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

Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones
We present crystal structures of the butenolide receptor AvaR1 in is olation, and in complex with avenolide, as well as AvaR1 bound to an oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal structures enable identification of 90 new actinobacteria that may be regulated by butenolides, two of which are experimentally verified. These studies provide a foundation for understanding regulation of microbial secondary metabolite production, which may be exploited for the discovery and production of novel medicines. (Source: eLife)
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Comprehensive exploration of the translocation, stability and substrate recognition requirements in VIM-2 lactamase
Metallo- β-lactamases (MBLs) degrade a broad spectrum of β-lactam antibiotics, and are a major disseminating source for multidrug resistant bacteria. Despite many biochemical studies in diverse MBLs, molecular understanding of the roles of residues in the enzyme's stability and function, and especially sub strate specificity, is lacking. Here, we employ deep mutational scanning (DMS) to generate comprehensive single amino acid variant data on a major clinical MBL, VIM-2, by measuring the effect of thousands of VIM-2 mutants on the degradation of three representative classes of β-lactams (ampicillin, cefotaxi...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Computational and Systems Biology Source Type: research

A Global Immunological Observatory to meet a time of pandemics
SARS-CoV-2 presents an unprecedented international challenge, but it will not be the last such threat. Here, we argue that the world needs to be much better prepared to rapidly detect, define and defeat future pandemics. We propose that a Global Immunological Observatory (GIO) and associated developments in systems immunology, therapeutics and vaccine design should be at the heart of this enterprise. (Source: eLife)
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Immunology and Inflammation Source Type: research

Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating
Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate b...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research

Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation
Mutations in the transcription factorFOXC2 are predominately associated with lymphedema. Herein, we demonstrate a key role for related factor FOXC1, in addition to FOXC2, in regulating cytoskeletal activity in lymphatic valves. FOXC1 is induced by laminar, but not oscillatory, shear and inducible, endothelial-specific deletion impaired postnatal lymphatic valve maturation in mice. However, deletion ofFoxc2 induced valve degeneration, which is exacerbated inFoxc1; Foxc2 mutants.FOXC1knockdown (KD) in human lymphatic endothelial cells increased focal adhesions and actin stress fibers whereasFOXC2-KD increased focal adherens ...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences
The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3 ′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadr...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

How the brain constructs dreams
Deep inside the temporal lobe of the brain, the hippocampus has a central role in our ability to remember, imagine and dream. (Source: eLife)
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

The dynamic transmission of positional information in < i > stau < /i > -mutants during < i > Drosophila < /i > embryogenesis
It has been suggested that Staufen (Stau) is key in controlling the variability of the posterior boundary of the Hb anterior domain (xHb). However, its underlying mechanism is elusive. Here, we quantified the dynamic 3D expression of segmentation genes inDrosophila embryos. With improved control of measurement errors, we showxHb ofstau- mutants reproducibly moves posteriorly by 10% of the embryo length (EL) to the wild type (WT) position in the nuclear cycle (nc) 14, and its variability at short time windows is comparable as that of the WT. Moreover, forstau- mutants, the upstream Bicoid (Bcd) gradients show equivalent rel...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research

Fibrillar A β triggers microglial proteome alterations and dysfunction in Alzheimer mouse models
Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier ...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Whole-organism behavioral profiling reveals a role for dopamine in state-dependent motor program coupling in < i > C. elegans < /i >
We describe a new imaging platform that permits automated, simultaneous quantification of each of the mainC. elegans motor programs over hours or days. Analysis of these whole-organism behavioral profiles shows that the motor programs coordinately change as animals switch behavioral states. Utilizing genetics, optogenetics, and calcium imaging, we identify a new role for dopamine in coupling locomotion and egg-laying together across states. These results provide new insights into how the diverse motor programs throughout an organism are coordinated and suggest that neuromodulators like dopamine can couple motor circuits to...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes
Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoes, must release their amphipathic helix 8 from ...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Cell Biology Structural Biology and Molecular Biophysics Source Type: research

A non-canonical role for the EDC4 decapping factor in regulating MARF1-mediated mRNA decay
EDC4 is a core component of processing (P)-bodies that binds the DCP2 decapping enzyme and stimulates mRNA decay. EDC4 also interacts with mammalian MARF1, a recently identified endoribonuclease that promotes oogenesis and contains a number of RNA binding domains, including two RRMs and multiple LOTUS domains. How EDC4 regulates MARF1 action and the identity of MARF1 target mRNAs is not known. Our transcriptome-wide analysis identifies bona fide MARF1 target mRNAs and indicates that MARF1 predominantly binds their 3 ’ UTRs via its LOTUS domains to promote their decay. We also show that a MARF1 RRM plays an essential ...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats
In conclusion, TMAO reduced mortality in SHHF, which was associated with diuretic, natriuretic and hypotensive effects. HPS and TMAO did not affect LDH protein structure. (Source: eLife)
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

CD56 regulates human NK cell cytotoxicity through Pyk2
Human natural killer (NK) cells are defined as CD56+CD3 −. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstra te that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member ...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Cell Biology Immunology and Inflammation Source Type: research

Predicting geographic location from genetic variation with deep neural networks
Most organisms are more closely related to nearby than distant members of their species, creating spatial autocorrelations in genetic data. This allows us to predict the location of a genetic sample by comparing it to a set of samples of known geographic origin. Here we describe a deep learning method, which we call Locator, to accomplish this task faster and more accurately than existing approaches. In simulations, Locator infers sample location to within 4.1 generations of dispersal and runs at least an order of magnitude faster than a recent model-based approach. We leverage Locator's computational efficiency to predict...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity
Lymphocyte migration is essential for the function of the adaptive immune system, and regulation of T cell entry into tissues is an effective therapy in autoimmune diseases. Little is known about the specific role of cytoskeletal effectors that mediate mechanical forces and morphological changes essential for migration in complex environments. We developed a new Formin-like-1 (FMNL1) knock-out mouse model and determined that the cytoskeletal effector FMNL1 is selectively required for effector T cell trafficking to inflamed tissues, without affecting na ïve T cell entry into secondary lymphoid organs. Here, we identify...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Cell Biology Immunology and Inflammation Source Type: research

Dreaming with hippocampal damage
The hippocampus is linked with both sleep and memory, but there is debate about whether a salient aspect of sleep – dreaming – requires its input. To address this question, we investigated if human patients with focal bilateral hippocampal damage and amnesia engaged in dreaming. We employed a provoked awakening protocol where participants were woken up at various points throughout the night, including durin g non-rapid eye movement and rapid eye movement sleep, to report their thoughts in that moment. Despite being roused a similar number of times, dream frequency was reduced in the patients compared to control...
Source: eLife - June 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

TGF β signaling is required for tenocyte recruitment and functional neonatal tendon regeneration
Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGF β signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFβ-dependent and  TGFβ-independent mechanisms underlying tendon regeneration. Importantly, functional recovery depend ed on canonical TGFβ signaling a...
Source: eLife - June 5, 2020 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Diverse nucleosome site-selectivity among histone deacetylase complexes
Histone acetylation regulates chromatin structure and gene expression and is removed by histone deacetylases (HDACs). HDACs are commonly found in various protein complexes to confer distinct cellular functions, but how the multi-subunit complexes influence deacetylase activities and site-selectivities in chromatin is poorly understood. Previously we reported the results of studies on the HDAC1 containing CoREST complex and acetylated nucleosome substrates which revealed a notable preference for deacetylation of histone H3 acetyl-Lys9 vs. acetyl-Lys14 (M. Wu et al, 2018). Here we analyze the enzymatic properties of five cla...
Source: eLife - June 5, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

We need to act now
eLife, like the rest of science, must tackle the many inequalities experienced by Black scientists. (Source: eLife)
Source: eLife - June 5, 2020 Category: Biomedical Science Source Type: research

An image-based data-driven analysis of cellular architecture in a developing tissue
Quantitative microscopy is becoming increasingly crucial in efforts to disentangle the complexity of organogenesis, yet adoption of the potent new toolbox provided by modern data science has been slow, primarily because it is often not directly applicable to developmental imaging data. We tackle this issue with a newly developed algorithm that uses point cloud-based morphometry to unpack the rich information encoded in 3D image data into a straightforward numerical representation. This enabled us to employ data science tools, including machine learning, to analyze and integrate cell morphology, intracellular organization, ...
Source: eLife - June 5, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research

Flexible motor sequence generation during stereotyped escape responses
We report that a feedforward excitation between neurons encoding distinct motor states underlies robust motor sequence generation, while mutual inhibition between these neurons controls the flexibility of timing in a motor sequence. Electrical synapses contribute to feedforward coupling whereas glutamatergic synapses contribute to inhibition. We conclude thatC. elegans generates robust and flexible motor sequences by combining an excitatory coupling and a winner-take-all operation via mutual inhibition between motor modules. (Source: eLife)
Source: eLife - June 5, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Mechanisms of nucleotide selection by telomerase
Telomerase extends telomere sequences at chromosomal ends to protect genomic DNA. During this process it must select the correct nucleotide from a pool of nucleotides with various sugars and base pairing properties, which is critically important for the proper capping of telomeric sequences by shelterin. Unfortunately, how telomerase selects correct nucleotides is unknown. Here, we determined structures ofTribolium castaneum telomerase reverse transcriptase (TERT) throughout its catalytic cycle and mapped the active site residues responsible for nucleoside selection, metal coordination, triphosphate binding, and RNA templa...
Source: eLife - June 5, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research