% of the TE polymorphisms that were not well tagged by SNPs (R2 < 0.5) that potentially represent information that has not been well captured in previous SNP based marker-trait association studies. This study provides a population scale genome-wide assessment of TE variation in maize, and provides valuable insight on variation in TEs in maize and factors that contribute to this variation.


title: Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis

abstract: Mechanical stimuli such as stretch and resistance training are essential to regulate growth and function of skeletal muscle. However, the molecular mechanisms involved in sensing mechanical stress during muscle formation remain unclear. Here, we investigate the role of the mechano-sensitive ion channel Piezo1 during myogenic progression. Direct manipulation of Piezo1 in muscle stem cells alters their myogenic progression. Indeed, Piezo1 knockdown suppresses myoblast fusion leading to smaller myotubes. Such event is accompanied by significant downregulation of the fusogenic protein Myomaker. In parallel, while Piezo1 knockdown also lowers Ca2+ influx in response to stretch, Piezo1 activation increases Ca2+ influx in response to stretch and enhances myoblasts fusion. We believe these findings may help understand molecular defects present in some muscle diseases. Altogether our study shows that Piezo1 is essential for terminal muscle differentiation acting on myoblast fusion, suggesting that Piezo1 deregulation may have implications in muscle aging and degenerative diseases including muscular dystrophies.

category: molecular biology


title: Predictive Maps in Rats and Humans for Spatial Navigation

abstract: Much of our understanding of navigation comes from the study of individual species, often with specific tasks tailored to those species. Here, we provide a novel experimental and analytic framework, integrating across humans, rats and simulated reinforcement learning (RL) agents to interrogate the dynamics of behaviour during spatial navigation. We developed a novel open-field navigation task ( Tartarus Maze) requiring dynamic adaptation (shortcuts and detours) to frequently changing obstructions in the path to a hidden goal. Humans and rats were remarkably similar in their trajectories. Both species showed the greatest similarity to RL agents utilising a  successor representation, which creates a predictive map. Humans also displayed trajectory features similar to model-based RL agents, which implemented an optimal tree-search planning procedure. Our results help refine models seeking to explain mammalian navigation in dynamic environments, and highlight the utility of modelling the behaviour of different species to uncover the shared mechanisms that support behaviour.


title: Completion of the gut microbial epi-bile acid pathway

abstract: Bile acids are detergent molecules that solubilize dietary lipids and lipid-soluble vitamins. Humans synthesize bile acids with -orientation hydroxyl groups which can be biotransformed by gut microbiota to toxic, hydrophobic bile acids, such as deoxycholic acid (DCA). Gut microbiota can also convert hydroxyl groups from the -orientation through an oxo-intermediate to the {beta}-orientation, resulting in more hydrophilic, less toxic bile acids. This interconversion is catalyzed by regio-(C-3 vs. C-7) and stereospecific ( vs. {beta}) hydroxysteroid dehydrogenases (HSDHs). So far, genes encoding the urso-(7-HSDH & 7{beta}-HSDH) and iso-(3-HSDH & 3{beta}-HSDH) bile acid pathways have been described. Recently, multiple human gut clostridia were reported to encode 12-HSDH, which interconverts DCA and 12-oxolithocholic acid (12-oxoLCA). 12{beta}-HSDH completes the epi-bile acid pathway by converting 12-oxoLCA to the 12{beta}-bile acid denoted epiDCA; however, gene(s) encoding this enzyme have yet to be identified. We confirmed 12{beta}-HSDH activity in cultures of Clostridium paraputrificum ATCC 25780. From six candidate C. paraputrificum ATCC 25780 oxidoreductase genes, we discovered the first gene (DR024_RS09610) encoding bile acid 12{beta}-HSDH. Phylogenetic analysis revealed unforeseen diversity for 12{beta}-HSDH, leading to validation of two additional bile acid 12{beta}-HSDHs through a synthetic biology approach. By comparison to a previous phylogenetic analysis of 12-HSDH, we identified the first potential C-12 epimerizing strains: Collinsella tanakaei YIT 12063 and Collinsella stercoris DSM 13279. A Hidden Markov Model search against human gut metagenomes located putative 12{beta}-HSDH genes in about 30% of subjects within the cohorts analyzed, indicating this gene is relevant in the human gut microbiome.

category: microbiology


title: Inferring the Total-Evidence Timescale of Marattialean Fern Evolution in the Face of Model Sensitivity

abstract: Phylogenetic divergence-time estimation has been revolutionized by two recent developments: 1) total-evidence dating (or "tip-dating") approaches that allow for the incorporation of fossils as tips in the analysis, with their phylogenetic and temporal relationships to the extant taxa inferred from the data, and 2) the fossilized birth-death (FBD) class of tree models that capture the processes that produce the tree (speciation, extinction, and fossilization), and thus provide a coherent and biologically interpretable tree prior. To explore the behaviour of these methods, we apply them to marattialean ferns, a group that was dominant in Carboniferous landscapes prior to declining to its modest extant diversity of slightly over 100 species. We show that tree models have a dramatic influence on estimates of both divergence times and topological relationships. This influence is driven by the strong, counter-intuitive informativeness of the uniform tree prior and the inherent nonidentifiability of divergence-time models. In contrast to the strong influence of the tree models, we find minor effects of differing the morphological transition model or the morphological clock model. We compare the performance of a large pool of candidate models using a combination of posterior-predictive simulation and Bayes factors. Notably, an FBD model with epoch-specific speciation and extinction rates was strongly favored by Bayes factors. Our best-fitting model infers stem and crown divergences for the Marattiales in the mid-Devonian and Late Cretaceous, respectively, with elevated speciation rates in the Mississippian and elevated extinction rates in the Cisuralian leading to a peak diversity of [~]2800 species at the end of the Carboniferous, representing the heyday of the Psaroniaceae. This peak is followed by the rapid decline and ultimate extinction of the Psaroniaceae, with their descendants, the Marattiaceae, persisting at approximately stable levels of diversity until the present. This general diversification pattern appears to be insensitive to potential biases in the fossil record; despite the preponderance of available fossils being from Pennsylvanian coal balls, incorporating fossilization-rate variation does not improve model fit. In addition, by incorporating temporal data directly within the model and allowing for the inference of the phylogenetic position of the fossils, our study makes the surprising inference that the clade of extant Marattiales is relatively young, younger than any of the fossils historically thought to be congeneric with extant species. This result is a dramatic demonstration of the dangers of node-based approaches to divergence-time estimation, where the assignment of fossils to particular clades are made a priori (earlier node-based studies that constrained the minimum ages of extant genera based on these fossils resulted in much older age estimates than in our study) and of the utility of explicit models of morphological evolution and lineage diversification.


title: Lyl-1 regulates primitive macrophages and microglia development

abstract:
During ontogeny, macrophages (M{Phi}) populations emerge in the Yolk Sac (YS) via two distinct progenitor waves, prior to hematopoietic stem cell development. M{Phi}-progenitors from the primitive/"early EMP" and transient-definitive/"late EMP" waves both contribute to various resident-M{Phi} populations in the developing embryonic organs. Identifying factors that modulates early stages of M{Phi}-progenitor development may lead to a better understanding of defective function of specific resident-M{Phi} subsets.

Here we show that primitive macrophage (M{Phi}Prim) progenitors in the YS express Lyl-1, a bHLH transcription factor related to SCL/Tal-1. Transcriptomic analysis of YS M{Phi}-progenitors indicated that M{Phi}Prim progenitors present at embryonic day (E) 9 are clearly distinct from those present at later stages. Disruption of Lyl-1 basic helix-loop-helix domain led initially to an early increased emergence of M{Phi}Prim progenitors, and later to their defective differentiation. These defects were associated with a disrupted expression of gene sets related to embryonic patterning and neurodevelopment. Lyl-1-deficiency also induced a reduced production of mature M{Phi}/microglia in the early brain, as well as a transient reduction of the microglia pool at midgestation and in the newborn.

We thus identify Lyl-1 as a critical regulator of M{Phi}Prim and microglia development, which disruption may impair resident-M{Phi} function during organogenesis.

Key points1- Yolk sac primitive macrophage progenitors and microglia/Border Associated macrophages express Lyl-1.

2- Lyl-1-deficiency impairs primitive macrophage and microglia development and leads to the up-regulation of gene sets related to embryo patterning and neuro-development.


title: Neurons learn by predicting future activity.

abstract: Understanding how the brain learns may lead to machines with human-like intellectual capacities. However, learning mechanisms in the brain are still not well understood. Here we demonstrate that the ability of a neuron to predict its future activity may provide an effective mechanism for learning in the brain. We show that comparing a neurons predicted activity with the actual activity provides a useful learning signal for modifying synaptic weights. Interestingly, this predictive learning rule can be derived from a metabolic principle, where neurons need to minimize their own synaptic activity (cost), while maximizing their impact on local blood supply by recruiting other neurons. This reveals an unexpected connection that learning in neural networks could result from simply maximizing the energy balance by each neuron. We show how this mathematically derived learning rule can provide a theoretical connection between diverse types of brain-inspired algorithms, such as: Hebbs rule, BCM theory, temporal difference learning and predictive coding. Thus, this may offer a step toward development of a general theory of neuronal learning. We validated this predictive learning rule in neural network simulations and in data recorded from awake animals. We found that in the sensory cortex it is indeed possible to predict a neurons activity [~]10-20ms into the future. Moreover, in response to stimuli, cortical neurons changed their firing rate to minimize surprise: i.e. the difference between actual and expected activity, as predicted by our model. Our results also suggest that spontaneous brain activity provides "training data" for neurons to learn to predict cortical dynamics. Thus, this work demonstrates that the ability of a neuron to predict its future inputs could be an important missing element to understand computation in the brain.


title: Context-Dependent Relationships between Locus Coeruleus Firing Patterns and Coordinated Neural Activity in the Anterior Cingulate Cortex

abstract: Ascending neuromodulatory projections from the locus coeruleus (LC) affect cortical neural networks via the release of norepinephrine (NE). However, the exact nature of these neuromodulatory effects on neural activity patterns in vivo is not well understood. Here we show that in awake monkeys, LC activation is associated with changes in coordinated activity patterns in the anterior cingulate cortex (ACC). These relationships, which are largely independent of changes in firing rates of individual ACC neurons, depend on the type of LC activation: ACC pairwise correlations tend to be reduced when ongoing (baseline) LC activity increases but enhanced when external events evoke transient LC responses. Both relationships covary with pupil changes that reflect LC activation and arousal. These results suggest that modulations of information processing that reflect changes in coordinated activity patterns in cortical networks can result partly from ongoing, context-dependent, arousal-related changes in activation of the LC-NE system.


title: Explaining distortions in metacognition with an attractor network model of decision uncertainty

abstract:
Metacognition is the ability to reflect on, and evaluate, our cognition and behaviour. Distortions in metacognition are common in mental health disorders, though the neural underpinnings of such dysfunction are unknown. One reason for this is that models of key components of metacognition, such as decision confidence, are generally specified at an algorithmic or process level. While such models can be used to relate brain function to psychopathology, they are difficult to map to a neurobiological mechanism. Here, we develop a biologically-plausible model of decision uncertainty in an attempt to bridge this gap. We first relate the models uncertainty in perceptual decisions to standard metrics of metacognition, namely mean confidence level (bias) and the accuracy of metacognitive judgments (sensitivity). We show that dissociable shifts in metacognition are associated with isolated disturbances at higher-order levels of a circuit associated with self-monitoring, akin to neuropsychological findings that highlight the detrimental effect of prefrontal brain lesions on metacognitive performance. Notably, we are able to account for empirical confidence judgements by fitting the parameters of our biophysical model to first-order performance data, specifically choice and response times. Lastly, in a reanalysis of existing data we show that self-reported mental health symptoms relate to disturbances in an uncertainty-monitoring component of the network. By bridging a gap between a biologically-plausible model of confidence formation and observed disturbances of metacognition in mental health disorders we provide a first step towards mapping theoretical constructs of metacognition onto dynamical models of decision uncertainty. In doing so, we provide a computational framework for modelling metacognitive performance in settings where access to explicit confidence reports is not possible.

Author SummaryIn this work, we use a biologically-plausible model of decision uncertainty to show that shifts in metacognition are associated with disturbances in the interaction between decision-making and higher-order uncertainty-monitoring networks. Specifically, we show that stronger uncertainty modulation is associated with decreased metacognitive bias, sensitivity, and efficiency, with no effect on perceptual sensitivity. Our approach not only enables inferences about uncertainty modulation (and, in turn, these facets of metacognition) from fits to first-order performance data alone - but also provides a first step towards relating dynamical models of decision-making to metacognition. We also relate our models uncertainty modulation to psychopathology, and show that it can offer an implicit, low-dimensional marker of metacognitive (dys)function - opening the door to richer analysis of the interaction between metacognitive performance and psychopathology from first-order performance data.


title: Road to ruin? Urbanization increases herbivory in a tropical wildflower but does not lead to the evolution of chemical defence traits.

abstract: Urbanization is associated with numerous changes to the biotic and abiotic environment, many of which degrade the environment and lead to a loss of biodiversity. Cities often have elevated pollution levels that harm wildlife; however, the increased concentration of some pollutants can fertilize urban plants, leading to corresponding positive effects on herbivore populations. Increases in herbivory rates may lead to natural selection for greater defence phenotypes in plants. However, evidence supporting increased herbivory leading to the evolution of plant defence in urban environments is contradictory, and entirely absent from tropical regions of the world. To address these research gaps, we evaluated herbivory on Turnera subulata, a common urban wildflower, along an urbanization gradient in Joao Pessoa, Brazil. We predicted that higher rates of herbivory in urban areas would lead these populations to evolve cyanogenesis, a chemical defence found in a closely related Turnera species. We assessed herbivory and screened for cyanogenesis in 32 populations along the urbanization gradient, quantified by the Human Footprint Index. Our results show that urbanization is significantly associated with increased herbivory rates in T. subulata populations. Despite elevated herbivory, we found no evidence for the evolution of cyanongenesis in any of the populations, suggesting that the fitness effects of leaf herbivory are not extreme enough to select for the evolution of plant defence in these populations. Habitat loss, predator release, and nutrient enrichment likely act together to increase the abundance of herbivorous arthropods, influencing the herbivory patterns observed in our study.


title: Estimating Multiple Latencies in the Auditory System from Auditory Steady-State Responses on a Single EEG Channel

abstract: The latency of the auditory steady-state response (ASSR) may provide valuable information regarding the integrity of the auditory system, as it could potentially reveal the presence of multiple intracerebral sources. To estimate multiple latencies from high-order ASSRs, we propose a novel two-stage procedure that consists of a nonparametric estimation method, called apparent latency from phase coherence (ALPC), followed by a heuristic sequential forward selection algorithm (SFS). Compared with existing methods, ALPC-SFS requires few prior assumptions, and is straightforward to implement for higher-order nonlinear responses to multi-cosine sound complexes with their initial phases set to zero. It systematically evaluates the nonlinear components of the ASSRs by estimating multiple latencies, automatically identifies involved ASSR components, and reports a latency consistency index (LCI). To verify the proposed method, we performed simulations for several scenarios: two nonlinear subsystems with different or overlapping outputs. We compared the results from our method with predictions from existing, parametric methods. We also recorded the EEG from ten normal-hearing adults by bilaterally presenting superimposed tones with four frequencies that evoke a unique set of ASSRs. From these ASSRs, two major latencies were found to be stable across subjects on repeated measurement days. The two latencies are dominated by low-frequency (LF) (near 40 Hz, at around 41-52 ms) and high-frequency (HF) (>80 Hz, at around 21-27 ms) ASSR components. The frontal-central (FC) brain region showed longer latencies on LF components, but shorter latencies on HF components, when compared with temporal-lobe regions. In conclusion, the proposed nonparametric ALPC-SFS method, applied to zero-phase, multi-cosine sound complexes is more suitable for evaluating embedded nonlinear systems underlying ASSRs than existing methods. It may therefore be a promising objective measure for hearing performance and auditory cortex (dys)function. The Matlab scripts for the ALPC-SFS method is available here: https://github.com/ieeeWang/ALPC-SFS-method-Matlab-scripts.


title: A cis-regulatory atlas in maize at single-cell resolution

abstract: Cis-regulatory elements (CREs) encode the genomic blueprints of spatiotemporal gene expression programs enabling highly specialized cell functions. To identify CREs at cell-type resolution in Zea mays, we implemented single-cell sequencing of Assay for Transposase Accessible Chromatin (scATAC-seq) in seedlings, embryonic roots, crown roots, axillary buds, and pistillate and staminate inflorescence. We describe 92 states of chromatin accessibility across 165,913 putative CREs and 52 known cell types. Patterns of transcription factor (TF) motif accessibility predicted cell identity with high accuracy, uncovered putative non-cell autonomous TFs, and revealed TF motifs underlying higher-order chromatin interactions. Comparison of maize and Arabidopsis thaliana developmental trajectories identified TF motifs with conserved patterns of accessibility. Cell type-specific CREs were enriched with enhancer activity, phenotype-associated genetic variants, and signatures of breeding-era selection. These data, along with companion software, Socrates, afford a comprehensive framework for understanding cellular heterogeneity, evolution, and cis-regulatory grammar of cell-type specification in a major crop.


title: Sequence-dependent mechanics of collagen reflect its structural and functional organization

abstract:
Extracellular matrix mechanics influence diverse cellular functions, yet surprisingly little is known about the mechanical properties of their constituent collagen proteins. In particular, network-forming collagen IV, an integral component of basement membranes, has been far less studied than fibril-forming collagens. A key feature of collagen IV is the presence of interruptions in the triple-helix-defining (Gly-X-Y) sequence along its collagenous domain. Here, we used atomic force microscopy (AFM) to determine the impact of sequence heterogeneity on the local flexibility of collagen IV and of the fibril-forming collagen III. Our extracted flexibility profile of collagen IV reveals that it possesses highly heterogeneous mechanics, ranging from semi-flexible regions as found for fibril-forming collagens to a lengthy region of high flexibility towards its N terminus. A simple model in which flexibility is dictated only by the presence of interruptions fit the extracted profile reasonably well, providing insight into the alignment of chains and demonstrating that interruptions - particularly when coinciding in multiple chains - significantly enhance local flexibility. To a lesser extent, sequence variations within the triple helix lead to variable flexibility, as seen along the continuously triple-helical collagen III. We found this fibril-forming collagen to possess a high-flexibility region around its matrix-metalloprotease (MMP) binding site, suggesting a unique mechanical fingerprint of this region that is key for matrix remodeling. Surprisingly, proline content did not correlate with local flexibility in either collagen type. We also found that physiologically relevant changes in pH and chloride concentration did not alter the flexibility of collagen IV, indicating such environmental changes are unlikely to control its compaction during secretion. Although extracellular chloride ions play a role in triggering collagen IV network formation, they do not appear to modulate the structure of its collagenous domain.

Significance StatementCollagens are the predominant proteins in vertebrates, forming diverse hierarchical structures to support cells and form connective tissues. Despite their mechanical importance, surprisingly little is established about the molecular encoding of mechanics. Here, we image single collagen proteins and find that they exhibit variable flexibility along their backbones. By comparing collagens with continuous and discontinuous triple-helix-forming sequences, we find that the type of helix interruption correlates with local flexibility, providing the first steps towards a much-needed map between sequence, structure, and mechanics in these large proteins. Our results inform our understanding of collagens ability to adopt compact conformations during cellular secretion and suggest a physical mechanism by which higher-order structure may be regulated by the distinct molecular properties of different collagens.


title: Acinetobacter baylyi regulates type IV pilus synthesis by employing two extension motors and a motor protein inhibitor

abstract: Bacteria use extracellular appendages called type IV pili (T4P) for diverse behaviors including DNA uptake, surface sensing, virulence, protein secretion, and twitching motility1. Dynamic extension and retraction of T4P is essential for their function, yet little is known about the mechanisms controlling these dynamics or the extent to which their regulation is conserved across bacterial species. Here, we develop Acinetobacter baylyi as a new model to study T4P by employing a recently developed pilus labeling method2,3. Our findings overturn the current dogma that T4P extension occurs through the action of a single, highly conserved motor, PilB, by showing that T4P synthesis in A. baylyi is dependent on an additional, phylogenetically distinct motor, TfpB. Furthermore, we uncover an inhibitor of T4P extension that specifically binds to and inhibits PilB but not TfpB. These results expand our understanding of T4P regulation and highlight how inhibitors might be exploited to inhibit T4P synthesis.


title: DEELIG: A Deep Learning-based approach to predictprotein-ligand binding affinity.

abstract: Protein-ligand binding prediction has extensive biological significance. Binding affinity helps in understanding the degree of protein-ligand interactions and has wide protein applications. Protein-ligand docking using virtual screening and molecular dynamic simulations are required to predict the binding affinity of a ligand to its cognate receptor. In order to perform such analyses, it requires intense computational power and it becomes impossible to cover the entire chemical space of small molecules. Recent developments using deep learning has enabled us to make sense of massive amounts of complex datasets where the ability of the model to "learn" intrinsic patterns in a complex plane of data is the strength of the approach. Here, we have incorporated Convolutional Neural Networks to find spatial relationships amongst data to help us predict affinity of binding of proteins in whole superfamilies towards a diverse set of ligands without the need of a docked pose or complex as input. The models were trained and validated using a detailed methodology for feature extraction. We have also tested DEELIG on protein complexes relevant to the current public health scenario. Our approach to network construction and training on protein-ligand dataset prepared in-house has yielded novel insights.

category: bioinformatics


title: CiliaQ - a simple, open-source software for automated quantification of ciliary morphology and fluorescence in 2D, 3D, and 4D images

abstract: Cilia are hair-like membrane protrusions that emanate from the surface of most vertebrate cells and are classified into motile and primary cilia. Motile cilia move fluid flow or propel cells, while also fulfilling sensory functions. Primary cilia are immotile and act as a cellular antenna, translating environmental cues into cellular responses. Ciliary dysfunction leads to severe diseases, commonly termed ciliopathies. The molecular details underlying ciliopathies and ciliary function are, however, not well understood. Since cilia are small subcellular compartments, imaging-based approaches have been used to study them. However, tools to comprehensively analyze images are lacking. Automatic analysis approaches require commercial software and are limited to 2D analysis and only a few parameters. The widely used manual analysis approaches are time consuming, user-biased, and difficult to compare. Here, we present CiliaQ, a package of open-source, freely-available, and easy-to-use ImageJ plugins. CiliaQ allows high throughput analysis of 2D and 3D, static or time-lapse images from fluorescence microscopy of cilia in cell culture or tissues, and outputs a comprehensive list of parameters for ciliary morphology, length, bending, orientation, and fluorescence intensity, making it broadly applicable. We envision CiliaQ as a resource and platform for reproducible and comprehensive analysis of ciliary function in health and disease.

category: cell biology


title: No evidence of Toxoplasma Gondii infection in urban and rural squirrels

abstract: Wildlife in cities can act as reservoirs for parasites that can infect domestic pets and have implications for human health. For example, the Coccidian parasite Toxoplasma gondii can infect all mammalian species, with felids acting as the only definitive hosts. Rodents, such as squirrels, could play an important role in urban infection dynamics of T. gondii, as squirrels occur at higher densities in cities than in natural environments and regularly share their territories with cats. In urban and suburban areas squirrels can encounter infectious oocysts shed in cat feces in contaminated soil or in the food they eat. They are also preyed upon by cats making them a potentially important species for completing the T. gondii life cycle in cities. We hypothesized that due to increased exposure to cats, urban squirrels would be more susceptible to T. gondii infection relative to squirrels in more natural areas. We investigated this using molecular and serological methods on samples collected from American red squirrels (Tamiasciurus hudsonicus), eastern grey squirrels (Sciurus carolinensis), northern flying squirrels (Glaucomys sabrinus), and least chipmunks (Tamias minimus) in and around the city of Winnipeg, Manitoba, Canada. We tested a total of 230 tissue samples from 46 squirrels for T. gondii DNA using quantitative PCR and supplemented these data with analyses of 13 serum samples from grey squirrels (Sciurus carolinensis) testing for T. gondii antibodies by indirect ELISA. We found no evidence of T. gondii infection in any squirrel. This suggests that squirrels may not be important intermediate hosts of T. gondii in cities and do not need to be considered as sources of infection to cats.

category: pathology


title: Understanding the origins of loss of protein function by analyzing the effects of thousands of variants on activity and abundance

abstract: Understanding and predicting how amino acid substitutions affect proteins is key to our basic understanding of protein function and evolution. Amino acid changes may affect protein function in a number of ways including direct perturbations of activity or indirect effects on protein folding and stability. We have analysed 6749 experimentally determined variant effects from multiplexed assays on abundance and activity in two proteins (NUDT15 and PTEN) to quantify these effects, and find that a third of the variants cause loss of function, and about half of loss-of-function variants also have low cellular abundance. We analyse the structural and mechanistic origins of loss of function, and use the experimental data to find residues important for enzymatic activity. We performed computational analyses of protein stability and evolutionary conservation and show how we may predict positions where variants cause loss of activity or abundance. In this way, our results link thermodynamic stability and evolutionary conservation to experimental studies of different properties of protein fitness landscapes.


title: Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Shell and Core

abstract:
Traditionally viewed as a motor control center, the cerebellum (CB) is now recognized as an integral part of a broad, long-range brain network that serves limbic functions and motivates behavior. This diverse CB functionality has been at least partly attributed to the multiplicity of its outputs. However, most studies have focused on cerebellar-cerebral cortical connections, at the expense of subcortical limbic structures. Nothing is known about how the CB connects to the nucleus accumbens (NAc), a subcortical region with which the CB shares functionality in motivated behaviors. Here, we report findings from in vivo electrophysiological experiments that investigated the functional connectivity between CB and NAc. We found that electrical microstimulation of deep cerebellar nuclei (DCN) modulates NAc spiking activity. This modulation differs in terms of directionality (excitatory vs. inhibitory) and temporal characteristics, in a manner that depends on NAc subregion: in the medial shell of NAc (NAcMed), slow inhibitory responses prevail over excitatory ones, whereas the proportion of fast excitatory responses is greater in the NAc core (NAcCore) compared to NAcMed.

Differences also exist in response onset latencies and dependence on CB stimulation intensity, which further argues for differential connectivity. If different pathways provide signal to each subregion, the divergence likely occurs downstream of the CB because we did not find any response-type clustering within DCN. We propose that the fast excitatory responses would be well poised to support rapid communication of information critical to the control of motivated behavior, such as prediction or prediction-error signals. The slower, less synchronous and longer-lasting modulation may be suggestive of a regulatory function, such as gain control of the communication between NAc and other brain regions. Finally, because there are no direct monosynaptic connections between CB and NAc, we performed viral tracing experiments to chart disynaptic pathways that could potentially mediate the newly discovered CB-NAc communication. We identified two anatomical pathways, which recruit the ventral tegmental area and intralaminar thalamus as nodes. These pathways and the functional connectivity they support could underlie the role of the CB in motivated behaviors.


title: FRUITFULL-like genes regulate flowering time and inflorescence architecture in tomato

abstract: The timing of flowering and inflorescence architecture are critical for the reproductive success of tomato, but the gene regulatory networks underlying these traits have not been fully explored. Here we show that the tomato FRUITFULL-like (FUL-like) genes FUL2 and MADS-BOX PROTEIN 20 (MBP20) induce flowering and repress inflorescence branching by promoting floral meristem determinacy. FUL1 fulfils a less prominent role and appears to depend on FUL2 and MBP20 for its upregulation in the inflorescence- and floral meristems. MBP10, the fourth tomato FUL-like gene, has probably lost its function. The tomato FUL-like proteins cannot homodimerize in in vitro assays, but heterodimerize with various other MADS-domain proteins, potentially forming distinct complexes in the transition meristem and floral meristem. Transcriptome analysis of the primary shoot meristems revealed various interesting downstream targets, including four repressors of cytokinin signalling that are upregulated during the vegetative-to-reproductive transition in ful1 ful2 mbp10 mbp20 mutants. FUL2 and MBP20 can also bind in vitro to the upstream regions of these genes, thereby probably directly stimulating cell division in the meristem upon the transition to flowering. The control of inflorescence branching does not occur via the CKXs, but appears regulated by repression of transcription factors such as TM3, APETALA 2b (AP2b) and AP2a.


title: Genomic sequencing confirms absence of introgression despite past hybridisation between a common and a critically endangered bird

abstract: Genetic swamping resulting from interspecific hybridisation can increase extinction risk for threatened species. The development of high-throughput and reduced-representation genomic sequencing and analyses to generate large numbers of high resolution genomic markers has the potential to reveal introgression previously undetected using small numbers of genetic markers. However, few studies to date have implemented genomic tools to assess the extent of interspecific hybridisation in threatened species. Here we investigate the utility of genome-wide single nucleotide polymorphisms (SNPs) to detect introgression resulting from past interspecific hybridisation in one of the worlds rarest birds. Anthropogenic impacts have resulted in hybridisation and subsequent backcrossing of the critically endangered Aotearoa New Zealand endemic kak[i] (black stilts; Himantopus novaezelandiae) with the non-threatened self-introduced congeneric poaka (Aotearoa New Zealand population of pied stilts, Himantopus himantopus leucocephalus), yet genetic analyses with a limited set of microsatellite markers revealed no evidence of introgression of poaka genetic material in kak[i], excluding one individual. We use genomic data for [~]63% of the wild adult kak[i] population to reassess the extent of introgression resulting from hybridisation between kak[i] and poaka. Consistent with previous genetic analyses, we detected no introgression from poaka into kak[i]. These collective results indicate that, for kak[i], existing microsatellite markers provide a robust, cost-effective approach to detect cryptic hybrids. Further, for well-differentiated species, the use of genomic markers may not be required to detect admixed individuals.


title: Genomic sequencing confirms absence of introgression despite past hybridisation between a critically endangered bird and its common congener


title: Structural and dynamical heterogeneity of water trapped inside Na+-pumping KR2 rhodopsin in the dark state

abstract: Photoisomerisation in retinal leads to a channel opening in the rhodopsins that triggers translocation or pumping of an ion/proton. Crystal structures of rhodopsins contain several structurally conserved water molecules. It has been suggested that water plays an active role in facilitating the ion pumping/translocation process by acting as a lubricant in these systems. In this work, we systematically investigate the localisation, structure, dynamics and energetics of the water molecules along the channel for the resting/dark state of KR2 rhodopsin. Employing several microseconds long atomistic molecular dynamics (MD) simulation of this trans-membrane protein system, we demonstrate the presence of five distinct water containing pockets/cavities separated by gateways controlled by the protein side-chains. There exists a strong hydrogen bonded network involving these buried water molecules and functionally important key residues. We present evidence of significant structural and dynamical heterogeneity in the water molecules present in these cavities with very rare exchange between them. The exchange time-scale of these buried water with bulk has an extremely wide range from tens of nanoseconds to > 1.5s! The translational and rotational dynamics of buried water are found to be strongly dependent on the protein cavity size and local interactions with classic signature of trapped diffusion and rotational anisotropy.


title: A direct interareal feedback-to-feedforward circuit in primate visual cortex

abstract: The mammalian sensory neocortex consists of hierarchically organized areas reciprocally connected via feedforward (FF) and feedback (FB) circuits. Several theories of hierarchical computation ascribe the bulk of the computational work of the cortex to looped FF-FB circuits between pairs of cortical areas. However, whether such corticocortical loops exist remains unclear. In higher mammals, individual FF-projection neurons send afferents almost exclusively to a single higher-level area. However, it is unclear whether FB-projection neurons show similar area specificity, and whether they influence FF-projection neurons directly or indirectly. Using viral-mediated monosynaptic circuit tracing in macaque primary visual cortex (V1), we show that V1 neurons sending FF projections to area V2 receive monosynaptic FB inputs from V2, but not other V1-projecting areas. We also find monosynaptic FB-to-FB neuron contacts as a second motif of FB connectivity. Our results support the existence of FF-FB loops in primate cortex, and suggest that FB can rapidly and selectively influence the activity of incoming FF signals.


title: Cocaine causes rapid remodeling of mesoaccumbens dopaminergic axons, synapses, and mitochondria

abstract: Dopaminergic (DA) neurons exert profound influences on behavior including addiction. However, how DA axons communicate with target neurons and how those communications change, for example, with drug exposure, remains poorly understood. We combine recent advances in cell type specific labeling for electron microscopy with large volume three-dimensional serial electron microscopy -  connectomics- to detail DA connections in the Nucleus Accumbens (NAc) across multiple animals and after exposure to cocaine. We find that DA axonal varicosities are of four general types: 38% are empty, 25% contain few small ([~]50 nm diameter) vesicles, 19% contain few large ([~]133 nm diameter) vesicles, and 18% have mixed small and large vesicles, suggesting that DA axons may use multiple types of neurotransmitters. Individual DA axons were significantly more likely to contain multiple varicosities of the same type relative to chance, suggesting a new method of DA axon classification. Across all categories, we find only rare examples (<2%, 6/410) of varicosities making specific synapses with any neighboring neuron with the few examples being made exclusively on the shafts and soma of resident NAc neurons. Instead, we find much more frequently (15%) that DA varicosities form spinule-like structures: physical membrane interdigitations with nearby dendrites or excitatory and inhibitory axons. Days after a brief exposure to cocaine, DA axons were extensively branched relative to controls but with similar densities of varicosities and spinules. Additionally, cocaine exposure results in the formation of blind-ended "bulbs" in DA axons, filled with mitochondria, and reminiscent of axonal retraction in the developing and damaged brain. Every bulb was surrounded by elaborated glia further suggestive of active remodeling. Finally, mitochondrial lengths increased by [~]2.2 times relative to control throughout DA axons and NAc spiny dendrites after cocaine exposure but not in DA soma or DA dendrites. We conclude that DA axonal transmission is unlikely to be mediated via classical synapses in the NAc and that the major locus of anatomical plasticity of DA circuits after exposure to cocaine are large scale axonal rearrangements with correlated changes in mitochondria.


title: Cell type specific labeling and partial connectomes of dopaminergic circuits reveal non-synaptic communication and large-scale axonal remodeling after exposure to cocaine


title: Probabilistic mapping of human functional brain networks identifies regions of high group consensus

abstract: Many recent developments surrounding the functional network organization of the human brain have focused on data that have been averaged across groups of individuals. While such group-level approaches have shed considerable light on the brains large-scale distributed systems, they conceal individual differences in network organization, which recent work has demonstrated to be common and widespread. This individual variability produces noise in group analyses, which may average together regions that are part of different functional systems across participants, limiting interpretability. However, cost and feasibility constraints may limit the possibility for individual-level mapping within studies. Here our goal was to leverage information about individual-level brain organization to probabilistically map common functional systems and identify locations of high inter-subject consensus for use in future group analyses. We probabilistically mapped 14 functional networks in multiple datasets with relatively high amounts of data. All networks show "core" (high-probability) regions, but differ from one another in the extent of their higher-variability components. These patterns replicate well across four datasets with different participants and scanning parameters. We produced a set of high-probability regions of interest (ROIs) from these probabilistic maps; these and the probabilistic maps are made publicly available, together with a tool for querying the network membership probabilities associated with any given cortical location. These quantitative estimates and public tools may allow researchers to apply information about inter-subject consensus to their own fMRI studies, improving inferences about systems and their functional specializations.


title: Zinc-binding motif acts as an oxidative stress sensor to regulate TRPM7 channel activity

abstract: TRPM7 channel activity is negatively regulated by intracellular Mg2+. We previously reported that TRPM7 was inhibited by oxidative stress due to an enhancement of the inhibition by intracellular Mg2+. In the present study, we aimed to clarify the precise mechanism underlying the TRPM7 inhibition by oxidative stress induced by hydrogen peroxide (H2O2). Site-directed mutagenesis on full-length TRPM7 revealed that none of the cysteines other than C1809 and C1813 within the zinc-binding motif of the TRPM7 kinase domain were involved in the H2O2-induced TRPM7 inhibition. When C1809 or C1813 was mutated, full-length TRPM7 was not expressed on the plasma membrane. We, therefore, developed a novel approach in which the full-length TRPM7 is functionally reconstituted by co-expressing the TRPM7 channel domain (M7cd) and the TRPM7 kinase domain (M7kd) as separate individual proteins in HEK293 cells. When M7cd was expressed alone, the current was inhibited by intracellular Mg2+ more strongly than in full-length TRPM7. Co-expression of M7cd and M7kd attenuated the current inhibition by intracellular Mg2+, and the current was sensitive to oxidative stress, indicating successful reconstitution of a full-length TRPM7-like current. A similar current reconstitution was observed when M7cd was co-expressed with the kinase inactive mutant M7kd-K1645R. Thus, it is suggested that the kinase activity is not essential for the reconstitution. Co-expression of M7cd and M7kd carrying a mutation at C1809 or C1813 failed to restore the full-length TRPM7-like current. No reconstitution was also observed with M7kd carrying a mutation at H1750 and H1807, which are involved in the zinc-binding motif formation together with C1809 and C1813. These data suggest that the zinc-binding motif is essential for the intracellular Mg2+-dependent regulation of the TRPM7 channel activity by M7kd, and the cysteines in the zinc-binding motif might play a role in the oxidative stress response of TRPM7.

category: physiology


title: Generated randomly and selected functionally? The nature of enterovirus recombination

abstract: Genetic recombination in RNA viruses is an important evolutionary mechanism. It contributes to population diversity, host/tissue adaptation and compromises vaccine efficacy. Both the molecular mechanism and initial products of recombination are relatively poorly understood. We used an established poliovirus-based in vitro recombination assay to investigate the roles of sequence identity and RNA structure, both implicated or inferred from analysis of circulating recombinant viruses, in the process. In addition, we used next generation sequencing to investigate the early products of recombination after cellular co-infection with different poliovirus serotypes. In independent studies we find no evidence for a role for RNA identity or structure in determining recombination junctions location. Instead, genome function and fitness are of greater importance in determining the identity of recombinant progeny. These studies provide further insights into this important evolutionary mechanism and emphasise the critical nature of the selection process on a mixed virus population.


title: The novel anti-CRISPR AcrIIA22 relieves DNA torsion in target plasmids and impairs SpyCas9 activity

abstract: To overcome CRISPR-Cas defense systems, many phages and mobile genetic elements encode CRISPR-Cas inhibitors called anti-CRISPRs (Acrs). Nearly all characterized Acrs directly bind Cas proteins to inactivate CRISPR immunity. Here, using functional metagenomic selection, we describe AcrIIA22, an unconventional Acr found in hypervariable genomic regions of clostridial bacteria and their prophages from human gut microbiomes. AcrIIA22 does not bind strongly to SpyCas9 but nonetheless potently inhibits its activity against plasmids. To gain insight into its mechanism, we obtained an X-ray crystal structure of AcrIIA22, which revealed homology to PC4-like nucleic-acid binding proteins. Based on mutational analyses and functional assays, we deduced that acrIIA22 encodes a DNA nickase that relieves torsional stress in supercoiled plasmids. This may render them less susceptible to SpyCas9, which uses free energy from negative supercoils to form stable R-loops. Modifying DNA topology may provide an additional route to CRISPR-Cas resistance in phages and mobile genetic elements.


title: Simulation of bacterial populations with SLiM

abstract: Simulation of genomic data is a key tool in population genetics, yet, to date, there is no forward-in-time simulator of bacterial populations that is both computationally efficient and adaptable to a wide range of scenarios. Here we demonstrate how to simulate bacterial populations with SLiM, a forward-in-time simulator built for eukaryotes. SLiM has gained many users in recent years, due to its speed and power, and has extensive documentation showcasing various scenarios that it can simulate. This paper focuses on a simple demographic scenario, to explore unique aspects of modeling bacteria in SLiMs scripting language. In addition, we illustrate the flexibility of SLiM by simulating the growth of bacteria on a Petri dish with antibiotic. To foster the development of bacterial simulations based upon this recipe, we explain the inner workings of its code. We also validate the simulator, by extensively testing the results of simulations against existing simulators, and against theoretical expectations for some summary statistics. This protocol, with the flexibility and power of SLiM, will enable the community to simulate bacterial populations efficiently under a wide range of evolutionary scenarios.


title: A framework for mutational signature analysis based on DNA shape parameters

abstract: The mutation risk of a DNA locus depends on its oligonucleotide context. In turn, mutability of oligonucleotides varies across individuals, due to exposure to mutagenic agents or due to variable efficiency and/or accuracy of DNA repair. Such variability is captured by mutational signatures, a mathematical construct obtained by a deconvolution of mutation frequency spectra across individuals. There is a need to enhance methods for inferring mutational signatures to make better use of sparse mutation data (e.g., resulting from exome sequencing of cancers), to facilitate insight into underlying biological mechanisms, and to provide more accurate mutation rate baselines for inferring positive and negative selection. We propose a conceptualization of mutational signatures that represents oligonucleotides via descriptors of DNA conformation: base pair, base pair step, and minor groove width parameters. We demonstrate how such DNA structural parameters can accurately predict mutation occurrence due to DNA repair failures or due to exposure to diverse mutagens such as radiation, chemical exposure, and the APOBEC cytosine deaminase enzymes. Furthermore, the mutation frequency of DNA oligomers classed by structural features can accurately capture systematic variability in mutagenesis of >1,000 tumors originating from diverse human tissues. A nonnegative matrix factorization was applied to mutation spectra stratified by DNA structural features, thereby extracting novel mutational signatures. Moreover, many of the known trinucleotide signatures were associated with an additional spectrum in the DNA structural descriptor space, which may aid interpretation and provide mechanistic insight. Overall, we suggest that the power of DNA sequence motif-based mutational signature analysis can be enhanced by drawing on DNA shape features.


title: A deep learning algorithm to translate and classify cardiac electrophysiology: From induced pluripotent stem cell-derived cardiomyocytes to adult cardiac cells

abstract: The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability and immature phenotype of the iPSC-CM platform. It was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.


title: Predicting age and clinical risk from the neonatal connectome

abstract:
The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and are complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible, and can give us clues as to how and why individual developmental trajectories differ.

In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (Mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p<0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p<0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to be predominantly thalamocortical. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome, and suggest that a neural substrate for later developmental outcome is detectable at term equivalent age.


title: Global Analysis of the Mammalian MHC class I Immunopeptidome at the Organism-Wide Scale

abstract: Understanding the molecular principles that govern the composition of the mammalian MHC-I immunopeptidome (MHC-Ii) across different primary tissues is fundamentally important to predict how T cell respond in different contexts in vivo. Here, we performed a global analysis of the mammalian MHC-Ii from 29 and 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, -B and -C allotypes do not contribute evenly to the global composition of the MHC-Ii across multiple human tissues. Second, we found that peptides that are presented in a tissue-dependent and -independent manner share very distinct properties. Third, we discovered that proteins that are evolutionarily hyperconserved represent the primary source of the MHC-Ii at the organism-wide scale. Finally, we uncovered new components of the antigen processing and presentation network that may drive the high level of heterogeneity of the MHC-Ii across different tissues in mammals. This study opens up new avenues toward a system-wide understanding of antigen presentation in vivo and may serve as ground work to understand tissue-dependent T cell responses in autoimmunity, infectious diseases and cancer.

category: immunology


title: Metabolomic signature of the maternal microbiota in the fetus

abstract: The maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. We investigated samples of placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. The concentrations of more than half of the annotated and differentially expressed metabolites were lower in the GF organs, suggesting their microbial origin or a metabolic response of the host to the presence of gut microbiota. The clearest separation was observed in the placenta. Metabolites that were detected in lower amounts in the fetal organs in the GF mice included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid, were also decreased in the absence of microbiota. Several metabolites had higher levels in the GF mice. These could be precursors of microbial metabolites or indicators of host metabolic response to the absence of gut microbiota. Ninety-nine molecular features were only detected in the SPF mice, suggesting the existence of yet unidentified microbially modified metabolites that potentially influence fetal development.


title: Restructured mitochondrial-nuclear interaction in Plasmodium falciparum dormancy and persister survival after artemisinin exposure

abstract:
Artemisinin and its semi-synthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into and later reactivate from a dormant persister state. Here we provide evidence that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Restructured mitochondrial-nuclear associations and an altered metabolic state are consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organelle communication and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment.

IMPORTANCEThe major first-line treatment for malaria, especially the deadliest form caused by Plasmodium falciparum, is combination therapy with an artemisinin-based drug (ART) plus a partner drug to assure complete cure. Without an effective partner drug, ART administration alone can fail because of the ability of small populations of blood-stage malaria parasites to enter into a dormant state and survive repeated treatments for a week or more. Understanding the nature of parasites in dormancy (persisters), and their ability to wake and reestablish actively-propagating parasitemias (recrudesce) after ART exposure, may suggest strategies to improve treatment outcomes and counter the threats posed by parasites that develop resistance to partner drugs. Here we show that persisters have dramatically altered mitochondria and mitochondrial-nuclear interactions associated with features of metabolic quiescence. Restructured associations between the mitochondria and nuclei may support signaling pathways that enable the ART survival responses of dormancy.


title: Chromosome-level genome assemblies of the malaria vectors Anopheles coluzzii and Anopheles arabiensis

abstract:
BackgroundAnopheles coluzzii and An. arabiensis belong to the An. gambiae complex and are among the major malaria vectors in Sub-Saharan Africa. However, chromosome-level reference genome assemblies are still lacking for these medically important mosquito species.

FindingsIn this study, we produced de novo chromosome-level genome assemblies for An. coluzzii and An. arabiensis using the long-read Oxford Nanopore sequencing technology and the Hi-C scaffolding approach. We obtained 273.4 Mbp and 256.8 Mbp of the total assemblies for An. coluzzii and An. arabiensis, respectively. Each assembly consists of three chromosome-scale scaffolds (X, 2, 3), complete mitochondrion, and unordered contigs identified as autosomal pericentromeric DNA, X pericentromeric DNA, and Y sequences. Comparison of these assemblies with the existing assemblies for these species demonstrated that we obtained improved reference-quality genomes. The new assemblies allowed us to identify genomiccoordinates for the breakpoint regions of fixed and polymorphic chromosomal inversions in An. coluzzii and An. arabiensis.

ConclusionThe new chromosome-level assemblies will facilitate functional and population genomic studies in An. coluzzii and An. arabiensis. The presented assembly pipeline will accelerate progress toward creating high-quality genome references for other disease vectors.


title: Combining computational controls with natural text reveals new aspects of meaning composition

abstract: To study a core component of human intelligence--our ability to combine the meaning of words--neuroscientists have looked to theories from linguistics. However, linguistic theories are insufficient to account for all brain responses that reflect linguistic composition. In contrast, we adopt a data-driven computational approach to study the combined meaning of words beyond their individual meaning. We term this product "supra-word meaning" and investigate its neural bases by devising a computational representation for it and using it to predict brain recordings from two imaging modalities with complementary spatial and temporal resolutions. Using functional magnetic resonance imaging, we reveal that hubs that are thought to process lexical-level meaning also maintain supra-word meaning, suggesting a common substrate for lexical and combinatorial semantics. Surprisingly, we cannot detect supra-word meaning in magnetoencephalography, which suggests the hypothesis that composed meaning might be maintained through a different neural mechanism than the synchronized firing of pyramidal cells. This sensitivity difference has implications for past neuroimaging results and future wearable neurotechnology.


title: Luxotonic signals in human prefrontal cortex as a possible substrate for effects of light on mood and cognition

abstract: Animal studies revealed a mood-regulating neural pathway linking intrinsically photosensitive retinal ganglion cells (ipRGCs) and the prefrontal cortex (PFC), involved in the pathophysiology of mood disorders. As humans too have luminance-encoding ipRGCs, we asked whether a similar pathway exist in humans. Here, fMRI was used to identify PFC regions and other areas exhibiting luminance-dependent signals. We report 29 human brain regions where activation either monotonically decreased or increased with luminance. Luxotonic activity was identified across the cerebral cortex, in diverse subcortical structures, and in the cerebellum, regions that have functions related to visual image formation, motor control, cognition, emotion, and reward processing. Light suppressed PFC activation level, the activation monotonically decreasing with increasing luminance. The sustained time course of light-evoked PFC responses, and their susceptibility to prior light exposure, most closely resembled those of ipRGCs. These findings offer a functional link between light exposure and PFC-mediated cognitive and affective phenomena.


title: Amyloid beta acts synergistically as a pro-inflammatory cytokine

abstract: The amyloid beta (A{beta}) peptide is believed to play a central role in Alzheimers disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily-selected functions of A{beta} are incompletely understood. Here, we report that nanomolar concentrations of A{beta} act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that A{beta} can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by A{beta} have a transcriptional signature similar to neurotoxic "A1" astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of A{beta} at low concentrations is distinct from the transcriptome changes induced by the high/supraphysiological doses of A{beta} often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for A{beta} and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.


title: Prediction Errors Disrupt Hippocampal Representations and Update Episodic Memories

abstract:
The brain supports adaptive behavior by generating predictions, learning from errors, and updating memories to incorporate new information. Prediction error, or surprise, triggers learning when reality contradicts expectations. Prior studies have shown that the hippocampus signals prediction errors, but the hypothesized link to memory updating has not been demonstrated. In a human fMRI study, we elicited mnemonic prediction errors by interrupting familiar narrative videos immediately before the expected endings. We found that prediction error reversed the relationship between univariate hippocampal activation and memory: greater hippocampal activation predicted memory preservation after expected endings, but memory updating after surprising endings. In contrast to previous studies, we showed that univariate activation was insufficient for understanding hippocampal prediction error signals. We explained this surprising finding by tracking both the evolution of hippocampal activation patterns and connectivity between the hippocampus and neuromodulatory regions. We found that hippocampal activation patterns stabilized as each narrative episode unfolded, suggesting sustained episodic representations. Prediction errors disrupted these sustained representations, and the degree of disruption predicted memory updating. The relationship between hippocampal activation and subsequent memory depended on concurrent basal forebrain activation, supporting the idea that cholinergic modulation regulates attention and memory. We conclude that prediction errors create conditions that favor memory updating, prompting the hippocampus to abandon ongoing predictions and make memories malleable.

SignificanceOur brains draw on memories to predict the future; when our predictions are incorrect, we must update our memories to improve future predictions. Past studies have demonstrated that the hippocampus signals prediction error, or surprise, but have not linked this neural signal to memory updating. Here, we uncover this missing connection: We show that mnemonic prediction errors change the role of the hippocampus, reversing the relationship between hippocampal activation and memory outcomes. We examine the mechanisms of this shift in neural processing, showing that prediction errors disrupt the temporal continuity of hippocampal patterns. We propose that prediction errors disrupt sustained representations and enable memory updating. Our findings bear implications for improving education, understanding eyewitness memory distortion, and treating pathological memories.


title: Addiction-associated genetic variants implicate brain cell type- and region-specific cis-regulatory elements in addiction neurobiology

abstract:
Recent large genome-wide association studies (GWAS) have identified multiple confident risk loci linked to addiction-associated behavioral traits. Genetic variants linked to addiction-associated traits lie largely in non-coding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied LD score regression to compare GWAS to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative CREs marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of mouse neuronal subtypes: cortical excitatory, D1, D2, and PV. Lastly, we developed machine learning models from mouse cell type-specific regions of open chromatin to further dissect human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuronal subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.

Significance StatementWe combine statistical genetic and machine learning techniques to find that the predisposition to for nicotine, alcohol, and cannabis use behaviors can be partially explained by genetic variants in conserved regulatory elements within specific brain regions and neuronal subtypes of the reward system. This computational framework can flexibly integrate open chromatin data across species to screen for putative causal variants in a cell type-and tissue-specific manner across numerous complex traits.


title: What we talk about when we talk about color

abstract: Names for colors vary widely across languages, but color categories are remarkably consistent (Berlin & Kay, 1969). Shared mechanisms of color perception help explain consistent partitions of visible light into discrete color vocabularies (Regier et al., 2007). But the mappings from colors to words are not identical across languages, which may reflect communicative needs - how often speakers must refer to objects of different color (Gibson et al., 2017). Here we quantify the communicative needs of colors in 130 different languages by means of a novel inference algorithm. We find that communicative needs are not uniform: some regions of color space exhibit 30-fold greater demand for communication than other regions. The regions of greatest demand correlate with the colors of salient objects, including ripe fruits in primate diets. Our analysis also reveals a hidden diversity in the communicative needs of colors across different languages, which is partly explained by differences in geographic location and the local biogeography of linguistic communities. Accounting for language-specific, non-uniform communicative needs improves predictions for how a language maps colors to words, and how these mappings vary across languages. Our account closes an important gap in the compression theory of color naming, while opening new directions to study cross-cultural variation in the need to communicate different colors and its impact on the cultural evolution of color categories.


title: Pathway dynamics can delineate the sources of transcriptional noise in gene expression

abstract: Single-cell expression profiling has opened up new vistas on cellular processes. Among other important results, one stand-out observation has been the confirmation of extensive cell-to-cell variability at the transcriptomic and proteomic level. Because most experimental analyses are destructive we only have access to snapshot data of cellular states. This loss of temporal information presents significant challenges in inferring dynamics, as well as causes of cell-to-cell variability. In particular, we are typically unable to separate dynamic variability from within individual systems ("intrinsic noise") from variability across the population ("extrinsic noise"). Here we mathematically formalise this non-identifiability; but we also use this to identify how new experimental set-ups coupled to statistical noise decomposition can resolve this non-identifiability. For single-cell transcriptomic data we find that systems subject to population variation invariably inflate the apparent degree of burstiness of the underlying process. Such identifiability problems can, in principle, be remedied by dual-reporter assays, which separates total gene expression noise into intrinsic and extrinsic contributions; unfortunately, however, this requires pairs of strictly independent and identical gene reporters to be integrated into the same cell, which is difficult to implement experimentally in most systems. Here we demonstrate mathematically that, in some cases decomposition of transcriptional noise is possible with non-identical and not-necessarily independent reporters. We use our result to show that generic reporters lying in the same biochemical pathways (e.g. mRNA and protein) can replace dual reporters, enabling the noise decomposition to be obtained from only a single gene. Stochastic simulations are used to support our theory, and show that our "pathway-reporter" method compares favourably to the dual-reporter method.


title: A non-canonical feedforward pathway for computing odor identity

abstract: Elucidating neural circuits that enable robust odor identification remains a fundamental challenge in olfaction. The current leading model states that odor identity is computed within the piriform cortex (PC), drawing from mitral cell input from the olfactory bulb. Here we find that tufted cells, the other principal cell-type of the bulb, which strongly innervate the anterior olfactory nucleus (AON) instead, substantially outperform mitral cells in decoding both odor identity and intensity, acting in a largely feedforward fashion. Cortical feedback from PC specifically restructures mitral cell responses, while feedback from AON preferentially controls the gain of tufted cell odor representations, matching biases in feedforward connectivity. Leveraging cell-type specific analyses, we identify a non-canonical feedforward pathway for odor recognition and discrimination mediated by the tufted cells, and propose that bulb target areas, other than the piriform cortex, such as AON and olfactory striatum, are well-positioned to compute odor identity.