Peroxiredoxin promotes longevity and H2O2-resistance in yeast through redox-modulation of protein kinase A
Peroxiredoxins are H2O2 scavenging enzymes that also carry H2O2 signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to H2O2 and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging H2O2, but by repressing the nutrient signaling Ras-cAMP-PKA pathway at the level of the protein kinase A (PKA) enzyme. Tsa1 stimulates sulfenylation of cysteines in the PKA catalytic subunit by H2O2 and a significant proportion of the catalytic subunits are glutathionylated on two cysteine residues. Redox modif...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Restricting the sizes of condensates
Computer simulations of model proteins with sticker-and-spacer architectures shed light on the formation of biomolecular condensates in cells. (Source: eLife)
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Physics of Living Systems Structural Biology and Molecular Biophysics Source Type: research

Recurrent circuitry is required to stabilize piriform cortex odor representations across brain states
Pattern completion, or the ability to retrieve stable neural activity patterns from noisy or partial cues, is a fundamental feature of memory. Theoretical studies indicate that recurrently connected auto-associative or discrete attractor networks can perform this process. Although pattern completion and attractor dynamics have been observed in various recurrent neural circuits, the role recurrent circuitry plays in implementing these processes remains unclear. In recordings from head-fixed mice, we found that odor responses in olfactory bulb degrade under ketamine/xylazine anesthesia while responses immediately downstream,...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults
Tanzanian adult male volunteers were immunized by direct venous inoculation with radiation-attenuated, aseptic, purified, cryopreservedPlasmodium falciparum(Pf) sporozoites (PfSPZ Vaccine) and protective efficacy assessed by homologous controlled human malaria infection (CHMI). Serum immunoglobulin G (IgG) responses were analyzed longitudinally using a Pf protein microarray covering 91% of the proteome, providing first insights into naturally acquired and PfSPZ Vaccine-induced whole parasite antibody profiles in malaria pre-exposed Africans. Immunoreactivity was identified against 2,239 functionally diverse Pf proteins, sh...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?
We report that co-transcription of ACE2 and TMPRSS2 is negligible in the placenta, thus not a likely path of vertical transmission for SARS-CoV-2. By contrast, receptors for Zika virus and cytomegalovirus, which cause congenital infections, are highly expressed by placental cell types. These data show that the placenta minimally expresses the canonical cell-entry mediators for SARS-CoV-2. (Source: eLife)
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Genetics and Genomics Human Biology and Medicine Source Type: research

Correction: Building customizable auto-luminescent luciferase-based reporters in plants
(Source: eLife)
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Plant Biology Source Type: research

Flotillin-mediated membrane fluidity controls peptidoglycan synthesis and MreB movement
The bacterial plasma membrane is an important cellular compartment. In recent years it has become obvious that protein complexes and lipids are not uniformly distributed within membranes. Current hypotheses suggest that flotillin proteins are required for the formation of complexes of membrane proteins including cell-wall synthetic proteins. We show here that bacterial flotillins are important factors for membrane fluidity homeostasis. Loss of flotillins leads to a decrease in membrane fluidity that in turn leads to alterations in MreB dynamics and, as a consequence, in peptidoglycan synthesis. These alterations are revert...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Sleep is bi-directionally modified by amyloid beta oligomers
Disrupted sleep is a major feature of Alzheimer ’s disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which A β affects sleep are unknown. We demonstrate in zebrafish that Aβ acutely and reversibly enhances or suppresses sleep as a function of oligomer length. Genetic disruptions revealed that short Aβ oligomers induce acute wakefulness through Adrenergic receptor b...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Risk of psychiatric disorders among the surviving twins after a co-twin loss
Losing a co-twin by death is a severely stressful event yet with unknown impact on the surviving twin ’s risk of psychiatric disorders. We identified all Swedish-born twins who lost a co-twin by death between 1973 and 2013 (n = 4,528), their 4939 non-twin full siblings, together with 22,640 age- and sex-matched non-bereaved twins. Compared to the non-bereaved twins, exposed twins were at increased risk of receiving a first diagnosis of psychiatric disorders (hazard ratio = 1.65, 95% confidence interval1.48–1.83), particularly during the first month after loss. Similarly, compared to non-twin full siblings, the ...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Stable task information from an unstable neural population
Over days and weeks, neural activity representing an animal's position and movement in sensorimotor cortex has been found to continually reconfigure or 'drift' during repeated trials of learned tasks, with no obvious change in behavior. This challenges classical theories which assume stable engrams underlie stable behavior. However, it is not known whether this drift occurs systematically, allowing downstream circuits to extract consistent information. Analyzing long-term calcium imaging recordings from posterior parietal cortex in mice (Mus musculus), we show that drift is systematically constrained far above chance, faci...
Source: eLife - July 14, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Cancer systems immunology
Tumor immunology is undergoing a renaissance due to the recent profound clinical successes of tumor immunotherapy. These advances have coincided with an exponential growth in the development of –omics technologies. Armed with these technologies and their associated computational and modeling toolsets, systems biologists have turned their attention to tumor immunology in an effort to understand the precise nature and consequences of interactions between tumors and the immune system. Such interactions are inherently multivariate, spanning multiple time and size scales, cell types, and organ systems, rendering systems b...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Cancer Biology Immunology and Inflammation Source Type: research

Sleep spindles mediate hippocampal-neocortical coupling during long-duration ripples
Sleep is pivotal for memory consolidation. According to two-stage accounts, memory traces are gradually translocated from hippocampus to neocortex during non-rapid-eye-movement (NREM) sleep. Mechanistically, this information transfer is thought to rely on interactions between thalamocortical spindles and hippocampal ripples. To test this hypothesis, we analyzed intracranial and scalp Electroencephalography sleep recordings from pre-surgical epilepsy patients. We first observed a concurrent spindle power increase in hippocampus (HIPP) and neocortex (NC) time-locked to individual hippocampal ripple events. Coherence analysis...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Growth cone-localized microtubule organizing center establishes microtubule orientation in dendrites
A polarized arrangement of neuronal microtubule arrays is the foundation of membrane trafficking and subcellular compartmentalization. Conserved among both invertebrates and vertebrates, axons contain exclusively 'plus-end-out' microtubules while dendrites contain a high percentage of 'minus-end-out' microtubules, the origins of which have been a mystery. Here we show that inCaenorhabditis elegans the dendritic growth cone contains a non-centrosomal microtubule organizing center, which generates minus-end-out microtubules along outgrowing dendrites and plus-end-out microtubules in the growth cone. RAB-11-positive endosomes...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Alzheimer's disease risk gene < i > BIN1 < /i > induces Tau-dependent network hyperexcitability
Genome-wide association studies identified theBIN1 locus as a leading modulator of genetic risk in Alzheimer's disease (AD). One limitation in understandingBIN1's contribution to AD is its unknown function in the brain. AD-associatedBIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured rat hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives g...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: Optogenetically induced low-frequency correlations impair perception
(Source: eLife)
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Umbilical cord blood-derived ILC1-like cells constitute a novel precursor for mature KIR < sup > + < /sup > NKG2A < sup > - < /sup > NK cells
Despite their identification several years ago, molecular identity and developmental relation between human ILC1 and NK cells, comprising group 1 ILCs, is still elusive. To unravel their connection, thorough transcriptional, epigenetic, and functional characterization was performed from umbilical cord blood (CB). Unexpectedly, ILC1-like cells lacked Tbet expression and failed to produce IFN γ. Moreover, in contrast to previously described ILC1 subsets they could be efficiently differentiated into NK cells. These were characterized by highly diversified KIR repertoires including late stage NKG2A-KIR+ effector cells th...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Assigning mitochondrial localization of dual localized proteins using a yeast Bi-Genomic Mitochondrial-Split-GFP
A single nuclear gene can be translated into a dual localized protein that distributes between the cytosol and mitochondria. Accumulating evidences show that mitoproteomes contain lots of these dual localized proteins termed echoforms. Unraveling the existence of mitochondrial echoforms using current GFP (Green Fluorescent Protein) fusion microscopy approaches is extremely difficult because the GFP signal of the cytosolic echoform will almost inevitably mask that of the mitochondrial echoform. We therefore engineered a yeast strain expressing a new type of Split-GFP that we termed Bi-Genomic Mitochondrial-Split-GFP (BiG Mi...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Ribosome collisions trigger cis-acting feedback inhibition of translation initiation
Translation of aberrant mRNAs can cause ribosomes to stall, leading to collisions with trailing ribosomes. Collided ribosomes are specifically recognized by ZNF598 to initiate protein and mRNA quality control pathways. Here we found using quantitative proteomics of collided ribosomes that EDF1 is a ZNF598-independent sensor of ribosome collisions. EDF1 stabilizes GIGYF2 at collisions to inhibit translation initiationin cis via 4EHP. The GIGYF2 axis acts independently of the ZNF598 axis, but each pathway's output is more pronounced without the other. We propose that the widely conserved and highly abundant EDF1 monitors the...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Phosphoinositides regulate force-independent interactions between talin, vinculin, and actin
The focal adhesion (FA) proteins talin and vinculin connect integrin to actomyosin networks, acting as the core mechanosensitive FA machinery. Both proteins bind to F-actin and each other, providing a foundation for network formation within FAs. However, the underlying mechanisms regulating their engagement remain unclear. Here, we performedin vitro reconstitution of talin-vinculin-actin assemblies using synthetic membrane systems. Neither talin nor vinculin alone recruit actin filaments to the membrane. In contrast, phosphoinositide-rich membranes recruit and activate talin, and the membrane-bound talin then activates vin...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Cell Biology Structural Biology and Molecular Biophysics Source Type: research

Microtubules originate asymmetrically at the somatic Golgi and are guided via Kinesin2 to maintain polarity in neurons
Neurons contain polarised microtubule arrays essential for neuronal function. How microtubule nucleation and polarity are regulated within neurons remains unclear. We show that γ-tubulin localises asymmetrically to the somatic Golgi withinDrosophila neurons. Microtubules originate from the Golgi with an initial growth preference towards the axon. Their growing plus ends also turn towards and into the axon, adding to the plus-end-out microtubule pool. Any plus ends that reach a dendrite, however, do not readily enter, maintaining minus-end-out polarity. Both turning towards the axon and exclusion from dendrites depend...
Source: eLife - July 13, 2020 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Miga-mediated endoplasmic reticulum –mitochondria contact sites regulate neuronal homeostasis
Endoplasmic reticulum (ER) –mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, and mitochondrial dynamics. However, the molecular organization, functions, regulation of ERMCS, and the physiological roles of altered ERMCSs are not fully understood in hi gher eukaryotes. We found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 ...
Source: eLife - July 10, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited incre...
Source: eLife - July 10, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Miga mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis
In this study, we found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga mediated ERMCS formation. The interac tion between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters,...
Source: eLife - July 10, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Real-time < i > in vivo < /i > imaging of extracellular ATP in the brain with a hybrid-type fluorescent sensor
Adenosine 5' triphosphate (ATP) is a ubiquitous extracellular signaling messenger. Here, we describe a method forin-vivo imaging of extracellular ATP with high spatiotemporal resolution. We prepared a comprehensive set of cysteine-substitution mutants of ATP-binding protein,Bacillus FoF1-ATP synthase e subunit, labeled with small-molecule fluorophores at the introduced cysteine residue. Screening revealed that the Cy3-labeled glutamine-105 mutant (Q105C-Cy3; designated ATPOS) shows a large fluorescence change in the presence of ATP, with submicromolar affinity, pH-independence, and high selectivity for ATP over ATP metabol...
Source: eLife - July 10, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Neuroscience Source Type: research

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice
Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mito...
Source: eLife - July 10, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Evolutionarily distant I domains can functionally replace the essential ligand-binding domain of < i > Plasmodium < /i > TRAP
Inserted (I) domains function as ligand-binding domains in adhesins that support cell adhesion and migration in many eukaryotic phyla. These adhesins include integrin αβ heterodimers in metazoans and single subunit transmembrane proteins in apicomplexans such as TRAP inPlasmodium and MIC2 inToxoplasma. Here we show that the I domain of TRAP is essential for sporozoite gliding motility, mosquito salivary gland invasion and mouse infection. Its replacement with the I domain from Toxoplasma MIC2 fully restores tissue invasion and parasite transmission, while replacement with the aX I domain from human integrins sti...
Source: eLife - July 10, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

A high-throughput small molecule screen identifies farrerol as a potentiator of CRISPR/Cas9-mediated genome editing
Directly modulating the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) - two independent pathways for repairing DNA double-strand breaks (DSBs) - has the potential to improve the efficiency of gene targeting by CRISPR/Cas9. Here, we have developed a rapid and easy-to-score screening approach for identifying small molecules that affect the choice between the two DSB repair pathways. Using this tool, we identified a small molecule, farrerol, that promotes HR but does not affect NHEJ. Further mechanistic studies indicate that farrerol functions through stimulating the recruitment of RAD51 t...
Source: eLife - July 9, 2020 Category: Biomedical Science Tags: Cell Biology Genetics and Genomics Source Type: research

Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo
Mutations inKCNC3, which encodes the Kv3.3 K+ channel, cause spinocerebellar ataxia 13 (SCA13). SCA13 exists in distinct forms with onset in infancy or adulthood. Using zebrafish, we tested the hypothesis that infant- and adult-onset mutations differentially affect the excitability and viability of Purkinje cells in vivo during cerebellar development. An infant-onset mutation dramatically and transiently increased Purkinje cell excitability, stunted process extension, impaired dendritic branching and synaptogenesis, and caused rapid cell death during cerebellar development. Reducing excitability increased early Purkinje ce...
Source: eLife - July 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Different dendritic domains of the GnRH neuron underlie the pulse and surge modes of GnRH secretion in female mice
The gonadotropin-releasing hormone (GnRH) neurons exhibit pulse and surge modes of activity to control fertility. They also exhibit an unusual bipolar morphology comprised of a classical soma-proximal dendritic zone and an elongated secretory process that can operate as both a dendrite and an axon, termed a ‘dendron’. We show using expansion microscopy that the highest density of synaptic inputs to a GnRH neuron exists at its distal dendron. In vivo, selective chemogenetic inhibition of the GnRH neuron distal dendron abolishes the luteinizing hormone (LH) surge and markedly dampens LH pulses. In co ntrast, inhi...
Source: eLife - July 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

An adipokine feedback regulating diurnal food intake rhythms in mice
Endogenous circadian clocks have evolved to anticipate 24-hour rhythms in environmental demands. Recent studies suggest that circadian rhythm disruption is a major risk factor for the development of metabolic disorders in humans. Conversely, alterations in energy state can disrupt circadian rhythms of behavior and physiology, creating a vicious circle of metabolic dysfunction. How peripheral energy state affects diurnal food intake, however, is still poorly understood. We here show that the adipokine adiponectin (ADIPOQ) regulates diurnal feeding rhythms through clocks in energy regulatory centers of the mediobasal hypotha...
Source: eLife - July 9, 2020 Category: Biomedical Science Tags: Genetics and Genomics Neuroscience Source Type: research

Cell lineage-dependent chiral actomyosin flows drive cellular rearrangements in early < i > C. elegans < /i > development
In conclusion, our work sheds light on the physical processes that underlie chiral morphogenesis in early development. (Source: eLife)
Source: eLife - July 9, 2020 Category: Biomedical Science Tags: Developmental Biology Physics of Living Systems Source Type: research

Mechanical inhibition of isolated V < sub > o < /sub > from V/A-ATPase for proton conductance
V-ATPase is an energy converting enzyme, coupling ATP hydrolysis/synthesis in the hydrophilic V1 domain, with proton flow through the Vo membrane domain, via rotation of the central rotor complex relative to the surrounding stator apparatus. Upon dissociation from the V1 domain, the Vo domain of the eukaryotic V-ATPase can adopt a physiologically relevant auto-inhibited form in which proton conductance through the Vo domain is prevented, however the molecular mechanism of this inhibition is not fully understood. Using cryo-electron microscopy, we determined the structure of both theholo V/A-ATPase and isolated Vo at near-a...
Source: eLife - July 8, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis
The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fast...
Source: eLife - July 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Concentration-dependent mortality of chloroquine in overdose
Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose.In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 62...
Source: eLife - July 8, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Learning-related population dynamics in the auditory thalamus
Learning to associate sensory stimuli with a chosen action involves a dynamic interplay between cortical and thalamic circuits. While the cortex has been widely studied in this respect, how the thalamus encodes learning-related information is still largely unknown. We studied learning-related activity in the medial geniculate body (MGB; Auditory thalamus), targeting mainly the dorsal and medial regions. Using fiber photometry, we continuously imaged population calcium dynamics as mice learned a go/no-go auditory discrimination task. The MGB was tuned to frequency and responded to cognitive features like the choice of the m...
Source: eLife - July 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Gradients in the biophysical properties of neonatal auditory neurons align with synaptic contact position and the intensity coding map of inner hair cells
Sound intensity is encoded by auditory neuron subgroups that differ in thresholds and spontaneous rates. Whether variations in neuronal biophysics contributes to this functional diversity is unknown. Because intensity thresholds correlate with synaptic position on sensory hair cells, we combined patch clamping with fiber labeling in semi-intact cochlear preparations in neonatal rats from both sexes. The biophysical properties of auditory neurons vary in a striking spatial gradient with synaptic position. Neurons with high thresholds to injected currents contact hair cells at synaptic positions where neurons with high thres...
Source: eLife - July 8, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Resident macrophages acquire innate immune memory in staphylococcal skin infection
Staphylococcus aureus (S. aureus) is a common colonizer of healthy skin and mucous membranes. At the same time,S. aureus is the most frequent cause of skin and soft tissue infections. Dermal macrophages (M φ) are critical for the coordinated defense against invadingS. aureus, yet they have a limited life span with replacement by bone marrow derived monocytes. It is currently poorly understood whether localizedS. aureus skin infections persistently alter the resident M φ subset composition and resistance to a subsequent infection. In a strictly dermal infection model we found that mice, which were previously infecte...
Source: eLife - July 8, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Eco-evolutionary dynamics of nested Darwinian populations and the emergence of community-level heredity
Interactions among microbial cells can generate new chemistries and functions, but exploitation requires establishment of communities that reliably recapitulate community-level phenotypes. Using mechanistic mathematical models, we show how simple manipulations to population structure can exogenously impose Darwinian-like properties on communities. Such scaffolding causes communities to participate directly in the process of evolution by natural selection and drives the evolution of cell-level interactions to the point where, despite underlying stochasticity, derived communities give rise to offspring communities that faith...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research

Ways to increase equity, diversity and inclusion
The eLife Early-Career Advisory Group (ECAG), an international group of early-career researchers committed to improving research culture, calls for radical changes at eLife and other journals to address racism in the scientific community and to make science more diverse and inclusive. (Source: eLife)
Source: eLife - July 7, 2020 Category: Biomedical Science Source Type: research

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death
Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties ofPcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type withPcdhg-deficient interneuron p...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Augmented curation of clinical notes from a massive EHR system reveals symptoms of impending COVID-19 diagnosis
This study introduces anAugmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis. (Source: eLife)
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Microbiology and Infectious Disease Source Type: research

Muscle-derived Myoglianin regulates < i > Drosophila < /i > imaginal disc growth
Organ growth and size are finely tuned by intrinsic and extrinsic signaling molecules. InDrosophila, the BMP family member Dpp is produced in a limited set of imaginal disc cells and functions as a classic morphogen to regulate pattern and growth by diffusing throughout imaginal discs. However, the role of TGF β/Activin-like ligands in disc growth control remains ill-defined. Here we demonstrate that Myoglianin (Myo), an Activin family member, and a close homolog of mammalian Myostatin (Mstn), is a muscle-derived extrinsic factor that uses canonical dSmad2 mediated signaling to regulate wing size. We pro pose that Myo...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Dopamine role in learning and action inference
This paper describes a framework for modelling dopamine function in the mammalian brain. It proposes that both learning and action planning involve processes minimizing prediction errors encoded by dopaminergic neurons. In this framework, dopaminergic neurons projecting to different parts of the striatum encode errors in predictions made by the corresponding systems within the basal ganglia. The dopaminergic neurons encode differences between rewards and expectations in the goal-directed system, and differences between the chosen and habitual actions in the habit system. These prediction errors trigger learning about rewar...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells
Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogeno...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Earliest infections predict the age distribution of seasonal influenza A cases
Seasonal variation in the age distribution of influenza A cases suggests that factors other than age shape susceptibility to medically attended infection. We ask whether these differences can be partly explained by protection conferred by childhood influenza infection, which has lasting impacts on immune responses to influenza and protection against new influenza A subtypes (phenomena known as original antigenic sin and immune imprinting). Fitting a statistical model to data from studies of influenza vaccine effectiveness (VE), we find that primary infection appears to reduce the risk of medically attended infection with t...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm
Neither the disease mechanism nor treatments for COVID-19 are currently known. Here we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS, that produces the nonapeptide angiotensin1-9 from angiotensin I. Bradykinin is a potent, but often forgotten, part of the vasopressor system that induces hypotension and vasodilation1, and is regulated by ACE and enhanced by angiotensin1-92. Here we perform a completely new a...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Human Biology and Medicine Source Type: research

Trends in snakebite deaths in India from 2000 to 2019 in a nationally representative mortality study
The World Health Organization call to halve global snakebite deaths by 2030 will require substantial progress in India. We analyzed 2833 snakebite deaths from 611,483 verbal autopsies in the nationally representative Indian Million Death Study from 2001 to 2014, and conducted a systematic literature review from 2000 to 2019 covering 87,590 snakebites. We estimate that India had 1.2 million snakebite deaths (average 58,000/year) from 2000 to 2019. Nearly half occurred at ages 30 –69 years and over a quarter in children
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/ γ-secretase at the cell surface
γ-Secretase is a multi-subunit enzyme whose aberrant activity is associated with Alzheimer’s disease and cancer. While its structure is atomically resolved, γ-secretase localization in the membrane in situ relies mostly on biochemical data. Here, we combined fluorescent tagging of γ-secretase s ubunits with super-resolution microscopy in fibroblasts. Structured illumination microscopy revealed single γ-secretase complexes with a monodisperse distribution and in a 1:1 stoichiometry of PSEN1 and nicastrin subunits. In living cells, sptPALM revealed PSEN1/γ-secretase mainly with directed mo...
Source: eLife - July 7, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Consistent patterns of distractor effects during decision making
The value of a third potential option or distractor can alter the way in which decisions are made between two other options. Two hypotheses have received empirical support: that a high value distractor improves the accuracy with which decisions between two other options are made and that it impairs accuracy. Recently, however, it has been argued that neither observation is replicable. Inspired by neuroimaging data showing that high value distractors have different impacts on prefrontal and parietal regions, we designed a dual route decision-making model that mimics the neural signals of these regions. Here we show in the d...
Source: eLife - July 6, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Stable and dynamic representations of value in the prefrontal cortex
Optimal decision-making requires that stimulus-value associations are kept up to date by constantly comparing the expected value of a stimulus with its experienced outcome. To do this, value information must be held in mind when a stimulus and outcome are separated in time. However, little is known about the neural mechanisms of working memory (WM) for value. Contradicting theories have suggested WM requires either persistent or transient neuronal activity, with stable or dynamic representations respectively. To test these hypotheses, we recorded neuronal activity in the orbitofrontal and anterior cingulate cortex of two m...
Source: eLife - July 6, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research