Towards novel herbicide modes of action by inhibiting lysine biosynthesis in plants
In this study, we exploited a novel herbicide target, dihydrodipicolinate synthase (DHDPS), which catalyses the first and rate-limiting step in lysine biosynthesis. The first class of plant DHDPS inhibitors with micromolar potency againstArabidopsis thaliana DHDPS were identified using a high throughput chemical screen. We determined that this class of inhibitors binds to a novel and unexplored pocket within DHDPS, which is highly conserved across plant species. The inhibitors also attenuated the germination and growth ofA. thaliana seedlings and confirmed their pre-emergence herbicidal activity in soil-grown plants. These...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Plant Biology Source Type: research

Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population
Background: Until COVID-19 drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Towards this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. (Source: eLife)
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research

Perception of microstimulation frequency in human somatosensory cortex
Microstimulation in the somatosensory cortex can evoke artificial tactile percepts and can be incorporated into bidirectional brain-computer interfaces (BCIs) to restore function after injury or disease. However, little is known about how stimulation parameters themselves affect perception. Here, we stimulated through microelectrode arrays implanted in the somatosensory cortex of two human participants with cervical spinal cord injury and varied the stimulus amplitude, frequency and train duration. Increasing the amplitude and train duration increased the perceived intensity on all tested electrodes. Surprisingly, we found...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Cortical excitability signatures for the degree of sleepiness in human
Sleep is essential in maintaining physiological homeostasis in the brain. While the underlying mechanism is not fully understood, a 'synaptic homeostasis' theory has been proposed that synapses continue to strengthen during awake, and undergo downscaling during sleep. This theory predicts that brain excitability increases with sleepiness. Here, we collected transcranial magnetic stimulation (TMS) measurements in 38 subjects in a 34-hour program, and decoded the relationship between cortical excitability and self-report sleepiness using advanced statistical methods. By utilizing a combination of partial least squares (PLS) ...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination
Upon viral RNA recognition, the RIG-I signalosome continuously generates IFNs and cytokines, leading to neutrophil recruitment and inflammation. Thus, attenuation of excessive immune and inflammatory responses is crucial to restore immune homeostasis and prevent unwarranted damage, yet few resolving mediators have been identified. In the present study, we demonstrated that RTN3 is strongly upregulated during RNA viral infection and acts as an inflammation-resolving regulator. Increased RTN3 aggregates on the endoplasmic reticulum and interacts with both TRIM25 and RIG-I, subsequently impairing K63-linked polyubiquitination...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Cell Biology Immunology and Inflammation Source Type: research

Quantitative mapping of dense microtubule arrays in mammalian neurons
The neuronal microtubule cytoskeleton underlies the polarization and proper functioning of neurons, amongst others by providing tracks for motor proteins that drive intracellular transport. Different subsets of neuronal microtubules, varying in composition, stability and motor preference, are known to exist, but the high density of microtubules has so far precluded mapping their relative abundance and three-dimensional organization. Here we use different super-resolution techniques (STED, Expansion Microscopy) to explore the nanoscale organization of the neuronal microtubule network in rat hippocampal neurons. This reveale...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

In vivo analysis reveals that ATP-hydrolysis couples remodeling to SWI/SNF release from chromatin
ATP-dependent chromatin remodelers control the accessibility of genomic DNA through nucleosome mobilization. However, the dynamics of genome exploration by remodelers, and the role of ATP hydrolysis in this process remain unclear. We used live-cell imaging ofDrosophila polytene nuclei to monitor Brahma (BRM) remodeler interactions with its chromosomal targets. In parallel, we measured local chromatin condensation and its effect on BRM association. Surprisingly, only a small portion of BRM is bound to chromatin at any given time. BRM binds decondensed chromatin but is excluded from condensed chromatin, limiting its genomic ...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD
Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically induced effects. Previously, using pharmacological neuroimaging, we found that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to agonism of the serotonin-2A receptor (Preller et al., 2018). Here, we integrate brain-wide transcriptomics with biophysically based circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical large-scale spatiotemp...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin
Conserved ATP-dependent chromatin remodelers establish and maintain genome-wide chromatin architectures of regulatory DNA during cellular lifespan, but the temporal interactions between remodelers and chromatin targets have been obscure. We performed live-cell single-molecule tracking for RSC, SWI/SNF, CHD1, ISW1, ISW2, and INO80 remodeling complexes in budding yeast and detected hyperkinetic behaviors for chromatin-bound molecules that frequently transition to the free state for all complexes. Chromatin-bound remodelers display notably higher diffusion than nucleosomal histones, and strikingly fast dissociation kinetics w...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

T cell stiffness is enhanced upon formation of immunological synapse
T cells are activated by target cells via an intimate contact, termed immunological synapse (IS). Cellular mechanical properties, especially stiffness, are essential to regulate cell functions. However, T cell stiffness at a subcellular level at the IS still remains largely elusive. In this work, we established an atomic force microscopy (AFM)-based elasticity mapping method on whole T cells to obtain an overview of the stiffness with a resolution of ~ 60 nm. Using primary human CD4+ T cells, we show that when T cells form IS with stimulating antibody-coated surfaces, the lamellipodia are stiffer than the cell body. Upon I...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Physics of Living Systems Source Type: research

Revisiting the guidelines for ending isolation for COVID-19 patients
Since the start of the COVID-19 pandemic, two mainstream guidelines for defining when to end the isolation of SARS-CoV-2-infected individuals have been in use: the one-size-fits-all approach (i.e. patients are isolated for a fixed number of days) and the personalized approach (i.e. based on repeated testing of isolated patients). We use a mathematical framework to model within-host viral dynamics and test different criteria for ending isolation. By considering a fixed time of 10 days since symptom onset as the criterion for ending isolation, we estimated that the risk of releasing an individual who is still infectious is l...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Co-circulation of multiple influenza A reassortants in swine harboring genes from seasonal human and swine influenza viruses
Since the influenza pandemic in 2009, there has been an increased focus on swine influenza A virus (swIAV) surveillance. This paper describes the results of the surveillance of swIAV in Danish swine from 2011 to 2018. In total, 3800 submissions were received with a steady increase in swIAV positive submissions, reaching 56% in 2018. Full genome sequences were obtained from 129 swIAV positive samples. Altogether, 17 different circulating genotypes were identified including six novel reassortants harboring human seasonal IAV gene segments. The phylogenetic analysis revealed substantial genetic drift and also evidence of posi...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact proteotoxicity and muscle function during aging
Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also plastic, and remodeled in response to stress, growth, neural and metabolic inputs. The conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle development, but whether it plays a role during aging is unknown. Here we investigatedCaenorhabditis elegans miR-1 in muscle function in response to proteostatic stress.mir-1 deletion improved mid-life muscle motility, pharyngeal pumping, and organismal longevity upon polyQ35 proteotoxic challenge. W...
Source: eLife - July 27, 2021 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Correction: Sensory restoration by epidural stimulation of the lateral spinal cord in upper-limb amputees
(Source: eLife)
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Medicine Neuroscience Source Type: research

Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment
Chondrocytes in the resting zone of the postnatal growth plate are characterized by slow cell cycle progression, and encompass a population of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem cells that contribute to the formation of columnar chondrocytes. However, how these chondrocytes are maintained in the resting zone remains undefined. We undertook a genetic pulse-chase approach to isolate slow cycling, label-retaining chondrocytes (LRCs) using a chondrocyte-specific doxycycline-controllable Tet-Off system regulating expression of histone 2B-linked GFP. Comparative RNA-seq analysis identified signi...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways
HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it ...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Cancer Biology Chromosomes and Gene Expression Source Type: research

Structure of Escherichia coli respiratory complex I reconstituted into lipid nanodiscs reveals an uncoupled conformation
Respiratory complex I is a multi-subunit membrane protein complex that reversibly couples NADH oxidation and ubiquinone reduction with proton translocation against trans-membrane potential. Complex I fromEscherichia coliis among the best functionally characterized complexes, but its structure remains unknown, hindering further mechanistic studies to understand the enzyme coupling mechanism. Here we describe the single particle cryo-electron microscopy (cryo-EM) structure of the entire catalytically activeE. coli complex I reconstituted into lipid nanodiscs. The structure of this mesophilic bacterial complex I displays high...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Spike frequency adaptation supports network computations on temporally dispersed information
For solving tasks such as recognizing a song, answering a question, or inverting a sequence of symbols, cortical microcircuits need to integrate and manipulate information that was dispersed over time during the preceding seconds. Creating biologically realistic models for the underlying computations, especially with spiking neurons and for behaviorally relevant integration time spans, is notoriously difficult. We examine the role of spike frequency adaptation in such computations and find that it has a surprisingly large impact. The inclusion of this well-known property of a substantial fraction of neurons in the neocorte...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Living with relatives offsets the harm caused by pathogens in natural populations
Living with relatives can be highly beneficial, enhancing reproduction and survival. High relatedness can, however, increase susceptibility to pathogens. Here, we examine whether the benefits of living with relatives offset the harm caused by pathogens, and if this depends on whether species typically live with kin. Using comparative meta-analysis of plants, animals, and a bacterium (nspecies = 56), we show that high within-group relatedness increases mortality when pathogens are present. In contrast, mortality decreased with relatedness when pathogens were rare, particularly in species that live with kin. Furthermore, acr...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research

A Brownian ratchet model for DNA loop extrusion by the cohesin complex
The cohesin complex topologically encircles DNA to promote sister chromatid cohesion. Alternatively, cohesin extrudes DNA loops, thought to reflect chromatin domain formation. Here, we propose a structure-based model explaining both activities. ATP and DNA binding promote cohesin conformational changes that guide DNA through a kleisin N-gate into a DNA gripping state. Two HEAT-repeat DNA binding modules, associated with cohesin ’s heads and hinge, are now juxtaposed. Gripping state disassembly, following ATP hydrolysis, triggers unidirectional hinge module movement, which completes topological DNA entry by directing ...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Computational and Systems Biology Source Type: research

Predominantly linear summation of metabotropic postsynaptic potentials follows coactivation of neurogliaform interneurons
Summation of ionotropic receptor-mediated responses is critical in neuronal computation by shaping input-output characteristics of neurons. However, arithmetics of summation for metabotropic signals are not known. We characterized the combined ionotropic and metabotropic output of neocortical neurogliaform cells (NGFCs) using electrophysiological and anatomical methods in the rat cerebral cortex. These experiments revealed that GABA receptors are activated outside release sites and confirmed coactivation of putative NGFCs in superficial cortical layers in vivo. Triple recordings from presynaptic NGFCs converging to a posts...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Cdc4 phospho-degrons allow differential regulation of Ame1 < sup > CENP-U < /sup > protein stability across the cell cycle
Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. It is still poorly understood how efficient, centromere-dependent kinetochore assembly is accomplished from hundreds of individual protein building blocks in a cell cycle dependent manner. Here, by combining comprehensive phosphorylation analysis of native Ctf19CCAN subunits with biochemical and functional assays in the model system budding yeast, we demonstrate that Cdk1 phosphorylation activates phospho-degrons on the essential subunit Ame1CENP-Uwhich are recognized by the E3 ubiquitin ligase comple...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Cell Biology Chromosomes and Gene Expression Source Type: research

The loopy world of cohesin
DNA loops can be formed by a mechanism in which the cohesin complex pulls DNA strands through its ring structure using biased Brownian motion. (Source: eLife)
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Computational and Systems Biology Source Type: research

Autoregulatory control of microtubule binding in doublecortin-like kinase 1
The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in p...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cancer Biology Source Type: research

Sequence structure organizes items in varied latent states of working memory neural network
In memory experiences, events do not exist independently but are linked with each other via structure-based organization. Structure context largely influences memory behavior, but how it is implemented in the brain remains unknown. Here, we combined magnetoencephalogram (MEG) recordings, computational modeling, and impulse-response approaches to probe the latent states when subjects held a list of items in working memory (WM). We demonstrate that sequence context reorganizes WM items into distinct latent states, i.e., being reactivated at different latencies during WM retention, and the reactivation profiles further correl...
Source: eLife - July 26, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

A transient postnatal quiescent period precedes emergence of mature cortical dynamics
Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synaptic and cellular activity patterns across development using high spatiotemporal resolutionin vivo electrophysiology in immature mice. We reveal that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the...
Source: eLife - July 23, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Repression of CHROMOMETHYLASE 3 prevents epigenetic collateral damage in Arabidopsis
DNA methylation has evolved to silence mutagenic transposable elements (TEs) while typically avoiding the targeting of endogenous genes. Mechanisms that prevent DNA methyltransferases from ectopically methylating genes are expected to be of prime importance during periods of dynamic cell cycle activities including plant embryogenesis. However, virtually nothing is known regarding how DNA methyltransferase activities are precisely regulated during embryogenesis to prevent the induction of potentially deleterious and mitotically stable genic epimutations. Here, we report that microRNA-mediated repression of CHROMOMETHYLASE 3...
Source: eLife - July 23, 2021 Category: Biomedical Science Tags: Genetics and Genomics Plant Biology Source Type: research

Impact of asymptomatic < i > Plasmodium falciparum < /i > infection on the risk of subsequent symptomatic malaria in a longitudinal cohort in Kenya
Background:AsymptomaticPlasmodium falciparum infections are common in sub-Saharan Africa, but their effect on subsequent symptomaticity is incompletely understood. (Source: eLife)
Source: eLife - July 23, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research

Retraction: Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling
(Source: eLife)
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Cancer Biology Cell Biology Source Type: research

Regulated delivery controls Drosophila Hedgehog, Wingless and Decapentaplegic signaling
Morphogen signaling proteins disperse across tissues to activate signal transduction in target cells. We investigated dispersion of Hedgehog (Hh), Wnt homolog Wingless (Wg), and Bone morphogenic protein homolog Decapentaplegic (Dpp) in the Drosophila wing imaginal disc. We discovered that delivery of Hh, Wg, and Dpp to their respective targets is regulated. We found that
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Relish plays a dynamic role in the niche to modulate < i > Drosophila < /i > blood progenitor homeostasis in development and infection
Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland ofDrosophila senses immune challenge and reacts to it quickly through the nuclear factor- κB (NF-κB), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche...
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output in male mice
GnRH neurons are the final central neural output regulating fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (KNDy neurons) are considered the main regulator of GnRH output. GnRH and KNDy neurons are surrounded by astrocytes, which can modulate neuronal activity and communicate over distances. Prostaglandin E2 (PGE2), synthesized primarily by astrocytes, increases GnRH neuron activity and downstream pituitary release of luteinizing hormone (LH). We hypothesized GFAP-expressing astrocytes play a role regulating GnRH and/or KNDy neuron activity and LH release. We used adenoassociated viruses to target design...
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Molecular characterization of projection neuron subtypes in the mouse olfactory bulb
Projection neurons (PNs) in the mammalian olfactory bulb (OB) receive input from the nose and project to diverse cortical and subcortical areas. Morphological and physiological studies have highlighted functional heterogeneity, yet no molecular markers have been described that delineate PN subtypes. Here, we used viral injections into olfactory cortex and fluorescent nucleus sorting to enrich PNs for high-throughput single nucleus and bulk RNA deep sequencing. Transcriptome analysis and RNAin situ hybridization identified distinct mitral and tufted cell populations with characteristic transcription factor network topology,...
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Evolutionary medicine
In recognition that evolutionary theory is critical for understanding modern human health, eLife is publishing a special issue on evolutionary medicine to showcase recent research in this growing and increasingly interdisciplinary field. (Source: eLife)
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

Topography and motion of the acid-sensing ion channel intracellular domains
Acid-sensing ion channels (ASICs) are trimeric cation-selective channels activated by decreases in extracellular pH. The intracellular N and C terminal tails of ASIC1 influence channel gating, trafficking, and signaling in ischemic cell death. Despite several x-ray and cryo-EM structures of the extracellular and transmembrane segments of ASIC1, these important intracellular tails remain unresolved. Here we describe the coarse topography of the chicken ASIC1 intracellular domains determined by FRET, measured using either fluorescent lifetime imaging or patch clamp fluorometry. We find the C terminal tail projects into the c...
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Neuroscience Structural Biology and Molecular Biophysics Source Type: research

Expansion of CD10 < sup > neg < /sup > neutrophils and HLA-DR < sup > neg/low < /sup > monocytes driving inflammatory responses after myocardial infarction
Background: Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. (Source: eLife)
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Medicine Source Type: research

Host-associated microbe PCR (hamPCR) enables convenient measurement of both microbial load and community composition
The ratio of microbial population size relative to the amount of host tissue, or 'microbial load', is a fundamental metric of colonization and infection, but it cannot be directly deduced from microbial amplicon data such as 16S rRNA gene counts. Because existing methods to determine load, such as serial dilution plating, quantitative PCR, and whole metagenome sequencing, add substantial cost and/or experimental burden, they are only rarely paired with amplicon sequencing. We introduce host-associated microbe PCR (hamPCR), a robust strategy to both quantify microbial load and describe interkingdom microbial community compo...
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Plant Biology Source Type: research

Price equation captures the role of drug interactions and collateral effects in the evolution of multidrug resistance
Bacterial adaptation to antibiotic combinations depends on the joint inhibitory effects of the two drugs (drug interaction, DI) and how resistance to one drug impacts resistance to the other (collateral effects, CE). Here we model these evolutionary dynamics on two-dimensional phenotype spaces that leverage scaling relations between the drug-response surfaces of drug sensitive (ancestral) and drug resistant (mutant) populations. We show that evolved resistance to the component drugs-and in turn, the adaptation of growth rate-is governed by a Price equation whose covariance terms encode geometric features of both the two-dr...
Source: eLife - July 22, 2021 Category: Biomedical Science Tags: Evolutionary Biology Physics of Living Systems Source Type: research

Pioneer neutrophils release chromatin within in vivo swarms
Neutrophils are rapidly recruited to inflammatory sites where their coordinated migration forms clusters, a process termed neutrophil swarming. The factors that modulate early stages of neutrophil swarming are not fully understood, requiring the development of new in vivo models. Using transgenic zebrafish larvae to study endogenous neutrophil migration in a tissue damage model, we demonstrate that neutrophil swarming is a conserved process in zebrafish immunity, sharing essential features with mammalian systems. We show that neutrophil swarms initially develop around an individual pioneer neutrophil. We observed the viole...
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

CTP and < i > parS < /i > coordinate ParB partition complex dynamics and ParA-ATPase activation for ParABS-mediated DNA partitioning
ParABS partition systems, comprising the centromere-like DNA sequenceparS, theparS-binding ParB-CTPase and the nucleoid-binding ParA-ATPase, ensure faithful segregation of bacterial chromosomes and low-copy-number plasmids. F-plasmid partition complexes containing ParBF andparSF move by generating and following a local concentration gradient of nucleoid-bound ParAF. However, the process through which ParBF activates ParAF-ATPase has not been defined. We studied CTP- andparSF-modulated ParAF-ParBF complex assembly, in which DNA-bound ParAF-ATP dimers are activated for ATP hydrolysis by interacting with two ParBF N-terminal ...
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

CDK1 controls CHMP7-dependent nuclear envelope reformation
Through membrane sealing and disassembly of spindle microtubules, the Endosomal Sorting Complex Required for Transport-III (ESCRT-III) machinery has emerged as a key player in the regeneration of a sealed nuclear envelope (NE) during mitotic exit, and in the repair of this organelle during interphase rupture. ESCRT-III assembly at the NE occurs transiently during mitotic exit and is initiated when CHMP7, an ER-localised ESCRT-II/ESCRT-III hybrid protein, interacts with the Inner Nuclear Membrane (INM) protein LEM2. Whilst classical nucleocytoplasmic transport mechanisms have been proposed to separate LEM2 and CHMP7 during ...
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

Effect of malaria parasite shape on its alignment at erythrocyte membrane
This study shows that the original egg-like shape performs not worse for parasite alignment than other considered shapes, but is more robust with respect to different adhesion interactions and RBC membrane rigidities. (Source: eLife)
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

Image3C, a multimodal image-based and label independent integrative method for single-cell analysis
Image-based cell classification has become a common tool to identify phenotypic changes in cell populations. However, this methodology is limited to organisms possessing well characterized species-specific reagents (e.g., antibodies) that allow cell identification, clustering and convolutional neural network (CNN) training. In the absence of such reagents, the power of image-based classification has remained mostly off-limits to many research organisms. We have developed an image-based classification methodology we named Image3C (Image-Cytometry Cell Classification) that does not require species-specific reagents nor pre-e...
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Two NLR immune receptors acquired high-affinity binding to a fungal effector through convergent evolution of their integrated domain
A subset of plant NLR immune receptors carry unconventional integrated domains in addition to their canonical domain architecture. One example is rice Pik-1 that comprises an integrated heavy metal-associated (HMA) domain. Here, we reconstructed the evolutionary history of Pik-1 and its NLR partner, Pik-2, and tested hypotheses about adaptive evolution of the HMA domain. Phylogenetic analyses revealed that the HMA domain integrated into Pik-1 before Oryzinae speciation over 15 million years ago and has been under diversifying selection. Ancestral sequence reconstruction coupled with functional studies showed that two Pik-1...
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Plant Biology Source Type: research

SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways
SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of a...
Source: eLife - July 21, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins
Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mi...
Source: eLife - July 20, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Conserved visual capacity of rats under red light
Recent studies examine the behavioral capacities of rats and mice with and without visual input, and the neuronal mechanisms underlying such capacities. These animals are assumed to be functionally blind under red light, an assumption that might originate in the fact that they are dichromats who possess ultraviolet and green but not red cones. But the inability to see red as a color does not necessarily rule out form vision based on red light absorption. We measured Long-Evans rats' capacity for visual form discrimination under red light of various wavelength bands. Upon viewing a black and white grating, they had to disti...
Source: eLife - July 20, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles
Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 may also lead to neurodevelopmental disorders (ND). Here we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed inXenopus tadpoles after early exposure to valproic acid (VPA), a known teratogen associated with ND in humans. InXenopus tadpoles, VPA exposure results in excess local synaptic connectivity, disrupted s...
Source: eLife - July 20, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Linking plasmid-based beta-lactamases to their bacterial hosts using single-cell fusion PCR
The horizonal transfer of plasmid-encoded genes allows bacteria to adapt to constantly shifting environmental pressures, bestowing functional advantages to their bacterial hosts such as antibiotic resistance, metal resistance, virulence factors, and polysaccharide utilization. However, common molecular methods such as short- and long-read sequencing of microbiomes cannot associate extrachromosomal plasmids with the genome of the host bacterium. Alternative methods to link plasmids to host bacteria are either laborious, expensive or prone to contamination. Here we present the One-step Isolation and Lysis PCR (OIL-PCR) metho...
Source: eLife - July 20, 2021 Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research

Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity
Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted usi...
Source: eLife - July 20, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Immunology and Inflammation Source Type: research