Ephrin-B3 controls excitatory synapse density through cell-cell competition for EphBs
Cortical networks are characterized by sparse connectivity, with synapses found at only a subset of axo-dendritic contacts. Yet within these networks, neurons can exhibit high connection probabilities, suggesting that cell-intrinsic factors, not proximity, determine connectivity. Here, we identify ephrin-B3 (eB3) as a factor that determines synapse density by mediating a cell-cell competition that requires ephrin-B-EphB signaling. In a microisland culture system designed to isolate cell-cell competition, we find that eB3 determines winning and losing neurons in a contest for synapses. In a Mosaic Analysis with Double Marke...
Source: eLife - February 21, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

An updated phylogeny of the < i > Alphaproteobacteria < /i > reveals that the < i > Rickettsiales < /i > and < i > Holosporales < /i > have independent origins
TheAlphaproteobacteria is an extraordinarily diverse and ancient group of bacteria. Previous attempts to infer its deep phylogeny have been plagued with methodological artefacts. To overcome this, we analyzed a dataset of 200 single-copy and conserved genes and employed diverse strategies to reduce compositional artefacts. Such strategies include using novel dataset-specific profile mixture models and recoding schemes, and removing sites, genes and taxa that are compositionally biased. We show that theRickettsiales andHolosporales (both groups of intracellular parasites of eukaryotes) are not sisters to each other, but ins...
Source: eLife - February 21, 2019 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

Activation mechanism of ATP-sensitive K < sup > + < /sup > channels explored with real-time nucleotide binding
The response of ATP-sensitive K+ channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATP in channel gating. Binding to NBS2 was Mg2+-independent, but Mg was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinate...
Source: eLife - February 21, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

MYOD1 functions as a clock amplifier as well as a critical co-factor for downstream circadian gene expression in muscle
In conclusion, these findings reveal mechanistic roles for the muscle specific transcription factor MYOD1 in the regulation of molecular clock amplitude as well as synergistic regulation of clock-controlled genes in skeletal muscle. (Source: eLife)
Source: eLife - February 21, 2019 Category: Biomedical Science Tags: Cell Biology Chromosomes and Gene Expression Source Type: research

Programmed conversion of hypertrophic chondrocytes into osteoblasts and marrow adipocytes within zebrafish bones
Much of the vertebrate skeleton develops from cartilage templates that are progressively remodeled into bone. Lineage tracing studies in mouse suggest that chondrocytes within these templates persist and become osteoblasts, yet the underlying mechanisms of this process and whether chondrocytes can generate other derivatives remain unclear. We find that zebrafish cartilages undergo extensive remodeling and vascularization during juvenile stages to generate fat-filled bones. Growth plate chondrocytes marked bysox10andcol2a1a contribute to osteoblasts, marrow adipocytes, and mesenchymal cells within adult bones. At the edge o...
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Schnyder corneal dystrophy-associated UBIAD1 Inhibits ER-associated degradation of HMG CoA reductase in mice
Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 ...
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F
The lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of murine TMEM16F (mTMEM16F) that underlie its function as a lipid scramblase and an ion channel. The cryo-EM data of mTMEM16F in absence and presence of Ca2+ define the ligand-free closed conformation of the protein and the structure of a Ca2+-bound intermediate. Both conformations resemble their counterparts of the scrambling-incompetent anion channel mTMEM16A,...
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Structural insights into SETD3-mediated histidine methylation on β-actin
In conclusion, this study is the first to show a catalytic mechanism of SETD3-mediated histidine methylation on β-actin, which not only throws light on the protein histidine methylation phenomenon, but also facilitates the design of small molecule inhibitors of SETD3. (Source: eLife)
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM
Scramblases catalyze the movement of lipids between both leaflets of a bilayer. Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a Ca2+-dependent lipid scramblase, its regulation mechanism has remained elusive. Here, we have used cryo-electron microscopy and functional assays to address this question. Ca2+-bound and Ca2+-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes underlying its activation. In this process, Ca2+-binding induces a stepwise transition of the catalytic ...
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

Pyrophosphate modulates plant stress responses via SUMOylation
Pyrophosphate (PPi), a byproduct of macromolecule biosynthesis is maintained at low levels by soluble inorganic pyrophosphatases (sPPase) found in all eukaryotes. In plants, H+-pumping pyrophosphatases (H+-PPase) convert the substantial energy present in PPi into an electrochemical gradient. We show here, that both cold- and heat stress sensitivity offugu5 mutants lacking the major H+-PPase isoform AVP1 is correlated with reduced SUMOylation. In addition, we show that increased PPi concentrations interfere with SUMOylation in yeast and we provide evidence that SUMO activating E1-enzymes are inhibited by micromolar concentr...
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Plant Biology Source Type: research

Hypothesis, analysis and synthesis, it's all Greek to me
The linguistic foundations of science and technology include many terms that have been borrowed from ancient languages. In the case of terms with origins in the Greek language, the modern meaning can often differ significantly from the original one. Here we use the PubMed database to demonstrate the prevalence of words of Greek origin in the language of modern science, and call for scientists to exercise care when coining new terms. (Source: eLife)
Source: eLife - February 20, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Genetics and Genomics Source Type: research

Compensatory growth renders Tcf7l1a dispensable for eye formation despite its requirement in eye field specification
In this study, we show that Tcf7l1a is one such transcription factor that acts cell-autonomously to specify the eye field in zebrafish. Despite the much-reduced eye field intcf7l1a mutants, these fish develop normal eyes revealing a striking ability of the eye to recover from a severe early phenotype. This robustness is not mediated through genetic compensation at neural plate stage; instead, the smaller optic vesicle oftcf7l1a mutants shows delayed neurogenesis and continues to grow until it achieves approximately normal size. Although the developing eye is robust to the lack of Tcf7l1a function, it is sensitised to the e...
Source: eLife - February 19, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Beyond protein-coding genes
A long non-coding RNA calledlnc-NR2F1 regulates several neuronal genes, including some involved in autism and intellectual disabilities. (Source: eLife)
Source: eLife - February 19, 2019 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Multiple pairs of allelic MLA immune receptor-powdery mildew AVR < sub > A < /sub > effectors argue for a direct recognition mechanism
We report here the isolation ofBghAVRa7,AVRa9,AVRa10,andAVRa22, which encode small secreted proteins recognized by allelic MLA7, MLA9, MLA10, and MLA22 receptors, respectively. These effectors are sequence-unrelated, except for allelicAVRa10andAVRa22 that are co-maintained in pathogen populations in the form of a balanced polymorphism. Contrary to numerous examples of indirect recognition of bacterial effectors by plant NLRs, co-expression experiments with matchingMla-AVRa pairs indicate direct detection of the sequence-unrelated fungal effectors by MLA receptors. (Source: eLife)
Source: eLife - February 19, 2019 Category: Biomedical Science Tags: Plant Biology Source Type: research

Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs
Hypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here we present single-particle cryo-electron microscopy structures ofMus musculus LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the chann...
Source: eLife - February 18, 2019 Category: Biomedical Science Tags: Neuroscience Structural Biology and Molecular Biophysics Source Type: research

Nuclear genetic regulation of the human mitochondrial transcriptome
Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing>11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with exp...
Source: eLife - February 18, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases
Perturbations in mitochondrial function and homeostasis are pervasive in lysosomal storage diseases, but the underlying mechanisms remain unknown. Here, we report a transcriptional program that represses mitochondrial biogenesis and function in lysosomal storage diseases Niemann-Pick type C (NPC) and acid sphingomyelinase deficiency (ASM), in patient cells and mouse tissues. This mechanism is mediated by the transcription factors KLF2 and ETV1, which are both induced in NPC and ASM patient cells. Mitochondrial biogenesis and function defects in these cells are rescued by the silencing of KLF2 or ETV1. Increased ETV1 expres...
Source: eLife - February 18, 2019 Category: Biomedical Science Tags: Cell Biology Human Biology and Medicine Source Type: research

Mechanics and dynamics of translocating MreB filaments on curved membranes
MreB is an actin homolog that is essential for coordinating the cell wall synthesis required for the rod shape of many bacteria. Previously we have shown that filaments of MreB bind to the curved membranes of bacteria and translocate in directions determined by principal membrane curvatures to create and reinforce the rod shape (Hussain et al., 2018). Here, in order to understand how MreB filament dynamics affects their cellular distribution, we model how MreB filaments bind and translocate on membranes with different geometries. We find that it is both energetically favorable and robust for filaments to bind and orient al...
Source: eLife - February 18, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Physics of Living Systems Source Type: research

Generation of the squamous epithelial roof of the 4 < sup > th < /sup > ventricle
We use the transparency of zebrafish embryos to reveal thede novo generation of a simple squamous epithelium and identify the cellular architecture in the epithelial transition zone that ties this squamous epithelium to the columnar neuroepithelium within the embryo's brain. The simple squamous epithelium of the rhombencephalic roof plate is pioneered by distinct mesenchymal cells at the dorsal midline of the neural tube. Subsequently, a progenitor zone is established at the interface between columnar epithelium of the rhombic lip and the expanding squamous epithelium of the roof plate. Surprisingly, this interface consist...
Source: eLife - February 18, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Arabidopsis RCD1 coordinates chloroplast and mitochondrial functions through interaction with ANAC transcription factors
Reactive oxygen species (ROS)-dependent signaling pathways from chloroplasts and mitochondria merge at the nuclear protein RADICAL-INDUCED CELL DEATH1 (RCD1). RCD1 interactsin vivo and suppresses the activity of the transcription factors ANAC013 and ANAC017, which mediate a ROS-related retrograde signal originating from mitochondrial complex III. Inactivation ofRCD1 leads to increased expression of mitochondrial dysfunction stimulon (MDS) genes regulated by ANAC013 and ANAC017. Accumulating MDS gene products, including alternative oxidases (AOXs), affect redox status of the chloroplasts, leading to changes in chloroplast R...
Source: eLife - February 15, 2019 Category: Biomedical Science Tags: Plant Biology Source Type: research

A Y-chromosome shredding gene drive for controlling pest vertebrate populations
Self-replicating gene drives that modify sex ratios or infer a fitness cost could be used to control populations of invasive alien species. The targeted deletion of Y sex chromosomes using CRISPR technology offers a new approach for sex bias that could be incorporated within gene-drive designs. We introduce a novel gene-drive strategy termed Y-CHromosome deletion using Orthogonal Programmable Endonucleases (Y-CHOPE), incorporating a programmable endonuclease that 'shreds' the Y chromosome, thereby converting XY males into fertile XO females. Firstly, we demonstrate that the CRISPR/Cas12a system can eliminate the Y chromoso...
Source: eLife - February 15, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Genetics and Genomics Source Type: research

A multicellular rosette-mediated collective dendrite extension
Coordination of neurite morphogenesis with surrounding tissues is crucial to the establishment of neural circuits, but the underlying cellular and molecular mechanisms remain poorly understood. We show that neurons in aC. eleganssensory organ, called the amphid, undergo a collective dendrite extension to form the sensory nerve. The amphid neurons first assemble into a multicellular rosette. The vertex of the rosette, which becomes the dendrite tips, is attached to the anteriorly migrating epidermis and carried to the sensory depression, extruding the dendrites away from the neuronal cell bodies. Multiple adhesion molecules...
Source: eLife - February 15, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Combined transcriptome and proteome profiling reveals specific molecular brain signatures for sex, maturation and circalunar clock phase
Many marine animals, ranging from corals to fishes, synchronise reproduction to lunar cycles. In the annelidPlatynereis dumerilii, this timing is orchestrated by an endogenous monthly (circalunar) clock entrained by moonlight. Whereas daily (circadian) clocks cause extensive transcriptomic and proteomic changes, the quality and quantity of regulations by circalunar clocks have remained largely elusive. By establishing a combined transcriptomic and proteomic profiling approach, we provide first systematic insight into the molecular changes inPlatynereis heads between circalunar phases, and across sexual differentiation and ...
Source: eLife - February 15, 2019 Category: Biomedical Science Tags: Ecology Neuroscience Source Type: research

Negative reciprocity, not ordered assembly, underlies the interaction of Sox2 and Oct4 on DNA
The mode of interaction of transcription factors (TFs) on eukaryotic genomes remains a matter of debate. Single-molecule data in living cells for the TFs Sox2 and Oct4 were previously interpreted as evidence of ordered assembly on DNA. However, the quantity that was calculated does not determine binding order but, rather, energy expenditure away from thermodynamic equilibrium. Here, we undertake a rigorous biophysical analysis which leads to the concept of reciprocity. The single-molecule data imply that Sox2 and Oct4 exhibit negative reciprocity, with expression of Sox2 increasing Oct4 ’s genomic binding but express...
Source: eLife - February 14, 2019 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

The structure of the Ctf19c/CCAN from budding yeast
We describe its implications for establishment of kinetochores and for their regulation by kinases throughout the cell cycle. (Source: eLife)
Source: eLife - February 14, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development
The origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins. Throughout renal organogenesis, most kidney macrophages are perivascular and express F4/80 and CD206. These macrophages are enriched for mRNAs linked to developmental processes, such as blood vessel morphogenesis. Using a...
Source: eLife - February 13, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Dystroglycan is a scaffold for extracellular axon guidance decisions
Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembra...
Source: eLife - February 13, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes
Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect...
Source: eLife - February 13, 2019 Category: Biomedical Science Tags: Cancer Biology Genetics and Genomics Source Type: research

Architectural principles for Hfq/Crc-mediated regulation of gene expression
This study reveals how Hfq cooperates with a partner protein to regulate translation, and provides a structural basis for an RNA code that guides global regulators to interact cooperatively and regulate different RNA targets. (Source: eLife)
Source: eLife - February 13, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Microtubule plus-ends act as physical signaling hubs to activate RhoA during cytokinesis
In this study cytokinesis regulators visualized inDrosophila melanogaster (Dm) cells were found to localize to and track MT plus-ends during cytokinesis. The RhoA GEF Pebble (DmECT2) did not evidently tip-track, but rather localized rapidly to cortical sites contacted by MT plus-tips, resulting in RhoA activation and enrichment of myosin-regulatory light chain. The MT plus-end localization of centralspindlin was compromised following EB1 depletion, which resulted in a higher incidence of cytokinesis failure. Centralspindlin plus-tip localization depended on the C-terminus and a putative EB1-interaction motif (hxxPTxh) in R...
Source: eLife - February 13, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

Quorums enable optimal pooling of independent judgements in biological systems
Collective decision-making is ubiquitous, and majority-voting and the Condorcet Jury Theorem pervade thinking about collective decision-making. Thus, it is typically assumed that majority-voting is the best possible decision mechanism, and that scenarios exist where individually-weak decision-makers should not pool information. Condorcet and its applications implicitly assume that only one kind of error can be made, yet signal detection theory shows two kinds of errors exist, ‘false positives’ and ‘false negatives’. We apply signal detection theory to collective decision-making to show that majority...
Source: eLife - February 13, 2019 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research

Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis
Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive ...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Three F-actin assembly centers regulate organelle inheritance, cell-cell communication and motility in < i > Toxoplasma gondii < /i >
This study offers a coherent model of the key players controlling actin polymerization, stressing the importance of well-timed post-translational modifications to power parasite motility. (Source: eLife)
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Defining host –pathogen interactions employing an artificial intelligence workflow
We present HRMAn (Host Response to Microbe Analysis), an open-source image analysis platform based on machine learning algorithms and deep learning. We show that HRMAn has the capacity to learn phenotypes from the data, without relying on researcher-based assumptions. UsingToxoplasma gondii andSalmonella enterica Typhimurium we demonstrate HRMAn ’s capacity to recognize, classify and quantify pathogen killing, replication and cellular defense responses. HRMAn thus presents the only intelligent solution operating at human capacity suitable for both single image and high content image analysis. (Source: eLife)
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

Individuals physically interacting in a group rapidly coordinate their movement by estimating the collective goal
How can a human collective coordinate, for example to move a banquet table, when each person is influenced by the inertia of others who may be inferior at the task? We hypothesized that large groups cannot coordinate through touch alone, accruing to a zero-sum scenario where individuals inferior at the task hinder superior ones. We tested this hypothesis by examining how dyads, triads and tetrads, whose right hands were physically coupled together, followed a common moving target. Surprisingly, superior individuals followed the target accurately even when coupled to an inferior group, and the interaction benefits increased...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Extensive transmission of microbes along the gastrointestinal tract
The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more gene...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor
The fish-hunting marine cone snailConus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins fromC. geographus,Conus tulipa andConus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in na...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

How significant are the public dimensions of faculty work in review, promotion, and tenure documents?
Much of the work done by faculty at both public and private universities has significant public dimensions: it is often paid for by public funds; it is often aimed at serving the public good; and it is often subject to public evaluation. To understand how the public dimensions of faculty work are valued, we analyzed review, promotion, and tenure documents from a representative sample of 129 universities in the US and Canada. Terms and concepts related to public and community are mentioned in a large portion of documents, but mostly in ways that relate to service, which is an undervalued aspect of academic careers. Moreover...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

Offline impact of transcranial focused ultrasound on cortical activation in primates
To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique. To date, investigations report short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting ‘offline’ changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 s of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity ...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

From venom peptides to a potential diabetes treatment
Cone snails have evolved a variety of insulin-like molecules that may help with the development of better treatments for diabetes. (Source: eLife)
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Regional complexity in enteric neuron wiring reflects diversity of motility patterns in the mouse large intestine
The enteric nervous system controls a variety of gastrointestinal functions including intestinal motility. The minimal neuronal circuit necessary to direct peristalsis is well-characterized but several intestinal regions display also other motility patterns for which the underlying circuits and connectivity schemes that coordinate the transition between those patterns are poorly understood. We investigated whether in regions with a richer palette of motility patterns, the underlying nerve circuits reflect this complexity. Using Ca2+ imaging, we determined the location and response fingerprint of large populations of enteri...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > CNTN5 < /i > < sup > - < /sup > < i > < sup > /+ < /sup > < /i > or < i > EHMT2 < /i > < sup > - < /sup > < i > < sup > /+ < /sup > < /i > human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks
Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, ‘isogenic’ iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo an d rare-inherited presumed-damaging variants were characterized i...
Source: eLife - February 12, 2019 Category: Biomedical Science Tags: Genetics and Genomics Neuroscience Source Type: research

LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus
In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them,lncEGFL7OS, located in the opposite strand of theEGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanist...
Source: eLife - February 11, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Electron cryo-tomography provides insight into procentriole architecture and assembly mechanism
We describe structure of the A-C linker that bridges neighboring triplets. The structure infers that POC1 is likely an integral component of A-C linker. Its conserved WD40 β-propeller domain provides attachment sites for other A-C linker components. The twist of A-C linker results in an iris diaphragm-like motion of the triplets in the longitudinal direction of procentriole. Finally, we identified two assembly intermediates at the growing ends of procentriole allowin g us to propose a model for the procentriole assembly. Our results provide a comprehensive structural framework for understanding the molecular mechanism...
Source: eLife - February 11, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

A causal role for the precuneus in network-wide theta and gamma oscillatory activity during complex memory retrieval
Complex memory of personal events is thought to depend on coordinated reinstatement of cortical representations by the medial temporal lobes (MTL). MTL-cortical theta and gamma coupling is believed to mediate such coordination, but which cortical structures are critical for retrieval and how they influence oscillatory coupling is unclear. We used magnetoencephalography (MEG) combined with continuous theta burst stimulation (cTBS) to (i) clarify the roles of theta and gamma oscillations in network-wide communication during naturalistic memory retrieval, and (ii) understand the causal relationship between cortical network no...
Source: eLife - February 11, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

The modular mechanism of chromocenter formation in < i > Drosophila < /i >
A central principle underlying the ubiquity and abundance of pericentromeric satellite DNA repeats in eukaryotes has remained poorly understood. Previously we proposed that the interchromosomal clustering of satellite DNAs into nuclear structures known as chromocenters ensures encapsulation of all chromosomes into a single nucleus (Jagannathan et al., 2018). Chromocenter disruption led to micronuclei formation, resulting in cell death. Here we show that chromocenter formation is mediated by a 'modular' network, where associations between two sequence-specific satellite DNA-binding proteins, D1 and Prod, bound to their cogn...
Source: eLife - February 11, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Developmental Biology Source Type: research

Human VPS13A is associated with multiple organelles and influences mitochondrial morphology and lipid droplet motility
The VPS13Agene is associated with the neurodegenerative disorder Chorea Acanthocytosis. It is unknown what the consequences are of impaired function of VPS13A at the subcellular level. We demonstrate that VPS13A is a peripheral membrane protein, associated with mitochondria, the endoplasmic reticulum and lipid droplets. VPS13A is localized at sites where the endoplasmic reticulum and mitochondria are in close contact. VPS13A interacts with the ER residing protein VAP-A via its FFAT domain. Interaction with mitochondria is mediated via its C-terminal domain. In VPS13A-depleted cells, ER-mitochondria contact sites are decrea...
Source: eLife - February 11, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

High-order thalamic inputs to primary somatosensory cortex are stronger and longer lasting than cortical inputs
Layer (L) 2/3 pyramidal neurons in the primary somatosensory cortex (S1) are sparsely active, spontaneously and during sensory stimulation. Long-range inputs from higher areas may gate L2/3 activity. We investigated their in vivo impact by expressing channelrhodopsin in three main sources of feedback to rat S1: primary motor cortex, secondary somatosensory cortex, and secondary somatosensory thalamic nucleus (the posterior medial nucleus, POm). Inputs from cortical areas were relatively weak. POm, however, more robustly depolarized L2/3 cells and, when paired with peripheral stimulation, evoked action potentials. POm trigg...
Source: eLife - February 11, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

The evolution of hearing and balance
New genetic tools have allowed researchers to compare how the brainstem auditory and vestibular nuclei develop in embryonic chicks and mice. (Source: eLife)
Source: eLife - February 8, 2019 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Connexin-43-dependent ATP release mediates macrophage activation during sepsis
In conclusion, inhibition of autocrine Connexin-43-dependent ATP signaling on macrophages improves sepsis outcome. (Source: eLife)
Source: eLife - February 8, 2019 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research