A limbic circuit selectively links active escape to food suppression
Stress has pleiotropic physiologic effects, but the neural circuits linking stress to these responses are not well understood. Here, we describe a novel population of lateral septum neurons expressing neurotensin (LSNts) in mice that are selectively tuned to specific types of stress. LSNts neurons increase their activity during active escape, responding to stress when flight is a viable option, but not when associated with freezing or immobility. Chemogenetic activation of LSNts neurons decreases food intake and body weight, without altering locomotion and anxiety. LSNts neurons co-express several molecules including Glp1r...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Pattern regulation in a regenerating jellyfish
Clytia hemisphaerica jellyfish, with their tetraradial symmetry, offer a novel paradigm for addressing patterning mechanisms during regeneration. Here we show that an interplay between mechanical forces, cell migration and proliferation allows jellyfish fragments to regain shape and functionality rapidly, notably by efficient restoration of the central feeding organ (manubrium). Fragmentation first triggers actomyosin-powered remodeling that restores body umbrella shape, causing radial smooth muscle fibers to converge around 'hubs' which serve as positional landmarks. Stabilization of these hubs, and associated expression ...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Extensive and diverse patterns of cell death sculpt neural networks in insects
Changes to the structure and function of neural networks are thought to underlie the evolutionary adaptation of animal behaviours. Among the many developmental phenomena that generate change programmed cell death appears to play a key role. We show that cell death occurs continuously throughout insect neurogenesis and happens soon after neurons are born. Mimicking an evolutionary role for increasing cell numbers, we artificially block programmed cell death in the medial neuroblast lineage inDrosophila melanogaster, which results in the production of 'undead' neurons with complex arborisations and distinct neurotransmitter ...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Regulation of stem/progenitor cell maintenance by BMP5 in prostate homeostasis and cancer initiation
Tissue homeostasis relies on the fine regulation between stem and progenitor cell maintenance and lineage commitment. In the adult prostate, stem cells have been identified in both basal and luminal cell compartments. However, basal stem/progenitor cell homeostasis is still poorly understood. We show that basal stem/progenitor cell maintenance is regulated by a balance between BMP5 self-renewal signal and GATA3 dampening activity. DeletingGata3 enhances adult prostate stem/progenitor cells self-renewal capacity in both organoid and allograft assays. This phenotype results from a local increase in BMP5 activity in basal cel...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Stem Cells and Regenerative Medicine Source Type: research

The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs
As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways ’ inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation o f SNr-projecting s...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Novel C1q receptor-mediated signaling controls neural stem cell behavior and neurorepair
C1q plays a key role as a recognition molecule in the immune system, driving autocatalytic complement cascade activation and acting as an opsonin. We have previously reported a non-immune role of complement C1q modulating the migration and fate of human neural stem cells (hNSC); however, the mechanism underlying these effects has not yet been identified. Here, we show for the first time that C1q acts as a functional hNSC ligand, inducing intracellular signaling to control cell behavior. Using an unbiased screening strategy, we identified five transmembrane C1q signaling/receptor candidates in hNSC (CD44, GPR62, BAI1, c-MET...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Stem Cells and Regenerative Medicine Source Type: research

Quantifying antibody kinetics and RNA detection during early-phase SARS-CoV-2 infection by time since symptom onset
Understanding and mitigating SARS-CoV-2 transmission hinges on antibody and viral RNA data that inform exposure and shedding, but extensive variation in assays, study group demographics and laboratory protocols across published studies confounds inference of true biological patterns. Our meta-analysis leverages 3,214 datapoints from 516 individuals in 21 studies to reveal that seroconversion of both IgG and IgM occurs around 12 days post symptom onset (range 1-40), with extensive individual variation that is not significantly associated with disease severity. IgG and IgM detection probabilities increase from roughly 10% at...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

The flagellar motor of < i > Vibrio alginolyticus < /i > undergoes major structural remodeling during rotational switching
We report that the C-ring maintained 34-fold symmetry in both rotational senses and the protein composition remained constant. The two structures show FliG conformational changes elicit a large conformational rearrangement of the rotor complex that coincides with rotational switching of the flagellum. FliM and FliN form a stable spiral-shaped base of the C-ring, likely stabilizing the C-ring during the conformational remodeling. (Source: eLife)
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Keratins and Plakin family cytolinker proteins control the length of epithelial microridge protrusions
Actin filaments and microtubules create diverse cellular protrusions, but intermediate filaments, the strongest and most stable cytoskeletal elements, are not known to directly participate in the formation of protrusions. Here we show that keratin intermediate filaments directly regulate the morphogenesis of microridges, elongated protrusions arranged in elaborate maze-like patterns on the surface of mucosal epithelial cells. We found that microridges on zebrafish skin cells contained both actin and keratin filaments. Keratin filaments stabilized microridges, and overexpressing keratins lengthened them. Envoplakin and Peri...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN inXenopusgastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of ke...
Source: eLife - September 7, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Molecular basis for N-terminal alpha-synuclein acetylation by human NatB
NatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and α-synuclein (aSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in Parkinson's disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-aSyn conjugate , together with structure-guided ...
Source: eLife - September 4, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Reactive oxygen species oxidize STING and suppress interferon production
Reactive oxygen species (ROS) are by-products of cellular respiration that can promote oxidative stress and damage cellular proteins and lipids. One canonical role of ROS is to defend the cell against invading bacterial and viral pathogens. Curiously, some viruses, including herpesviruses, thrive despite the induction of ROS, suggesting that ROS are beneficial for the virus. However, the underlying mechanisms remain unclear. Here, we found that ROS impaired interferon response during murine herpesvirus infection and that the inhibition occurred downstream of cytoplasmic DNA sensing. We further demonstrated that ROS suppres...
Source: eLife - September 4, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Why is cyclic dominance so rare?
Natural populations can contain multiple types of coexisting individuals. How does natural selection maintain such diversity within and across populations? A popular theoretical basis for the maintenance of diversity is cyclic dominance, illustrated by the rock-paper-scissor game. However, it appears difficult to find cyclic dominance in nature. Why is this the case? Focusing on continuously produced novel mutations, we theoretically addressed the rareness of cyclic dominance. We developed a model of an evolving population and studied the formation of cyclic dominance. Our results showed that the chance for cyclic dominanc...
Source: eLife - September 4, 2020 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research

Upregulation of TRPM3 in nociceptors innervating inflamed tissue
Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates inflammatory heat hyperalgesia, but the underlying mechanisms are unknown. We induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increasedTrpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, and augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endi...
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Fishing for protective compounds
A new zebrafish study identifies compounds that shield ears and kidneys against an anticancer drug. (Source: eLife)
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Co-expression analysis reveals interpretable gene modules controlled by < i > trans < /i > -acting genetic variants
Understanding the causal processes that contribute to disease onset and progression is essential for developing novel therapies. Althoughtrans-acting expression quantitative trait loci (trans-eQTLs) can directly reveal cellular processes modulated by disease variants, detectingtrans-eQTLs remains challenging due to their small effect sizes. Here, we analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We used co-expression modules inferred from gene expression data with five methods as traits intrans-eQTL analysis to limit multiple testing and improve interpretability. In additi...
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

A connectome and analysis of the adult < i > Drosophila < /i > central brain
The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit flyDrosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing...
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

The Mla pathway in < i > Acinetobacter baumannii < /i > has no demonstrable role in anterograde lipid transport
The asymmetric outer membrane (OM) of Gram-negative bacteria functions as a selective permeability barrier to the environment. Perturbations to OM lipid asymmetry sensitize the cell to antibiotics. As such, mechanisms involved in lipid asymmetry are fundamental to our understanding of OM lipid homeostasis. One such mechanism, the Maintenance of lipid asymmetry (Mla) pathway has been proposed to extract mislocalized glycerophospholipids from the outer leaflet of the OM and return them to the inner membrane (IM). Work on this pathway inAcinetobacter baumannii support conflicting models for the directionality of the Mla syste...
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

The visual pigment xenopsin is widespread in protostome eyes and impacts the view on eye evolution
In this study, we provide clear evidence that xenopsin enters cilia in the eye of the larval bryozoanTricellaria inopinata and triggers phototaxis. As reported from a mollusc, we find xenopsin coexpressed with rhabdomeric-opsin in eye photoreceptor cells bearing both microvilli and cilia in larva of the annelidMalacoceros fuliginosus. This is the first organism known to have both xenopsin and ciliary opsin, showing that these opsins are not necessarily mutually exclusive. Compiling existing data, we propose that xenopsin may play an important role in many protostome eyes and provides new insights into the function, evoluti...
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Evolutionary Biology Neuroscience Source Type: research

Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma
Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett's oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged dur...
Source: eLife - September 3, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Identification of protein-protected mRNA fragments and structured excised intron RNAs in human plasma by TGIRT-seq peak calling
Human plasma contains>40,000 different coding and non-coding RNAs that are potential biomarkers for human diseases. Here, we used thermostable group II intron reverse transcriptase sequencing (TGIRT-seq) combined with peak calling to simultaneously profile all RNA biotypes in apheresis-prepared human plasma pooled from healthy individuals. Extending previous TGIRT-seq analysis, we found that human plasma contains largely fragmented mRNAs from>19,000 protein-coding genes, abundant full-length, mature tRNAs and other structured small non-coding RNAs, and less abundant tRNA fragments and mature and pre-miRNAs. Many of t...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

< i > Cdon < /i > mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly
We report here that, unexpectedly, Nodal signaling is a major point of synergistic interaction betweenCdon mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure ofCdon mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect. (Source: eLife)
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Structural analysis of the < i > Legionella pneumophila < /i > Dot/Icm Type IV Secretion System Core Complex
We present models of known core complex proteins, DotC, DotD, and DotH, and two structurally similar proteins within the core complex, DotK and Lpg0657. This analysis reveals the stoichiometry and contact interfaces between the key proteins of the Dot/Icm T4SS core complex and provides a framework for understanding a complex molecular machine. (Source: eLife)
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Structural Biology and Molecular Biophysics Source Type: research

Identification of protein-protected mRNA fragments and structured excisedintron RNAs in human plasma by TGIRT-seq peak calling
Human plasma contains>40,000 different coding and non-coding RNAs that are potential biomarkers for human diseases. Here, we used thermostable group II intron reverse transcriptase sequencing (TGIRT-seq) combined with peak calling to simultaneously profile all RNA biotypes in apheresis-prepared human plasma pooled from healthy individuals. Extending previous TGIRT-seq analysis, we found that human plasma contains largely fragmented mRNAs from>19,000 protein-coding genes, abundant full-length, mature tRNAs and other structured small non-coding RNAs, and less abundant tRNA fragments and mature and pre-miRNAs. Many of t...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Cadherin clusters stabilized by a combination of specific and nonspecific cis-interactions
We demonstrate a combined experimental and computational approach for the quantitative characterization of lateral interactions between membrane-associated proteins. In particular, weak, lateral (cis) interactions between E-cadherin extracellular domains tethered to supported lipid bilayers, were studied using a combination of dynamic single-molecule F örster Resonance Energy Transfer (FRET) and kinetic Monte Carlo (kMC) simulations. Cadherins are intercellular adhesion proteins that assemble into clusters at cell-cell contacts through cis- and trans- (adhesive) interactions. A detailed and quantitative understanding ...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Multiple Wnts act synergistically to induce Chk1/Grapes expression and mediate G2 arrest in Drosophila tracheoblasts
We report that Wnt signaling is high in tracheoblasts and is necessary for high levels of activated (phosphorylated) Chk1. We find that canonical Wnt signaling facilitates this by transcriptional upregulation of Chk1 in cells that have ATR kinase activity. Wnt signalling is dependent on four Wnts (Wg, Wnt5, 6,10) that are expressed at high levels in arrested tracheoblasts and downregulated at mitotic re-entry. Interestingly, none of the Wnts are dispensable and act synergistically to induce Chk1. Finally, we show that downregulation of Wnt signalling and Chk1 expression leads to mitotic re-entry and the concomitant upregul...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex
Outer radial glial (oRG) cells are a population of neural stem cells prevalent in the developing human cortex that contribute to its cellular diversity and evolutionary expansion. The mammalian Target of Rapamycin (mTOR) signaling pathway is active in human oRG cells. Mutations in mTOR pathway genes are linked to a variety of neurodevelopmental disorders and malformations of cortical development. We find that dysregulation of mTOR signaling specifically affects oRG cells, but not other progenitor types, by changing the actin cytoskeleton through the activity of the Rho-GTPase, CDC42. These effects change oRG cellular morph...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Neuroscience Stem Cells and Regenerative Medicine Source Type: research

Resource plasticity-driven carbon-nitrogen budgeting enables specialization and division of labor in a clonal community
Previously, we found that in glucose-limitedSaccharomyces cerevisiae colonies, metabolic constraints drive cells into groups exhibiting gluconeogenic or glycolytic states. In that study, threshold amounts of trehalose - a limiting, produced carbon-resource, controls the emergence and self-organization of cells exhibiting the glycolytic state, serving as a carbon source that fuels glycolysis (Varahan et al., 2019). We now discover that the plasticity of use of a non-limiting resource, aspartate, controls both resource production and the emergence of heterogeneous cell states, based on differential metabolic budgeting. In gl...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Physics of Living Systems Source Type: research

Cryo-EM reveals species-specific components within the < i > Helicobacter pylori < /i > Cag type IV secretion system core complex
The pathogenesis ofHelicobacter pylori-associated gastric cancer is dependent on delivery of CagA into host cells through a type IV secretion system (T4SS). TheH. pylori Cag T4SS includes a large membrane-spanning core complex containing 5 proteins, organized into an outer membrane cap (OMC), a periplasmic ring (PR) and a stalk. Here, we report cryo-EM reconstructions of a core complex lacking Cag3 and an improved map of the wild-type complex. We define the structures of two unique species-specific components (Cag3 and CagM) and show that Cag3 is structurally similar to CagT. Unexpectedly, components of the OMC are organiz...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Mesoscopic-scale functional networks in the primate amygdala
The primate amygdala performs multiple functions that may be related to the anatomical heterogeneity of its nuclei. Individual neurons with stimulus- and task-specific responses are not clustered in any of the nuclei, suggesting that single-units may be too-fine grained to shed light on the mesoscale organization of the amygdala. We have extracted from local field potentials recorded simultaneously from multiple locations within the primate (Macaca mulatta) amygdala spatially defined and statistically separable responses to visual, tactile, and auditory stimuli. A generalized eigendecomposition-based method of source separ...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution
Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constra...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

What do adversarial images tell us about human vision?
Deep convolutional neural networks (DCNNs) are frequently described as the best current models of human and primate vision. An obvious challenge to this claim is the existence ofadversarial images that fool DCNNs but are uninterpretable to humans. However, recent research has suggested that there may be similarities in how humans and DCNNs interpret these seemingly nonsense images. We reanalysed data from a high-profile paper and conducted five experiments controlling for different ways in which these images can be generated and selected. We show human-DCNN agreement is much weaker and more variable than previously reporte...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > CD163 < /i > and < i > pAPN < /i > double-knockout pigs are resistant to PRRSV and TGEV and exhibit decreased susceptibility to PDCoV while maintaining normal production performance
Porcine reproductive and respiratory syndrome virus (PRRSV) and transmissible gastroenteritis virus (TGEV) are two highly infectious and lethal viruses causing major economic losses to pig production. Here, we report generation of double-gene-knockout (DKO) pigs harboring edited knockout alleles for known receptor proteins CD163 and pAPN and show that DKO pigs are completely resistant to genotype 2 PRRSV and TGEV. We found no differences in meat-production or reproductive-performance traits between wild-type and DKO pigs, but detected increased iron in DKO muscle. Additional infection challenge experiments showed that DKO ...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Complement opsonization of HIV affects primary infection of human colorectal mucosa and subsequent activation of T cells
HIV transmission via genital and colorectal mucosa are the most common routes of dissemination. Here, we explored the effects of free and complement-opsonized HIV on colorectal tissue. Initially, there was higher antiviral responses in the free HIV compared to complement-opsonized virus. The mucosal transcriptional response at 24h revealed the involvement of activated T cells, which was mirrored in cellular responses observed at 96h in isolated mucosal T cells. Further, HIV exposure led to skewing of T cell phenotypes predominantly to inflammatory CD4+ T cells, i.e. Th17 and Th1Th17 subsets. Of note, HIV exposure created a...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Ultra-high field imaging reveals increased whole brain connectivity underpins cognitive strategies that attenuate pain
We investigated how the attenuation of pain with cognitive interventions affects brain connectivity using neuroimaging and a whole brain novel analysis approach. While receiving tonic cold pain, 20 healthy participants performed three different pain attenuation strategies during simultaneous collection of functional imaging data at 7 tesla. Participants were asked to rate their pain after each trial. We related the trial-by-trial variability of the attenuation performance to the trial-by-trial functional connectivity strength change of brain data. Across all conditions, we found that a higher performance of pain attenuatio...
Source: eLife - September 2, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Activation of astrocytes in hippocampus decreases fear memory through adenosine A < sub > 1 < /sub > receptors
Astrocytes respond to and regulate neuronal activity, yet their role in mammalian behavior remains incompletely understood. Especially unclear is whether, and if so how, astrocyte activity regulates contextual fear memory, the dysregulation of which leads to pathological fear-related disorders. We generatedGFAP-ChR2-EYFP rats to allow the specific activation of astrocytes in vivo by optogenetics. We found that after memory acquisition within a temporal window, astrocyte activation disrupted memory consolidation and persistently decreased contextual but not cued fear memory accompanied by reduced fear-related anxiety behavi...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Does culture shape hunting behavior in bonobos?
New evidence that neighboring communities of bonobos hunt different prey species, despite extensive overlaps in where they live and hunt, is difficult to explain without invoking cultural factors. (Source: eLife)
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Behavioural diversity of bonobo prey preference as a potential cultural trait
The importance of cultural processes to behavioural diversity in our closest living relatives is central to revealing the evolutionary origins of human culture. However, the bonobo is often overlooked as a candidate model. Further, a prominent critique to many examples of proposed animal cultures is premature exclusion of environmental confounds known to shape behavioural phenotypes. We addressed these gaps by investigating variation in prey preference between neighbouring bonobo groups that associate and overlap space use. We find group preference for duiker or anomalure hunting otherwise unexplained by variation in spati...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

KATANIN-dependent mechanical properties of the stigmatic cell wall mediate the pollen tube path in Arabidopsis
Successful fertilization in angiosperms depends on the proper trajectory of pollen tubes through the pistil tissues to reach the ovules. Pollen tubes first grow within the cell wall of the papilla cells, applying pressure to the cell. Mechanical forces are known to play a major role in plant cell shape by controlling the orientation of cortical microtubules (CMTs), which in turn mediate deposition of cellulose microfibrils (CMFs). Here, by combining imaging, genetic and chemical approaches, we show that isotropic reorientation of CMTs and CMFs in aged Col-0 andkatanin1-5 (ktn1-5) papilla cells is accompanied by a tendency ...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Plant Biology Source Type: research

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release
Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Structural basis for histone variant H3tK27me3 recognition by PHF1 and PHF19
The PRC2 (Polycomb repressive complex 2) complex is a multi-component histone H3K27 methyltransferase, best known for silencingHox genes during embryonic development. The Polycomb-like proteins PHF1, MTF2 and PHF19 are critical components of PRC2 by stimulating its catalytic activity in embryonic stem (ES) cells. The Tudor domains of PHF1/19 have been previously shown to be readers of H3K36me3in vitro. However, some other studies suggest that PHF1 and PHF19 co-localize with the H3K27me3 mark, but not H3K36me3 in cells. Here, we provide further evidence that PHF1 co-localizes with H3t in testis, and its Tudor domain prefere...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Recurrent processes support a cascade of hierarchical decisions
Perception depends on a complex interplay between feedforward and recurrent processing. Yet, while the former has been extensively characterized, the computational organization of the latter remains largely unknown. Here, we use magneto-encephalography to localize, track and decode the feedforward and recurrent processes of reading, as elicited by letters and digits whose level of ambiguity was parametrically manipulated. We first confirm that a feedforward response propagates through the ventral and dorsal pathways within the first 200 ms. The subsequent activity is distributed across temporal, parietal and prefrontal cor...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Extensive and spatially variable within-cell-type heterogeneity across the basolateral amygdala
The basolateral amygdala complex (BLA), extensively connected with both local amygdalar nuclei as well as long-range circuits, is involved in a diverse array of functional roles. Understanding the mechanisms of such functional diversity will be greatly informed by understanding the cell-type-specific landscape of the BLA. Here, beginning with single-cell RNA sequencing, we identified both discrete and graded continuous gene-expression differences within the mouse BLA. Viain situhybridization, we next mapped this discrete transcriptomic heterogeneity onto a sharp spatial border between the basal and lateral amygdala nuclei,...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Growing straight through walls
The pollen tube in a flowering plant grows in a direction that is influenced by the mechanical properties of the stigma papillae and the organization of structures called cortical microtubules inside these cells. (Source: eLife)
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Plant Biology Source Type: research

Structural basis for the reaction cycle of DASS dicarboxylate transporters
We report multiple cryo-EM and X-ray structures in four different states, inclu ding three hitherto unseen states, along with molecular dynamics simulations, of both a cotransporter and an exchanger. Comparison of these outward- and inward-facing structures reveal how the transport domain translates and rotates within the framework of the scaffold domain through the transport c ycle. Additionally, we propose that DASS transporters ensure substrate coupling by a charge-compensation mechanism, and by structural changes upon substrate release. (Source: eLife)
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact
Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR ’s pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense v ariants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Ordered dephosphorylation initiated by the selective proteolysis of cyclin B drives mitotic exit
APC/C-mediated proteolysis of cyclin B and securin promotes anaphase entry, inactivating CDK1 and permitting chromosome segregation, respectively. Reduction of CDK1 activity relieves inhibition of the CDK1-counteracting phosphatases PP1 and PP2A-B55, allowing wide-spread dephosphorylation of substrates. Meanwhile, continued APC/C activity promotes proteolysis of other mitotic regulators. Together, these activities orchestrate a complex series of events during mitotic exit. However, the relative importance of regulated proteolysis and dephosphorylation in dictating the order and timing of these events remains unclear. Using...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Intra-species differences in population size shape life history and genome evolution
The evolutionary forces shaping life history divergence within species are largely unknown. Turquoise killifish display differences in lifespan among wild populations, representing an ideal natural experiment in evolution and diversification of life history. By combining genome sequencing and population genetics, we investigate the evolutionary forces shaping lifespan among wild turquoise killifish populations. We generate an improved reference genome assembly and identify genes under positive and purifying selection, as well as those evolving neutrally. Short-lived populations from the outer margin of the species range ha...
Source: eLife - September 1, 2020 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons
Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses in mice, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRPPBN neurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRPPBN neurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar pr...
Source: eLife - August 28, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Neural signatures of α2-Adrenergic agonist-induced unconsciousness and awakening by antagonist
How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They generate unconsciousness selectively through α2-adrenergic receptors and related circuits. We studied intracortical neuronal dynamics during transitions of loss of consciousness (LOC) with the α2-adrenergic agonist dexmedetomidine and return of consciousnes s (ROC) in a functionally interconnecting somatosensory and ventral premotor network in non-human primates. LOC, ROC and full task performance recovery were all associated with distinct neural...
Source: eLife - August 28, 2020 Category: Biomedical Science Tags: Medicine Neuroscience Source Type: research