title: Genome-wide characterization of human minisatellite VNTRs: population-specific alleles and gene expression differences

abstract: Variable Number Tandem Repeats (VNTRs) are tandem repeat (TR) loci that vary in copy number across a population. Using our program, VNTRseek, we analyzed human whole genome sequencing datasets from 2,770 individuals in order to detect minisatellite VNTRs, i.e., those with pattern sizes [≥]7 bp. We detected 35,638 VNTR loci and classified 5,676 as commonly polymorphic (i.e., with non-reference alleles occurring in >5% of the population). Commonly polymorphic VNTR loci were found to be enriched in genomic regions with regulatory function, i.e., transcription start sites and enhancers. Investigation of the commonly polymorphic VNTRs in the context of population ancestry revealed that 1,096 loci contained population-specific alleles and that those could be used to classify individuals into super-populations with near-perfect accuracy. Search for quantitative trait loci (eQTLs), among the VNTRs proximal to genes, indicated that in 187 genes expression differences correlated with VNTR genotype. We validated our predictions in several ways, including experimentally, through the identification of predicted alleles in long reads, and by comparisons showing consistency between sequencing platforms. This study is the most comprehensive analysis of minisatellite VNTRs in the human population to date.


title: Molecular physiology of pumiliotoxin sequestration in a poison frog

abstract: Poison frogs bioaccumulate alkaloids for chemical defense from their arthropod diet. Although many alkaloids are accumulated without modification, some poison frog species can metabolize pumiliotoxin (PTX 251D) into the more potent allopumiliotoxin (aPTX 267A). Despite extensive research characterizing the chemical arsenal of poison frogs, the physiological mechanisms involved in the sequestration and metabolism of individual alkaloids remain unclear. We first performed a feeding experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if this species can metabolize PTX 251D into aPTX 267A and what gene expression changes are associated with PTX 251D exposure in the intestines, liver, and skin. We found that D. tinctorius can metabolize PTX 251D into aPTX 267A, and that PTX 251D exposure changed the expression level of genes involved in immune system function and small molecule metabolism and transport. To better understand the functional significance of these changes in gene expression, we then conducted a series of high-throughput screens to determine the molecular targets of PTX 251D and identify potential proteins responsible for metabolism of PTX 251D into aPTX 267A. Although screens of PTX 251D binding human voltage-gated ion channels and G-protein coupled receptors were inconclusive, we identified human CYP2D6 as a rapid metabolizer of PTX 251D in a cytochrome P450 screen. Furthermore, a CYP2D6-like gene had increased expression in the intestines of animals fed PTX, suggesting this protein may be involved in PTX metabolism. These results show that individual alkaloids can modify gene expression across tissues, including genes involved in alkaloid metabolism. More broadly, this work suggests that specific alkaloid classes in wild diets may induce physiological changes for targeted accumulation and metabolism.

category: physiology


title: Conjunctive spatial and idiothetic codes are topographically organized in the GABAergic cells of the lateral septum

abstract: The hippocampal spatial codes relevance for downstream neuronal populations - particularly its major subcortical output the lateral septum (LS) - is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animals location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior-posterior and dorsal-ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using trans-synaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.

category: neuroscience


title: Intracellular sterol sensing controls intestinal B cell differentiation

abstract: Intestinal B cell responses are critical for the maintenance of gut homeostasis, yet environmental signals that control B cell metabolism and effector function remain poorly characterized. Here, we show that Peyers patches germinal center (GC) B cells are sensitive to 25-hydroxycholesterol (25-HC), an oxidized metabolite of cholesterol produced by the enzyme cholesterol 25-hydroxylase (CH25H). In mice lacking CH25H, antigen-specific GC B cells show an increased cholesterol metabolic signature and preferentially differentiate in plasma cells (PCs), thereby inducing a stronger intestinal IgA response upon immunization or infection. GC B cells express the sterol sensor SREBP2 and use it to sense 25-HC. Deletion of SREBP2 from GC B cells prevents PC differentiation and forces the maintenance of GC identity. GC localized oxysterol production by follicular dendritic cells is central in dictating GC metabolism and imposing B cell fate. Our findings show that the 25-HC-SREBP2 axis shapes B cell effector function in intestinal lymphoid organs and indicate that dietary cholesterol can instruct local B cell response.

category: immunology


title: Prevalence of sustainable and unsustainable use of wild species inferred from the IUCN Red List

abstract: Unsustainable exploitation of wild species represents a serious threat to biodiversity and to the livelihoods of local communities and indigenous peoples. However, managed, sustainable use has the potential to forestall extinctions, aid recovery, and meet human needs. Research to date has focused on unsustainable biological resource use with little consideration of sustainable use; we infer the current prevalence of both. We analyzed species-level data for 30,923 species from 13 taxonomic groups on the IUCN Red List. Our results demonstrate the broad taxonomic prevalence of use, with 40% of species (10,098 of 25,009 species from 10 data-sufficient taxonomic groups) documented as being used. The main purposes of use are pets, display animals and horticulture, and human consumption. Use often has an adverse impact on species extinction risk (we define this as biologically unsustainable): intentional use is currently contributing to elevated extinction risk for over a quarter of all threatened or Near Threatened (NT) species (2,752 - 2,848 of 9,753 species). Intentional use also threatens 16% of all species used (1,597 - 1,631 of 10,098). However, 72% of species that are used (7,291 of 10,098) are Least Concern (LC), of which nearly half (3,469) also have stable or improving population trends. The remainder of used species are not documented as threatened by biological resource use, including 172 threatened or NT species with stable or improving populations. Around a third of species that have use documented as a threat do not currently receive targeted species management actions to directly address this threat. We offer suggestions for improving use-related Red List data. Our findings on the prevalence of sustainable and unsustainable use, and variation across taxa, can inform international policymaking, including the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, the Convention on Biological Diversity, and the Convention on International Trade in Endangered Species.

category: ecology


title: Computational identification of splicing phenotypes from single cell transcriptomic experiments

abstract: RNA splicing is an important driver of heterogeneity in single cells, both through the expression of alternative transcripts and as a major determinant of transcriptional kinetics. However, the intrinsic coverage limitations of scRNA-seq technologies make it challenging to associate specific splicing events to cell-level phenotypes. Here, we present BRIE2, a scalable computational method that resolves these issues by regressing single-cell transcriptomic data against cell-level features. We show that BRIE2 effectively identifies differential alternative splicing events that are associated with a disease. Additionally, BRIE2 allows a principled selection of genes (differential momentum genes) that capture heterogeneity in transcriptional kinetics and improve quantitatively RNA velocity analyses. BRIE2, therefore, extends the scope of single-cell transcriptomic experiments towards the identification of splicing phenotypes associated with biological changes at the single-cell level.

category: bioinformatics


title: The post-acute phase of SARS-CoV-2 infection in two macaques species is associated with signs of ongoing virus replication and pathology in pulmonary and extrapulmonary tissues

abstract:
The post-acute phase of SARS-CoV-2 infection was investigated in rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via nose and throat, and viral RNA was occasionally detected in feces. This phase coincided with a transient change in systemic immune activation. Even after the alleged resolution of the infection, as suggested by the absence of viral RNA in nasal and tracheal swabs, computed tomography (CT) and positron emission tomography (PET)-CT were able to reveal pulmonary lesions and activated tracheobronchial lymph nodes in all animals. Post-mortem histological examination of the lung tissue revealed mostly marginal or resolving minimal lesions that were indicative of SARS-CoV-2 infection. Evidence for SARS-CoV-2-induced histopathology was also found in extrapulmonary tissue samples, like conjunctiva, cervical and mesenteric lymph nodes.

However, 5-6 weeks after SARS-CoV-2 exposure, upon necropsy, viral RNA was still detectable in a wide range of tissue samples in 50% of the macaques and included amongst others the heart, the respiratory tract and surrounding lymph nodes, salivary gland, and conjunctiva. Subgenomic messenger RNA was detected in the lungs and tracheobronchial lymph nodes, indicative of ongoing virus replication during the post-acute phase. These results could be relevant for understanding the long-term consequences of COVID-19 in humans.

Author summaryMore than a year after the start of the pandemic, the long-term consequences of SARS-CoV-2 infection start to surface. The variety of clinical manifestations associated with post-acute COVID-19 suggests the involvement of multiple biological mechanisms. In this study, we show that rhesus and cynomolgus macaques shed virus from their respiratory tract, generate virus-specific humoral immune responses, and show signs of SARS-CoV-2-induced lung pathology. PET-CT revealed that both species showed ongoing mild to moderate pulmonary disease, even after the virus was no longer detectable in nasal and tracheal swabs. Five to six weeks after infection, necropsy confirmed minimal to mild histopathological manifestations in various tissues, like the lungs, heart, lymph nodes, and conjunctiva. We detected Viral RNA in the heart, respiratory tract, and tracheobronchial lymph nodes, and subgenomic messenger RNA in the lungs and surrounding lymph nodes, indicative of ongoing virus replication. We show widespread tissue dissemination of SARS-CoV-2 in infected macaques and the presence of replicating virus in lungs and surrounding lymph nodes after alleged convalescence of infection. This finding is intriguing in the light of long-COVID disease symptoms seen in humans as it has been hypothesized that persistent infection may contribute to this phenomenon.

category: microbiology


title: Cytokinin inhibits fungal development and virulence by targeting cellular trafficking

abstract:
Cytokinin (CK) is an important plant developmental regulator, having activities in many aspects of plant life and its response to the environment. CKs are involved in diverse processes in the plant, including stem-cell maintenance, vascular differentiation, growth and branching of roots and shoots, leaf senescence, nutrient balance and stress tolerance. In some cases, phytopathogens secrete CKs. It has been suggested that to achieve pathogenesis in the host, CK-secreting biotrophs manipulate CK signaling to regulate the host cell cycle and nutrient allocation. CK is known to induce host plant resistance to several classes of phytopathogens from a handful of works, with induced host immunity via salicylic acid signaling suggested to be the prevalent mechanism for this host resistance.

Here, we show that CK directly inhibits the growth, development, and virulence of fungal phytopathogens. Focusing on Botrytis cinerea (Bc), we demonstrate that various aspects of fungal development can be reversibly inhibited by CK. We also found that CK affects both budding and fission yeast in a similar manner. Investigating the mechanism by which CK influences fungal development, we conducted RNA-NGS on mock and CK treated B. cinerea samples, finding that CK inhibits the cell cycle, cytoskeleton, and endocytosis. Cell biology experiments demonstrated that CK affects cytoskeleton structure and cellular trafficking in Bc, lowering endocytic rates and endomembrane compartment sizes, likely leading to reduced growth rates and arrested developmental programs. Mutant analyses in yeast confirmed that the endocytic pathway is altered by CK.

Our work uncovers a remarkably conserved role for a plant growth hormone in fungal biology, suggesting that pathogen-host interactions resulted in fascinating molecular adaptations on fundamental processes in eukaryotic biology.

ImportanceCytokinins (CKs), important plant growth/ developmental hormones, have previously been associated with host disease resistance. Here, we demonstrate that CK directly inhibits the growth, development, and virulence of B. cinerea (Bc) and many additional phytopathogenic fungi. Molecular and cellular analyses revealed that CK is not toxic to Bc, but rather, Bc likely recognizes CK and responds to it, resulting in cell cycle and individual cell growth retardation, via downregulation of cytoskeletal components and endocytic trafficking. Mutant analyses in yeast confirmed that the endocytic pathway is a CK target. Our work demonstrates a conserved role for CK in yeast and fungal biology, suggesting that suggesting that pathogen-host interactions may cause molecular adaptations on fundamental processes in eukaryotic biology.


title: Scaling up biodiversity ecosystem functioning relationships: the role of environmental heterogeneity in space and time

abstract: The biodiversity and ecosystem functioning (BEF) relationship is expected to be scale-dependent. The autocorrelation of environmental heterogeneity is hypothesized to explain this scale dependence because it influences how quickly biodiversity accumulates over space or time. However, this link has yet to be demonstrated in a formal model. Here we use a Lotka-Volterra competition model to simulate community dynamics when environmental conditions vary across either space or time. Species differ in their optimal environmental conditions, which results in turnover in community composition. We vary biodiversity by modelling communities with different sized regional species pools and ask how the amount of biomass per unit area depends on the number of species present, and the spatial or temporal scale at which it is measured. We find that more biodiversity is required to maintain functioning at larger temporal and spatial scales. The number of species required increases quickly when environmental autocorrelation is low, and slowly when autocorrelation is high. Both spatial and temporal environmental heterogeneity led to scale dependence in BEF, but autocorrelation had larger impacts when environmental change was temporal. These findings show how the biodiversity required to maintain functioning is expected to increase over space and time.


title: Age-related degradation of optic radiation white matter predicts visual, but not verbal executive functions

abstract: Healthy aging is accompanied by degraded white matter connectivity, which has been suggested to contribute to cognitive dysfunction observed in aging, especially in relation to fluid measures of cognition. Prior research linking white matter microstructure and cognition, however, has largely been limited to major association and heteromodal white matter tracts. The optic radiations (OR), which transfer visual sensory-perceptual information from thalamic lateral geniculate nucleus to primary visual cortex, are generally considered lower-level input-relay white matter tracts. However, the role of this prominent white-matter visual relay system in supporting higher-order cognition is understudied, especially in regard to healthy aging. The present study used deterministic tractography to isolate OR fractional anisotropy (FA) in 130 participants aged 20-94 to assess age effects on OR tract white matter. We also examined associations between age-related differences in the OR and cognitive domains involving visual processing speed, and visual- and non-visual executive function (EF). OR microstructure, as indexed by FA, exhibited a significant linear decrease across age. A significant interaction between age, FA, and cognitive domain on cognitive task performance indicated that in older age, more degraded OR white matter was associated with poorer visual EF, but no age-related association between FA in the OR and visual processing speed or verbal EF was observed. These findings suggest the optic radiations are not merely sensory-perceptual relays, but also influence higher-order visual cognition differentially with age.


title: Embedding optimization reveals long-lasting history dependence in neural spiking activity

abstract:
Information processing can leave distinct footprints on the statistics of neural spiking. For example, efficient coding minimizes the statistical dependencies on the spiking history, while temporal integration of information may require the maintenance of information over different timescales. To investigate these footprints, we developed a novel approach to quantify history dependence within the spiking of a single neuron, using the mutual information between the entire past and current spiking. This measure captures how much past information is necessary to predict current spiking. In contrast, classical time-lagged measures of temporal dependence like the autocorrelation capture how long--potentially redundant--past information can still be read out. Strikingly, we find for model neurons that our method disentangles the strength and timescale of history dependence, whereas the two are mixed in classical approaches. When applying the method to experimental data, which are necessarily of limited size, a reliable estimation of mutual information is only possible for a coarse temporal binning of past spiking, a so called past embedding. To still account for the vastly different spiking statistics and potentially long history dependence of living neurons, we developed an embedding-optimization approach that does not only vary the number and size, but also an exponential stretching of past bins. For extra-cellular spike recordings, we found that the strength and timescale of history dependence indeed can vary independently across experimental preparations. While hippocampus indicated strong and long history dependence, in visual cortex it was weak and short, while in vitro the history dependence was strong but short. This work enables an information theoretic characterization of history dependence in recorded spike trains, which captures a footprint of information processing that is beyond time-lagged measures of temporal dependence. To facilitate the application of the method, we provide practical guidelines and a toolbox.

Author summaryEven with exciting advances in recording techniques of neural spiking activity, experiments only provide a comparably short glimpse into the activity of only a tiny subset of all neurons. How can we learn from these experiments about the organization of information processing in the brain? To that end, we exploit that different properties of information processing leave distinct footprints on the firing statistics of individual spiking neurons. In our work, we focus on a particular statistical footprint: How much does a single neurons spiking depend on its own preceding activity, which we call history dependence. By quantifying history dependence in neural spike recordings, one can, in turn, infer some of the properties of information processing. Because recording lengths are limited in practice, a direct estimation of history dependence from experiments is challenging. The embedding optimization approach that we present in this paper aims at extracting a maximum of history dependence within the limits set by a reliable estimation. The approach is highly adaptive and thereby enables a meaningful comparison of history dependence between neurons with vastly different spiking statistics, which we exemplify on a diversity of spike recordings. In conjunction with recent, highly parallel spike recording techniques, the approach could yield valuable insights on how hierarchical processing is organized in the brain.


title: A Paradigm Change in Functional Brain Mapping: Suppressing the Thermal Noise in fMRI

abstract: Functional magnetic resonance imaging (fMRI) has become one of the most powerful tools for investigating the human brain. However, virtually all fMRI studies have relatively poor signal-to-noise ratio (SNR). Here we introduce a novel fMRI denoising technique, which suppresses noise that is indistinguishable from zero-mean, Gaussian-distributed noise. Thermal noise, falling in this category, is a major source of noise in fMRI, particularly, but not exclusively, at high spatial and/or temporal resolutions. Using 7-Tesla high-resolution data, we demonstrate improvements in temporal-SNR, the detection of stimulus-induced signal changes, and functional maps, while leaving stimulus-induced signal change amplitudes, image spatial precision, and functional point-spread-function unaltered. We also show that the method is equally applicable when using supra-millimeter resolution 3- and 7-Tesla fMRI data, different cortical regions, stimulation/task paradigms, and acquisition strategies. This denoising approach improves key metrics of functional activation detection while preserving spatial precision.


title: Lowering the Thermal Noise Barrier in Functional Brain Mapping with Magnetic Resonance Imaging


title: Deep generative selection models of T and B cell receptor repertoires with soNNia

abstract: Subclasses of lymphocytes carry different functional roles to work together and produce an immune response and lasting immunity. Additionally to these functional roles, T and B-cell lymphocytes rely on the diversity of their receptor chains to recognize different pathogens. The lymphocyte subclasses emerge from common ancestors generated with the same diversity of receptors during selection processes. Here we leverage biophysical models of receptor generation with machine learning models of selection to identify specific sequence features characteristic of functional lymphocyte repertoires and subrepertoires. Specifically, using only repertoire level sequence information, we classify CD4+ and CD8+ T-cells, find correlations between receptor chains arising during selection, and identify T-cell subsets that are targets of pathogenic epitopes. We also show examples of when simple linear classifiers do as well as more complex machine learning methods.


title: Transcription and splicing dynamics during early Drosophila development

abstract: Widespread co-transcriptional splicing has been demonstrated from yeast to human. However, most studies to date addressing the kinetics of splicing relative to transcription used either Saccharomyces cerevisiae or metazoan cultured cell lines. Here, we adapted native elongating transcript sequencing technology (NET-seq) to measure co-transcriptional splicing dynamics during the early developmental stages of Drosophila melanogaster embryos. Our results reveal the position of RNA polymerase II (Pol II) when both canonical and recursive splicing occur. We found heterogeneity in splicing dynamics, with some RNAs spliced immediately after intron transcription, whereas for other transcripts no splicing was observed over the first 100 nucleotides of the downstream exon. Introns that show splicing completion before Pol II has reached the end of the downstream exon are necessarily intron-defined. We studied the splicing dynamics of both nascent pre-mRNAs transcribed in the early embryo, which have few and short introns, as well as pre-mRNAs transcribed later in embryonic development, which contain multiple long introns. As expected, we found a relationship between the proportion of spliced reads and intron size. However, intron definition was observed at all intron sizes. We further observed that genes transcribed in the early embryo tend to be isolated in the genome whereas genes transcribed later are often overlapped by a neighboring convergent gene. In isolated genes, transcription termination occurred soon after the polyadenylation site, while in overlapped genes Pol II persisted associated with the DNA template after cleavage and polyadenylation of the nascent transcript. Taken together, our data unravels novel dynamic features of Pol II transcription and splicing in the developing Drosophila embryo.

category: molecular biology


title: Temporal and trophic partitioning promote coexistence between mesocarnivores in a Mediterranean landscape

abstract:
O_LIThe partition of the ecological niche can enhance the coexistence of predators due to differences in how they exploit three main resources: food, space, and time, the latter being an axis that often remains unexplored.
C_LIO_LIWe studied niche segregation in a Mediterranean mesocarnivore community composed by Vulpes vulpes, Genetta genetta, Meles meles and Herpestes ichneumon, addressing simultaneously different niche axes: the temporal, trophic and spatial axes.
C_LIO_LIWe assessed temporal segregation between mesopredators and prey and between potential competitors, using camera trap data between 2018-2020 in a Mediterranean landscape in Southern Spain. We deployed camera traps in 35 stations in three sites with varying vegetation cover within Donana National Park. We further examined the spatial overlap in activity centers and trophic preferences between potential competitors using diet information from studies performed in the study area.
C_LIO_LIWe found an overall temporal segregation between trophic generalist species, with species showing higher temporal overlap differing in their trophic preferences and/or showing limited spatial overlap. Furthermore, we observed an overall high overlap between the activity patterns of predators and their major prey in the area (the common genet vs small mammals and the red fox vs European rabbit).
C_LIO_LIOur study suggests that coexistence of the different species that compose the mesocarnivore assemblage in Mediterranean landscapes can be facilitated by subtle differences along the three main niche axes, with temporal segregation being a most pronounced mechanism. Our findings reinforce the idea that the coexistence mechanisms underlying community structure are multidimensional.
C_LI


title: Fine-scale coexistence between Mediterranean mesocarnivores is mediated by spatial, temporal and trophic resource partitioning


title: Mechanistic inferences from analysis of measurements of protein phase transitions in live cells

abstract: The combination of phase separation and disorder-to-order transitions can give rise to ordered, semi-crystalline fibrillar assemblies that underlie prion phenomena namely, the non-Mendelian transfer of information across cells. Recently, a method known as Distributed Amphifluoric Forster Resonance Energy Transfer (DAmFRET) was developed to study the convolution of phase separation and disorder-to-order transitions in live cells. In this assay, a protein of interest is expressed to a broad range of concentrations and the acquisition of local density and order, measured by changes in FRET, is used to map phase transitions for different proteins. The high-throughput nature of this assay affords the promise of uncovering sequence-to-phase behavior relationships in live cells. Here, we report the development of a supervised method to obtain automated and accurate classifications of phase transitions quantified using the DAmFRET assay. Systems that we classify as undergoing two-state discontinuous transitions are consistent with prion-like behaviors, although the converse is not always true. We uncover well-established and surprising new sequence features that contribute to two-state phase behavior of prion-like domains. Additionally, our method enables quantitative, comparative assessments of sequence-specific driving forces for phase transitions in live cells. Finally, we demonstrate that a modest augmentation of DAmFRET measurements, specifically time-dependent protein expression profiles, can allow one to apply classical nucleation theory to extract sequence-specific lower bounds on the probability of nucleating ordered assemblies. Taken together, our approaches lead to a useful analysis pipeline that enables the extraction of mechanistic inferences regarding phase transitions in live cells.

category: biophysics


title: Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

abstract:
Background and PurposeUp to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Subcortical regions play critical roles in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behavior at different timepoints after stroke.

MethodsWe pooled high-resolution T1-weighted MRI brain scans and behavioral data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behavior to non-lesioned subcortical volumes (Bonferroni-corrected, p<0.004). We tested subacute ([≤]90 days) and chronic ([≥]180 days) stroke subgroups separately, with exploratory analyses in early stroke ([≤]21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere.

ResultsWorse sensorimotor behavior was associated with a smaller ipsilesional thalamic volume in both early (n=179; d=0.68) and subacute (n=274, d=0.46) stroke. In chronic stroke (n=404), worse sensorimotor behavior was associated with smaller ipsilesional putamen (d=0.52) and nucleus accumbens (d=0.39) volumes, and a larger ipsilesional lateral ventricle (d=-0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n=256) was associated with smaller ipsilesional putamen (d=0.72) and larger lateral ventricle (d=-0.41) volumes, while several measures of activity limitations (n=116) showed no significant relationships. In the full cohort across all time (n=828), sensorimotor behavior was associated with the volumes of the ipsilesional nucleus accumbens (d=0.23), putamen (d=0.33), thalamus (d=0.33), and lateral ventricle (d=-0.23).

ConclusionsWe demonstrate significant relationships between post-stroke sensorimotor behavior and reduced volumes of subcortical gray matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings may provide additional targets for improving post-stroke sensorimotor outcomes.


title: Identification of blood autosomal cis-expression quantitative trait methylation (cis-eQTMs) in children

abstract:
BackgroundThe identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in childrens blood, using data from 832 children of the Human Early Life Exposome (HELIX) project.

MethodsBlood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition.

ResultsWe identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGenes TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. 40.4% of eQTMs had at least one genetic variant associated with methylation and expression levels. The overlap of autosomal cis eQTMs in childrens blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants.

ConclusionsThis catalogue of autosomal cis eQTMs in childrens blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/.

Funding: The study has received funding from the European Communitys Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Unions Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the project PI17/01225, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, "A way to make Europe") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII).

category: genomics


title: Spatially resolved transcriptomics reveals the architecture of the tumor/microenvironment interface

abstract: During tumor progression, cancer cells come into contact with novel non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct "interface" cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. An ETS-driven interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.

category: cancer biology


title: Memory shapes microbial populations

abstract: Correct decision making is fundamental for all living organisms to thrive under environmental changes. The patterns of environmental variation and the quality of available information define the most favourable strategy among multiple options, from randomly adopting a phenotypic state to sensing and reacting to environmental cues. Memory - a phenomenon often associated with, but not restricted to, higher multicellular organisms - can help when temporal correlations exist. How does memory manifest itself in unicellular organisms? Through a combination of deterministic modelling and stochastic simulations, we describe the population-wide fitness consequences of phenotypic memory in microbial populations. Moving beyond binary switching models, our work highlights the need to consider a broader range of switching behaviours when describing microbial adaptive strategies. We show that multiple cellular states capture the empirical observations of lag time distributions, overshoots, and ultimately the phenomenon of phenotypic heterogeneity. We emphasise the implications of our work in understanding antibiotic tolerance, and, in general, survival under fluctuating environments.


title: The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal cord injury in male mice

abstract: Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two ApoE4 alleles show worse functional outcomes and longer hospital stays after SCI but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly-ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post-SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.


title: Aryl hydrocarbon receptor and TGF-β inducible early gene mediate a transcriptional axis modulating immune homeostasis in mosquitoes

abstract:
Immune homeostasis ensures effective pathogen defense and avoids overactivity, which is achieved through an orchestrated transcriptional network. Here we demonstrate that mosquito AhR and TIEG mediate a transcriptional axis to modulate the immune response. The AhR agonist compromised the immunity with reduced survival upon the challenge with bacterium Serratia fonticola, while the AhR antagonists enhanced the immunity with increased survival. The phenotype of pharmacological immune enhancement was corroborated genetically by the AhR gene silencing. The transcriptome comparison following AhR manipulations highlighted a set of AhR regulated genes, from which transcription factor TIEG, the ortholog of Kruppel-like factor 10, was chosen for further study. TIEG was required for the AhR mediated immune modulation. Silencing TIEG increased survival and reversed the immune suppression mediated by agonist-activated AhR. Among the transcriptomes, there were genes sharing co-expression patterns in the cohorts with AhR manipulation pharmacologically or genetically. Moreover, the mosquitoes with silenced TIEG and AhR shared ~68% altered genes upon infection. Together, the data suggest TIEG is downstream of AhR, acting as a major transcription factor mediating the immune modulation. The TIEG targets include genes involved in sugar metabolism and circadian rhythms, both processes are critical for immune homeostasis. In the naive mosquitoes, the AhR-TIEG axis prevents the adverse effect of the overactivated IMD pathway created by silencing the inhibitor Caspar. In summary, AhR and TIEG constitute a transcriptional axis that mediates a gene network critical for maintaining immune homeostasis.

SignificanceImmune homeostasis is sustained by various parameters involving different transcriptional regulatory networks. Such knowledge in mosquitoes remains scarce. Here, using AhR manipulation and transcriptome interrogation, we demonstrate that AhR and TIEG (a KLF10 ortholog) constitute a transcriptional axis to mediate immune modulation using an antibacterial immune model in the malaria vector Anopheles gambiae. AhR is a ligand-activated transcription factor that senses environmental signals and transcribes relevant genes to modulate immune responses. TIEG/KLF10, conserved from invertebrates to mammals, mediates various transcriptional networks. Our data show that the AhR-TIEG axis controls the genes involving in sugar sensing and circadian rhythms in the infection context. This finding warrants further study to elucidate the transcriptional control of metabolic and circadian behind immune homeostasis.


title: Viscophobic turning dictates microalgae transport in viscosity gradients

abstract: Gradients in fluid viscosity characterize microbiomes ranging from mucus layers on marine organisms1 and human viscera2,3 to biofilms4. While such environments are widely recognized for their protective effects against pathogens and their ability to influence cell motility2,5, the physical mechanisms regulating cell transport in viscosity gradients remain elusive6-8, primarily due to a lack of quantitative observations. Through microfluidic experiments, we directly observe the transport of model biflagellated microalgae (Chlamydomonas reinhardtii) in controlled viscosity gradients. We show that despite their locally reduced swimming speed, the expected cell accumulation in the viscous region9,10 is stifled by a viscophobic turning motility. This deterministic cell rotation - consistent with a flagellar thrust imbalance11,12 - reorients the swimmers down the gradient, causing their accumulation in the low viscosity zones for sufficiently strong gradients. Corroborated by Langevin simulations and a three-point force model of cell propulsion, our results illustrate how the competition between viscophobic turning and viscous slowdown ultimately dictates the fate of population scale microbial transport in viscosity gradients.


title: The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence of Leptospira interrogans.

abstract:
Leptospira interrogans, the causative agent of most cases of human leptospirosis, must respond to myriad environmental signals during its free-living and pathogenic lifestyles. Previously, we compared L. interrogans cultivated in vitro and in vivo using a dialysis membrane chamber (DMC) peritoneal implant model. From these studies emerged the importance of genes encoding the Peroxide responsive regulators PerRA and PerRB. First described in in Bacillus subtilis, PerRs are widespread in Gram-negative and -positive bacteria, where regulate the expression of gene products involved in detoxification of reactive oxygen species and virulence. Using perRA and perRB single and double mutants, we establish that L. interrogans requires at least one functional PerR for infectivity and renal colonization in a reservoir host. Our finding that the perRA/B double mutant survives at wild-type levels in DMCs is noteworthy as it demonstrates that the loss of virulence is not due to a metabolic lesion (i.e., metal starvation) but instead reflects dysregulation of virulence-related gene products. Comparative RNA-Seq analyses of perRA, perRB and perRA/B mutants cultivated within DMCs identified 106 genes that are dysregulated in the double mutant, including ligA, ligB and lvrA/B sensory histidine kinases. Decreased expression of LigA and LigB in the perRA/B mutant was not due to loss of LvrAB signaling. The majority of genes in the perRA and perRB single and double mutant DMC regulons were differentially expressed only in vivo, highlighting the importance of host signals for regulating gene expression in L. interrogans. Importantly, the PerRA, PerRB and PerRA/B DMC regulons each contain multiple genes related to environmental sensing and/or transcriptional regulation. Collectively, our data suggest that PerRA and PerRB are part of a complex regulatory network that promotes host adaptation by L. interrogans within mammals.

Author SummaryLeptospirosis is a neglected tropical disease with a worldwide distribution. Globally, ~1 million cases and ~60,000 deaths are reported each year. The majority of cases of human leptospirosis are associated with Leptospira interrogans. Infection begins when a naive reservoir (or incidental) host comes into direct or indirect contact with urine from an infected reservoir host. While infection in reservoir hosts, including rats and mice, is generally asymptomatic, incidental hosts, including humans, may develop clinical symptoms ranging from mild flu-like illness to fulminant disease. The gene products required by leptospires for infection remain poorly understood. Herein, we establish that the FUR family regulators PerRA and PerRB function in parallel, contributing to infectivity and renal colonization in mice. By comparative transcriptomics, we identified >100 genes that were dysregulated in the perRA/B double mutant cultivated in rat peritoneal cavities, including the virulence determinants LigA and LigB. Importantly, the PerRA, PerRB and PerRA/B DMC regulons contain multiple genes related to environmental sensing and/or transcriptional regulation. Our data suggest that PerRA and PerRB are part of a complex regulatory network that promotes host adaptation by L. interrogans within mammals.


title: Working Memory Capacities Neurally Dissociate: Evidence from Acute Stroke

abstract: Substantial behavioral evidence implies the existence of separable working memory (WM) components for maintaining phonological and semantic information. In contrast, only a few studies have addressed the neural basis of phonological vs. semantic WM using functional neuroimaging and none has used a lesion-symptom mapping (LSM) approach. Here we address this gap, reporting a multivariate LSM study of phonological and semantic WM for 94 individuals at the acute stage of left hemisphere stroke. Testing at the acute stage avoids issues of brain reorganization and the adoption of patient strategies for task performance. The LSM analyses for each WM component controlled for the other WM component and semantic and phonological knowledge at the single word level. For phonological WM, the regions uncovered included the supramarginal gyrus, argued to be the site of phonological storage, and several cortical and subcortical regions plausibly related to inner rehearsal. For semantic WM, inferior frontal regions and the angular gyrus were uncovered. The findings thus provide converging evidence for separable systems for phonological and semantic WM that are distinguished from the systems supporting long-term knowledge representations in those domains.


title: Do congruent lip movements facilitate speech processing in a dynamic audiovisual multi-talker scenario? An ERP study with older and younger adults

abstract: In natural conversations, visible mouth and lip movements play an important role in speech comprehension. There is evidence that visual speech information improves speech comprehension, especially for older adults and under difficult listening conditions. However, the neurocognitive basis is still poorly understood. The present EEG experiment investigated the benefits of audiovisual speech in a dynamic cocktail-party scenario with 22 (aged 20 to 34 years) younger and 20 (aged 55 to 74 years) older participants. We presented three simultaneously talking faces with a varying amount of visual speech input (still faces, visually unspecific and audiovisually congruent). In a two-alternative forced-choice task, participants had to discriminate target words ("yes" or "no") among two distractors (one-digit number words). In half of the experimental blocks, the target was always presented from a central position, in the other half, occasional switches to a lateral position could occur. We investigated behavioral and electrophysiological modulations due to age, location switches and the content of visual information, analyzing response times and accuracy as well as the P1, N1, P2, N2 event-related potentials (ERPs) and the contingent negative variation (CNV) in the EEG. We found that audiovisually congruent speech information improved performance and modulated ERP amplitudes in both age groups, suggesting enhanced preparation and integration of the subsequent auditory input. In the older group, larger amplitude measures were found in early phases of processing (P1-N1). Here, amplitude measures were reduced in response to audiovisually congruent stimuli. In later processing phases (P2-N2) we found decreased amplitude measures in the older group, while an amplitude reduction for audiovisually congruent compared to visually unspecific stimuli was still observable. However, these benefits were only observed as long as no location switches occurred, leading to enhanced amplitude measures in later processing phases (P2-N2). To conclude, meaningful visual information in a multi-talker setting, when presented from the expected location, is shown to be beneficial for both younger and older adults.


title: Sexual selection drives maladaptive learning under climate warming

abstract:
O_LIEmpirical studies predicting the effects of the climate crisis on biodiversity loss that take into account learning ability and sexual selection are currently lacking.
C_LIO_LIUsing the African butterfly Bicyclus anynana, which shows strong phenotypic plasticity (i.e., polyphenism) in response to temperature, we find that learning produces a maladaptive mate preference under climate warming.
C_LIO_LIWe first modelled climate warming scenarios and then showed experimentally that as temperature becomes an unreliable cue to the onset of the dry season, adult butterflies displayed the wet season rather than the dry season form.
C_LIO_LIFemale learning further suppressed their innate, adaptive sexual preference for dry season males. Instead, females learned to prefer a phenotype transiently present during the seasonal transition.
C_LIO_LIFemale fertility and longevity were also indirectly affected by learning, likely reducing female fitness following climate warming.
C_LIO_LIOur results emphasize the importance of sexual selection, learning, and their fitness consequences for understanding (mal)adaptation of natural populations to climate warming.
C_LI

category: evolutionary biology


title: Warmer temperatures result in maladaptive learning of sexual preferences


title: Exosome-Mediated mRNA Delivery For SARS-CoV-2 Vaccination

abstract: Expression-dependent, Spike-only vaccines have been developed, deployed, and shown to be effective in the fight against SARS-CoV-2. However, additional approaches to vaccine development may be needed to meet existing and future challenges posed by emerging Spike variant strains, as well as a likely need for different antigen-delivery systems that are safe and effective for regular, periodic re-administration. We report here the development of mRNA-loaded exosomes, demonstrate that they can mediate the functional expression of heterologous proteins in vitro and in vivo, and have fewer adverse effects than comparable doses of lipid nanoparticles. Furthermore, we applied this approach to the development of an exosome-based, multiplexed mRNA vaccine that drives expression of immunogenic SARS-CoV-2 Nucleocapsid and Spike proteins. This vaccine elicited long-lasting cellular and humoral responses to Nucleocapsid and to Spike, demonstrating that exosome-based mRNA formulations represent a previously unexplored platform in the fight against COVID-19 and other infectious diseases.


title: Utility of polygenic embryo screening for disease depends on the selection strategy

abstract: Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. Our main finding is that a strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. Specifically, when only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. For example, a relative risk reduction of {approx}50% for schizophrenia can be achieved by selecting the embryo with the lowest PRS out of five viable embryos. We systematically examine the impact of several factors on the utility of screening, including the variance explained by the PRS, the number of embryos, the disease prevalence, the parental PRSs, and the parental disease status. When quantifying the utility, we consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions. We also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating "virtual" couples and offspring based on real genomes from schizophrenia and Crohns disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.

category: genetics


title: Population receptive field shapes in early visual cortex are nearly circular

abstract:
The visual field region where a stimulus evokes a neural response is called the receptive field (RF). Analytical tools combined with functional MRI can estimate the receptive field of the population of neurons within a voxel. Circular population RF (pRF) methods accurately specify the central position of the pRF and provide some information about the spatial extent (diameter) of the receptive field. A number of investigators developed methods to further estimate the shape of the pRF, for example whether the shape is more circular or elliptical. There is a report that there are many pRFs with highly elliptical pRFs in early visual cortex (V1-V3; Silson et al., 2018). Large aspect ratios (>2) are difficult to reconcile with the spatial scale of orientation columns or visual field map properties in early visual cortex. We started to replicate the experiments and found that the software used in the publication does not accurately estimate RF shape: it produces elliptical fits to circular ground-truth data. We analyzed an independent data set with a different software package that was validated over a specific range of measurement conditions, to show that in early visual cortex the aspect ratios are less than 2. Furthermore, current empirical and theoretical methods do not have enough precision to discriminate ellipses with aspect ratios of 1.5 from circles. Through simulation we identify methods for improving sensitivity that may estimate ellipses with smaller aspect ratios. The results we present are quantitatively consistent with prior assessments using other methodologies.

Significance StatementWe evaluated whether the shape of many population receptive fields in early visual cortex is elliptical and differs substantially from circular. We evaluated two tools for estimating elliptical models of the pRF; one tool was valid over the measured compliance range. Using the validated tool, we found no evidence that confidently rejects circular fits to the pRF in visual field maps V1, V2 and V3. The new measurements and analyses are consistent with prior theoretical and experimental assessments in the literature.


title: Expectancy-based rhythmic entrainment as continuous Bayesian inference

abstract: When presented with complex rhythmic auditory stimuli, humans are able to track underlying temporal structure (e.g., a "beat"), both covertly and with their movements. This capacity goes far beyond that of a simple entrained oscillator, drawing on contextual and enculturated timing expectations and adjusting rapidly to perturbations in event timing, phase, and tempo. Previous modeling work has described how entrainment to rhythms may be shaped by event timing expectations, but sheds little light on any underlying computational principles that could unify the phenomenon of expectation-based entrainment with other brain processes. Inspired by the predictive processing framework, we propose that the problem of rhythm tracking is naturally characterized as a problem of continuously estimating an underlying phase and tempo based on precise event times and their correspondence to timing expectations. We present two inference problems formalizing this insight: PIPPET (Phase Inference from Point Process Event Timing) and PATIPPET (Phase and Tempo Inference). Variational solutions to these inference problems resemble previous "Dynamic Attending" models of perceptual entrainment, but introduce new terms representing the dynamics of uncertainty and the influence of expectations in the absence of sensory events. These terms allow us to model multiple characteristics of covert and motor human rhythm tracking not addressed by other models, including sensitivity of error corrections to inter-event interval and perceived tempo changes induced by event omissions. We show that positing these novel influences in human entrainment yields a range of testable behavioral predictions. Guided by recent neurophysiological observations, we attempt to align the phase inference framework with a specific brain implementation. We also explore the potential of this normative framework to guide the interpretation of experimental data and serve as building blocks for even richer predictive processing and active inference models of timing.


title: Conserved visual capacity of rats under red light

abstract: Recent studies examine the behavioral capacities of rats and mice with and without visual input, and the neuronal mechanisms underlying such capacities. These animals are assumed to be functionally blind under red light, an assumption that might originate in the fact that they are dichromats who possess ultraviolet and green but not red cones. But the inability to see red as a color does not necessarily rule out form vision based on red light absorption. We measured Long-Evans rats capacity for visual form discrimination under red light of various wavelength bands. Upon viewing a black and white grating, they had to distinguish between two categories of orientation, horizontal and vertical. Psychometric curves plotting judged orientation versus angle demonstrate the conserved visual capacity of rats under red light. Investigations aiming to explore rodent physiological and behavioral functions in the absence of visual input should not assume red-light blindness.


title: Cortical feedback and gating in odor discrimination and generalization

abstract: A central question in neuroscience is how context changes perception of sensory stimuli. In the olfactory system, for example, experiments show that task demands can drive divergence and convergence of cortical odor responses, likely underpinning olfactory discrimination and generalization. Here, we propose a simple statistical mechanism for this effect based on unstructured feedback from the central brain to the olfactory bulb, which represents the context associated with an odor, and sufficiently selective cortical gating of sensory inputs. Strikingly, the model predicts that both convergence and divergence of cortical odor patterns should increase when odors are initially more similar, an effect reported in recent experiments. The theory in turn predicts reversals of these trends following experimental manipulations and in neurological conditions that increase cortical excitability.


title: Modelling the neural code in large populations of correlated neurons

abstract: Neurons respond selectively to stimuli, and thereby define a code that associates stimuli with population response patterns. Certain correlations within population responses (noise correlations) significantly impact the information content of the code, especially in large populations. Understanding the neural code thus necessitates response models that quantify the coding properties of modelled populations, while fitting large-scale neural recordings and capturing noise correlations. In this paper we propose a class of response model based on mixture models and exponential families. We show how to fit our models with expectation-maximization, and that they capture diverse variability and covariability in recordings of macaque primary visual cortex. We also show how they facilitate accurate Bayesian decoding, provide a closed-form expression for the Fisher information, and are compatible with theories of probabilistic population coding. Our framework could allow researchers to quantitatively validate the predictions of neural coding theories against both large-scale neural recordings and cognitive performance.


title: Interspecies variation of larval locomotion kinematics in the genus Drosophila and its relation to habitat temperature

abstract: Speed and trajectory of locomotion are characteristic traits of individual species. During evolution, locomotion kinematics is likely to have been tuned for survival in the habitats of each species. Although kinematics of locomotion is thought to be influenced by habitats, the quantitative relation between the kinematics and environmental factors has not been fully revealed. Here, we performed comparative analyses of larval locomotion in 11 Drosophila species. We found that larval locomotion kinematics are divergent among the species. The diversity is not correlated to the body length but is correlated instead to the habitat temperature of the species. Phylogenetic analyses using Bayesian inference suggest that the evolutionary rate of the kinematics is diverse among phylogenetic trees. The results of this study imply that the kinematics of larval locomotion has diverged in the evolutionary history of the genus Drosophila and evolved under the effects of the ambient temperature of habitats.


title: Decomposing the role of alpha oscillations during brain maturation

abstract: Childhood and adolescence are critical stages of the human lifespan, in which fundamental neural reorganizational processes take place. A substantial body of literature investigated neurophysiological changes during brain maturation by focusing on the most dominant feature of the human EEG signal: the alpha oscillation. Ambiguous results were reported for the developmental trajectory of the power of the alpha oscillation. Simulations in this study show that conventional measures of alpha power are confounded by various factors and need to be decomposed into periodic and aperiodic components, which represent distinct underlying brain mechanisms. It is therefore unclear how each part of the signal relates to changes during brain maturation. Using multivariate Bayesian generalized linear mixed models, we examined aperiodic and periodic parameters of alpha activity in the largest openly available pediatric dataset (N=2529, age range 5-21 years) and replicated these findings in a preregistered analysis of an independent validation sample (N=369, age range 6-21yrs). First, the well documented age-related decrease in total alpha power was replicated. However, when controlling for the aperiodic signal component, our findings provide strong evidence for a reversed developmental trajectory of the periodic alpha power, whereas the aperiodic signal components, slope and offset, decreased. Consequently, earlier interpretations on age related changes of alpha power need to be fundamentally reconsidered, incorporating changes in the aperiodic signal. The interpretation of decreased total alpha power as elimination of active synapses rather links to decreases in the aperiodic intercept. Instead, additional analyses of diffusion tensor imaging data indicate that the maturational increase in periodic alpha power is related to increased thalamocortical connectivity. Functionally, our results suggest that increased thalamic control of cortical alpha power is linked to improved attentional performance during brain maturation.


title: Insula cortex gates the interplay of action observation and preparation for controlled imitation

abstract: Perceiving, anticipating and responding to the actions of another person are fundamentally entwined processes such that seeing anothers movement can prompt automatic imitation, as in social mimicry and contagious yawning. Yet the direct-matching of others movements is not always appropriate, so this tendency must be controlled. This necessitates the hierarchical integration of the systems for action mirroring with domain-general control networks. Here we use functional magnetic resonance imaging (fMRI) and computational modelling to examine the top-down and context-dependent modulation of mirror representations and their influence on motor planning. Participants performed actions that either intentionally or incidentally imitated, or counter-imitated, an observed action. Analyses of these fMRI data revealed a region in the mid-occipital gyrus (MOG) where activity differed between imitation versus counter-imitation in a manner that depended on whether this was intentional or incidental. To identify broader cortical network mechanisms underlying this interaction between intention and imitativeness, we used dynamic causal modelling to pose specific hypotheses which embody assumptions about inter-areal interactions and contextual modulations. These models each incorporated four regions - medial temporal V5 (early motion perception), MOG (action-observation), supplementary motor area (action planning), and anterior insula (executive control) - but differ in their interactions and hierarchical structure. The best model of our data afforded a crucial role for the anterior insula, gating the interaction of supplementary motor area and MOG activity. This provides a novel brain network-based account of task-dependent control over the integration of motor planning and mirror systems, with mirror responses suppressed for intentional counter-imitation.


title: Epigenetic dynamics of centromeres and neocentromeres in Cryptococcus deuterogattii

abstract: Deletion of native centromeres in the human fungal pathogen Cryptococcus deuterogattii leads to neocentromere formation. Native centromeres span truncated transposable elements, while neocentromeres do not and instead span actively expressed genes. To explore the epigenetic organization of neocentromeres, we analyzed the distribution of the heterochromatic histone modification H3K9me2, 5mC DNA methylation and the euchromatin mark H3K4me2. Native centromeres are enriched for both H3K9me2 and 5mC DNA methylation marks and are devoid of H3K4me2, while neocentromeres do not exhibit any of these features. Neocentromeres in cen10{Delta} mutants are unstable and chromosome-chromosome fusions occur. After chromosome fusion, the neocentromere is inactivated and the native centromere of the chromosome fusion partner remains as the sole, active centromere. In the present study, the active centromere of a fused chromosome was deleted to investigate if epigenetic memory promoted the re-activation of the inactive neocentromere. Our results show that the inactive neocentromere is not re-activated and instead a novel neocentromere forms directly adjacent to the deleted centromere of the fused chromosome. To study the impact of transcription on centromere stability, the actively expressed URA5 gene was introduced into the CENP-A bound regions of a native centromere. The introduction of the URA5 gene led to a loss of CENP-A from the native centromere, and a neocentromere formed adjacent to the native centromere location. Remarkably, the inactive, native centromere remained enriched for heterochromatin, yet the integrated gene was expressed and devoid of H3K9me2. A cumulative analysis of multiple CENP-A distribution profiles revealed centromere drift in C. deuterogattii, a previously unreported phenomenon in fungi. The CENP-A-binding shifted within the ORF-free regions and showed a possible association with a truncated transposable element. Taken together, our findings reveal that neocentromeres in C. deuterogattii are highly unstable and are not marked with an epigenetic memory, distinguishing them from native centromeres.


title: Dorsomedial prefrontal neural ensembles reflect changes in task utility

abstract:
When performing a physically demanding behavior, sometimes the optimal choice is to quit the behavior rather than persist in order to minimize energy expenditure for the benefits gained. The dorsomedial prefrontal cortex (dmPFC), consisting of the anterior cingulate cortex and secondary motor area, likely contributes towards such utility assessments. Here, we examined how male rat dmPFC single unit and ensemble level activity corresponded to changes in task utility and quitting in an effortful weight lifting task. Rats carried out two task paradigms: one that became progressively more physically demanding over time and a second fixed effort version. Rats could quit the task at any time. Dorsomedial PFC neurons were highly responsive to each behavioral stage of the task, consisting of rope pulling, reward retrieval, and reward area leaving. Activity was highest early in sessions, commensurate with the highest relative task utility, then decreased until the point of quitting. Neural ensembles consistently represented the sequential behavioral phases of the task. However, these representations were modified over time and became more distinct over the course of the session. These results suggest that dmPFC neurons represent behavioral states that are dynamically modified as behaviors lose their utility, culminating in task quitting.

New & NoteworthyWhen carrying out a physically demanding task animals must continually assess whether to persist or quit. In this study we recorded neurons in the dorsomedial prefrontal cortex (dmPFC) of rats as they carried out a challenging weightlifting task, up to the point of quitting. We demonstrate that dmPFC neurons form a representation of the task that is modified, via a decrease in firing rate, by the decreasing utility of the task that may signal quitting.


title: Auditory Stimulus-response Modeling with a Match-Mismatch Task

abstract: An auditory stimulus can be related to the brain response that it evokes by a stimulus-response model fit to the data. This offers insight into perceptual processes within the brain and is also of potential use for devices such as Brain Computer Interfaces (BCI). The quality of the model can be quantified by measuring the fit with a regression problem, or by applying it to a classification task and measuring its performance. Here we focus on a match-mismatch (MM) task that entails deciding whether a segment of brain signal matches, via a model, the auditory stimulus that evoked it. The MM task allows stimulus-response models to be evaluated in the limit of very high model accuracy, making it an attractive alternative to the more commonly used task of auditory attention detection (AAD). The MM task does not require class labels, so it is immune to mislabeling, and it is applicable to data recorded in listening scenarios with only one sound source, thus it is cheap to obtain large quantities of training and testing data. Performance metrics from this task, associated with regression accuracy, provide complementary insights into the relation between stimulus and response, as well as information about discriminatory power directly applicable to BCI applications. Using these metrics, we describe a range of models of increasing complexity that we compare to methods in the literature, showing state-of-the-art performance. We document in detail one particular implementation, calibrated on a publicly-available database, that can serve as a robust reference to evaluate future developments.


title: Age-dependent contribution of domain-general networks to semantic cognition

abstract: Aging is characterized by a decline of cognitive control. In semantic cognition, this leads to the paradox that older adults usually show poorer task performance than young adults despite their greater semantic knowledge. So far, the underlying neural changes of these behavioral differences are poorly understood. In the current neuroimaging study, we investigated the contribution of domain-general networks to a verbal semantic fluency task in young and older adults. In both age groups, task processing was characterized by a strong positive integration within the multiple-demand as well as between the multiple-demand and the default mode system during semantic fluency. However, the behavioral relevance of strengthened connectivity differed between groups: While within-network functional connectivity in both networks predicted greater efficiency in semantic fluency in young adults, it was associated with a slower performance in older adults. Moreover, only young adults profited from increased connectivity between networks for their semantic memory performance. Our results suggest that the functional coupling of usually anti-correlated networks is critical for successful task processing, independent of age, when access to semantic memory is required. Furthermore, our findings lend novel support to the notion of reduced efficiency in the aging brain, due to neural dedifferentiation in semantic cognition.


title: Rhinovirus reduces the severity of subsequent respiratory viral infections by interferon-dependent and -independent mechanisms

abstract:
Coinfection by unrelated viruses in the respiratory tract is common and can result in changes in disease severity compared to infection by individual virus strains. We have previously shown that inoculation of mice with rhinovirus (RV) two days prior to inoculation with a lethal dose of influenza A virus (PR8), provides complete protection against mortality and reduces morbidity. In this study, we extended that finding to a second lethal respiratory virus, pneumonia virus of mice (PVM) and analyzed potential mechanisms whereby RV reduces lethal viral pneumonia caused by PR8 and PVM. RV prevented mortality and weight loss associated with PVM infection, suggesting that RV-mediated protection is more effective against PVM than PR8. Major changes in host gene expression upon PVM infection were delayed compared to PR8, which likely provides a larger time frame for RV-induced gene expression to alter the course of disease. Overall, RV induced earlier recruitment of inflammatory cells, while these populations were reduced at later times in RV-inoculated mice. Findings common to both virus pairs included upregulated expression of mucin-associated genes and dampening of inflammation-related genes in mice that were inoculated with RV prior to lethal virus infection. However, type I IFN signaling was required for RV-mediated protection against PR8, but not PVM. IFN signaling had minor effects on PR8 replication and contributed to controlling neutrophilic inflammation and subsequent hemorrhagic lung pathology in RV/PR8 infected mice. These findings, combined with differences in virus replication levels and disease severity, suggest that the suppression of inflammation in RV/PVM infected mice may be due to early, IFN-independent suppression of viral replication, while in RV/PR8 infected mice may be due to IFN-dependent modulation of immune responses. Thus, a mild upper respiratory viral infection can reduce the severity of a subsequent severe viral infection in the lungs through virus-dependent mechanisms.

Author SummaryRespiratory viruses from diverse families co-circulate in human populations and are frequently detected within the same host. Though clinical studies suggest that infection by more than one unrelated respiratory virus may alter disease severity, animal models in which we can control the doses, timing, and strains of coinfecting viruses are critical to understand how coinfection affects disease severity. In this study, we compared gene expression and immune cell recruitment between two pairs of viruses (RV/PR8 and RV/PVM) inoculated sequentially in mice that both result in reduced severity compared to lethal infection by PR8 or PVM alone. Reduced disease severity was associated with suppression of inflammatory responses in the lungs. However, differences in disease kinetics and host and viral gene expression suggest that protection by coinfection with RV may be due to distinct molecular mechanisms. Indeed, we found that antiviral cytokine signaling was required for RV-mediated protection against lethal infection by PR8, but not PVM.


title: The oxidative stress response of pathogenic Leptospira is controlled by two peroxide stress regulators which putatively cooperate in controlling virulence.

abstract:
Pathogenic Leptospira are the causative agents of leptospirosis, the most widespread zoonotic infectious disease. Leptospirosis is a potentially severe and life-threatening emerging disease with highest burden in sub-tropical areas and impoverished populations. Mechanisms allowing pathogenic Leptospira to survive inside a host and induce acute leptospirosis are not fully understood. The ability to resist deadly oxidants produced by the host during infection is pivotal for Leptospira virulence. We have previously shown that genes encoding defenses against oxidants in L. interrogans are repressed by PerRA (encoded by LIMLP_10155), a peroxide stress regulator of the Fur family. In this study, we describe the identification and characterization of another putative PerR-like regulator (LIMLP_05620) in L. interrogans. Protein sequence and phylogenetic analyses indicated that LIMLP_05620 displayed all the canonical PerR amino acid residues and is restricted to pathogenic Leptospira clades. We therefore named this PerR-like regulator PerRB. In L. interrogans, the PerRB regulon is distinct from that of PerRA. While a perRA mutant had a greater tolerance to peroxide, inactivating perRB led to a higher tolerance to superoxide, suggesting that these two regulators have a distinct function in the adaptation of L. interrogans to oxidative stress. The concomitant inactivation of perRA and perRB resulted in a higher tolerance to both peroxide and superoxide and, unlike the single mutants, a double perRAperRB mutant was avirulent. Interestingly, this correlated with major changes in gene and non-coding RNA expression. Notably, several virulence-associated genes (clpB, ligA/B, and lvrAB) were repressed. By obtaining a double mutant in a pathogenic Leptospira strain, our study has uncovered an interplay of two PerRs in the adaptation of Leptospira to oxidative stress with a putative role in virulence and pathogenicity, most likely through the transcriptional control of a complex regulatory network.

Author summaryLeptospirosis is a widespread infectious disease responsible for over one million of severe cases and 60 000 fatalities annually worldwide. This neglected and emerging disease has a worldwide distribution, but it mostly affects populations from developing countries in sub-tropical areas. The causative agents of leptospirosis are pathogenic bacterial Leptospira spp. There is a considerable deficit in our knowledge of these atypical bacteria, including their virulence mechanisms. In addition to the Leptospira PerRA regulator that represses defenses against peroxide, we have identified and characterized a second PerR regulator in pathogenic Leptospira species (PerRB) that participates in Leptospira tolerance to superoxide. Phenotypic and transcriptomic analyses of single PerRA and PerRB mutants suggest that the two PerRs fulfill distinct functions in the adaptation to oxidative stress. Concomitant inactivation of PerRA and PerRB resulted in a higher tolerance to both peroxide and superoxide. Moreover, the perRAperRB mutant lost its virulence. Major changes in gene expression, including a decreased expression of several virulence factors, were observed in the double perRAperRB mutant. Our study suggests that PerRA and PerRB cooperate to orchestrate a complex regulatory network involved in Leptospira virulence.


title: Single gene targeted nanopore sequencing enables simultaneous identification and antimicrobial resistance detection of sexually transmitted infections

abstract:
ObjectivesTo develop a simple DNA sequencing test for simultaneous identification and antimicrobial resistance (AMR) detection of multiple sexually transmitted infections (STIs).

MethodsReal-time PCR (qPCR) was initially performed to identify Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Mycoplasma genitalium (MG) and Trichomonas vaginalis (TV) infections among a total of 200 vulvo-vaginal swab samples from female sex workers in Ecuador. qPCR positive samples plus qPCR negative controls for these STIs were subjected to single gene targeted PCR MinION-nanopore sequencing using the smartphone operated MinIT.

ResultsAmong 200 vulvo-vaginal swab samples 43 were qPCR positive for at least one of the STIs. Single gene targeted nanopore sequencing generally yielded higher pathogen specific read counts in qPCR positive samples than qPCR negative controls. Of the 26 CT, NG or MG infections identified by qPCR, 25 were clearly distinguishable from qPCR negative controls by read count. Discrimination of TV qPCR positives from qPCR negative controls was poorer as many had low pathogen loads (qPCR cycle threshold >35) which produced few specific reads. Real-time AMR profiling revealed that 3/3 NG samples identified had gyrA mutations associated with fluoroquinolone resistance, while none of the MG samples possessed 23S rRNA gene mutations contributing to macrolide resistance.

ConclusionsSingle gene targeted nanopore sequencing for diagnosing and simultaneously identifying key antimicrobial resistance markers for four common genital STIs shows promise. Further work to optimise accuracy, reduce costs and improve speed may allow sustainable approaches for managing STIs and emerging AMR in resource poor and laboratory limited settings.


title: Predatory selection of mucoid, antibiotic resistant Pseudomonas putida phenotype by myxobacterium Cystobacter ferrugineus

abstract: Predation contributes to the structure and diversity of microbial communities. Predatory myxobacteria are ubiquitous to a variety of microbial habitats and capably consume a broad diversity of microbial prey. Predator-prey experiments utilizing myxobacteria have provided details into predatory mechanisms and features that facilitate consumption of prey. However, prey resistance to myxobacterial predation remains underexplored, and prey resistances have been observed exclusively from predator-prey experiments that included the model myxobacterium Myxococcus xanthus. Utilizing a predator-prey pairing that instead included the myxobacterium, Cystobacter ferrugineus, with Pseudomonas putida as prey, we infrequently observed surviving phenotypes capable of eluding predation. Comparative transcriptomics between P. putida unexposed to C. ferrugineus and the survivor phenotype suggested that increased expression of efflux pumps, genes associated with mucoid conversion, and various membrane features contribute to predator avoidance. The P. putida survivor phenotype was confirmed to be resistant to the antibiotics kanamycin, gentamicin, and tetracycline and to produce more alginate, pyoveridine, and phenazine-1-carboxylic acid than predator-unexposed P. putida. Unique features observed from the survivor phenotype including small colony variation, efflux-mediated antibiotic resistance, phenazine-1-carboxylic acid production, and increased mucoid conversion overlap with traits associated with Pseudomonas aeruginosa predator avoidance and pathogenicity. The survivor phenotype also benefited from increased predator resistance during subsequent predation assays. These results demonstrate the utility of myxobacterial predator-prey models and provide insight into prey resistances in response to predatory stress might contribute to the phenotypic diversity and structure of bacterial communities.


title: The spatial-temporal dynamics of respiratory syncytial virus infections across the east-west coasts of Australia during 2016-17

abstract: Respiratory syncytial virus (RSV) is an important human respiratory pathogen. In temperate regions a distinct seasonality is observed, where peaks of infections typically occur in early winter, often preceding the annual influenza season. Infections are associated with high rates of morbidity and mortality, and in some populations exceeds that of influenza. Two subtypes, RSV-A and RSV-B, have been described, and molecular epidemiological studies have shown that both viruses mostly co-circulate. This trend also appears to be the case for Australia, however previous genomic studies have been limited to cases from one Eastern state - New South Wales. As such, the broader spatial patterns and viral traffic networks across the continent are not known. Here, we conducted a whole genome study of RSV comparing strains across eastern and western Australia during the period January 2016 to June 2017. In total, 96 new RSV genomes were sequenced, compiled with previously generated data, and examined using a phylodynamic approach. This analysis revealed that both RSV-A and RSV-B strains were circulating, and each subtype was dominated by a single genotype, RSV-A/ON1-like and RSV-B/BA10-like viruses. Some geographical clustering was evident in strains from both states with multiple distinct sub-lineages observed and relatively low mixing across jurisdictions suggesting that endemic transmission was likely seeded from imported, unsampled locations. Overall, the RSV phylogenies reflected a complex pattern of interactions across multiple epidemiological scales from fluid virus traffic across global and regional networks to fine-scale local transmission events.


title: Genetic demultiplexing of pooled single-cell RNA-sequencing samples in cancer facilitates effective experimental design

abstract:
BackgroundPooling cells from multiple biological samples prior to library preparation within the same single-cell RNA sequencing experiment provides several advantages, including lower library preparation costs and reduced unwanted technological variation, such as batch effects. Computational demultiplexing tools based on natural genetic variation between individuals provide a simple approach to demultiplex samples, which does not require complex additional experimental procedures. However, these tools have not been evaluated in cancer, where somatic variants, which could differ between cells from the same sample, may obscure the signal in natural genetic variation.

ResultsHere, we performed in silico benchmark evaluations by combining raw sequencing reads from multiple single-cell samples in high-grade serous ovarian cancer, which has a high copy number burden, and lung adenocarcinoma, which has a high tumor mutational burden. Our results confirm that genetic demultiplexing tools can be effectively deployed on cancer tissue using a pooled experimental design, although high proportions of ambient RNA from cell debris reduce performance.

ConclusionsThis strategy provides significant cost savings through pooled library preparation. To facilitate similar analyses at the experimental design phase, we provide freely accessible code and a reproducible Snakemake workflow built around the best-performing tools found in our in silico benchmark evaluations, available at https://github.com/lmweber/snp-dmx-cancer.


title: A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine

abstract: Gut microbial products direct growth, differentiation, and development in the animal host. Disruptions to host-microbe interactions have profound health consequences, that include onset of chronic inflammatory illnesses. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled transcriptional activity in individual cells from the intestine, and associated tissue, of zebrafish larvae that we raised in the presence or absence of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome that included regulatory effects on patterning, metabolic and immune activity. For example, we showed that removal of microbes hindered pro-angiogenic signals in the developing vasculature, resulting in impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type. Furthermore, we provide a web-based resource for single-cell gene expression visualization under conventional and germ-free conditions to facilitate exploration of this dataset.

category: developmental biology


title: Identifying latent behavioral states in animal movement with M4, a non-parametric Bayesian method

abstract:
O_LIUnderstanding animal movement often relies upon telemetry and biologging devices. These data are frequently used to estimate latent behavioral states to help understand why animals move across the landscape. While there are a variety of methods that make behavioral inferences from biotelemetry data, some features of these methods (e.g., analysis of a single data stream, use of parametric distributions) may limit their generality to reliably discriminate among behavioral states.
C_LIO_LITo address some of the limitations of existing behavioral state estimation models, we introduce a non-parametric Bayesian framework called the mixed-membership method for movement (M4), which is available within the open-source bayesmove R package. This framework can analyze multiple data streams (e.g., step length, turning angle, acceleration) without relying on parametric distributions, which may capture complex behaviors more successfully than current methods. We tested our Bayesian framework using simulated trajectories and compared model performance against two segmentation methods (behavioral change point analysis (BCPA) and segclust2d), one machine learning method (expectation-maximization binary clustering (EMbC)), and one type of state-space model (hidden Markov model (HMM)). We also illustrated this Bayesian framework using movements of juvenile snail kites (Rostrhamus sociabilis) in Florida, USA.
C_LIO_LIThe Bayesian framework estimated breakpoints more accurately than the other segmentation methods for tracks of different lengths. Likewise, the Bayesian framework provided more accurate estimates of behavior than the other state estimation methods when simulations were generated from less frequently considered distributions (e.g., truncated normal, beta, uniform). Three behavioral states were estimated from snail kite movements, which were labeled as  encamped,  area-restricted search, and  transit. Changes in these behaviors over time were associated with known dispersal events from the nest site, as well as movements to and from possible breeding locations.
C_LIO_LIOur non-parametric Bayesian framework estimated behavioral states with comparable or superior accuracy compared to the other methods when step lengths and turning angles of simulations were generated from less frequently considered distributions. Since the most appropriate parametric distributions may not be obvious a priori, methods (such as M4) that are agnostic to the underlying distributions can provide powerful alternatives to address questions in movement ecology.
C_LI


title: Cortical representation of touch in silico

abstract: With its six layers and ~12000 neurons, a cortical column is a complex network whose function is plausibly greater than the sum of its constituents. Functional characterization of its network components will require going beyond the brute-force modulation of the neural activity of a small group of neurons. Here we introduce an open-source, biologically inspired, computationally efficient network model of the somatosensory cortexs granular and supragranular layers after reconstructing the barrel cortex in soma resolution. Comparisons of the network activity to empirical observations showed that the in silico network replicates the known properties of touch representations and whisker deprivation-induced changes in synaptic strength induced in vivo. Simulations show that the history of the membrane potential acts as a spatial filter that determines the presynaptic population of neurons contributing to a post-synaptic action potential; this spatial filtering might be critical for synaptic integration of top-down and bottom-up information.


title: Cognitive insights from evolutionarily new brain structures in prefrontal cortex

abstract: While the disproportionate expansion of lateral prefrontal cortex (LPFC) in humans compared to non-human primates is accepted, the relationship between evolutionarily new LPFC brain structures and uniquely human cognitive skills is largely unknown. Here, we tested the relationship between variability in evolutionarily new LPFC tertiary sulci and reasoning skills in a pediatric cohort. A novel data-driven approach in independent discovery and replication samples revealed that the depth of specific LPFC tertiary sulci predicts individual differences in reasoning skills beyond age. These findings support a classic, yet untested, theory linking the protracted development of tertiary sulci to late-developing cognitive processes. We suggest that deeper LPFC tertiary sulci reflect reduced short-range connections in white matter, which in turn, improve the efficiency of local neural signals underlying cognitive skills such as reasoning that are central to human cognitive development. To expedite discoveries in future neuroanatomical-behavioural studies, we share sulcal definitions with the field.


title: The stringent factor Rel from Mycobacterium abscessus regulates metabolism and works as a (p)ppGpp hydrolase

abstract:
The stringent response is a broadly conserved stress response system that exhibits functional variability across bacterial clades. Here, we characterize the role of the stringent factor Rel in the non-tuberculous mycobacterial pathogen, Mycobacterium abscessus (Mab). We found that deletion of rel does not ablate (p)ppGpp synthesis, and that rel does not provide a survival advantage in several stress conditions, or in antibiotic treatment. Transcriptional data show that RelMab is involved in regulating expression of anabolism and growth genes in stationary phase. However, it does not activate transcription of stress response or antibiotic resistance genes, and actually represses transcription of many antibiotic resistance genes. This work shows that there is an unannotated (p)ppGpp synthetase in Mab.

ImportanceIn this study, we examined the functional roles of the stringent factor Rel in Mycobacterium abscessus (Mab). In most species, stringent factors synthesize the alarmone (p)ppGpp, which globally alters transcription to promote growth arrest and survival under stress and in antibiotic treatment. Our work shows that in Mab, an emerging pathogen which is resistant to many antibiotics, the stringent factor Rel is not solely responsible for synthesizing (p)ppGpp. We find that RelMab downregulates many metabolic genes under stress, but does not upregulate stress response genes and does not promote antibiotic tolerance. This study implies that there is another critical but unannotated (p)ppGpp synthetase in Mab, and suggests that RelMab inhibitors are unlikely to sensitize Mab infections to antibiotic treatment.


title: In Mycobacterium abscessus, the stringent factor Rel regulates metabolism, but is not the only (p)ppGpp synthase