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Intracellular antibody signalling is regulated by phosphorylation of the Fc receptor TRIM21
Cell surface Fc receptors activate inflammation and are tightly controlled to prevent autoimmunity. Antibodies also simulate potent immune signalling from inside the cell via the cytosolic antibody receptor TRIM21, but how this is regulated is unknown. Here we show that TRIM21 signalling is constitutively repressed by its B-Box domain and activated by phosphorylation. The B-Box occupies an E2 binding site on the catalytic RING domain by mimicking E2-E3 interactions, inhibiting TRIM21 ubiquitination and preventing immune activation. TRIM21 is derepressed by IKK β and TBK1 phosphorylation of an LxxIS motif in the RING d...
Source: eLife - April 18, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Back from the brink of obscurity
A mutation in a transcription factor makes people susceptible toTropheryma whipplei, the bacterium that causes a rare condition called Whipple's disease. (Source: eLife)
Source: eLife - April 18, 2018 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Biophysics of object segmentation in a collision-detecting neuron
Collision avoidance is critical for survival, including in humans, and many species possess visual neurons exquisitely sensitive to objects approaching on a collision course. Here, we demonstrate that a collision-detecting neuron can detect the spatial coherence of a simulated impending object, thereby carrying out a computation akin to object segmentation critical for proper escape behavior. At the cellular level, object segmentation relies on a precise selection of the spatiotemporal pattern of synaptic inputs by dendritic membrane potential-activated channels. One channel type linked to dendritic computations in many ne...
Source: eLife - April 18, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Histone deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T-Cells
We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, and diverts V α14/Jα18 TCR transgenic thymocytes into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

A genetic program mediates cold-warming response and promotes stress-induced phenoptosis in < i > C. elegans < /i >
How multicellular organisms respond to and are impacted by severe hypothermic stress is largely unknown. FromC. elegans screens for mutants abnormally responding to cold-warming stimuli, we identify a molecular genetic pathway comprising ISY-1, a conserved uncharacterized protein, and ZIP-10, a bZIP-type transcription factor. ISY-1 gatekeeps the ZIP-10 transcriptional program by regulating the microRNAmir-60. Downstream of ISY-1 andmir-60,zip-10 levels rapidly and specifically increase upon transient cold-warming exposure. Prolongedzip-10 up-regulation induces several protease-encoding genes and promotes stress-induced org...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus
Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequenc y at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mamm...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Rat anterior cingulate cortex recalls features of remote reward locations after disfavoured reinforcements
The anterior cingulate cortex (ACC) encodes information supporting mnemonic and cognitive processes. We show here that a rat's position can be decoded with high spatiotemporal resolution from ACC activity. ACC neurons encoded the current state of the animal and task, except for brief excursions that sometimes occurred at target feeders. During excursions, the decoded position became more similar to a remote target feeder than the rat's physical position. Excursions recruited activation of neurons encoding choice and reward, and the likelihood of excursions at a feeder was inversely correlated with feeder preference. These ...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Computer-guided design of optimal microbial consortia for immune system modulation
Manipulation of the gut microbiota holds great promise for the treatment of diseases. However, a major challenge is the identification of therapeutically potent microbial consortia that colonize the host effectively while maximizing immunologic outcome. Here, we propose a novel workflow to select optimal immune-inducing consortia from microbiome composition and immune effectors measurements. Using published and newly generated microbial and regulatory T-cell (Treg) data from germ-free mice, we estimate the contribution of twelve Clostridia strains with known immune-modulating effect to Treg induction. Combining this with a...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Immunology and Inflammation Source Type: research

The nucleosomal acidic patch relieves auto-inhibition by the ISWI remodeler SNF2h
ISWI family chromatin remodeling motors use sophisticated autoinhibition mechanisms to control nucleosome sliding. Yet how the different autoinhibitory domains are regulated is not well understood. Here we show that an acidic patch formed by histones H2A and H2B of the nucleosome relieves the autoinhibition imposed by the AutoN and the NegC regions of the human ISWI remodeler SNF2h. Further, by single molecule FRET we show that the acidic patch helps control the distance travelled per translocation event. We propose a model in which the acidic patch activates SNF2h by providing a landing pad for the NegC and AutoN auto-inh...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Chromosomes and Gene Expression Structural Biology and Molecular Biophysics Source Type: research

Free energy simulations reveal molecular mechanism for functional switch of a DNA helicase
Helicases play key roles in genome maintenance, yet it remains elusive how these enzymes change conformations and how transitions between different conformational states regulate nucleic acid reshaping. Here we developed a computational technique combining structural bioinformatics approaches and atomic-level free energy simulations to characterize how theE. coli DNA repair enzyme UvrD changes its conformation at the fork junction to switch its function from unwinding to rezipping DNA. The lowest free energy path shows that UvrD opens the interface between two domains, allowing the bound ssDNA to escape. The simulation res...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Structural Biology and Molecular Biophysics Source Type: research

Hexameric and pentameric complexes of the ExbBD energizer in the Ton system
Gram-negative bacteria import essential nutrients such as iron and vitamin B12 through outer membrane receptors. This process utilizes proton motive force harvested by the Ton system made up of three inner membrane proteins, ExbB, ExbD and TonB. ExbB and ExbD form the proton channel that energizes uptake through TonB. Recently, crystal structures suggest that the ExbB pentamer is the scaffold. Here, we present structures of hexameric complexes of ExbB and ExbD revealed by X-ray crystallography and single particle cryo-EM. Image analysis shows that hexameric and pentameric complexes coexist, with the proportion of hexamer i...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Antimicrobial peptide expression in a wild tobacco plant reveals the limits of host-microbe-manipulations in the field
Plant-microbe associations are thought to be beneficial for plant growth and resistance against biotic or abiotic stresses, but for natural ecosystems, the ecological analysis of microbiome function remains in its infancy. We used transformed wild tobacco plants (Nicotiana attenuata) which constitutively express an antimicrobial peptide (Mc-AMP1) of the common ice plant, to establish an ecological tool for plant-microbe studies in the field. Transgenic plants showed in planta activity against plant-beneficial bacteria and were phenotyped within the plants ´ natural habitat regarding growth, fitness and the resistance...
Source: eLife - April 17, 2018 Category: Biomedical Science Tags: Plant Biology Source Type: research

Negative regulation of G2-M by ATR (mei-41)/Chk1(Grapes) facilitates tracheoblast growth and tracheal hypertrophy in Drosophila
We report that tracheoblasts pause in G2 for ~48-56 h and grow in size over this period. Surprisingly, tracheoblasts arrested in G2 express drivers of G2-M like Cdc25/String (Stg). We find that mechanisms that prevent G2-M are also in place in this interval. Tracheoblasts activate Checkpoint Kinase 1/Grapes (Chk1/Grp) in an ATR/mei-41-dependent manner. Loss of ATR/Chk1 led to precocious mitotic entry ~24-32 h earlier. These divisions were apparently normal as there was no evidence of increased DNA damage or cell death. However, induction of precocious mitoses impaired growth of tracheoblasts and the tracheae they comprise....
Source: eLife - April 16, 2018 Category: Biomedical Science Tags: Developmental Biology and Stem Cells Source Type: research

Control of voluntary and optogenetically perturbed locomotion by spike rate and timing of neurons of the mouse cerebellar nuclei
Neurons of the cerebellar nuclei (CbN), which generate cerebellar output, are inhibited by Purkinje cells. With extracellular recordings during voluntary locomotion in head-fixed mice, we tested how the rate and coherence of inhibition influence CbN cell firing and well-practiced movements. Firing rates of Purkinje and CbN cells were modulated systematically through the stride cycle (~200 –300 ms). Optogenetically stimulating ChR2-expressing Purkinje cells with light steps or trains evoked either asynchronous or synchronous inhibition of CbN cells. Steps slowed CbN firing. Trains suppressed CbN cell firing less effec...
Source: eLife - April 16, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Crystal structure of intraflagellar transport protein 80 reveals a homo-dimer required for ciliogenesis
Oligomeric assemblies of intraflagellar transport (IFT) particles build cilia through sequential recruitment and transport of ciliary cargo proteins within cilia. Here we present the 1.8 Å resolution crystal structure of theChlamydomonas IFT-B protein IFT80, which reveals the architecture of two N-terminal b-propellers followed by an a-helical extension. The N-terminal b-propeller tethers IFT80 to the IFT-B complex via IFT38 whereas the second b-propeller and the C-terminal a-helical extension result in IFT80 homo-dimerization. Using CRISPR/Cas to create biallelicIft80frameshift mutations in IMCD3 mouse cells, we dem...
Source: eLife - April 16, 2018 Category: Biomedical Science Tags: Cell Biology Structural Biology and Molecular Biophysics Source Type: research

Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle
Circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. More extensive rhythmic transcription was observed in human skeletal muscle compared to in vitro cell culture as a large part of the in vivo mRNA rhythmicity was lost in vitro. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in G...
Source: eLife - April 16, 2018 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

First spikes in visual cortex enable perceptual discrimination
Visually guided perceptual decisions involve the sequential activation of a hierarchy of cortical areas. It has been hypothesized that a brief time window of activity in each area is sufficient to enable the decision but direct measurements of this time window are lacking. To address this question, we develop a visual discrimination task in mice that depends on visual cortex and in which we precisely control the time window of visual cortical activity as the animal performs the task at different levels of difficulty. We show that threshold duration of activity in visual cortex enabling perceptual discrimination is between ...
Source: eLife - April 16, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

A question of time
How does a scientist balance establishing a career and starting a family? (Source: eLife)
Source: eLife - April 16, 2018 Category: Biomedical Science Source Type: research

Clathrin coat controls synaptic vesicle acidification by blocking vacuolar ATPase activity
Newly-formed synaptic vesicles (SVs) are rapidly acidified by vacuolar adenosine triphosphatases (vATPases), generating a proton electrochemical gradient that drives neurotransmitter loading. Clathrin-mediated endocytosis is needed for the formation of new SVs, yet it is unclear when endocytosed vesicles acidify and refill at the synapse. Here, we isolated clathrin-coated vesicles (CCVs) from mouse brain to measure their acidification directly at the single vesicle level. We observed that the ATP-induced acidification of CCVs was strikingly reduced in comparison to SVs. Remarkably, when the coat was removed from CCVs, unco...
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Comment on "Magnetosensitive neurons mediate geomagnetic orientation in < i > Caenorhabditis elegans" < /i >
A diverse array of species on the planet employ the Earth's magnetic field as a navigational aid. As the majority of these animals are migratory, their utility to interrogate the molecular and cellular basis of the magnetic sense is limited. Vidal-Gadea and colleagues recently argued that the wormCaenorhabditis elegans possesses a magnetic sense that guides their vertical movement in soil. In making this claim, they relied on three different behavioral assays that involved magnetic stimuli. Here, we set out to replicate their results employing blinded protocols and double wrapped coils that control for heat generation. We ...
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Microtubule assembly governed by tubulin allosteric gain in flexibility and lattice induced fit
Microtubules (MTs) are key components of the cytoskeleton and play a central role in cell division and development. MT assembly is known to be associated with a structural change in αβ-tubulin dimers from kinked to straight conformations. How GTP binding renders individual dimers polymerization-competent, however, is still unclear. Here, we have characterized the conformational dynamics and energetics of unassembled tubulin using atomistic molecular dynamics and free energy c alculations. Contradictory to existing allosteric and lattice models, we find that GTP-tubulin favors a broad range of almost isoenergetic...
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Response to comment on "Magnetosensitive neurons mediate geomagnetic orientation in < i > Caenorhabditis elegans" < /i >
Many animals can orient using the earth ’s magnetic field. In a recent study, we performed three distinct behavioral assays providing evidence that the nematodeCaenorhabditis elegans orients to earth-strength magnetic fields (Vidal-Gadea et al., 2015). A new study by Landler et al. suggests thatC. elegans does not orient to magnetic fields (Landler et al., 2018). They also raise conceptual issues that cast doubt on our study. Here, we explain how they appear to have missed positive results in part by omitting controls and running assays longer than prescribed, so that worms switched their preferred migratory directio...
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Smart bats click twice
The acoustic representation of the outside world in the midbrain of a bat becomes more precise as it uses double clicks to locate closer objects. (Source: eLife)
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

IFN- λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission
Host factors restricting the transmission of respiratory viruses are poorly characterized. We analyzed the contribution of type I and type III interferon (IFN) using a mouse model in which the virus is selectively administered to the upper airways, mimicking a natural respiratory virus infection. Mice lacking functional IFN- λ receptors (Ifnlr1-/-) no longer restricted virus dissemination from the upper airways to the lungs.Ifnlr1-/- mice shed significantly more infectious virus particles via the nostrils and transmitted the virus much more efficiently to na ïve contacts compared with wild-type mice or mice lac...
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Motor selection dynamics in FEF explain the reaction time variance of saccades to single targets
In studies of voluntary movement, a most elemental quantity is the reaction time (RT) between the onset of a visual stimulus and a saccade toward it. However, this RT demonstrates extremely high variability which, in spite of extensive research, remains unexplained. It is well established that, when a visual target appears, oculomotor activity gradually builds up until a critical level is reached, at which point a saccade is triggered. Here, based on computational work and single-neuron recordings from monkey frontal eye field (FEF), we show that this rise-to-threshold process starts from a dynamic initial state that alrea...
Source: eLife - April 13, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Evidence for loss and reacquisition of alcoholic fermentation in a fructophilic yeast lineage
Fructophily is a rare trait that consists of the preference for fructose over other carbon sources. Here, we show that in a yeast lineage (theWickerhamiella/Starmerella, W/S clade) comprised of fructophilic species thriving in the high-sugar floral niche, the acquisition of fructophily is concurrent with a wider remodeling of central carbon metabolism. Coupling comparative genomics with biochemical and genetic approaches, we gathered ample evidence for the loss of alcoholic fermentation in an ancestor of the W/S clade and subsequent reinstatement through either horizontal acquisition of homologous bacterial genes or modifi...
Source: eLife - April 12, 2018 Category: Biomedical Science Tags: Genomics and Evolutionary Biology Source Type: research

The conformation of the histone H3 tail inhibits association of the BPTF PHD finger with the nucleosome
Histone tails harbor a plethora of post-translational modifications that direct the function of chromatin regulators, which recognize them through effector domains. Effector domain/histone interactions have been broadly studied, but largely using peptide fragments of histone tails. Here, we extend these studies into the nucleosome context and find that the conformation adopted by the histone H3 tails is inhibitory to BPTF PHD finger binding. Using NMR spectroscopy and MD simulations, we show that the H3 tails interact robustly but dynamically with nucleosomal DNA, substantially reducing PHD finger association. Altering the...
Source: eLife - April 12, 2018 Category: Biomedical Science Tags: Genes and Chromosomes Structural Biology and Molecular Biophysics Source Type: research

Silencing of transposable elements may not be a major driver of regulatory evolution in primate iPSCs
Transposable elements (TEs) comprise almost half of primate genomes and their aberrant regulation can result in deleterious effects. In pluripotent stem cells, rapidly-evolving KRAB-ZNF genes target TEs for silencing by H3K9me3. To investigate the evolution of TE silencing, we performed H3K9me3 ChIP-seq experiments in induced pluripotent stem cells from ten human and seven chimpanzee individuals. We identified four million orthologous TEs and found the SVA and ERV families to be marked most frequently by H3K9me3. We found little evidence of inter-species differences in TE silencing, with as many as 82% of putatively silenc...
Source: eLife - April 12, 2018 Category: Biomedical Science Tags: Genomics and Evolutionary Biology Source Type: research

Chromatin-associated RNA sequencing (ChAR-seq) maps genome-wide RNA-to-DNA contacts
RNA is a critical component of chromatin in eukaryotes, both as a product of transcription, and as an essential constituent of ribonucleoprotein complexes that regulate both local and global chromatin states. Here we present a proximity ligation and sequencing method called Chromatin-Associated RNA sequencing (ChAR-seq) that maps all RNA-to-DNA contacts across the genome. UsingDrosophilacells we show that ChAR-seq provides unbiased,de novo identification of targets of chromatin-bound RNAs including nascent transcripts, chromosome-specific dosage compensation ncRNAs, and genome-wide trans-associated RNAs involved in co-tran...
Source: eLife - April 12, 2018 Category: Biomedical Science Tags: Genes and Chromosomes Source Type: research

Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior
Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT...
Source: eLife - April 12, 2018 Category: Biomedical Science Tags: Cancer Biology Cell Biology Source Type: research

Retraction: A mathematical model explains saturating axon guidance responses to molecular gradients
(Source: eLife)
Source: eLife - April 12, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling
Insulin-like growth factor-I receptor (IGF-IR) preferentially regulates the long-term IGF activities including growth and metabolism. Kinetics of ligand-dependent IGF-IR endocytosis determines how IGF induces such downstream signaling outputs. Here, we find that the insulin receptor substrate (IRS) −1 modulates how long ligand-activated IGF-IR remains at the cell surface before undergoing endocytosis in mammalian cells. IRS-1 interacts with the clathrin adaptor complex AP2. IRS-1, but not an AP2-binding-deficient mutant, delays AP2-mediated IGF-IR endocytosis after the ligand stimulation. Me chanistically, IRS-1 inhi...
Source: eLife - April 11, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

The genetic landscape of a physical interaction
A key question in human genetics and evolutionary biology is how mutations in different genes combine to alter phenotypes. Efforts to systematically map genetic interactions have mostly made use of gene deletions. However, most genetic variation consists of point mutations of diverse and difficult to predict effects. Here, by developing a new sequencing-based protein interaction assay –deepPCA– we quantified the effects of>120,000 pairs of point mutations on the formation of the AP-1 transcription factor complex between the products of the FOS and JUN proto-oncogenes. Genetic interactions are abundant both i...
Source: eLife - April 11, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

Two distinct DNA sequences recognized by transcription factors represent enthalpy and entropy optima
Most transcription factors (TFs) can bind to a population of sequences closely related to a single optimal site. However, some TFs can bind to two distinct sequences that represent two local optima in the Gibbs free energy of binding ( ΔG). To determine the molecular mechanism behind this effect, we solved the structures of human HOXB13 and CDX2 bound to their two optimal DNA sequences, CAATAAA and TCGTAAA. Thermodynamic analyses by isothermal titration calorimetry revealed that both sites were bound with similar ΔG. However, th e interaction with the CAA sequence was driven by change in enthalpy (ΔH), wh...
Source: eLife - April 11, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

An efficient and scalable pipeline for epitope tagging in mammalian stem cells using Cas9 ribonucleoprotein
CRISPR/Cas9 can be used for precise genetic knock-in of epitope tags into endogenous genes, simplifying experimental analysis of protein function. However, Cas9-assisted epitope tagging in primary mammalian cell cultures is often inefficient and reliant on plasmid-based selection strategies. Here we demonstrate improved knock-in efficiencies of diverse tags (V5, 3XFLAG, Myc, HA) using co-delivery of Cas9 protein pre-complexed with two-part synthetic modified RNAs (annealed crRNA:tracrRNA) and single-stranded oligodeoxynucleotide (ssODN) repair templates. Knock-in efficiencies of ~5-30%, were achieved without selection in e...
Source: eLife - April 11, 2018 Category: Biomedical Science Tags: Cell Biology Developmental Biology and Stem Cells Source Type: research

Proprioceptive and cutaneous sensations in humans elicited by intracortical microstimulation
Pioneering work with nonhuman primates and recent human studies established intracortical microstimulation (ICMS) in primary somatosensory cortex (S1) as a method of inducing discriminable artificial sensation. However, these artificial sensations do not yet provide the breadth of cutaneous and proprioceptive percepts available through natural stimulation. In a tetraplegic human with two microelectrode arrays implanted in S1, we report replicable elicitations of sensations in both the cutaneous and proprioceptive modalities localized to the contralateral arm, dependent on both amplitude and frequency of stimulation. Furthe...
Source: eLife - April 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Dynamic representation of 3D auditory space in the midbrain of the free-flying echolocating bat
Essential to spatial orientation in the natural environment is a dynamic representation of direction and distance to objects. Despite the importance of 3D spatial localization to parse objects in the environment and to guide movement, most neurophysiological investigations of sensory mapping have been limited to studies of restrained subjects, tested with 2D, artificial stimuli. Here, we show for the first time that sensory neurons in the midbrain superior colliculus (SC) of the free-flying echolocating bat encode 3D egocentric space, and that the bat ’s inspection of objects in the physical environment sharpens tuni...
Source: eLife - April 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in < i > Drosophila < /i >
(Source: eLife)
Source: eLife - April 10, 2018 Category: Biomedical Science Tags: Cell Biology Genes and Chromosomes Source Type: research

Glutamatergic drive along the septo-temporal axis of hippocampus boosts prelimbic oscillations in the neonatal mouse
The long-range coupling within prefrontal-hippocampal networks that account for cognitive performance emerges early in life. The discontinuous hippocampal theta bursts have been proposed to drive the generation of neonatal prefrontal oscillations, yet the cellular substrate of these early interactions is still unresolved. Here, we selectively target optogenetic manipulation of glutamatergic projection neurons in the CA1 area of either dorsal or intermediate/ventral hippocampus at neonatal age to elucidate their contribution to the emergence of prefrontal oscillatory entrainment. We show that despite stronger theta and ripp...
Source: eLife - April 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Regaining the senses of touch and movement
Artificially activating neurons in the cortex can make a tetraplegic patient feel naturalistic sensations of skin pressure and arm movement. (Source: eLife)
Source: eLife - April 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Small molecule induced oligomerization, clustering and clathrin-independent endocytosis of the dopamine transporter
Clathrin-independent endocytosis (CIE) mediates internalization of many transmembrane proteins but the mechanisms of cargo recruitment during CIE are poorly understood. We found that the cell-permeable furopyrimidine AIM-100 promotes dramatic oligomerization, clustering and CIE of human and mouse dopamine transporters (DAT), but not of their close homologues, norepinephrine and serotonin transporters. All effects of AIM-100 on DAT and the occupancy of substrate binding sites in the transporter were mutually exclusive, suggesting that AIM-100 may act by binding to DAT. Surprisingly, AIM-100-induced DAT endocytosis was indep...
Source: eLife - April 9, 2018 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis
Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouringLgr5+ stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lin...
Source: eLife - April 9, 2018 Category: Biomedical Science Tags: Cell Biology Developmental Biology and Stem Cells Source Type: research

Communities creating change
Women scientists across India are working together to build and advocate for family-friendly policies at their institutes. (Source: eLife)
Source: eLife - April 9, 2018 Category: Biomedical Science Source Type: research

A population of adult satellite-like cells in < i > Drosophila < /i > is maintained through a switch in RNA-isoforms
Adult stem cells are important for tissue maintenance and repair. One key question is how such cells are specified and then protected from differentiation for a prolonged period. Investigating the maintenance ofDrosophila muscle progenitors (MPs) we demonstrate that it involves a switch inzfh1/ZEB1 RNA-isoforms. Differentiation into functional muscles is accompanied by expression ofmiR-8/miR-200, which targets the majorzfh1-long RNA isoform and decreases Zfh1 protein. Through activity of the Notch pathway, a subset of MPs produce an alternatezfh1-short isoform, which lacks themiR-8 seed site. Zfh1 protein is thus maintaine...
Source: eLife - April 9, 2018 Category: Biomedical Science Tags: Developmental Biology and Stem Cells Source Type: research

Multivalency of NDC80 in the outer kinetochore is essential to track shortening microtubules and generate forces
Presence of multiple copies of the microtubule-binding NDC80 complex is an evolutionary conserved feature of kinetochores, points of attachment of chromosomes to spindle microtubules. This may enable multivalent interactions with microtubules, with implications that remain unexplored. Using recombinant human kinetochore components, we show that while single NDC80 complexes do not track depolymerizing microtubules, reconstituted particles containing the NDC80 receptor CENP-T bound to three or more NDC80 complexes do so effectively, as expected for a kinetochore force coupler. To study multivalency systematically, we enginee...
Source: eLife - April 9, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

Research: A comprehensive and quantitative exploration of thousands of viral genomes
The complete assembly of viral genomes from metagenomic datasets (short genomic sequences gathered from environmental samples) has proven to be challenging, so there still remain significant blind spots in our view of viral genomes through the lens of metagenomics. One approach to overcoming this problem is to leverage the thousands of complete viral genomes that are publicly available. Here we describe our efforts to assemble a comprehensive resource that provides a quantitative snapshot of viral genomic trends – such as gene density, noncoding percentage, and abundances of functional gene categories – across ...
Source: eLife - April 6, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock
Segmentation of the axial skeleton in amniotes depends on the segmentation clock which patterns the paraxial mesoderm and the sclerotome. While the segmentation clock clearly operates in teleosts, the role of the sclerotome in establishing the axial skeleton is unclear. We severely disrupt zebrafish paraxial segmentation, yet observe a largely normal segmentation process of the chordacentra. We demonstrate that axialentpd5+ notochord sheath cells are responsible for chordacentrum mineralization, and serve as a marker for axial segmentation. While autonomous within the notochord sheath,entpd5 expression and centrum formatio...
Source: eLife - April 6, 2018 Category: Biomedical Science Tags: Developmental Biology and Stem Cells Source Type: research

Proteasome storage granules protect proteasomes from autophagic degradation upon carbon starvation
26S proteasome abundance is tightly regulated at multiple levels, including the elimination of excess or inactive particles by autophagy. In yeast, this proteaphagy occurs upon nitrogen starvation but not carbon starvation, which instead stimulates the rapid sequestration of proteasomes into cytoplasmic puncta termed proteasome storage granules (PSGs). Here, we show that PSGs help protect proteasomes from autophagic degradation. Both the core protease and regulatory particle sub-complexes are sequestered separately into PSGs via pathways dependent on the accessory proteins Blm10 and Spg5, respectively. Modulating PSG forma...
Source: eLife - April 6, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Age-related islet inflammation marks the proliferative decline of pancreatic beta-cells in zebrafish
The pancreatic islet, a cellular community harboring the insulin-producing beta-cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment oftnf α-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta-cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We lin...
Source: eLife - April 6, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation
Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic Homeostatic Plasticity (PHP) stabilizes neurotransmission at theDrosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We...
Source: eLife - April 5, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research