Hypoxia-inducible factor cell non-autonomously regulates < i > C. elegans < /i > stress responses and behavior via a nuclear receptor
The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, theC. elegansgenecyp-36A1, is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior.cyp-36A1 encodes a cytochrome P450 enzyme that we show controls e...
Source: eLife - July 16, 2018 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Synergy between the small intrinsically disordered protein Hsp12 and trehalose sustain viability after desiccation
Anhydrobiotes are rare microbes, plants and animals that tolerate severe water loss. Understanding the molecular basis for their desiccation tolerance may provide novel insights into stress biology and critical tools for engineering drought-tolerant crops. Using the anhydrobiote, budding yeast, we show that trehalose and Hsp12, a small intrinsically disordered protein (sIDP) of the hydrophilin family, synergize to mitigate completely the inviability caused by the lethal stresses of desiccation. We show that these two molecules help to stabilize the activity and prevent aggregation of model proteins bothin vivo and in vitro...
Source: eLife - July 16, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Membrane insertion of α-xenorhabdolysin in near-atomic detail
α-Xenorhabdolysins (Xax) are α-pore-forming toxins (α-PFT) that form 1-1.3 MDa large pore complexes to perforate the host cell membrane. PFTs are used by a variety of bacterial pathogens to attack host cells. Due to the lack of structural information, the molecular mechanism of action of Xax toxi ns is poorly understood. Here, we report the cryo-EM structure of the XaxAB pore complex fromXenorhabdus nematophila and the crystal structures of the soluble monomers of XaxA and XaxB. The structures reveal that XaxA and XaxB are built similarly and appear as heterodimers in the 12-15 subunits containing pore, c...
Source: eLife - July 16, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Structural Biology and Molecular Biophysics Source Type: research

Lipoate-binding proteins and specific lipoate-protein ligases in microbial sulfur oxidation reveal an atypcial role for an old cofactor
Many Bacteria and Archaea employ the heterodisulfide reductase (Hdr)-like sulfur oxidation pathway. The relevant genes are inevitably associated with genes encoding lipoate-binding proteins (LbpA). Here, deletion of the gene identified LbpA as an essential component of the Hdr-like sulfur-oxidizing system in the AlphaproteobacteriumHyphomicrobium denitrificans. Thus, a biological function was established for the universally conserved cofactor lipoate that is markedly different from its canonical roles in central metabolism. LbpAs likely function as sulfur-binding entities presenting substrate to different catalytic sites o...
Source: eLife - July 13, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Microbiology and Infectious Disease Source Type: research

Cryo-EM structure of the polycystin 2-l1 ion channel
We report the near atomic resolution (3.3 Å) of the human polycystic kidney disease 2-like 1 (polycystin 2-l1) ion channel. Encoded by PKD2L1, polycystin 2-l1 is a calcium and monovalent cation-permeant ion channel in primary cilia and plasma membranes. The related primary cilium-specific polycystin-2 protein, encoded by PKD2, shares a hig h degree of sequence similarity, yet has distinct permeability characteristics. Here we show that these differences are reflected in the architecture of polycystin 2-l1. (Source: eLife)
Source: eLife - July 13, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in theC9ORF72 (C9) gene. Previously we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al. 2016). Here we show that this signature also occurs in half of 50 post-mortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these 'like-C9...
Source: eLife - July 13, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Human Biology and Medicine Source Type: research

SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion
The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identifiedSLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role ofSlc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption ofSlc6a14 worsened the intestinal fluid secretion defect characteristic of these mice.In vitro studies of m...
Source: eLife - July 13, 2018 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size
Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T0) and liganded (R4) tetramers are stable in solution, the published MD simulations of T0 undergo a rapid quaternary transition to an R-like structure. We show that T0 is stable only when the periodic solvent box contains ten times more water molecules than the standard size for such simulations. The results suggest that such a large box is required for the hydrophobic effect, which stabilizes the T0 tetramer, to be manifested. Even in the largest box, T0 is not stable...
Source: eLife - July 12, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions
Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these hav...
Source: eLife - July 12, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic 'fusion loops'. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments (Chao et al., 2014). Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the cont...
Source: eLife - July 12, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

E-cadherin binds to desmoglein to facilitate desmosome assembly
Desmosomes are adhesive junctions composed of two desmosomal cadherins: desmocollin (Dsc) and desmoglein (Dsg). Previous studies demonstrate that E-cadherin (Ecad), an adhesive protein that interacts in bothtransandcis conformations, facilitates desmosome assembly via an unknown mechanism. Here we use structure-function analysis to resolve the mechanistic roles of Ecad in desmosome formation. Using AFM force measurements, we demonstrate that Ecad interacts with isoform 2 of Dsg via a conserved Leu-175 on the Ecadcisbinding interface. Super-resolution imaging reveals that Ecad is enriched in nascent desmosomes, supporting a...
Source: eLife - July 12, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

Embryonic hematopoiesis modulates the inflammatory response and larval hematopoiesis in < i > Drosophila < /i >
Recent lineage tracing analyses have significantly improved our understanding of immune system development and highlighted the importance of the different hematopoietic waves. The current challenge is to understand whether these waves interact and whether this affects the function of the immune system. Here we report a molecular pathway regulating the immune response and involving the communication between embryonic and larval hematopoietic waves inDrosophila. Down-regulating the transcription factor Gcm specific to embryonic hematopoiesis enhances the larval phenotypes induced by over-expressing the pro-inflammatory Jak/S...
Source: eLife - July 11, 2018 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Highly multiplexed immunofluorescence imaging of human tissues and tumors using t-CyCIF and conventional optical microscopes
We describe a tissue-based cyclic immunofluorescence (t-CyCIF) method for highly multiplexed immuno-fluorescence imaging of formalin-fixed, paraffin-embedded (FFPE) specimens mounted on glass slides, the most widely used specimens for histopathological diagnosis of cancer and other diseases. t-CyCIF generates up to 60-plex images using an iterative process (a cycle) in which conventional low-plex fluorescence images are repeatedly collected from the same sample and then assembled into a high dimensional representation. t-CyCIF requires no specialized instruments or reagents and is compatible with super-resolution imaging; ...
Source: eLife - July 11, 2018 Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research

The voice of evidence
In an era in which evidence is being disregarded, scientists need to speak up in support of the pursuit for truth. (Source: eLife)
Source: eLife - July 11, 2018 Category: Biomedical Science Source Type: research

Adaptive coding for dynamic sensory inference
Behavior relies on the ability of sensory systems to infer properties of the environment from incoming stimuli. The accuracy of inference depends on the fidelity with which behaviorally relevant properties of stimuli are encoded in neural responses. High-fidelity encodings can be metabolically costly, but low-fidelity encodings can cause errors in inference. Here, we discuss general principles that underlie the tradeoff between encoding cost and inference error. We then derive adaptive encoding schemes that dynamically navigate this tradeoff. These optimal encodings tend to increase the fidelity of the neural representatio...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Down regulation of vestibular balance stabilizing mechanisms to enable transition between motor states
The neural control of transition between posture and movement encompasses the regulation of reflex-stabilizing mechanisms to enable motion. Optimal feedback theory suggests that such transitions require the disengagement of one motor control policy before the implementation of another. To test this possibility, we investigated the continuity of the vestibular control of balance during transitions between quiet standing and locomotion and between two standing postures. Healthy subjects initiated and terminated locomotion or shifted the distribution of their weight between their feet, while exposed to electrical vestibular s...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS....
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Variations in HLA-B cell surface expression, half-life and extracellular antigen receptivity
The highly polymorphic human leukocyte antigen (HLA) class I molecules present peptide antigens to CD8+ T cells, inducing immunity against infections and cancers. Quality control mediated by peptide loading complex (PLC) components is expected to ensure the cell surface expression of stable peptide-HLA class I complexes. This is exemplified by HLA-B*08:01 in primary human lymphocytes, with both expression level and half-life at the high end of the measured HLA-B expression and stability hierarchies. Conversely, low expression on lymphocytes is measured for three HLA-B allotypes that bind peptides with proline at position 2...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

A promoter interaction map for cardiovascular disease genetics
Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), however most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin m...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Chromosomes and Gene Expression Human Biology and Medicine Source Type: research

The two shapes of the Tau protein
Tau proteins can convert from an inert shape to a misfolded shape that seeds the growth of fibers that contribute to the pathology of Alzheimer ’s disease. (Source: eLife)
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Neuroscience Source Type: research

Presenilin mutations deregulate mitochondrial Ca < sup > 2+ < /sup > homeostasis and metabolic activity causing neurodegeneration in < i > Caenorhabditis elegans < /i >
Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (PSEN1 andPSEN2) cause most cases of familial Alzheimer's disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in theC. elegans gene encoding a PSEN homolog,sel-12 result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. Insel-12 mutants, elevated endoplasmic reticulum (ER)-mitochondrial Ca2+ signaling leads to an increase in mitochondrial Ca2+ content wh...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

CYK-4 functions independently of its centralspindlin partner ZEN-4 to cellularize oocytes in germline syncytia
Throughout metazoans, germ cells undergo incomplete cytokinesis to form syncytia connected by intercellular bridges. Gamete formation ultimately requires bridge closure, yet how bridges are reactivated to close is not known. The most conserved bridge component is centralspindlin, a complex of the Rho family GTPase-activating protein (GAP) CYK-4/MgcRacGAP and the microtubule motor ZEN-4/kinesin-6. Here, we show that oocyte production by the syncytialC. elegans germline requires CYK-4 but not ZEN-4, which contrasts with cytokinesis, where both are essential. Longitudinal imaging after conditional inactivation revealed that C...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

Stem cell heterogeneity drives the parasitic life cycle of < i > Schistosoma mansoni < /i >
Schistosomes are parasitic flatworms infecting hundreds of millions of people. These parasites alternate between asexual reproduction in molluscan hosts and sexual reproduction in mammalian hosts; short-lived, water-borne stages infect each host. Thriving in such disparate environments requires remarkable developmental plasticity, manifested by five body plans deployed throughout the parasite ’s life cycle. Stem cells inSchistosoma mansoni provide a potential source for such plasticity; however, the relationship between stem cells from different life-cycle stages remains unclear, as does the origin of the germline, r...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Stem Cells and Regenerative Medicine Source Type: research

Biophysical clocks face a trade-off between internal and external noise resistance
Many organisms use free running circadian clocks to anticipate the day night cycle. However, others organisms use simple stimulus-response strategies ('hourglass clocks') and it is not clear when such strategies are sufficient or even preferable to free running clocks. Here, we find that free running clocks, such as those found in the cyanobacteriumSynechococcus elongatus and humans, can efficiently project out light intensity fluctuations due to weather patterns ('external noise') by exploiting their limit cycle attractor. However, such limit cycles are necessarily vulnerable to 'internal noise'. Hence, at sufficiently hi...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research

Characterization of developmental and molecular factors underlying release heterogeneity at < i > Drosophila < /i > synapses
Neurons communicate through neurotransmitter release at specialized synaptic regions known as active zones (AZs). Using biosensors to visualize single synaptic vesicle fusion events atDrosophila neuromuscular junctions, we analyzed the developmental and molecular determinants of release probability (Pr) for a defined connection with ~300 AZs.Pr was heterogeneous but represented a stable feature of each AZ.Prremained stable during high frequency stimulation and retained heterogeneity in mutants lacking the Ca2+ sensor Synaptotagmin 1.Pr correlated with both presynaptic Ca2+ channel abundance and Ca2+ influx at individual re...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Inert and seed-competent tau monomers suggest structural origins of aggregation
Tauopathies feature progressive accumulation of tau amyloids. Pathology may begin when these amplify from a protein template, or seed, whose structure is unknown. We have purified and characterized distinct forms of tau monomer —inert (Mi) and seed-competent (Ms). Recombinant Ms triggered intracellular tau aggregation, induced tau fibrillization in vitro, and self-assembled. Ms from Alzheimer ’s disease also seeded aggregation and self-assembled in vitro to form seed-competent multimers. We used crosslinking with mass spectrometry to probe structural differences in Mi vs. Ms. Crosslinks informed models of local...
Source: eLife - July 10, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Neuroscience Source Type: research

Removing physiological motion from intravital and clinical functional imaging data
Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmarkGalene, a versatile multi-platform software tool for image-based correction of sample motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimension...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Cell Biology Computational and Systems Biology Source Type: research

PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading
The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activi...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Engineering ER-stress dependent non-conventional mRNA splicing
The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER membrane-resident kinase/RNase Ire1 maintains ER protein homeostasis through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. InSaccharomyces cerevisiae andSchizosaccharomyces pombe, the two Ire1 functions have been evolutionarily separated. Here, we show that th...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Vertex sliding drives intercalation by radial coupling of adhesion and actomyosin networks during < i > Drosophila < /i > germband extension
Oriented cell intercalation is an essential developmental process that shapes tissue morphologies through the directional insertion of cells between their neighbors. Previous research has focused on properties of cell–cellinterfaces, while the function of tricellularvertices has remained unaddressed. Here, we identify a highly novel mechanism in which vertices demonstrate independent sliding behaviors along cell peripheries to produce the topological deformations responsible for intercalation. Through systematic analysis, we find that the motion of vertices connected by contracting interfaces is not physically couple...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Rad52-Rad51 association is essential to protect Rad51 filaments against Srs2, but facultative for filament formation
Homology search and strand exchange mediated by Rad51 nucleoprotein filaments are key steps of the homologous recombination process. In budding yeast, Rad52 is the main mediator of Rad51 filament formation, thereby playing an essential role. The current model assumes that Rad51 filament formation requires the interaction between Rad52 and Rad51. However, we report here that Rad52 mutations that disrupt this interaction do not affect γ-ray- or HO endonuclease-induced gene conversion frequencies.In vivo andin vitro studies confirmed that Rad51 filaments formation is not affected by these mutations. Instead, we found th...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

NSF-mediated disassembly of on and off-pathway SNARE complexes and inhibition by complexin
SNARE complex disassembly by the ATPase NSF is essential for neurotransmitter release and other membrane trafficking processes. We developed a single molecule FRET assay to monitor repeated rounds of NSF-mediated disassembly and reassembly of individual SNARE complexes. For ternary neuronal SNARE complexes, disassembly proceeds in a single step within 100 msec. We observed short- (
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Inferring circuit mechanisms from sparse neural recording and global perturbation in grid cells
A goal of systems neuroscience is to discover the circuit mechanisms underlying brain function. Despite experimental advances that enable circuit-wide neural recording, the problem remains open in part because solving the 'inverse problem' of inferring circuity and mechanism by merely observing activity is hard. In the grid cell system, we show through modeling that a technique based on global circuit perturbation and examination of a novel theoretical object calleddistribution of relative phase shifts (DRPS) the could reveal the mechanisms of a cortical circuit at unprecedented detail using extremely sparse neural recordi...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

JNK signaling triggers spermatogonial dedifferentiation during chronic stress to maintain the germline stem cell pool in the < i > Drosophila < /i > testis
Exhaustion of stem cells is a hallmark of aging. In theDrosophila testis, dedifferentiated germline stem cells (GSCs) derived from spermatogonia increases during lifespan, leading to the model that dedifferentiation counteracts the decline of GSCs in aged males. To test this, we blocked dedifferentiation by mis-expressing the differentiation factorbag of marbles (bam) in spermatogonia while lineage-labeling these cells. Strikingly, blockingbam-lineage dedifferentiation under normal conditions in virgin males has no impact on the GSC pool. However, in mated males or challenging conditions, inhibitingbam-lineage dedifferenti...
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Shining light on spindle positioning
Optogenetic approaches are leading to a better understanding of the forces that determine the plane of cell division. (Source: eLife)
Source: eLife - July 9, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

An automated high-resolution < i > in vivo < /i > screen in zebrafish to identify chemical regulators of myelination
Myelinating oligodendrocytes are essential for central nervous system (CNS) formation and function. Their disruption is implicated in numerous neurodevelopmental, neuropsychiatric and neurodegenerative disorders. However, recent studies have indicated that oligodendrocytes may be tractable for treatment of disease. In recent years, zebrafish have become well established for the study of myelinating oligodendrocyte biology and drug discoveryin vivo. Here, by automating the delivery of zebrafish larvae to a spinning disk confocal microscope, we were able to automate high-resolution imaging of myelinating oligodendrocytesin v...
Source: eLife - July 6, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: Membranes, Energetics, and Evolution Across the Prokaryote-Eukaryote Divide
(Source: eLife)
Source: eLife - July 5, 2018 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Timing of ESCRT-III protein recruitment and membrane scission during HIV-1 assembly
The Endosomal Sorting Complexes Required for Transport III (ESCRT-III) proteins are critical for cellular membrane scission processes with topologies inverted relative to clathrin-mediated endocytosis. Some viruses appropriate ESCRT-IIIs for their release. By imaging single assembling viral-like particles of HIV-1, we observed that ESCRT-IIIs and the ATPase VPS4 arrive after most of the virion membrane is bent, linger for tens of seconds, and depart ~20 seconds before scission. These observations suggest ESCRT-IIIs are recruited by a combination of membrane curvature and the late domains of the HIV-1 Gag protein. ESCRT-III...
Source: eLife - July 4, 2018 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Multiple inputs ensure yeast cell size homeostasis during cell cycle progression
Coordination of cell growth with division is essential for proper cell function. In budding yeast, although some molecular mechanisms responsible for cell size control during G1 have been elucidated, the mechanism by which cell size homeostasis is established remains to be discovered. Here, we developed a new technique based on quantification of histone levels to monitor cell cycle progression in individual cells with unprecedented accuracy. Our analysis establishes the existence of a mechanism controlling bud size in G2/M that prevents premature onset of anaphase, and controls the overall size variability. While most G1 m...
Source: eLife - July 4, 2018 Category: Biomedical Science Tags: Cell Biology Computational and Systems Biology Source Type: research

Loss of < i > Atoh1 < /i > from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice
Atoh1-null mice die at birth from respiratory failure, but the precise cause has remained elusive. Loss ofAtoh1 from various components of the respiratory circuitry (e.g., the retrotrapezoid nucleus (RTN)) have so far produced at most 50% neonatal lethality. To identify otherAtoh1-lineage neurons that contribute to postnatal survival, we examined parabrachial complex neurons derived from the rostral rhombic lip (rRL) and found that they are activated during respiratory chemochallenges.Atoh1-deletion from the rRL does not affect survival, but causes apneas and respiratory depression during hypoxia, likely due to loss of pro...
Source: eLife - July 4, 2018 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

A multispecies coalescent model for quantitative traits
We present a multispecies coalescent model for quantitative traits that allows for evolutionary inferences at micro- and macroevolutionary scales. A major advantage of this model is its ability to incorporate genealogical discordance underlying a quantitative trait. We show that discordance causes a decrease in the expected trait covariance between more closely related species relative to more distantly related species. If unaccounted for, this outcome can lead to an overestimation of a trait's evolutionary rate, to a decrease in its phylogenetic signal, and to errors when examining shifts in mean trait values. The number ...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Single-color, ratiometric biosensors for detecting signaling activities in live cells
Genetically encoded fluorescent biosensors have revolutionized the study of signal transduction by enabling the real-time tracking of signaling activities in live cells. Investigating the interaction between signaling networks has become increasingly important to understanding complex cellular phenomena, necessitating an update of the biosensor toolkit to allow monitoring and perturbing multiple activities simultaneously in the same cell. We therefore developed a new class of fluorescent biosensors based on homo-FRET, deemed FLuorescence Anisotropy REporters (FLAREs), which combine the multiplexing ability of single-color ...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Recurrent network model for learning goal-directed sequences through reverse replay
Reverse replay of hippocampal place cells occurs frequently at rewarded locations, suggesting its contribution to goal-directed path learning. Symmetric spike-timing dependent plasticity (STDP) in CA3 likely potentiates recurrent synapses for both forward (start to goal) and reverse (goal to start) replays during sequential activation of place cells. However, how reverse replay selectively strengthens forward synaptic pathway is unclear. Here, we show computationally that firing sequences bias synaptic transmissions to the opposite direction of propagation under symmetric STDP in the co-presence of short-term synaptic depr...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury
Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK;Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking ...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

We are not so special
New sequence data from choanoflagellates improves our understanding of the genetic changes that occurred along the branch of the evolutionary tree that gave rise to animals. (Source: eLife)
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Cryo-EM structure of alpha-synuclein fibrils
Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy structure at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Neuroscience Structural Biology and Molecular Biophysics Source Type: research

Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase
A fundamental issue in developmental biology and in organ homeostasis is understanding the molecular mechanisms governing the balance between stem cell maintenance and differentiation into a specific lineage. Accumulating data suggest that cell cycle dynamics play a major role in the regulation of this balance. Here we show that the G2/M cell cycle regulator CDC25B phosphatase is required in mammals to finely tune neuronal production in the neural tube. We show that in chick neural progenitors, CDC25B activity favors fast nuclei departure from the apical surface in early G1, stimulates neurogenic divisions and promotes neu...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Structural basis of malodour precursor transport in the human axilla
Mammals produce volatile odours that convey different types of societal information. InHomo sapiens, this is now recognised as body odour, a key chemical component of which is the sulphurous thioalcohol, 3-methyl-3-sulfanylhexan-1-ol (3M3SH). Volatile 3M3SH is produced in the underarm as a result of specific microbial activity, which act on the odourless dipeptide-containing malodour precursor molecule, S-Cys-Gly-3M3SH, secreted in the axilla (underarm) during colonisation. The mechanism by which these bacteria recognise S-Cys-Gly-3M3SH and produce body odour is still poorly understood. Here we report the structural and bi...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Structural Biology and Molecular Biophysics Source Type: research

Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis
Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis; however, pathologic changes in extracellular matrix (ECM) that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue, we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with ...
Source: eLife - July 3, 2018 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

A positive feedback-based mechanism for constriction rate acceleration during cytokinesis in < i > C. elegans < /i >
To ensure timely cytokinesis, the equatorial actomyosin contractile ring constricts at a relatively constant rate despite its progressively decreasing size. Thus, the per-unit-length constriction rate increases as ring perimeter decreases. To understand this acceleration, we monitored cortical surface and ring component dynamics during the first cytokinesis of theC. elegans embryo. We found that, per-unit-length, the amount of ring components (myosin, anillin) and the constriction rate increase with parallel exponential kinetics. Quantitative analysis of cortical flow indicated that the cortex within the ring is compressed...
Source: eLife - July 2, 2018 Category: Biomedical Science Tags: Cell Biology Computational and Systems Biology Source Type: research