An abundant quiescent stem cell population in < i > Drosophila < /i > Malpighian tubules protects principal cells from kidney stones
AdultDrosophila Malpighian tubules have low rates of cell turnover but are vulnerable to damage caused by stones, like their mammalian counterparts, kidneys. We show thatDrosophila renal stem cells (RSCs) in the ureter and lower tubules comprise a unique, unipotent regenerative compartment. RSCs respond only to loss of nearby principal cells (PCs), cells critical for maintaining ionic balance. Large polyploid PCs are outnumbered by RSCs, which replace each lost cell with multiple PCs of lower ploidy. Notably, RSCs do not replenish principal cells or stellate cells in the upper tubules. RSCs generate daughters by asymmetric...
Source: eLife - March 16, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation
The inability of cells to adapt to increased environmental tonicity can lead to inflammatory gene expression and pathogenesis. The Rel family of transcription factors TonEBP and NF- κB p65 play critical roles in the switch from osmoadaptive homeostasis to inflammation, respectively. Here we identified PACT-mediated PKR kinase activation as a marker of the termination of adaptation and initiation of inflammation inMus musculus embryonic fibroblasts. We found that high stress-induced PACT-PKR activation inhibits the interaction between NF- κB c-Rel and TonEBP essential for the increased expression of TonEBP-depen...
Source: eLife - March 16, 2020 Category: Biomedical Science Tags: Genetics and Genomics Immunology and Inflammation Source Type: research

Hippocampal theta coordinates memory processing during visual exploration
The hippocampus supports memory encoding and retrieval, which may occur at distinct phases of the theta cycle. These processes dynamically interact over rapid timescales, especially when sensory information conflicts with memory. The ability to link hippocampal dynamics to memory-guided behaviors has been limited by experiments that lack the temporal resolution to segregate encoding and retrieval. Here, we simultaneously tracked eye movements and hippocampal field potentials while neurosurgical patients performed a spatial memory task. Phase-locking at the peak of theta preceded fixations to retrieved locations, indicating...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

It is time to get real when trying to predict educational performance
A study of 3,500 children in the UK shows that data on socioeconomic background and previous educational achievements can better predict how students will perform at school than genetic data. (Source: eLife)
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

A loop structure allows TAPBPR to exert its dual function as MHC I chaperone and peptide editor
Adaptive immunity vitally depends on major histocompatibility complex class I (MHC I) molecules loaded with peptides. Selective loading of peptides onto MHC I, referred to as peptide editing, is catalyzed by tapasin and the tapasin-related TAPBPR. An important catalytic role has been ascribed to a structural feature in TAPBPR called the scoop loop, but the exact function of the scoop loop remains elusive. Here, using a reconstituted system of defined peptide-exchange components including human TAPBPR variants, we uncover a substantial contribution of the scoop loop to the stability of the MHC I-chaperone complex and to pep...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Immunology and Inflammation Source Type: research

Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling
Injury to the newborn mouse heart is efficiently regenerated, but this capacity is lost by one week after birth. We found that IGF2, an important mitogen in heart development, is required for neonatal heart regeneration. IGF2 originates from the endocardium/endothelium and is transduced in cardiomyocytes by the insulin receptor. Following injury on postnatal day 1, absence of IGF2 abolished injury-induced cell cycle entry during the early part of the first postnatal week. Consequently, regeneration failed despite the later presence of additional cell cycle-inducing activities 7 days following injury. Most cardiomyocytes tr...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Effect of helical kink in antimicrobial peptides on membrane pore formation
Every cell is protected by a semipermeable membrane. Peptides with the right properties, for example Antimicrobial peptides (AMPs), can disrupt this protective barrier by formation of leaky pores. Unfortunately, matching peptide properties with their ability to selectively form pores in bacterial membranes remains elusive. In particular, the proline/glycine kink in helical peptides was reported to both increase and decrease antimicrobial activity. We used computer simulations and fluorescence experiments to show that a kink in helices affects the formation of membrane pores by stabilizing toroidal pores but disrupting barr...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Spatiotemporal patterns of neocortical activity around hippocampal sharp-wave ripples
A prevalent model is that sharp-wave ripples (SWR) arise 'spontaneously' in CA3 and propagate recent memory traces outward to the neocortex to facilitate memory consolidation there. Using voltage and extracellular glutamate transient recording over widespread regions of mice dorsal neocortex in relation to CA1 multiunit activity (MUA) and SWR, we find that the largest SWR-related modulation occurs in retrosplenial cortex; however, contrary to the unidirectional hypothesis, neocortical activation exhibited a continuum of activation timings relative to SWRs, varying from leading to lagging. Thus, contrary to the model in whi...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Global phenotypic profiling identifies a conserved actinobacterial cofactor for a bifunctional PBP-type cell wall synthase
Members of theCorynebacterineaesuborder of Actinobacteria have a unique cell surface architecture and, unlike most well-studied bacteria, grow by tip-extension. To investigate the distinct morphogenic mechanisms shared by these organisms, we performed a genome-wide phenotypic profiling analysis usingCorynebacterium glutamicum as a model. A high-density transposon mutagenized library was challenged with a panel of antibiotics and other stresses. The fitness of mutants in each gene under each condition was then assessed by transposon-sequencing. Clustering of the resulting phenotypic fingerprints revealed a role for several ...
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Monoubiquitination by the human Fanconi Anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays
We report that monoubiquitination does not promote any specific exogenous protein:protein interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA. This clamping requires monoubiquitination of only the FANCD2 subunit. We further show that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA using electron microscopy. Our results reveal how monoubiquitinated FANCI:FANCD2, defective in many cancer types and all cases of FA, is activated upon DNA binding. (Source: eLife)
Source: eLife - March 13, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

HIPK4 is essential for murine spermiogenesis
Mammalian spermiogenesis is a remarkable cellular transformation, during which round spermatids elongate into chromatin-condensed spermatozoa. The signaling pathways that coordinate this process are not well understood, and we demonstrate here that homeodomain-interacting protein kinase 4 (HIPK4) is essential for spermiogenesis and male fertility in mice. HIPK4 is predominantly expressed in round and early elongating spermatids, andHipk4 knockout males are sterile, exhibiting phenotypes consistent with oligoasthenoteratozoospermia.Hipk4 mutant sperm have reduced oocyte binding and are incompetent for in vitro fertilization...
Source: eLife - March 12, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Adaptation of hydroxymethylbutenyl diphosphate reductase enables volatile isoprenoid production
Volatile isoprenoids produced by plants are emitted in vast quantities into the atmosphere, with substantial effects on global carbon cycling. Yet, the molecular mechanisms regulating the balance between volatile and non-volatile isoprenoid production remain unknown. Isoprenoids are synthesised via sequential condensation of isopentenyl pyrophosphate (IPP) to dimethylallyl pyrophosphate (DMAPP), with volatile isoprenoids containing fewer isopentenyl subunits. The DMAPP:IPP ratio could affect the balance between volatile and non-volatile isoprenoids, but the plastidic DMAPP:IPP ratio is generally believed to be similar acro...
Source: eLife - March 12, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Plant Biology Source Type: research

Feedback inhibition and its control in an insect olfactory circuit
Inhibitory neurons play critical roles in regulating and shaping olfactory responses in vertebrates and invertebrates. In insects, these roles are performed by relatively few neurons, which can be interrogated efficiently, revealing fundamental principles of olfactory coding. Here, with electrophysiological recordings from the locust and a large-scale biophysical model, we analyzed the properties and functions of GGN, a unique giant GABAergic neuron that plays a central role in structuring olfactory codes in the locust mushroom body. Our simulations suggest that depolarization of GGN at its input branch can globally inhibi...
Source: eLife - March 12, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

ATR expands embryonic stem cell fate potential in response to replication stress
Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated byDux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX tri...
Source: eLife - March 12, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Whale breaching says it loud and clear
A whale leaping above the surface expends an enormous amount of energy, displaying its health and strength to peers and potential mates. (Source: eLife)
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

Energetic and physical limitations on the breaching performance of large whales
In this study we deployed whale-borne tags to measure the kinematics of breaching to test the hypothesis that these spectacular aerial displays are metabolically expensive. We found that breaching whales use variable underwater trajectories, and that high-emergence breaches are faster and require more energy than predatory lunges. The most expensive breaches approach the upper limits of vertebrate muscle performance, and the energetic cost of breaching is high enough that repeated breaching events may serve as honest signaling of body condition. Furthermore, the confluence of muscle contractile properties, hydrodynamics, a...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

Losing Dnmt3a dependent methylation in inhibitory neurons impairs neural function by a mechanism impacting Rett syndrome
Methylated cytosine is an effector of epigenetic gene regulation. In the brain, Dnmt3a is the sole ‘writer’ of atypical non-CpG methylation (mCH), and MeCP2 is the only known ‘reader’ for mCH. We asked if MeCP2 is the sole reader for Dnmt3a dependent methylation by comparing mice lacking either protein in GABAergic inhibitory neurons. Loss of either protein causes overlapping and distinct features from the behavioral to molecular level. Loss of Dnmt3a causes global loss of mCH and a subset of mCG sites resulting in more widespread transcriptional alterations and severe neurological dysfunction than ...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Neuroscience Source Type: research

Adjusting for age improves identification of gut microbiome alterations in multiple diseases
Interaction between disease-microbiome associations and ageing has not been explored in detail. Here, using age/region-matched sub-sets, we analysed the gut microbiome differences across five major diseases in a multi-cohort dataset constituting more than 2500 individuals from 20 to 89 years old. We show that disease-microbiome associations display specific age-centric trends. Ageing-associated microbiome alterations towards a disease-like configuration occur in colorectal cancer patients, thereby masking disease signatures. We identified a microbiome disease response shared across multiple diseases in elderly subjects tha...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

A synthetic dataset primer for the biobehavioural sciences to promote reproducibility and hypothesis-generation
This article introduces the concept of synthetic datasets, which is an emerging method originally developed to permit the sharing of confidential census data. Synthetic datasets mimic real datasets by preserving their statistical properties and the relationships between variables. Importantly, this method also reduces disclosure risk to essentially nil as no record in the synthetic dataset represents a real individual. This practical guide with accompanying R script enables biobehavioural researchers to create synthetic datasets and assess their utility via thesynthpop R package. By sharing synthetic datasets that mimic or...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Movement-related coupling of human subthalamic nucleus spikes to cortical gamma
Cortico-basal ganglia interactions continuously shape the way we move. Ideas about how this circuit works are based largely on models that consider only firing rate as the mechanism of information transfer. A distinct feature of neural activity accompanying movement, however, is increased motor cortical and basal ganglia gamma synchrony. To investigate the relationship between neuronal firing in the basal ganglia and cortical gamma activity during movement, we analysed human ECoG and subthalamic nucleus (STN) unit activity during hand gripping. We found that fast reaction times were preceded by enhanced STN spike-to-cortic...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

LIS1 determines cleavage plane positioning by regulating actomyosin-mediated cell membrane contractility
Heterozygous loss of humanPAFAH1B1 (coding for LIS1) results in the disruption of neurogenesis and neuronal migration via dysregulation of microtubule (MT) stability and dynein motor function/localization that alters mitotic spindle orientation, chromosomal segregation, and nuclear migration. Recently, human induced pluripotent stem cell (iPSC) models revealed an important role for LIS1 in controlling the length of terminal cell divisions of outer radial glial (oRG) progenitors, suggesting cellular functions of LIS1 in regulating neural progenitor cell (NPC) daughter cell separation. Here we examined the late mitotic stage...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

An asymmetric sheath controls flagellar supercoiling and motility in the leptospira spirochete
Spirochete bacteria, including important pathogens, exhibit a distinctive means of swimming via undulations of the entire cell. Motility is powered by the rotation of supercoiled 'endoflagella' that wrap around the cell body, confined within the periplasmic space. To investigate the structural basis of flagellar supercoiling, which is critical for motility, we determined the structure of native flagellar filaments from the spirocheteLeptospira by integrating high-resolution cryo-electron tomography and X-ray crystallography. We show that these filaments are coated by a highly asymmetric, multi-component sheath layer, contr...
Source: eLife - March 11, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Structural Biology and Molecular Biophysics Source Type: research

PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells
The Polycomb-like protein PHF19/PCL3 associates with PRC2 and mediates its recruitment to chromatin in embryonic stem cells. PHF19 is also overexpressed in many cancers. However, neither PHF19 targets nor misregulated pathways involving PHF19 are known. Here, we investigate the role of PHF19 in prostate cancer cells. We find that PHF19 interacts with PRC2 and binds to PRC2 targets on chromatin. PHF19 target genes are involved in proliferation, differentiation, angiogenesis, and extracellular matrix organization. Depletion of PHF19 triggers an increase in MTF2/PCL2 chromatin recruitment, with a genome-wide gain in PRC2 occu...
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Fatal amyloid formation in a patient ’s antibody light chain is caused by a single point mutation
In this study, we performed an in-depth analysis of the factors and mutations responsible for the pathogenic transformation of a patient-derived λ LC, by recombinantly expressing variants inE. coli. We show that proteolytic cleavage of the patient LC resulting in an isolated VL domain is essential for fibril formation. Out of 11 mutations in the patient VL, only one, a leucine to valine mutation, is responsible for fibril formation. It disrupts a hydrophobic network rendering the C-terminal segment of VL more dynamic and decreasing domain stability. Thus, the combination of proteolytic cleavage and the destabilizing...
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Representation of visual landmarks in retrosplenial cortex
The process by which visual information is incorporated into the brain ’s spatial framework to represent landmarks is poorly understood. Studies in humans and rodents suggest that retrosplenial cortex (RSC) plays a key role in these computations. We developed an RSC-dependent behavioral task in which head-fixed mice learned the spatial relationship between visual lan dmark cues and hidden reward locations. Two-photon imaging revealed that these cues served as dominant reference points for most task-active neurons and anchored the spatial code in RSC. This encoding was more robust after task acquisition. Decoupling th...
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells
(Source: eLife)
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Structural model for differential cap maturation at growing microtubule ends
Microtubules (MTs) are hollow cylinders made of tubulin, a GTPase responsible for essential functions during cell growth and division, and thus, key target for anti-tumor drugs. In MTs, GTP hydrolysis triggers structural changes in the lattice, which are responsible for interaction with regulatory factors. The stabilizing GTP-cap is a hallmark of MTs and the mechanism of the chemical-structural link between the GTP hydrolysis site and the MT lattice is a matter of debate. We have analyzed the structure of tubulin and MTs assembled in the presence of fluoride salts that mimic the GTP-bound and GDP •Pi transition states...
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Can education be personalised using pupils ’ genetic data?
The increasing predictive power of polygenic scores for education has led to their promotion by some as a potential tool for genetically informed policy. How accurately polygenic scores predict an individual pupil's educational performance conditional on other phenotypic data is however not well understood. Using data from a UK cohort study with data linkage to national schooling records, we investigated how accurately polygenic scores for education predicted pupils ’ test score achievement. We also assessed the performance of polygenic scores over and above phenotypic data that are available to schools. Across our s...
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Metabolic and non-metabolic liver zonation is established non-synchronously and requires sinusoidal Wnts
The distribution of complementary metabolic functions in hepatocytes along a portocentral axis is called liver zonation. Endothelial secreted Wnt ligands maintain metabolic zonation in the adult murine liver but whether those ligands are necessary to initiate zonation in the immature liver has been only partially explored. Also, numerous non-metabolic proteins display zonated expression in the adult liver but it is not entirely clear if their localization requires endothelial Wnts. Here we used a novel transgenic mouse model to compare the spatial distribution of zonated non-metabolic proteins with that of typical zonated ...
Source: eLife - March 10, 2020 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Microglial depletion disrupts normal functional development of adult-born neurons in the olfactory bulb
Microglia play key roles in regulating synapse development and refinement in the developing brain, but it is unknown whether they are similarly involved during adult neurogenesis. By transiently depleting microglia from the healthy adult mouse brain, we show that microglia are necessary for the normal functional development of adult-born granule cells (abGCs) in the olfactory bulb. Microglial depletion reduces the odor responses of developing, but not preexisting GCs in vivo in both awake and anesthetized mice. Microglia preferentially target their motile processes to interact with mushroom spines on abGCs, and when microg...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Fully automated, sequential focused ion beam milling for cryo-electron tomography
Cryo-electron tomography (cryoET) has become a powerful technique at the interface of structural biology and cell biology, due to its unique ability for imaging cells in their native state and determining structures of macromolecular complexes in their cellular context. A limitation of cryoET is its restriction to relatively thin samples. Sample thinning by cryo-focused ion beam (cryoFIB) milling has significantly expanded the range of samples that can be analyzed by cryoET. Unfortunately, cryoFIB milling is low-throughput, time-consuming and manual. Here we report a method for fully automated sequential cryoFIB preparatio...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Structural basis for pharmacological modulation of the TRPC6 channel
Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed b...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Inference of nonlinear receptive field subunits with spike-triggered clustering
We present a method for maximum likelihood estimation of subunits by soft-clustering spike-triggered stimuli, and demonstrate its effectiveness in visual neurons. For parasol retinal ganglion cells in macaque retina, estimated subunits partitioned the receptive field into compact regions, likely representing aggregated bipolar cell inputs. Joint clustering revealed shared subunits between neighboring cells, producing a parsimonious population model. Closed-loop validation, using stimuli lying in the null space of the linear receptive field, revealed stronger nonlinearities in OFF cells than ON cells. Responses to natural i...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
The many variants of human Ca2+/calmodulin-dependent protein kinase II (CaMKII) differ in the lengths and sequences of disordered linkers connecting the kinase domains to the oligomeric hub of the holoenzyme. CaMKII activity depends on the balance between activating and inhibitory autophosphorylation (on Thr 286 and Thr 305/306, respectively, in the human a isoform). Variation in the linkers could alter transphosphorylation rates within a holoenzyme and the balance of autophosphorylation outcomes. We show, using mammalian-cell expression and a single-molecule assay, that the balance of autophosphorylation is flipped betwee...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

Temporal chunking as a mechanism for unsupervised learning of task-sets
Depending on environmental demands, humans can learn and exploit multiple concurrent sets of stimulus-response associations. Mechanisms underlying the learning of such task-sets remain unknown. Here we investigate the hypothesis that task-set learning relies on unsupervised chunking of stimulus-response associations that occur in temporal proximity. We examine behavioral and neural data from a task-set learning experiment using a network model. We first show that task-set learning can be achieved provided the timescale of chunking is slower than the timescale of stimulus-response learning. Fitting the model to behavioral d...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Sperm chemotaxis is driven by the slope of the chemoattractant concentration field
Spermatozoa of marine invertebrates are attracted to their conspecific female gamete by diffusive molecules, called chemoattractants, released from the egg investments in a process known as chemotaxis. The information from the egg chemoattractant concentration field is decoded into intracellular Ca2+ concentration ([Ca2+]i) changes that regulate the internal motors that shape the flagellum as it beats. By studying sea urchin species-specific differences in sperm chemoattractant-receptor characteristics we show that receptor density constrains the steepness of the chemoattractant concentration gradient detectable by spermat...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

Bacterial cell cycle control by citrate synthase independent of enzymatic activity
Proliferating cells must coordinate central metabolism with the cell cycle. How central energy metabolism regulates bacterial cell cycle functions is not well understood. Our forward genetic selection unearthed the Krebs cycle enzyme citrate synthase (CitA) as a checkpoint regulator controlling the G1 →S transition in the polarized alpha-proteobacteriumCaulobacter crescentus, a model for cell cycle regulation and asymmetric cell division. We find that loss of CitA promotes the accumulation of active CtrA, an essential cell cycle transcriptional regulator that maintains cells in G1-phase, provided that the (p)ppGpp ala...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Reversal of contractility as a signature of self-organization in cytoskeletal bundles
Bundles of cytoskeletal filaments and molecular motors generate motion in living cells, and have internal structures ranging from very organized to apparently disordered. The mechanisms powering the disordered structures are debated, and existing models predominantly predict that they are contractile. We reexamine this prediction through a theoretical treatment of the interplay between three well-characterized internal dynamical processes in cytoskeletal bundles: filament assembly and disassembly, the attachment-detachment dynamics of motors and that of crosslinking proteins. The resulting self-organization is easily under...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

The single-cell eQTLGen consortium
In recent years, functional genomics approaches combining genetic information with bulk RNA-sequencing data have identified the downstream expression effects of disease-associated genetic risk factors through so-called expression quantitative trait locus (eQTL) analysis. Single-cell RNA-sequencing creates enormous opportunities for mapping eQTLs across different cell types and in dynamic processes, many of which are obscured when using bulk methods. Rapid increase in throughput and reduction in cost per cell now allow this technology to be applied to large-scale population genetics studies. To fully leverage these emerging...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Visual cue-related activity of cells in the medial entorhinal cortex during navigation in virtual reality
During spatial navigation, animals use self-motion to estimate positions through path integration. However, estimation errors accumulate over time and it is unclear how they are corrected. Here we report a new cell class ('cue cell') encoding visual cues that could be used to correct errors in path integration in mouse medial entorhinal cortex (MEC). During virtual navigation, individual cue cells exhibited firing fields only near visual cues and their population response formed sequences repeated at each cue. These cells consistently responded to cues across multiple environments. On a track with cues on left and right si...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Male meiotic spindle features that efficiently segregate paired and lagging chromosomes
Chromosome segregation during male meiosis is tailored to rapidly generate multitudes of sperm. Little is known about mechanisms that efficiently partition chromosomes to produce sperm. Using live imaging and tomographic reconstructions of spermatocyte meiotic spindles inCaenorhabditis elegans, we find the lagging X chromosome, a distinctive feature of anaphase I inC. elegans males, is due to lack of chromosome pairing. The unpaired chromosome remains tethered to centrosomes by lengthening kinetochore microtubules, which are under tension, suggesting that a 'tug of war' reliably resolves lagging. We find spermatocytes exhi...
Source: eLife - March 9, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

A highly responsive pyruvate sensor reveals pathway-regulatory role of the mitochondrial pyruvate carrier MPC
We report that cultured mouse astrocytes maintain mitochondrial pyruvate in the low micromolar range, below cytosolic pyruvate, which means that the mitochondrial pyruvate carrier MPC is poised to exert ultrasensitive control on the balance between respiration and anaplerosis/gluconeogenesis. The functionality of the sensor in living tissue is demonstrated in the brain ofDrosophila melanogaster larvae. Mitochondrial subpopulations are known to coexist within a given cell, which differ in their morphology, mobility, membrane potential, and vicinity to other organelles. The present tool can be used to investigate how mitocho...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Presynaptic PTP σ regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms
Synaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include trans-synaptic adhesion; however, whether they regulate postsynaptic receptor functions remains unknown. Here we report that presynaptic PTP σ, a LAR-RPTP, enhances postsynaptic NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity in the hippocampus. This regulation does not involve trans-...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

RNA-guided retargeting of < i > Sleeping Beauty < /i > transposition in human cells
An ideal tool for gene therapy would enable efficient gene integration at predetermined sites in the human genome. Here we demonstrate biased genome-wide integration of theSleeping Beauty (SB) transposon by combining it with components of the CRISPR/Cas9 system. We provide proof-of-concept that it is possible to influence the target site selection of SB by fusing it to a catalytically inactive Cas9 (dCas9) and by providing a single guide RNA (sgRNA) against the humanAlu retrotransposon. Enrichment of transposon integrations was dependent on the sgRNA, and occurred in an asymmetric pattern with a bias towards sites in a rel...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

A large genomic insertion containing a duplicated follistatin gene is linked to the pea aphid male wing dimorphism
Wing dimorphisms have long served as models for examining the ecological and evolutionary tradeoffs associated with alternative phenotypes. Here, we investigated the genetic cause of the pea aphid (Acyrthosiphon pisum) male wing dimorphism, wherein males exhibit one of two morphologies that differ in correlated traits that include the presence or absence of wings. We mapped this trait difference to a single genomic region and, using third generation, long-read sequencing, we identified a 120 kb insertion in the wingless allele. This insertion includes a duplicatedfollistatin gene, which is a strong candidate gene in the mi...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Meta-Research: Reader engagement with medical content on Wikipedia
Articles on Wikipedia about health and medicine are maintained by WikiProject Medicine (WPM), and are widely used by health professionals, students and others. We have compared these articles, and reader engagement with them, to other articles on Wikipedia. We found that WPM articles are longer, possess a greater density of external links, and are visited more often than other articles on Wikipedia. Readers of WPM articles are more likely to hover over and view footnotes than other readers, but are less likely to visit the hyperlinked sources in these footnotes. Our findings suggest that WPM readers appear to use links to ...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Contextual and cross-modality modulation of auditory cortical processing through pulvinar mediated suppression
Lateral posterior nucleus (LP) of thalamus, the rodent homologue of primate pulvinar, projects extensively to sensory cortices. However, its functional role in sensory cortical processing remains largely unclear. Here, bidirectional activity modulations of LP or its projection to the primary auditory cortex (A1) in awake mice reveal that LP improves auditory processing in A1 supragranular-layer neurons by sharpening their receptive fields and frequency tuning, as well as increasing the signal-to-noise ratio (SNR). This is achieved through a subtractive-suppression mechanism, mediated largely by LP-to-A1 axons preferentiall...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration
How salamanders accomplish progenitor cell proliferation while faithfully maintaining genomic integrity and regenerative potential remains elusive. Here we found an innate DNA damage response mechanism that is evident during blastema proliferation (early- to late-bud) and studied its role during tissue regeneration by ablating the function of one of its components, Eyes absent 2. Ineya2mutant axolotls, we found that DNA damage signaling through the H2AX histone variant was deregulated, especially within the proliferating progenitors during limb regeneration. Ultimately, cell cycle progression was impaired at the G1/S and G...
Source: eLife - March 6, 2020 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Identification of scavenger receptor B1 as the airway microfold cell receptor for < i > Mycobacterium tuberculosis < /i >
Mycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify S...
Source: eLife - March 5, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research