Antibody escape by polyomavirus capsid mutation facilitates neurovirulence
JCPyV polyomavirus, a member of the human virome, causes Progressive Multifocal Leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb)in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of...
Source: eLife - September 17, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions
Cortical lesions represent a hallmark of multiple sclerosis and are proposed as a predictor of disease severity. microRNAs are suggested to be important players in the disease pathogenesis and the experimental autoimmune encephalomyelitis animal model. We implemented a mouse model recapitulating more closely the human pathology as it is characterized by both an autoimmune heterogeneity and the presence of cortical lesions, two parameters missing in experimental autoimmune encephalomyelitis. In our model, mice clustered in two groups displaying high or low clinical scores. Upon cortical cytokine injection, lesions appeared ...
Source: eLife - September 17, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Neuroscience Source Type: research

Reading the epigenetic code for exchanging DNA
Three independent studies show that a protein called ZCWPW1 is able to recognize the histone modifications that initiate the recombination of genetic information during meiosis. (Source: eLife)
Source: eLife - September 16, 2020 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein
Heterotrimeric G-proteins are signal transducers involved in mediating the action of many natural extracellular stimuli as well as of many therapeutic agents. Non-invasive approaches to manipulate the activity of G-proteins with high precision are crucial to understand their regulation in space and time. Here, we developed LOV2GIVe, an engineered modular protein that allows the activation of heterotrimeric G-proteins with blue light. This optogenetic construct relies on a versatile design that differs from tools previously developed for similar purposes, i.e. metazoan opsins, which are light-activated GPCRs. Instead, LOV2G...
Source: eLife - September 16, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

< i > IER5 < /i > , a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation
Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, includingIER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes.IER5 is epistatic toPPP2R2A, a gene that encodes the PP2A B55a subunit, which we sh...
Source: eLife - September 16, 2020 Category: Biomedical Science Tags: Cancer Biology Cell Biology Source Type: research

Mutational resilience of antiviral restriction favors primate TRIM5 α in host-virus evolutionary arms races
Host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5 α uses its rapidly evolving ‘v1’ loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Usi ng deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restrictio...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

Erasable labeling of neuronal activity using a reversible calcium marker
Understanding how the brain encodes and processes information requires the recording of neural activity that underlies different behaviors. Recent efforts in fluorescent protein engineering have succeeded in developing powerful tools for visualizing neural activity, in general by coupling neural activity to different properties of a fluorescent protein scaffold. Here, we take advantage of a previously unexploited class of reversibly switchable fluorescent proteins to engineer a new type of calcium sensor. We introduce rsCaMPARI, a genetically encoded calcium marker engineered from a reversibly switchable fluorescent protei...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Neuroscience Source Type: research

Efficient sampling and noisy decisions
Human decisions are based on finite information, which makes them inherently imprecise. But what determines the degree of such imprecision? Here, we develop an efficient coding framework for higher-level cognitive processes in which information is represented by a finite number of discrete samples. We characterize the sampling process that maximizes perceptual accuracy or fitness under the often-adopted assumption that full adaptation to an environmental distribution is possible, and show how the optimal process differs when detailed information about the current contextual distribution is costly. We tested this theory on ...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Performance of a deep learning based neural network in the selection of human blastocysts for implantation
Deep learning in in-vitro fertilization is currently being evaluated in the development of assistive tools for the determination of transfer order and implantation potential using time-lapse data collected through expensive imaging hardware. Assistive tools and algorithms that can work with static images, however, can help in improving the access to care by enabling their use with images acquired from traditional microscopes that are available to virtually all fertility centers. Here, we evaluated the use of a deep convolutional neural network (CNN), trained using single timepoint images of embryos collected at 113 hours p...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Medicine Source Type: research

Global landscape of phenazine biosynthesis and biodegradation reveals species-specific colonization patterns in agricultural soils and crop microbiomes
Phenazines are natural bacterial antibiotics that can protect crops from disease. However, for most crops it is unknown which producers and specific phenazines are ecologically relevant, and whether phenazine biodegradation can counter their effects. To better understand their ecology, we developed and environmentally-validated a quantitative metagenomic approach to mine for phenazine biosynthesis and biodegradation genes, applying it to>800 soil and plant-associated shotgun-metagenomes. We discover novel producer-crop associations and demonstrate that phenazine biosynthesis is prevalent across habitats and preferential...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Ecology Microbiology and Infectious Disease Source Type: research

Transmission of West Nile and five other temperate mosquito-borne viruses peaks at temperatures between 23 °C and 26°C
The temperature-dependence of many important mosquito-borne diseases has never been quantified. These relationships are critical for understanding current distributions and predicting future shifts from climate change. We used trait-based models to characterize temperature-dependent transmission of 10 vector –pathogen pairs of mosquitoes (Culex pipiens,Cx. quinquefascsiatus,Cx. tarsalis, and others) and viruses (West Nile, Eastern and Western Equine Encephalitis, St. Louis Encephalitis, Sindbis, and Rift Valley Fever viruses), most with substantial transmission in temperate regions. Transmission is optimized at inter...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Ecology Epidemiology and Global Health Source Type: research

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral –bacterial interactions
Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Medicine Source Type: research

SWELL1 regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism
Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism, however the molecular mechanosensor remains unknown. Here, we show that SWELL1 (Lrrc8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. LRRC8A over-expression inLrrc8aKO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle targetedLr...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

Transport of DNA within cohesin involves clamping on top of engaged heads by Scc2 and entrapment within the ring by Scc3
In addition to extruding DNA loops, cohesin entraps within its SMC-kleisin ring (S-K) individual DNAs during G1 and sister DNAs during S-phase. All three activities require related hook-shaped proteins called Scc2 and Scc3. Using thiol-specific crosslinking we provide rigorous proof of entrapment activity in vitro. Scc2 alone promotes entrapment of DNAs in the E-S and E-K compartments, between ATP-bound engaged heads and the SMC hinge and associated kleisin, respectively. This does not require ATP hydrolysis nor is it accompanied by entrapment within S-K rings, which is a slower process requiring Scc3. Cryo-EM reveals that...
Source: eLife - September 15, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Meta Research: Questionable research practices may have little effect on replicability
This article examines why many studies fail to replicate statistically significant published results. We address this issue within a general statistical framework that also allows us to include various questionable research practices (QRPs) that are thought to reduce replicability. The analyses indicate that the base rate of true effects is the major factor that determines the replication rate of scientific results. Specifically, for purely statistical reasons, replicability is low in research domains where true effects are rare (e.g., search for effective drugs in pharmacology). This point is under-appreciated in current ...
Source: eLife - September 15, 2020 Category: Biomedical Science Source Type: research

TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis
Wnt signaling through the Frizzled (FZD) family of serpentine receptors is essential for embryogenesis and homeostasis, and stringent control of the FZD protein level is critical for stem cell regulation. Through CRISPR/Cas9 genome-wide screening in human cells, we identified TMEM79/MATTRIN, an orphan multi-span transmembrane protein, as a specific inhibitor of Wnt/FZD signaling. TMEM79 interacts with FZD during biogenesis and promotes FZD degradation independent of ZNRF3/RNF43 ubiquitin ligases (R-spondin receptors). TMEM79 interacts withubiquitin-specificprotease 8 (USP8), whose activating mutations underlie human tumori...
Source: eLife - September 14, 2020 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Meta-Research: Evaluating the impact of open access policies on research institutions
The proportion of research outputs published in open access journals or made available on other freely-accessible platforms has increased over the past two decades, driven largely by funder mandates, institutional policies, grass-roots advocacy, and changing attitudes in the research community. However, the relative effectiveness of these different interventions has remained largely unexplored. Here we present a robust, transparent and updateable method for analysing how these interventions affect the open access performance of individual institutes. We studied 1,207 institutions from across the world, and found that, in 2...
Source: eLife - September 14, 2020 Category: Biomedical Science Source Type: research

A large accessory protein interactome is rewired across environments
To characterize how protein-protein interaction (PPI) networks change, we quantified the relative PPI abundance of 1.6 million protein pairs in the yeastSaccharomyces cerevisiae across 9 growth conditions, with replication, for a total of 44 million measurements. Our multi-condition screen identified 13,764 pairwise PPIs, a 3-fold increase over PPIs identified in one condition. A few 'immutable' PPIs are present across all conditions, while most 'mutable' PPIs are rarely observed. Immutable PPIs aggregate into highly connected 'core' network modules, with most network remodeling occurring within a loosely connected 'access...
Source: eLife - September 14, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

The many roles of C1q
The ability of a well-known component of the complement cascade to bind to a variety of receptors has implications for signaling biology, spinal cord injury and, possibly, the evolution of the complement system. (Source: eLife)
Source: eLife - September 14, 2020 Category: Biomedical Science Tags: Stem Cells and Regenerative Medicine Source Type: research

Structure of the bacterial ribosome at 2 Å resolution
Using cryo-electron microscopy (cryo-EM), we determined the structure of theEscherichia coli70S ribosome with a global resolution of 2.0 A ̊. The maps reveal unambiguous positioning of protein and RNA residues, their detailed chemical interactions, and chemical modifications. Notable features include the first examples of isopeptide and thioamide backbone substitutions in ribosomal proteins, the former likely conserved in all domains of life. The maps also reveal extensive solvation of the small (30S) ribosomal subunit, and interactions with A-site and P-site tRNAs, mRNA, and the antibiotic paromomycin. The maps and model...
Source: eLife - September 14, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Vascular control of the CO < sub > 2 < /sub > /H < sup > + < /sup > dependent drive to breathe
Respiratory chemoreceptors regulate breathing in response to changes in tissue CO2/H+. Blood flow is a fundamental determinant of tissue CO2/H+, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO2/H+-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al. 2017). Here, we show in mice that CO2/H+ dilates arterioles in other chemoreceptor regions, thus demonstrating CO2/H+ vascular reactivity in the RTN is unique. We also identify P2Y2 receptors...
Source: eLife - September 14, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

When pH comes to the rescue
In starving yeast exposed to thermal stress, a transient drop in intracellular pH helps to trigger the heat shock response. (Source: eLife)
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Large domains of heterochromatin direct the formation of short mitotic chromosome loops
During mitosis chromosomes reorganise into highly compact, rod-shaped forms, thought to consist of consecutive chromatin loops around a central protein scaffold. Condensin complexes are involved in chromatin compaction, but the contribution of other chromatin proteins, DNA sequence and histone modifications is less understood. A large region of fission yeast DNA inserted into a mouse chromosome was previously observed to adopt a mitotic organisation distinct from that of surrounding mouse DNA. Here we show that a similar distinct structure is common to a large subset of insertion events in both mouse and human cells and is...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Cell Biology Chromosomes and Gene Expression Source Type: research

Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity
Post-transcriptional mechanisms regulating cell surface synaptic organizing complexes that control the properties of connections in brain circuits are poorly understood. Alternative splicing regulates the prototypical synaptic organizing complex, neuroligin-neurexin. In contrast to the well-studied neuroligin splice site B, little is known about splice site A. We discovered that inclusion of the positively charged A1 insert in mouse neuroligin-1 increases its binding to heparan sulphate, a modification on neurexin. The A1 insert increases neurexin recruitment, presynaptic differentiation, and synaptic transmission mediated...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Stress-activated MAPK signalling controls fission yeast actomyosin ring integrity by modulating formin For3 levels
Cytokinesis, which enables the physical separation of daughter cells once mitosis has been completed, is executed in fungal and animal cells by a contractile actin- and myosin-based ring (CAR). In the fission yeastSchizosaccharomyces pombethe formin For3 nucleates actin cables and also co-operates for CAR assembly during cytokinesis. Mitogen-Activated Protein Kinases (MAPKs) regulate essential adaptive responses in eukaryotic organisms to environmental changes. We show that the Stress Activated Protein Kinase pathway (SAPK) and its effector, MAPK Sty1, downregulates CAR assembly inS. pombe when its integrity becomes compro...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Neural variability determines coding strategies for natural self-motion in macaque monkeys
We have previously reported that central neurons mediating vestibulo-spinal reflexes and self-motion perception optimally encode natural self-motion (Mitchell et al., 2018). Importantly however, the vestibular nuclei also comprise other neuronal classes that mediate essential functions such as the vestibulo-ocular reflex (VOR) and its adaptation. Here we show that heterogeneities in resting discharge variability mediate a trade-off between faithful encoding and optimal coding via temporal whitening. Specifically, neurons displaying lower variability did not whiten naturalistic self-motion but instead faithfully represented...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Structural Insights into Human Acid-sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1
Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. Peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, showing an analgesic effect. However, the detailed inhibitory mechanism of Mamba1 on ASIC1s, especially how Mamba1 binding to extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

More than just a pool
An intricate stem cell niche boundary formed by finger-like extensions generates asymmetry in stem cell divisions. (Source: eLife)
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Structural basis of αE-catenin-F-actin catch bond behavior
Cell-cell and cell-matrix junctions transmit mechanical forces during tissue morphogenesis and homeostasis. α-Catenin links cell-cell adhesion complexes to the actin cytoskeleton, and mechanical load strengthens its binding to F-actin in a direction-sensitive manner. Specifically, optical trap experiments revealed that force promotes a transition between weak and strong actin-bound states. Here, we descr ibe the cryo-electron microscopy structure of the F-actin-bound αE-catenin actin-binding domain, which in solution forms a 5-helix bundle. In the actin-bound structure, the first helix of the bundle dissociates...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors
Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally-enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and ti...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Cancer Biology Stem Cells and Regenerative Medicine Source Type: research

Nutrient levels and trade-offs control diversity in a serial dilution ecosystem
Microbial communities feature an immense diversity of species and this diversity is linked to outcomes ranging from ecosystem stability to medical prognoses. Yet the mechanisms underlying microbial diversity are under debate. While simple resource-competition models don't allow for coexistence of a large number of species, it was recently shown that metabolic trade-offs can allow unlimited diversity. Does this diversity persist with more realistic, intermittent nutrient supply? Here, we demonstrate theoretically that in serial dilution culture, metabolic trade-offs allow for high diversity. When a small amount of nutrient ...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Ecology Physics of Living Systems Source Type: research

Dichotomous role of the human mitochondrial Na < sup > + < /sup > /Ca < sup > 2+ < /sup > /Li < sup > + < /sup > exchanger NCLX in colorectal cancer growth and metastasis
Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor s...
Source: eLife - September 11, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation
Autophagy is a proteolytic pathway conserved from yeasts to mammals. Atg1 kinase is essential for autophagy but how its activity is controlled remains insufficiently understood. Here, we show that, in the fission yeastSchizosaccharomyces pombe, Atg1 kinase activity requires Atg11, the ortholog of mammalian FIP200/RB1CC1, but does not require Atg13, Atg17, or Atg101. Remarkably, a 62-amino-acid region of Atg11 is sufficient for the autophagy function of Atg11 and for supporting the Atg1 kinase activity. This region harbors an Atg1-binding domain and a homodimerization domain. Dimerizing Atg1 is the main role of Atg11, as it...
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Cell Biology Source Type: research

The host exosome pathway underpins biogenesis of the human cytomegalovirus virion
Human Cytomegalovirus (HCMV) infects over half the world's population, is a leading cause of congenital birth defects, and poses serious risks for immuno-compromised individuals. To expand the molecular knowledge governing virion maturation, we analysed HCMV virions using proteomics, and identified a significant proportion of host exosome constituents. To validate this acquisition, we characterized exosomes released from uninfected cells, and demonstrated that over 99% of the protein cargo was subsequently incorporated into HCMV virions during infection. This suggested a common membrane origin, and utilization of host exos...
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific ‘GBM-on-a-Chip’ microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosupp...
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Cancer Biology Physics of Living Systems Source Type: research

Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth
The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by...
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells
SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. HighSOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency comp...
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Cancer Biology Developmental Biology Source Type: research

Soluble collectin-12 mediates C3-independent docking of properdin that activates the alternative pathway of complement
In conclusion, a prerequisite for properdin binding and in situ C3bBb assembly was the initial docking of sCL-12. This implies a new important function of properdin in host defence bridging pattern recognition and specific AP activation. (Source: eLife)
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Response to comment on 'Lack of evidence for associative learning in pea plants'
In 2016 Gagliano et al. reported evidence for associative learning in plants (Gagliano et al., 2016). A subsequent attempt to replicate this finding by the present author was not successful (Markel, 2020). Gagliano et al. attribute this lack of replication to differences in the experimental set-ups used in the original work and the replication attempt (Gagliano et al., 2020). Here, based on a comparison of the two set-ups, I argue that these differences are unable to explain the lack of replication in Markel, 2020. (Source: eLife)
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Plant Biology Source Type: research

Comment on 'Lack of evidence for associative learning in pea plants'
In 2016 we reported evidence for associative learning in plants (Gagliano et al., 2016). In view of the far-reaching implications of this finding we welcome the attempt made by Markel to replicate our study (Markel, 2020). However, as we discuss here, the protocol employed by Markel was unsuitable for testing for associative learning. (Source: eLife)
Source: eLife - September 10, 2020 Category: Biomedical Science Tags: Ecology Plant Biology Source Type: research

Minimally dependent activity subspaces for working memory and motor preparation in the lateral prefrontal cortex
The lateral prefrontal cortex is involved in the integration of multiple types of information, including working memory and motor preparation. However, it is not known how downstream regions can extract one type of information without interference from the others present in the network. Here, we show that the lateral prefrontal cortex of non-human primates contains two minimally dependent low-dimensional subspaces: one that encodes working memory information, and another that encodes motor preparation information. These subspaces capture all the information about the target in the delay periods, and the information in both...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Speciation and the developmental alarm clock
New species arise as the genomes of populations diverge. The developmental ‘alarm clock’ of speciation sounds off when sufficient divergence in genetic control of development leads hybrid individuals to infertility or inviability, the world awoken to the dawn of new species with intrinsic post-zygotic reproductive isolation. Some developmental stages will be more prone to hybrid dysfunction due to how molecular evolution interacts with the ontogenetic timing of gene expression. Considering the ontogeny of hybrid incompatibilities provides a profitable connection between ‘evo-devo’ and speciation gen...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Nurturing nature
Mutant zebrafish exhibit different behaviours depending on the genetic background of the fish they were raised with. (Source: eLife)
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Ecology Neuroscience Source Type: research

Genetic variation in the social environment affects behavioral phenotypes of oxytocin receptor mutants in zebrafish
Oxytocin-like peptides have been implicated in the regulation of a wide range of social behaviors across taxa. On the other hand, the social environment, which is composed of conspecifics that may vary in their genotypes, also influences social behavior, creating the possibility for indirect genetic effects. Here, we used a zebrafish oxytocin receptor knockout line to investigate how the genotypic composition of the social environment (Gs) interacts with the oxytocin genotype of the focal individual (Gi) in the regulation of its social behavior. For this purpose, we have raised wild-type or knock-out zebrafish in either wi...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Ecology Neuroscience Source Type: research

Neurofascin and Kv7.3 are delivered to somatic and axon terminal surface membranes en route to the axon initial segment
This study reveals how key proteins are delivered to the AIS and thereby how they may contribute to its functional plasticity. (Source: eLife)
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Breakage of the Oligomeric CaMKII Hub by the Regulatory Segment of the Kinase
Ca2+/calmodulin dependent protein kinase II (CaMKII) is an oligomeric enzyme with crucial roles in neuronal signaling and cardiac function. Previously, we showed that activation of CaMKII triggers the exchange of subunits between holoenzymes, potentially increasing the spread of the active state (Stratton et al. 2014; Bhattacharyya et al. 2016). Using mass spectrometry, we show now that unphosphorylated and phosphorylated peptides derived from the CaMKII- α regulatory segment bind to the CaMKII-α hub and break it into smaller oligomers. Molecular dynamics simulations show that the regulatory segments dock spont...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations
Absence seizures result from 3-5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens human seizures. Here, we show that blocking GABA transporters (GATs) in acute rat brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations i...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Natural variation in autumn expression is the major adaptive determinant distinguishing Arabidopsis < i > FLC < /i > haplotypes
InArabidopsis thaliana, winter is registered during vernalization through the temperature-dependent repression and epigenetic silencing of floral repressorFLOWERING LOCUS C (FLC). Natural Arabidopsis accessions show considerable variation in vernalization. However, which aspect of theFLCrepression mechanism is most important for adaptation to different environments is unclear. By analyzingFLC dynamics in natural variants and mutants throughout winter in three field sites, we find that autumnalFLCexpression, rather than epigenetic silencing, is the major variable conferred by the distinct ArabidopsisFLC haplotypes. This var...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Plant Biology Source Type: research

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones
Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing c...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Cancer Biology Chromosomes and Gene Expression Source Type: research

Topology-driven protein-protein interaction network analysis detects genetic sub-networks regulating reproductive capacity
Understanding the genetic regulation of organ structure is a fundamental problem in developmental biology. Here, we use egg-producing structures of insect ovaries, called ovarioles, to deduce systems-level gene regulatory relationships from quantitative functional genetic analysis. We previously showed that Hippo signalling, a conserved regulator of animal organ size, regulates ovariole number inDrosophila melanogaster. To comprehensively determine how Hippo signalling interacts with other pathways in this regulation, we screened all known signalling pathway genes, and identified Hpo-dependent and Hpo-independent signallin...
Source: eLife - September 9, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research