Can sleep protect memories from catastrophic forgetting?
Continual learning remains to be an unsolved problem in artificial neural networks. The brain has evolved mechanisms to prevent catastrophic forgetting of old knowledge during new training. Building upon data suggesting importance of sleep in learning and memory, we tested a hypothesis that sleep protects old memories from forgetting. In the thalamocortical model, training a new memory interfered with previously learned old memories leading to degradation and forgetting of the old memory traces. Simulating sleep immediately after new learning reversed the damage and enhanced all memories. We found that when a new memory co...
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Membrane voltage dysregulation driven by metabolic dysfunction underlies bactericidal activity of aminoglycosides
Aminoglycosides are broad-spectrum antibiotics whose mechanism of action is under debate. It is widely accepted that membrane voltage potentiates aminoglycoside activity, which is ascribed to voltage-dependent drug uptake. In this paper, we measured the response of Escherichia coli treated with aminoglycosides and discovered that the bactericidal action arises not from the downstream effects of voltage dependent drug uptake, but rather directly from dysregulated membrane potential. In the absence of voltage, aminoglycosides are taken into cells and exert bacteriostatic effects by inhibiting translation. However, cell killi...
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

A flexible framework for simulating and fitting generalized drift-diffusion models
The drift-diffusion model (DDM) is an important decision-making model in cognitive neuroscience. However, innovations in model form have been limited by methodological challenges. Here, we introduce the generalized drift-diffusion model (GDDM) framework for building and fitting DDM extensions, and provide a software package which implements the framework. The GDDM framework augments traditional DDM parameters through arbitrary user-defined functions. Models are solved numerically by directly solving the Fokker-Planck equation using efficient numerical methods, yielding a 100-fold or greater speedup over standard methodolog...
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Expression of different L1 isoforms of < i > Mastomys natalensis < /i > papillomavirus as mechanism to circumvent adaptive immunity
Although many high-risk mucosal and cutaneous human papillomaviruses (HPVs) theoretically have the potential to synthesize L1 isoforms differing in length, previous seroepidemiological studies only focused on the short L1 variants, co-assembling with L2 to infectious virions. Using the multimammate mouseMastomys coucha as preclinical model, this is the first study demonstrating seroconversion against different L1 isoforms during the natural course of papillomavirus infection. Intriguingly, positivity with the cutaneous MnPV was accompanied by a strong seroresponse against a longer L1 isoform, but to our surprise, the raise...
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women
Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, i...
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

The diversity of decay
To predict how species loss will affect ecosystems, it is important to consider how biodiversity influences processes such as decomposition. (Source: eLife)
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Ecology Source Type: research

Balancing excitation and inhibition in the autistic brain
A metric called the Hurst exponent could be a useful biomarker for studies exploring brain differences between men and women with autism spectrum disorder. (Source: eLife)
Source: eLife - August 4, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

EDF1 coordinates cellular responses to ribosome collisions
Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collis...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Alternative splicing of < i > coq-2 < /i > controls the level of rhodoquinone in animals
Parasitic helminths use two benzoquinones as electron carriers in the electron transport chain. In normoxia they use ubiquinone (UQ), but in the anaerobic conditions inside the host, they require rhodoquinone (RQ) and greatly increase RQ levels. We previously showed the switch from UQ to RQ synthesis is driven by a change in substrates by the polyprenyltransferase COQ-2 (Del Borrello et al., 2019; Roberts Buceta et al., 2019) - how this substrate choice is made is unknown. Here, we show helminths make twocoq-2 splice forms,coq-2aandcoq-2e, and thecoq-2e-specific exon is only found in species that make RQ. We show that inC....
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research

Efficient coding of natural scene statistics predicts discrimination thresholds for grayscale textures
Previously, in (Hermundstad et al., 2014), we showed that when sampling is limiting, the efficient coding principle leads to a 'variance is salience' hypothesis, and that this hypothesis accounts for visual sensitivity to binary image statistics. Here, using extensive new psychophysical data and image analysis, we show that this hypothesis accounts for visual sensitivity to a large set of grayscale image statistics at a striking level of detail, and also identify the limits of the prediction. We define a 66-dimensional space of local grayscale light-intensity correlations, and measure the relevance of each direction to nat...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Neuroscience Physics of Living Systems Source Type: research

The Structural Determinants of PH Domain-Mediated Regulation of Akt Revealed by Segmental Labeling
Akt is a critical protein kinase that governs cancer cell growth and metabolism. Akt appears to be autoinhibited by an intramolecular interaction between its N-terminal pleckstrin homology (PH) domain and kinase domain, which is relieved by C-tail phosphorylation, but the precise molecular mechanisms remain elusive. Here we use a combination of protein semisynthesis, NMR, and enzymological analysis to characterize structural features of the PH domain in its autoinhibited and activated states. We find that Akt autoinhibition depends on the length/flexibility of the PH-kinase linker. We identify a role for a dynamic short se...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair
During meiosis, homologous chromosomes pair and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, double-strand breaks (DSBs) initiate recombination within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have been identified. We identifiedZcwpw1, containing H3K4me3 and H3K36me3 recognition domains, as having highly correlated expression withPrdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with hi...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Gene autoregulation by 3 ’ UTR-derived bacterial small RNAs
Negative feedback regulation, that is the ability of a gene to repress its own synthesis, is the most abundant regulatory motif known to biology. Frequently reported for transcriptional regulators, negative feedback control relies on binding of a transcription factor to its own promoter. Here, we report a novel mechanism for gene autoregulation in bacteria relying on small regulatory RNA (sRNA) and the major endoribonuclease, RNase E. TIER-seq analysis (transiently-inactivating-an-endoribonuclease-followed-by-RNA-seq) revealed ~25,000 RNase E-dependent cleavage sites inVibrio cholerae, several of which resulted in the accu...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Microbiology and Infectious Disease Source Type: research

A human ESC-based screen identifies a role for the translated lncRNA < i > LINC00261 < /i > in pancreatic endocrine differentiation
Long noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Using a human embryonic stem cell (hESC)-based pancreatic differentiation system, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for pancreatic endocrin...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research

Activation of a neural stem cell transcriptional program in parenchymal astrocytes
Adult neural stem cells, located in discrete brain regions, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar ...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Neuroscience Stem Cells and Regenerative Medicine Source Type: research

NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency
The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Single molecule poly(A) tail-seq shows LARP4 opposes deadenylation through mRNA lifespan with most impact on short tails
La-related protein 4 (LARP4) directly binds both poly(A) and poly(A)-binding protein (PABP). LARP4 was shown to promote poly(A) tail (PAT) lengthening and stabilization of individual mRNAs presumably by protection from deadenylation (Mattijssen et al., 2017). We developed a nucleotide resolution transcriptome-wide, single molecule SM-PAT-seq method. This revealed LARP4 effects on a wide range of PAT lengths for human mRNAs and mouse mRNAs from LARP4 knockout (KO) and control cells. LARP4 effects are clear on long PAT mRNAs but become more prominent at 30-75 nucleotides. We also analyzed time courses of PAT decay transcript...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids
How cells adjust nutrient transport across their membranes is incompletely understood. Previously, we have shown thatS. cerevisiae broadly re-configures the nutrient transporters at the plasma membrane in response to amino acid availability, through endocytosis of sugar- and amino acid transporters (AATs) (M üller et al., 2015). A genome-wide screen now revealed that the selective endocytosis of four AATs during starvation required the α-arrestin family protein Art2/Ecm21, an adaptor for the ubiquitin ligase Rsp5, and its induction through the general amino acid control pathway. Art2 uses a basic patc h to recog...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Boosts in brain signal variability track liberal shifts in decision bias
Adopting particular decision biases allows organisms to tailor their choices to environmental demands. For example, a liberal response strategy pays off when target detection is crucial, whereas a conservative strategy is optimal for avoiding false alarms. Using conventional time-frequency analysis of human electroencephalographic (EEG) activity, we previously showed that bias setting entails adjustment of evidence accumulation in sensory regions (Kloosterman et al., 2019), but the presumed prefrontal signature of a conservative-to-liberal bias shift has remained elusive. Here, we show that a liberal bias shift is reflecte...
Source: eLife - August 3, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Drainage of inflammatory macromolecules from brain to periphery targets the liver for macrophage infiltration
Many brain pathologies are associated with liver damage, but a direct link has long remained elusive. Here, we establish a new paradigm for interrogating brain-periphery interactions by leveraging zebrafish for its unparalleled access to the intact whole animal forin vivo analysis in real time after triggering focal brain inflammation. Using traceable lipopolysaccharides (LPS), we reveal that drainage of these inflammatory macromolecules from the brain led to a strikingly robust peripheral infiltration of macrophages into the liver independent of Kupffer cells. We further demonstrate that this macrophage recruitment requir...
Source: eLife - July 31, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Neuroscience Source Type: research

Structure and mechanism of the Mrp complex, an ancient cation/proton antiporter
Multiple resistance and pH adaptation (Mrp) antiporters are multi-subunit Na+ (or K+)/H+ exchangers representing an ancestor of many essential redox-driven proton pumps, such as respiratory complex I. The mechanism of coupling between ion or electron transfer and proton translocation in this large protein family is unknown. Here, we present the structure of the Mrp complex fromAnoxybacillus flavithermussolved by cryo-EM at 3.0 Å resolution. It is a dimer of seven-subunit protomers with 50 trans-membrane helices each. Surface charge distribution within each monomer is remarkably asymmetric, revealing probable proton a...
Source: eLife - July 31, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Gap junctions deliver malonyl-CoA from soma to germline to support embryogenesis in Caenorhabditis elegans
Gap junctions are ubiquitous in metazoans and play critical roles in important biological processes, including electrical conduction and development. Yet, only a few defined molecules passing through gap junction channels have been linked to specific functions. We isolated gap junction channel mutants that reduce coupling between the soma and germ cells in theC. elegans gonad. We provide evidence that malonyl-CoA, the rate-limiting substrate for fatty acid synthesis (FAS), is produced in the soma and delivered through gap junctions to the germline; there it is used in fatty acid synthesis to critically support embryonic de...
Source: eLife - July 31, 2020 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Molecular principles of assembly, activation, and inhibition in epithelial sodium channel
The molecular bases of heteromeric assembly and link between Na+ self-inhibition and protease-sensitivity in epithelial sodium channels (ENaCs) are not fully understood. Previously, we demonstrated that ENaC subunits – α, β, and γ – assemble in a counterclockwise configuration when viewed from outside the cell with the protease-sensitive GRIP domains in the periphery (Noreng et al., 2018). Here we describe the structure of ENaC resolved by cryo-electron microscopy at 3 Å. We find that a combination of pr ecise domain arrangement and complementary hydrogen bonding network defines the subun...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

An atlas of cell types in the mammalian epididymis and vas deferens
Following testicular spermatogenesis, mammalian sperm continue to mature in a long epithelial tube known as the epididymis, which plays key roles in remodeling sperm protein, lipid, and RNA composition. To understand the roles for the epididymis in reproductive biology, we generated a single cell atlas of the murine epididymis and vas deferens. We recovered key epithelial cell types including principal cells, clear cells, and basal cells, along with associated support cells that include fibroblasts, smooth muscle, macrophages and other immune cells. Moreover, our data illuminate extensive regional specialization of princip...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Revealing the structure of information flows discriminates similar animal social behaviors
Behavioral correlations stretching over time are an essential but often neglected aspect of interactions among animals. These correlations pose a challenge to current behavioral-analysis methods that lack effective means to analyze complex series of interactions. Here we show that non-invasive information-theoretic tools can be used to reveal communication protocols that guide complex social interactions by measuring simultaneous flows of different types of information between subjects. We demonstrate this approach by showing that the tandem-running behavior of the antTemnothorax rugatulus and that of the termitesCoptoterm...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Ecology Physics of Living Systems Source Type: research

Keratinocytes contribute to normal cold and heat sensation
The molecular bases of heteromeric assembly and link between Na+ self-inhibition and protease-sensitivity in epithelial sodium channels (ENaCs) are not fully understood. Previously, we demonstrated that ENaC subunits – α, β, and γ – assemble in a counterclockwise configuration when viewed from outside the cell with the protease-sensitive GRIP domains in the periphery (Noreng et al., 2018). Here we describe the structure of ENaC resolved by cryo-electron microscopy at 3 Å. We find that a combination of pr ecise domain arrangement and complementary hydrogen bonding network defines the subun...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Convergent changes in muscle metabolism depend on duration of high-altitude ancestry across Andean waterfowl
We examined seven high-altitude waterfowl that have inhabited the Andes (3812-4806m elevation) over varying evolutionary time scales, to elucidate changes in biochemical pathways of energy metabolism in flight muscle relative to low-altitude sister-taxa. Convergent changes across high-altitude taxa included increased hydroxyacyl-coA dehydrogenase and succinate dehydrogenase activities, decreased lactate dehydrogenase, pyruvate kinase, creatine kinase, and cytochrome c oxidase activities, and increased myoglobin content. ATP synthase activity increased in only the longest established high-altitude taxa, whereas hexokinase a...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Long non-coding RNAs in regulation of adipogenesis and adipose tissue function
Complex interaction between genetics, epigenetics, environment, and nutrition affect the physiological activities of adipose tissues and their dysfunctions, which lead to several metabolic diseases including obesity or type 2 diabetes. Here, adipogenesis appears to be a process characterized by an intricate network that involves many transcription factors and long noncoding RNAs (lncRNAs) that regulate gene expression. LncRNAs are being investigated to determine their contribution to adipose tissue development and function. LncRNAs possess multiple cellular functions, and they regulate chromatin remodeling, along with tran...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

A unified computational model for cortical post-synaptic plasticity
Signalling pathways leading to post-synaptic plasticity have been examined in many types of experimental studies, but a unified picture on how multiple biochemical pathways collectively shape neocortical plasticity is missing. We built a biochemically detailed model of post-synaptic plasticity describing CaMKII, PKA, and PKC pathways and their contribution to synaptic potentiation or depression. We developed a statistical AMPA-receptor-tetramer model, which permits the estimation of the AMPA-receptor-mediated maximal synaptic conductance based on numbers of GluR1s and GluR2s predicted by the biochemical signalling model. W...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Structure and dynamics of a nanodisc by integrating NMR, SAXS and SANS experiments with molecular dynamics simulations
Nanodiscs are membrane mimetics that consist of a protein belt surrounding a lipid bilayer, and are broadly used for characterization of membrane proteins. Here, we investigate the structure, dynamics and biophysical properties of two small nanodiscs, MSP1D1 ΔH5 and ΔH4H5. We combine our SAXS and SANS experiments with molecular dynamics simulations and previously obtained NMR and EPR data to derive and validate a conformational ensemble that represents the structure and dynamics of the nanodisc. We find that it displays conformational heterogeneity wi th various elliptical shapes, and with substantial differenc...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Neuropathogenesis of SARS-CoV-2 infection
The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Neuroscience Source Type: research

Apoptotic neurodegeneration in whitefly promotes the spread of TYLCV
The mechanism by which plant viruses manipulate the behavior of insect vectors has largely been described as indirect manipulation through modifications of the host plant. However, little is known about the direct interaction of the plant virus on the nervous system of its insect vector, and the substantial behavioral effect on virus transmission. Using a system consisting of aTomato yellow leaf curl virus (TYLCV) and its insect vector whitefly, we found that TYLCV caused caspase-dependent apoptotic neurodegeneration with severe vacuolar neuropathological lesions in the brain of viruliferous whitefly by inducing a putative...
Source: eLife - July 30, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Accurate and versatile 3D segmentation of plant tissues at cellular resolution
We present results of PlantSeg applications in diverse developmental contexts. PlantSeg is free and open-source, with both a command line and a user-friendly graphical interface (https://github.com/hci-unihd/plant-seg). (Source: eLife)
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Plant Biology Source Type: research

Lichen mimesis in mid-Mesozoic lacewings
Animals mimicking other organisms or using camouflage to deceive predators are vital survival strategies. Modern and fossil insects can simulate diverse objects. Lichens are an ancient symbiosis between a fungus and an alga or a cyanobacterium that sometimes have a plant-like appearance and occasionally are mimicked by modern animals. Nevertheless, lichen models are almost absent in fossil record of mimicry. Here, we provide the earliest fossil evidence of a mimetic relationship between the moth lacewing mimicLichenipolystoechotes gen. nov. and its co-occurring fossil lichen modelDaohugouthallus ciliiferus. We corroborate ...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling
The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therape...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

A mechanism for the extension and unfolding of parallel G-quadruplexes by human telomerase at single-molecule resolution
Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) microscopy and bulk-phase enzymology to propose a mechanism for the resolution and extension of parallel G4 by telomerase. Bindi...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

Cryo-EM structures of human ZnT8 in both outward- and inward-facing conformations
ZnT8 is a Zn2+/H+ antiporter that belongs to SLC30 family and plays an essential role in regulating Zn2+accumulation in the insulin secretory granules of pancreatic β cells. Dysfunction of ZnT8 is associated with both type 1 and 2 diabetes. However, the Zn2+/H+ exchange mechanism of ZnT8 remains unclear due to the lack of high-resolution structures. Here, we report the cryo-EM structures of human ZnT8 (HsZnT8) in both outward- and inward-facing conformations. HsZnT8 forms a dimeric structure with four Zn2+ binding sites within each subunit: a highly conserved primary site in transmembrane domain (TMD) housing the Zn2+...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Notch and TLR signaling coordinate monocyte cell fate and inflammation
Conventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte devel...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Virus infection is controlled by hematopoietic and stromal cell sensing of murine cytomegalovirus through STING
Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to M...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

A mechanism for < i > hunchback < /i > promoters to readout morphogenetic positional information in less than a minute
Cell fate decisions in the fly embryo are rapid: hunchback genes decide in minutes whether nuclei follow the anterior/posterior developmental blueprint by reading out positional information in the Bicoid morphogen. This developmental system is a prototype of regulatory decision processes that combine speed and accuracy. Traditional arguments based on fixed-time sampling of Bicoid concentration indicate that an accurate readout is impossible within the experimental times. This raises the general issue of how speed-accuracy tradeoffs are achieved. Here, we compare fixed-time to on-the-fly decisions, based on comparing the li...
Source: eLife - July 29, 2020 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

Growth factor-mediated coupling between lineage size and cell fate choice underlies robustness of mammalian development
Precise control and maintenance of population size is fundamental for organismal development and homeostasis. The three cell types of the mammalian blastocyst are generated in precise proportions over a short time, suggesting a mechanism to ensure a reproducible outcome. We developed a minimal mathematical model demonstrating growth factor signaling is sufficient to guarantee this robustness and which anticipates an embryo's response to perturbations in lineage composition. Addition of lineage-restricted cells bothin vivo andin silico, causes a shift of the fate of progenitors away from the supernumerary cell type, while e...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe thein vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neuro...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

An electrophysiological marker of arousal level in humans
Deep non-rapid eye movement sleep (NREM) and general anesthesia with propofol are prominent states of reduced arousal linked to the occurrence of synchronized oscillations in the electroencephalogram (EEG). Although rapid eye movement (REM) sleep is also associated with diminished arousal levels, it is characterized by a desynchronized, 'wake-like' EEG. This observation implies that reduced arousal states are not necessarily only defined by synchronous oscillatory activity. Using intracranial and surface EEG recordings in four independent data sets, we demonstrate that the 1/f spectral slope of the electrophysiological pow...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

The identification of dual protective agents against cisplatin-induced oto-and nephrotoxicity using the zebrafish model
This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin. (Source: eLife)
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Cancer Biology Human Biology and Medicine Source Type: research

Deciphering the neural signature of human cardiovascular regulation
Cardiovascular regulation is integral to life. Animal studies have identified both neural and endocrine pathways, by which the central nervous system adjusts cardiac output and peripheral vascular resistance to changing physiological demands. The outflow of these pathways is coordinated by various central nervous regions based on afferent information from baroreceptors, chemoreceptors, nociceptors, and circulating hormones, and is modulated by physiologic and behavioural state. In humans, however, knowledge on central cardiovascular regulation below the cortical level is scarce. Here, we show using functional MRI (fMRI) th...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation
During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzymeN-glycanase 1 (NGLY1) is proposed to removeN-glycans from misfoldedN-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulatesDrosophila BMP signaling in a tissue-specific manner (Galeone et al. 2017). Here, we establish theDrosophilaDpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress a...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging
Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Genetics and Genomics Human Biology and Medicine Source Type: research

An analog to digital converter controls bistable transfer competence of a widespread integrative and conjugative element
Conjugative transfer of the integrative and conjugative element ICEclc in Pseudomonas requires development of a transfer competence state in stationary phase, which arises only in 3-5% of individual cells. The mechanisms controlling this bistable switch between non-active and transfer competent cells have long remained enigmatic. Using a variety of genetic tools and epistasis experiments in P. putida, we uncovered an 'upstream' cascade of three consecutive transcription factor-nodes, which controls transfer competence initiation. One of the uncovered transcription factors (named BisR) is representative for a new regulator ...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research

Identifying prostate cancer and its clinical risk in asymptomatic men using machine learning of high dimensional peripheral blood flow cytometric natural killer cell subset phenotyping data
We demonstrate that prostate cancer can be identified by flow cytometric profiling of blood immune cell subsets. Herein, we profiled natural killer (NK) cell subsets in the blood of 72 asymptomatic men with Prostate-Specific Antigen (PSA) levels
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research

Shared and specific signatures of locomotor ataxia in mutant mice
Several spontaneous mouse mutants with deficits in motor coordination and associated cerebellar neuropathology have been described. Intriguingly, both visible gait alterations and neuroanatomical abnormalities throughout the brain differ across mutants. We previously used the LocoMouse system to quantify specific deficits in locomotor coordination in mildly ataxicPurkinje cell degeneration mice (pcd; Machado et al., 2015). Here, we analyze the locomotor behavior of severely ataxicreeler mutants and compare and contrast it with that ofpcd. Despite clearly visible gait differences, direct comparison of locomotor kinematics a...
Source: eLife - July 28, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research