Nucleosome-CHD4 chromatin remodeller structure maps human disease mutations
Chromatin remodelling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodelling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here we report the cryo-electron microscopy (cryo-EM) structure ofHomo sapiensCHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 Å. The ATPase motor of CHD4 binds and distorts nucleosomal DNA at superhelical location (SHL) +2, supporting the 'twist defect' model of chromatin remodelling. CHD4 does ...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

Pupil-linked phasic arousal predicts a reduction of choice bias across species and decision domains
Decisions are often made by accumulating ambiguous evidence over time. The brain ’s arousal systems are activated during such decisions. In previous work in humans, we found that evoked responses of arousal systems during decisions are reported by rapid dilations of the pupil and track a suppression of biases in the accumulation of decision-relevant evidence (de Gee et al., 20 17). Here, we show that this arousal-related suppression in decision bias acts on both conservative and liberal biases, and generalizes from humans to mice, and from perceptual to memory-based decisions. In challenging sound-detection tasks, th...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Dietary sugar inhibits satiation by decreasing the central processing of sweet taste
From humans to vinegar flies, exposure to diets rich in sugar and fat lowers taste sensation, changes food choices, and promotes feeding. However, how these peripheral alterations influence eating is unknown. Here we used the genetically tractable organismD. melanogaster to define the neural mechanisms through which this occurs. We characterized a population of protocerebral anterior medial dopaminergic neurons (PAM DANs) that innervates the β’2 compartment of the mushroom body and responds to sweet taste. In animals fed a high sugar diet, the response of PAM-β’2 to sweet stimuli was reduced and delay...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > Pyphe < /i > , a python toolbox for assessing microbial growth and cell viability in high-throughput colony screens
We present an all-in-one solution,pyphe, for automating and improving data analysis pipelines associated with large-scale fitness screens, including image acquisition and quantification, data normalisation, and statistical analysis.Pyphe is versatile and processes fitness data from colony sizes, viability scores from phloxine B staining or colony growth curves, all obtained with inexpensive transilluminating flatbed scanners. We applypyphe to show that the fitness information contained in late endpoint measurements of colony sizes is similar to maximum growth slopes from time series. We phenotype gene-deletion strains of f...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research

Hepatitis C virus exploits cyclophilin A to evade PKR
Counteracting innate immunity is essential for successful viral replication. Host cyclophilins (Cyps) have been implicated in viral evasion of host antiviral responses, although the mechanisms are still unclear. Here, we show that hepatitis C virus (HCV) co-opts the host protein CypA to aid evasion of antiviral responses dependent on the effector protein kinase R (PKR). Pharmacological inhibition of CypA rescues PKR from antagonism by HCV NS5A, leading to activation of an interferon regulatory factor-1 (IRF1)-driven cell intrinsic antiviral program that inhibits viral replication. These findings further the understanding o...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

The unlimited potential of the great pond snail, < i > Lymnaea stagnalis < /i >
Only a limited number of animal species lend themselves to becoming model organisms in multiple biological disciplines: one of these is the great pond snail,Lymnaea stagnalis. Extensively used since the 1970s to study fundamental mechanisms in neurobiology, the value of this freshwater snail has been also recognised in fields as diverse as host –parasite interactions, ecotoxicology, evolution, genome editing and 'omics', and human disease modelling. While there is knowledge about the natural history of this species, what is currently lacking is an integration of findings from the laboratory and the field. With this i...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Vessel noise levels drive behavioural responses of humpback whales with implications for whale-watching
Disturbance from whale-watching can cause significant behavioural changes with fitness consequences for targeted whale populations. However, the sensory stimuli triggering these responses are unknown, preventing effective mitigation. Here, we test the hypothesis that vessel noise level is a driver of disturbance, using humpback whales (Megaptera novaeangliae) as a model species. We conducted controlled exposure experiments (n= 42) on resting mother-calf pairs on a resting ground off Australia, by simulating whale-watch scenarios with a research vessel (range 100 m, speed 1.5 knts) playing back vessel noise at control/low (...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Ecology Source Type: research

Topologically correct synthetic reconstruction of pathogen social behavior found during < i > Yersinia < /i > growth in deep tissue sites
Within deep tissue sites, extracellular bacterial pathogens often replicate in clusters that are surrounded by immune cells. Disease is modulated by interbacterial interactions as well as bacterial-host cell interactions resulting in microbial growth, phagocytic attack and secretion of host antimicrobial factors. To overcome the limited ability to manipulate these infection sites, we established a system forYersinia pseudotuberculosis (Yptb)growth in microfluidics-driven microdroplets that regenerates microbial social behavior in tissues. Chemical generation of nitric oxide (NO) in the absence of immune cells was sufficien...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Magnetic alignment enhances homing efficiency of hunting dogs
Despite anecdotal reports of the astonishing homing abilities in dogs, their homing strategies are not fully understood. We equipped 27 hunting dogs with GPS collars and action cams, let them freely roam in forested areas, and analyzed components of homing in over 600 trials. When returning to the owner (homewards), dogs either followed their outbound track ( ‘tracking’) or used a novel route (‘scouting’). The inbound track during scouting started mostly with a short (about 20 m) run along the north-south geomagnetic axis, irrespective of the actual direction homewards. Performing such a ‘comp...
Source: eLife - June 16, 2020 Category: Biomedical Science Tags: Ecology Source Type: research

COVID-19 medical papers have fewer women first authors than expected
The COVID-19 pandemic has resulted in school closures and distancing requirements that have disrupted both work and family life for many. Concerns exist that these disruptions caused by the pandemic may not have influenced men and women researchers equally. Many medical journals have published papers on the pandemic, which were generated by researchers facing the challenges of these disruptions. Here we report the results of an analysis that compared the gender distribution of authors on 1893 medical papers related to the pandemic with that on papers published in the same journals in 2019, for papers with first authors and...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137
The HIV-1 Vpr accessory protein induces ubiquitin/proteasome-dependent degradation of many cellular proteins by recruiting them to a cullin4A-DDB1-DCAF1 complex. In so doing, Vpr enhances HIV-1 gene expression and induces (G2/M) cell cycle arrest. However, the identities of Vpr target proteins through which these biological effects are exerted are unknown. We show that a chromosome periphery protein, CCDC137/cPERP-B, is targeted for depletion by HIV-1 Vpr, in a cullin4A-DDB1-DCAF1 dependent manner. CCDC137 depletion caused G2/M cellcycle arrest, while Vpr-resistant CCDC137 mutants conferred resistance to Vpr-induced G2/M a...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

PreB ötzinger complex neurons drive respiratory modulation of blood pressure and heart rate
Heart rate and blood pressure oscillate in phase with respiratory activity. A component of these oscillations is generated centrally, with respiratory neurons entraining the activity of pre-sympathetic and parasympathetic cardiovascular neurons. Using a combination of optogenetic inhibition and excitationin vivo andin situ in rats, as well as neuronal tracing, we demonstrate that preB ötzinger Complex (preBötC) neurons, which form the kernel for inspiratory rhythm generation, directly modulate cardiovascular activity. Specifically, inhibitory preBötC neurons modulate cardiac parasympathetic neuron activity w...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60
Splicing is a vital cellular process that modulates important aspects of animal physiology, yet roles in regulating innate immunity are relatively unexplored. From genetic screens inC. elegans, we identified splicing factor RNP-6/PUF60 whose activity suppresses immunity, but promotes longevity, suggesting a tradeoff between these processes. Bacterial pathogen exposure affects gene expression and splicing in arnp-6 dependent manner, andrnp-6 gain and loss-of-function activities reveal an active role in immune regulation. Another longevity promoting splicing factor, SFA-1, similarly exerts an immuno-suppressive effect, worki...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Genetics and Genomics Immunology and Inflammation Source Type: research

Isolation and transcriptomic analysis of < i > Anopheles gambiae < /i > oenocytes enables the delineation of hydrocarbon biosynthesis
The surface of insects is coated in cuticular hydrocarbons (CHCs); variations in the composition of this layer affect a range of traits including adaptation to arid environments and defence against pathogens and toxins. In the African malaria vector,Anopheles gambiae quantitative and qualitative variance in CHC composition have been associated with speciation, ecological habitat and insecticide resistance. Understanding how these modifications arise will inform us of how mosquitoes are responding to climate change and vector control interventions. CHCs are synthesised in sub-epidermal cells called oenocytes that are very d...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Genetics and Genomics Source Type: research

Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice
The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR in human and mouse cells. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result ofSIRT1deficiency in c...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Meta-Research: COVID-19 medical papers have fewer women first authors than expected
The COVID-19 pandemic has resulted in school closures and distancing requirements that have disrupted both work and family life for many. Concerns exist that these disruptions caused by the pandemic may not have influenced men and women researchers equally. Many medical journals have published papers on the pandemic, which were generated by researchers facing the challenges of these disruptions. Here we report the results of an analysis that compared the gender distribution of authors on 1,893 medical papers related to the pandemic with that on papers published in the same journals in 2019, for papers with first authors an...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Quantitative modeling of the effect of antigen dosage on B-cell affinity distributions in maturating germinal centers
Affinity maturation is a complex dynamical process allowing the immune system to generate antibodies capable of recognizing antigens. We introduce a model for the evolution of the distribution of affinities across the antibody population in germinal centers. The model is amenable to detailed mathematical analysis, and gives insight on the mechanisms through which antigen availability controls the rate of maturation and the expansion of the antibody population. It is also capable, upon maximum-likelihood inference of the parameters, to reproduce accurately the distributions of affinities of IgG-secreting cells we measure in...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Physics of Living Systems Source Type: research

Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus
Whether leptin acts in the paraventricular nucleus (PVN) to increase sympathetic nerve activity (SNA) is unclear, since PVN leptin receptors (LepR) are sparse. We show in rats that PVN leptin slowly increases SNA to muscle and brown adipose tissue, because it induces the expression of its own receptor and synergizes with local glutamatergic neurons. PVN LepR are not expressed in astroglia and rarely in microglia; instead, glutamatergic neurons express LepR, some of which project to a key presympathetic hub, the rostral ventrolateral medulla (RVLM). In PVN slices from mice expressing GCaMP6, leptin excites glutamatergic neu...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

The transition state and regulation of γ-TuRC-mediated microtubule nucleation revealed by single molecule microscopy
Determining how microtubules (MTs) are nucleated is essential for understanding how the cytoskeleton assembles. While the MT nucleator, γ-tubulin ring complex (γ-TuRC) has been identified, precisely how γ-TuRC nucleates a MT remains poorly understood. Here we developed a single molecule assay to directly visualize nucleation of a MT from purifiedXenopus laevisγ-TuRC. We reveal a high γ-/αβ-tubulin affinity, which facilitates assembly of a MT from γ-TuRC. Whereas spontaneous nucleation requires assembly of 8 αβ-tubulins, nucleation from γ-TuRC occurs efficientl...
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Cell Biology Physics of Living Systems Source Type: research

Unravelling the evolutionary history of kisspeptin
Experiments in sea cucumbers reveal how the physiological responses regulated by a neuropeptide called kisspeptin have evolved. (Source: eLife)
Source: eLife - June 15, 2020 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Being vulnerable
Early-career researchers feel discouraged from exposing vulnerability even during a global crisis. (Source: eLife)
Source: eLife - June 15, 2020 Category: Biomedical Science Source Type: research

A survey-based analysis of the academic job market
Many postdoctoral researchers apply for faculty positions knowing relatively little about the hiring process or what is needed to secure a job offer. To address this lack of knowledge about the hiring process we conducted a survey of applicants for faculty positions: the survey ran between May 2018 and May 2019, and received 317 responses. We analyzed the responses to explore the interplay between various scholarly metrics and hiring outcomes. We concluded that, above a certain threshold, the benchmarks traditionally used to measure research success – including funding, number of publications or journals published in...
Source: eLife - June 12, 2020 Category: Biomedical Science Source Type: research

Fatty acid β-oxidation is required for the differentiation of larval hematopoietic progenitors in < i > Drosophila < /i >
Cell-intrinsic and extrinsic signals regulate the state and fate of stem and progenitor cells. Recent advances in metabolomics illustrate that various metabolic pathways are also important in regulating stem cell fate. However, our understanding of the metabolic control of the state and fate of progenitor cells is in its infancy. UsingDrosophila hematopoietic organ: lymph gland, we demonstrate that Fatty Acid Oxidation (FAO) is essential for the differentiation of blood cell progenitors. In the absence of FAO, the progenitors are unable to differentiate and exhibit altered histone acetylation. Interestingly, acetate supple...
Source: eLife - June 12, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

The challenges of lockdown for early-career researchers
Thousands of UK doctoral students and early-career researchers shared the repercussions of lockdown on their work and wellbeing. (Source: eLife)
Source: eLife - June 12, 2020 Category: Biomedical Science Source Type: research

FoxO suppresses endoplasmic reticulum stress to inhibit growth of Tsc1-deficient tissues under nutrient restriction
The transcription factor FoxO has been shown to block proliferation and progression in mTORC1-driven tumorigenesis but the picture of the relevant FoxO target genes remains incomplete. Here, we employed RNA-seq profiling on single clones isolated using laser capture microdissection fromDrosophila larval eye imaginal discs to identify FoxO targets that restrict the proliferation of Tsc1-deficient cells under nutrient restriction (NR). Transcriptomics analysis revealed downregulation of endoplasmic reticulum-associated protein degradation pathway components uponfoxo knockdown. Induction of ER stress pharmacologically or by s...
Source: eLife - June 11, 2020 Category: Biomedical Science Tags: Cancer Biology Genetics and Genomics Source Type: research

mPFC spindle cycles organize sparse thalamic activation and recently active CA1 cells during non-REM sleep
We report that the cycles of neocortical spindles provide a key temporal window that coordinates CA1 SWRs with sparse but consistent activation of thalamic units. Thalamic units were phase-locked to delta and spindles in mPFC, and fired at consistent lags with other thalamic units within spindles, while CA1 units that were active during spatial exploration were engaged in SWR-coupled spindles after behavior. The sparse thalamic firing could promote an incremental integration of recently acquired memory traces into neocortical schemas through the interleaved activation of thalamocortical cells. (Source: eLife)
Source: eLife - June 11, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

The neurons that mistook a hat for a face
Despite evidence that context promotes the visual recognition of objects, decades of research have led to the pervasive notion that the object processing pathway in primate cortex consists of multiple areas that each process the intrinsic features of a few particular categories (e.g. faces, bodies, hands, objects, and scenes). Here we report that such category-selective neurons do not in fact code individual categories in isolation but are also sensitive to object relationships that reflect statistical regularities of the experienced environment. We show by direct neuronal recording that face-selective neurons respond not ...
Source: eLife - June 10, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Globus pallidus dynamics reveal covert strategies for behavioral inhibition
Flexible behavior requires restraint of actions that are no longer appropriate. This behavioral inhibition critically relies on frontal cortex - basal ganglia circuits. Within the basal ganglia the globus pallidus pars externa (GPe), has been hypothesized to mediate selective proactive inhibition: being prepared to stop a specific action, if needed. Here we investigate population dynamics of rat GPe neurons during preparation-to-stop, stopping, and going. Rats selectively engaged proactive inhibition towards specific actions, as shown by slowed reaction times (RTs). Under proactive inhibition, GPe population activity occup...
Source: eLife - June 10, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Learning lessons from a toddler
Struggling to get her research project up and running in a new country, a mother gets inspiration from her young daughter. (Source: eLife)
Source: eLife - June 10, 2020 Category: Biomedical Science Source Type: research

CRISPR-Cas12a exploits R-loop asymmetry to form double-strand breaks
Type V CRISPR-Cas interference proteins use a single RuvC active site to make RNA-guided breaks in double-stranded DNA substrates, an activity essential for both bacterial immunity and genome editing. The best-studied of these enzymes, Cas12a, initiates DNA cutting by forming a 20-nucleotide R-loop in which the guide RNA displaces one strand of a double-helical DNA substrate, positioning the DNase active site for first-strand cleavage. However, crystal structures and biochemical data have not explained how the second strand is cut to complete the double-strand break. Here, we detect intrinsic instability in DNA flanking th...
Source: eLife - June 10, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times
Dopamine (DA) neurons are known to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in supporting learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction, a behavior we observed to generate spatially segregated RPE and salience signals. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed that DA neurons in medial and lateral VTA have distinct activity profiles during fear exti...
Source: eLife - June 10, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Different neuronal populations mediate inflammatory pain analgesia by exogenous and endogenous opioids
Mu-opioid receptors (MORs) are crucial for analgesia by both exogenous and endogenous opioids. However, the distinct mechanisms underlying these two types of opioid analgesia remains largely unknown. Here, we demonstrate that analgesic effects of exogenous and endogenous opioids on inflammatory pain are mediated by MORs expressed in distinct subpopulations of neurons in mouse. We found that the exogenous opioid-induced analgesia of inflammatory pain is mediated by MORs in Vglut2+ glutamatergic but not GABAergic neurons. In contrast, analgesia by endogenous opioids is mediated by MORs in GABAergic rather than Vglut2+ glutam...
Source: eLife - June 10, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Putting epigenetic biomarkers to the test for clinical trials
Reliable biomarkers are needed to test the effectiveness of interventions intended to improve health and extend lifespan. (Source: eLife)
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

G protein-regulated endocytic trafficking of adenylyl cyclase type 9
GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires β-arrestin but ...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Cohesion is established during DNA replication utilising chromosome associated cohesin rings as well as those loaded de novo onto nascent DNAs
Sister chromatid cohesion essential for mitotic chromosome segregation is thought to involve the co-entrapment of sister DNAs within cohesin rings. Although cohesin can load onto chromosomes throughout the cell cycle, it only builds cohesion during S phase. A key question is whether cohesion is generated by conversion of cohesin complexes associated with un-replicated DNAs ahead of replication forks into cohesive structures behind them, or from nucleoplasmic cohesin that is loaded de novo onto nascent DNAs associated with forks, a process that would be dependent on cohesin ’s Scc2 subunit. We show here that inS. cere...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

Squalene-based adjuvants stimulate CD8 T cell, but not antibody responses, through a RIPK3-dependent pathway
In this study we demonstrate that immunization of mice with MF59 or its mimetic AddaVax (AV) plus soluble antigen results in robust antigen-specific antibody and CD8 T cell responses in lymph nodes and non-lymphoid tissues. Immunization triggered rapid RIPK3-kinase dependent necroptosis in the lymph node which peaked at 6 hours, followed by a sequential wave of apoptosis. Immunization with alum plus antigen did not induce RIPK3 kinase-dependent signaling. RIPK3-dependent signaling induced by MF59 or AV was essential for cross-presentation of antigen to CD8T cells by Batf3-dependent CD8+ DCs. Consistent with this, RIPK3-kin...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGF β signaling in triple-negative breast cancer
Cancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival of human TNBC cells. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that a...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Acute disruption of the synaptic vesicle membrane protein synaptotagmin 1 using knockoff in mouse hippocampal neurons
The success of comparative cell biology for determining protein function relies on quality disruption techniques. Long-lived proteins, in postmitotic cells, are particularly difficult to eliminate. Moreover, cellular processes are notoriously adaptive; for example, neuronal synapses exhibit a high degree of plasticity. Ideally, protein disruption techniques should be both rapid and complete. Here, we describe knockoff, a generalizable method for the druggable control of membrane protein stability. We developed knockoff for neuronal use but show it also works in other cell types. Applying knockoff to synaptotagmin 1 (SYT1) ...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop
Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using ...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Delineating the early transcriptional specification of the mammalian trachea and esophagus
The genome-scale transcriptional programs that specify the mammalian trachea and esophagus are unknown. Though NKX2-1 and SOX2 are hypothesized to be co-repressive master regulators of tracheoesophageal fates, this is untested at a whole transcriptomic scale and their downstream networks remain unidentified. By combining single-cell RNA-sequencing with bulk RNA-sequencing ofNkx2-1 mutants and NKX2-1 ChIP-sequencing in mouse embryos, we delineate the NKX2-1 transcriptional program in tracheoesophageal specification, and discover that the majority of the tracheal and esophageal transcriptome is NKX2-1 independent. To decoupl...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Mobile DNAs and switching mating types in yeast
The gene that allows budding yeast cells to switch their mating type evolved from a newly discovered family of genes named weirdHO. (Source: eLife)
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Social aversive generalization learning sharpens the tuning of visuocortical neurons to facial identity cues
Defensive system activation promotes heightened perception of threat signals, and excessive attention to threat signals has been discussed as a contributory factor in the etiology of anxiety disorders. However, a mechanistic account of attentional modulation during fear-relevant processes, especially during fear generalization remains elusive. To test the hypothesis that social fear generalization prompts sharpened tuning in the visuocortical representation of social threat cues, 67 healthy participants underwent differential fear conditioning, followed by a generalization test in which participants viewed faces varying in...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

An ECF-type transporter scavenges heme to overcome iron-limitation in < i > Staphylococcus lugdunensis < /i >
Energy-coupling factor type (ECF-transporters) represent trace nutrient acquisition systems. Substrate binding components of ECF-transporters are membrane proteins with extraordinary affinity, allowing them to scavenge trace amounts of ligand. A number of molecules have been described as substrates of ECF-transporters, but an involvement in iron-acquisition is unknown. Host-induced iron limitation during infection represents an effective mechanism to limit bacterial proliferation. We identified the iron-regulated ECF-transporter Lha in the opportunistic bacterial pathogenStaphylococcus lugdunensis and show that the transpo...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Hippocampal remapping as hidden state inference
Cells in the hippocampus tuned to spatial location (place cells) typically change their tuning when an animal changes context, a phenomenon known as remapping. A fundamental challenge to understanding remapping is the fact that what counts as a ‘‘context change’’ has never been precisely defined. Furthermore, different remapping phenomena have been classified on the basis of how much the tuning changes after different types and degrees of context change, but the relationship between these variables is not clear. We address these am biguities by formalizing remapping in terms of hidden state inferenc...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulphate production
Myelin destruction is followed by resident glia activation and mobilization of endogenous progenitors (OPC) which participate in myelin repair. Here we show that in response to demyelination, mature oligodendrocytes (OLG) bordering the lesion express Ndst1, a key enzyme for heparan sulfates (HS) synthesis. Ndst1+ OLG form a belt that demarcates lesioned from intact white matter. Mice with selective inactivation of Ndst1 in the OLG lineage display increased lesion size, sustained microglia and OPC reactivity. HS production around the lesion allows Sonic hedgehog (Shh) binding and favors the local enrichment of this morphoge...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Modulation of dopamine D < sub > 1 < /sub > receptors via histamine H < sub > 3 < /sub > receptors is a novel therapeutic target for Huntington's disease
Early Huntington's disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found t...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Analysis of pulsed cisplatin signalling dynamics identifies effectors of resistance in lung adenocarcinoma
The identification of clinically viable strategies for overcoming resistance to platinum chemotherapy in lung adenocarcinoma has previously been hampered by inappropriately tailored in vitro assays of drug response. Therefore, using a pulse model that closely mimics the in vivo pharmacokinetics of platinum therapy, we profiled cisplatin-induced signalling, DNA-damage and apoptotic responses across a panel of human lung adenocarcinoma cell lines. By coupling this data to real-time, single-cell imaging of cell cycle and apoptosis we provide a fine-grained stratification of response, where a P70S6K-mediated signalling axis pr...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Existence and functions of a kisspeptin neuropeptide signaling system in a non-chordate deuterostome species
The kisspeptin system is a central modulator of the hypothalamic-pituitary-gonadal axis in vertebrates. Its existence outside the vertebrate lineage remains largely unknown. Here, we report the identification and characterization of the kisspeptin system in the sea cucumberApostichopus japonicus. The gene encoding the kisspeptin precursor generates two mature neuropeptides, AjKiss1a and AjKiss1b. The receptors for these neuropeptides, AjKissR1 and AjKissR2, are strongly activated by syntheticA. japonicus and vertebrate kisspeptins, triggering a rapid intracellular mobilization of Ca2+, followed by receptor internalization....
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

A 10-year follow-up study of sex inclusion in the biological sciences
In 2016, to address the historical overrepresentation of male subjects in biomedical research, the US National Institutes of Health implemented a policy requiring investigators to consider sex as a biological variable. In order to assess the impact of this policy, we conducted a bibliometric analysis across nine biological disciplines for papers published in 34 journals in 2019, and compared our results with those of a similar study carried out by Beery and Zucker in 2009. There was a significant increase in the proportion of studies that included both sexes across all nine disciplines, but in eight of the disciplines ther...
Source: eLife - June 9, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

A non-linear system patterns Rab5 GTPase on the membrane
Proteins can self-organize into spatial patterns via non-linear dynamic interactions on cellular membranes. Modelling and simulations have shown that small GTPases can generate patterns by coupling guanine nucleotide exchange factors (GEF) to effectors, generating a positive feedback of GTPase activation and membrane recruitment. Here, we reconstituted the patterning of the small GTPase Rab5 and its GEF/effector complex Rabex5/Rabaptin5 on supported lipid bilayers. We demonstrate a ‘handover’ of Rab5 from Rabex5 to Rabaptin5 upon nucleotide exchange. A minimal system consisting of Rab5, RabGDI and a complex of ...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research