KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D
Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, e.g. in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAM...
Source: eLife - May 17, 2019 Category: Biomedical Science Tags: Cancer Biology Source Type: research

FOXP2 exhibits neuron class specific expression, but is not required for multiple aspects of cortical histogenesis
The expression patterns of the transcription factor FOXP2 in the developing mammalian forebrain have been described, and some studies have tested the role of this protein in the development and function of specific forebrain circuits by diverse methods and in multiple species. Clinically, mutations inFOXP2are associated with severe developmental speech disturbances, and molecular studies indicate that impairment ofFoxp2 may lead to dysregulation of genes involved in forebrain histogenesis. Here, anatomical and molecular phenotypes of the cortical neuron populations that express FOXP2 were characterized in mice. Additionall...
Source: eLife - May 17, 2019 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits
This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of...
Source: eLife - May 17, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis
Regulated exocytosis establishes a narrow fusion pore as initial aqueous connection to the extracellular space, through which small transmitter molecules such as ATP can exit. Co-release of polypeptides and hormones like insulin requires further expansion of the pore. There is evidence that pore expansion is regulated and can fail in diabetes and neurodegenerative disease. Here we report that the cAMP-sensor Epac2 (Rap-GEF4) controls fusion pore behavior by acutely recruiting two pore-restricting proteins, amisyn and dynamin-1, to the exocytosis site in insulin-secreting beta-cells. cAMP elevation restricts and slows fusio...
Source: eLife - May 17, 2019 Category: Biomedical Science Tags: Cell Biology Human Biology and Medicine Source Type: research

Accelerated redevelopment of vocal skills is preceded by lasting reorganization of the song motor circuitry
Complex motor skills take considerable time and practice to learn. Without continued practice the level of skill performance quickly degrades, posing a problem for the timely utilization of skilled motor behaviors. Here we quantified the recurring development of vocal motor skills and the accompanying changes in synaptic connectivity in the brain of a songbird, while manipulating skill performance by consecutively administrating and withdrawing testosterone. We demonstrate that a songbird with prior singing experience can significantly accelerate the re-acquisition of vocal performance. We further demonstrate that an incre...
Source: eLife - May 17, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons
Direct conversion of human somatic fibroblasts into induced neurons (iNs) allows for the generation of functional neurons while bypassing any stem cell intermediary stages. Although iN technology has an enormous potential for modeling age-related diseases, as well as therapeutic approaches, the technology faces limitations due to variable conversion efficiencies and a lack of thorough understanding of the signaling pathways directing iN conversion. Here, we introduce a new all-in-one inducible lentiviral system that simplifies fibroblast transgenesis for the two pioneer transcription factors, Ngn2 and Ascl1, and markedly i...
Source: eLife - May 17, 2019 Category: Biomedical Science Tags: Stem Cells and Regenerative Medicine Source Type: research

Asymmetry between the two acidic patches dictates the direction of nucleosome sliding by the ISWI chromatin remodeler
The acidic patch is a functionally important epitope on each face of the nucleosome that affects chromatin remodeling. Although related by 2-fold symmetry of the nucleosome, each acidic patch is uniquely positioned relative to a bound remodeler. An open question is whether remodelers are distinctly responsive to each acidic patch. Previously we reported a method for homogeneously producing asymmetric nucleosomes with distinct H2A/H2B dimers (Levendosky et al., 2016). Here, we use this methodology to show that the Chd1 remodeler from Saccharomyces cerevisiae and ISWI remodelers from human and Drosophila have distinct spatia...
Source: eLife - May 16, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

The < i > Plasmodium < /i > Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development
Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites,in vitro(P. cynomolgi) andin vivo (P. vivax), reveals that LISP2 expression discriminates between d...
Source: eLife - May 16, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Misfolded GPI-anchored proteins are escorted through the secretory pathway by ER-derived factors
We have used misfolded prion protein (PrP*) as a model to investigate how mammalian cells recognize and degrade misfolded GPI-anchored proteins. While most misfolded membrane proteins are degraded by proteasomes, misfolded GPI-anchored proteins are primarily degraded in lysosomes. Quantitative flow cytometry analysis showed that at least 85% of PrP* molecules transiently access the plasma membraneen route to lysosomes. Unexpectedly, time-resolved quantitative proteomics revealed a remarkably invariant PrP* interactome during its trafficking from the ER to lysosomes. Hence, PrP* arrives at the plasma membrane in complex wit...
Source: eLife - May 16, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice
Mechanisms driving the initiation of brain folding are incompletely understood. We have previously characterized mouse models recapitulating humanPIK3CA-related brain overgrowth, epilepsy, dysplastic gyrification and hydrocephalus (Roy et al., 2015). Using the same, highly regulatable brain-specific model, here we report PI3K-dependent mechanisms underlying gyrification of the normally smooth mouse cortex, and hydrocephalus. We demonstrate that a brief embryonic Pik3ca activation was sufficient to drive subtle changes in apical cell adhesion and subcellular Yap translocation, causing focal proliferation and subsequent init...
Source: eLife - May 16, 2019 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

Symmetry transitions during gating of the TRPV2 ion channel in lipid membranes
The Transient Receptor Potential Vanilloid 2 (TRPV2) channel is a member of the temperature-sensing thermoTRPV family. Recent advances in cryo-electronmicroscopy (cryo-EM) and X-ray crystallography have provided many important insights into the gating mechanisms of thermoTRPV channels. Interestingly, crystallographic studies of ligand-dependent TRPV2 gating have shown that the TRPV2 channel adopts two-fold symmetric arrangements during the gating cycle. However, it was unclear if crystal packing forces played a role in stabilizing the two-fold symmetric arrangement of the channel. Here we employ cryo-EM to elucidate the st...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Elevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockouts
Synaptophysins 1 and 2 and synaptogyrins 1 and 3 constitute a major family of synaptic vesicle membrane proteins. Unlike other widely expressed synaptic vesicle proteins such as vSNAREs and synaptotagmins, the primary function has not been resolved. Here, we report robust elevation in the probability of release of readily releasable vesicles with both high and low release probabilities at a variety of synapse types from knockout mice missing all four family members. Neither the number of readily releasable vesicles, nor the timing of recruitment to the readily releasable pool was affected. The results suggest that family m...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Silicone oil-induced ocular hypertension and glaucomatous neurodegeneration in mouse
Understanding the molecular mechanism of glaucoma and development of neuroprotectants are significantly hindered by the lack of a reliable animal model that accurately recapitulates human glaucoma. Here we sought to develop a mouse model for the secondary glaucoma that is often observed in humans after silicone oil (SO) blocks the pupil or migrates into the anterior chamber following vitreoretinal surgery. We observed significant intraocular pressure (IOP) elevation after intracameral injection of SO, and that SO removal allows IOP to return quickly to normal. This simple, inducible and reversible mouse ocular hypertension...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Reciprocal action of Casein Kinase I ε on core planar polarity proteins regulates clustering and asymmetric localisation
The conserved core planar polarity pathway is essential for coordinating polarised cell behaviours and the formation of polarised structures such as cilia and hairs. Core planar polarity proteins localise asymmetrically to opposite cell ends and form intercellular complexes that link the polarity of neighbouring cells. This asymmetric segregation is regulated by phosphorylation through poorly understood mechanisms. We show that loss of phosphorylation of the core protein Strabismus in theDrosophilapupal wing increases its stability and promotes its clustering at intercellular junctions, and that Prickle negatively regulate...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Predominance of < i > cis < /i > -regulatory changes in parallel expression divergence of sticklebacks
Regulation of gene expression is thought to play a major role in adaptation but the relative importance ofcis- andtrans- regulatory mechanisms in the early stages of adaptive divergence is unclear. Using RNAseq of threespine stickleback fish gill tissue from four independent marine-freshwater ecotype pairs and their F1 hybrids, we show thatcis-acting (allele-specific) regulation consistently predominates gene expression divergence. Genes showing parallel marine-freshwater expression divergence are found near to adaptive genomic regions, show signatures of natural selection around their transcription start sites and are enr...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Hierarchical stem cell topography splits growth and homeostatic functions in the fish gill
While lower vertebrates contain adult stem cells (aSCs) that maintain homeostasis and drive un-exhaustive organismal growth, mammalian aSCs display mainly the homeostatic function. Here we use lineage analysis in the fish gill to address aSCs and report separate stem cell populations for homeostasis and growth. These aSCs are fate-restricted during the entire post-embryonic life and even during re-generation paradigms. We use chimeric animals to demonstrate that p53 mediates growth coordination among fate-restricted aSCs, suggesting a hierarchical organisation among lineages in composite organs like the fish gill. Homeosta...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

HSV-1 single cell analysis reveals anti-viral and developmental programs activation in distinct sub-populations
Viral infection is usually studied at the population level by averaging over millions of cells. However, infection at the single-cell level is highly heterogeneous, where most infected cells give rise to none or few viral progeny while some cells produce thousands. Analysis of HSV-1 infection by population averaged measurements has taught us a lot about the course of viral infection, but has also produced contradictory results, such as the concurrent activation and inhibition of type I interferon signaling during infection. Here, we combine live-cell imaging and single-cell RNA sequencing to characterize viral and host tra...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

IFN γ induces epigenetic programming of human T-bet < sup > hi < /sup > B cells and promotesTLR7/8 and IL-21 induced differentiation
Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet drive autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNg signaling in human antibody responses is unknown. We show that elevated levels of IFNg in SLE patients correlate with expansion of the T-betexpressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that na ïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced ...
Source: eLife - May 15, 2019 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

A 3D culture model of innervated human skeletal muscle enables studies of the adult neuromuscular junction
Two-dimensional (2D) human skeletal muscle fiber cultures are ill-equipped to support the contractile properties of maturing muscle fibers. This limits their application to the study of adult human neuromuscular junction (NMJ) development, a process requiring maturation of muscle fibers in the presence of motor neuron endplates. Here we describe a three-dimensional (3D) co-culture method whereby human muscle progenitors mixed with human pluripotent stem cell-derived motor neurons self-organize to form functional NMJ connections. Functional connectivity between motor neuron endplates and muscle fibers is confirmed with calc...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Neck linker docking is critical for Kinesin-1 force generation in cells but at a cost to motor speed and processivity
Kinesin force generation involves ATP-induced docking of the neck linker (NL) along the motor core. However, the roles of the proposed steps of NL docking, cover-neck bundle (CNB) and asparagine latch (N-latch) formation, during force generation are unclear. Furthermore, the necessity of NL docking for transport of membrane-bound cargo in cells has not been tested. We generated kinesin-1 motors impaired in CNB and/or N-latch formation based on molecular dynamics simulations. The mutant motors displayed reduced force output and inability to stall in optical trap assays but exhibited increased speeds, run lengths, and landin...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Cell Biology Structural Biology and Molecular Biophysics Source Type: research

Independent amylase gene copy number bursts correlate with dietary preferences in mammals
The amylase gene (AMY), which codes for a starch-digesting enzyme in animals, underwent several gene copy number gains in humans (Perry et al., 2007), dogs (Axelsson et al., 2013), and mice (Schibler et al., 1982), possibly along with increased starch consumption during the evolution of these species. Here, we present comprehensive evidence forAMY copy number expansions that independently occurred in several mammalian species which consume diets rich in starch. We also provide correlative evidence thatAMY gene duplications may be an essential first step for amylase to be expressed in saliva. Our findings underscore the ove...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Dynamic relocalization of replication origins by Fkh1 requires execution of DDK function and Cdc45 loading at origins
Chromosomal DNA elements are organized into spatial domains within the eukaryotic nucleus. Sites undergoing DNA replication, high-level transcription, and repair of double-strand breaks coalesce into foci, although the significance and mechanisms giving rise to these dynamic structures are poorly understood. InS. cerevisiae, replication origins occupy characteristic subnuclear localizations that anticipate their initiation timing during S phase. Here, we link localization of replication origins in G1 phase with Fkh1 activity, which is required for their early replication timing. Using a Fkh1-dependent origin relocalization...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis
Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/Fc εRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Spatial control of irreversible protein aggregation
Liquid cellular compartments form in the cyto- or nucleoplasm and can regulate aberrant protein aggregation. Yet, the mechanisms by which these compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that even for weak interactions aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the ph...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

A multiplexed DNA FISH strategy for assessing genome architecture in < i > Caenorhabditis elegans < /i >
We describe a hybridization strategy that provides flexibility to DNA FISH experiments by coupling a single primary probe synthesis reaction to dye conjugated detection oligos via bridge oligos, eliminating the time and cost typically associated with labeling probe sets for individual experiments. The approach allows visualization of genome organization at varying scales in all/most cells across all stages of development in an intact animal model system. (Source: eLife)
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Of starch and spit
Animals living alongside humans have multiple copies of the gene for alpha-amylase, the enzyme that breaks down starchy foods, and high levels of this protein in their saliva. (Source: eLife)
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Painting chromosomes in the nucleus
A multiplexed approach to DNA FISH experiments has been used to visualize the three-dimensional organization of chromosomes and specific chromosomal regions inC. elegans. (Source: eLife)
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Identification of potential biomarkers of vaccine inflammation in mice
Systems vaccinology approaches have been used to successfully define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate/surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, and three agonists of TLRs with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Influenza A virus surface proteins are organized to help penetrate host mucus
Influenza A virus (IAV) enters cells by binding to sialic acid on the cell surface. To accomplish this while avoiding immobilization by sialic acid in host mucus, viruses rely on a balance between the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Although genetic aspects of this balance are well-characterized, little is known about how the spatial organization of these proteins in the viral envelope may contribute. Using site-specific fluorescent labeling and super-resolution microscopy, we show that HA and NA are asymmetrically distributed on the surface of filamentous v...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Physics of Living Systems Source Type: research

Imaging single-cell blood flow in the smallest to largest vessels in the living retina
Tissue light scatter limits the visualization of the microvascular network deep inside the living mammal. The transparency of the mammalian eye provides a noninvasive view of the microvessels of the retina, a part of the central nervous system. Despite its clarity, imperfections in the optics of the eye blur microscopic retinal capillaries, and single blood cells flowing within. This limits early evaluation of microvascular diseases that originate in capillaries. To break this barrier, we use 15 kHz adaptive optics imaging to noninvasively measure single-cell blood flow, in one of the most widely used research animals: the...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research

Increased anxiety and decreased sociability induced by paternal deprivation involve the PVN-PrL OTergic pathway
Early adverse experiences often have devastating consequences. However, whether preweaning paternal deprivation (PD) affects emotional and social behaviors and their underlying neural mechanisms remain unexplored. Using monogamous mandarin voles, we found that PD increased anxiety-like behavior and attenuated social preference in adulthood. PD also decreased the number of oxytocin (OT)-positive neurons projecting from the paraventricular nucleus (PVN) and reduced the levels of the medial prefrontal cortex OT receptor protein in females and of the OT receptor and V1a receptor proteins in males. Intra-prelimbic cortical OT i...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

A non-archaeopterygid avialan theropod from the Late Jurassic of southern Germany
The Late Jurassic ‘Solnhofen Limestones’ are famous for their exceptionally preserved fossils, including the urvogelArchaeopteryx, which has played a pivotal role in the discussion of bird origins. Here we describe a new, non-archaeopterygid avialan from the Lower Tithonian M örnsheim Formation of the Solnhofen Archipelago,Alcmonavis poeschli gen. et sp. nov. Represented by a right wing,Alcmonavis shows several derived characters, including a pronounced attachment for the pectoralis muscle, a pronounced tuberculum bicipitale radii, and a robust second manual digit, indicating that it is a more derived avia...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

A multidisciplinary approach to a unique Palaeolithic human ichnological record from Italy (B àsura Cave)
Based on the integration of laser scans, sedimentology, geochemistry, archeobotany, geometric morphometrics and photogrammetry, here we present evidence testifying that a Palaeolithic group of people explored a deep cave in northern Italy about 14 ky cal. BP. Ichnological data enable us to shed light on individual and group level behavior, social relationship, and mode of exploration of the uneven terrain. Five individuals, two adults, an adolescent and two children, entered the cave barefoot and illuminated the way with a bunch of wooden sticks. Traces of crawling locomotion are documented for the first time in the global...
Source: eLife - May 14, 2019 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

A combination of transcription factors mediates inducible interchromosomal contacts
The genome forms specific three-dimensional contacts in response to cellular or environmental conditions. However, it remains largely unknown which proteins specify and mediate such contacts. Here we describe an assay, MAP-C (Mutation Analysis in Pools by Chromosome conformation capture), that simultaneously characterizes the effects of hundreds of cis or trans-acting mutations on a chromosomal contact. Using MAP-C, we show that inducible interchromosomal pairing between HAS1pr-TDA1pr alleles in saturated cultures of Saccharomyces yeast is mediated by three transcription factors, Leu3, Sdd4 (Ypr022c), and Rgt1. The coincid...
Source: eLife - May 13, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing
Information processing by cerebellar molecular layer interneurons (MLIs) plays a crucial role in motor behavior. MLI recruitment is tightly controlled by the profile of short-term plasticity (STP) at granule cell (GC)-MLI synapses. While GCs are the most numerous neurons in the brain, STP diversity at GC-MLI synapses is poorly documented. Here, we studied how single MLIs are recruited by their distinct GC inputs during burst firing. Using slice recordings at individual GC-MLI synapses of mice, we revealed four classes of connections segregated by their STP profile. Each class differentially drives MLI recruitment. We show ...
Source: eLife - May 13, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Fast and flexible sequence induction in spiking neural networks via rapid excitability changes
Cognitive flexibility likely depends on modulation of the dynamics underlying how biological neural networks process information. While dynamics can be reshaped by gradually modifying connectivity, less is known about mechanisms operating on faster timescales. A compelling entrypoint to this problem is the observation that exploratory behaviors can rapidly cause selective hippocampal sequences to 'replay' during rest. Using a spiking network model, we asked whether simplified replay could arise from three biological components: fixed recurrent connectivity; stochastic 'gating' inputs; and rapid gating input scaling via lon...
Source: eLife - May 13, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Mapping the emerging burden of dengue
The first nationally-representative survey of dengue has revealed the growing burden of the disease in Bangladesh. (Source: eLife)
Source: eLife - May 13, 2019 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Plant-necrotroph co-transcriptome networks illuminate a metabolic battlefield
A central goal of studying host-pathogen interaction is to understand how host and pathogen manipulate each other to promote their own fitness in a pathosystem. Co-transcriptomic approaches can simultaneously analyze dual transcriptomes during infection and provide a systematic map of the cross-kingdom communication between two species. Here we used the Arabidopsis-B. cinerea pathosystem to test how plant host and fungal pathogen interact at the transcriptomic level. We assessed the impact of genetic diversity in pathogen and host by utilization of a collection of 96 isolates infection on Arabidopsis wild-type and two muta...
Source: eLife - May 13, 2019 Category: Biomedical Science Tags: Plant Biology Source Type: research

The dynamic conformational landscape of the protein methyltransferase SETD8
Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these approaches to illuminate the conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT), which functionsin vivo via the methylation of histone and nonhistone targets. Utilizing covalent inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse X-ray structures of SETD8. These structures were used to...
Source: eLife - May 13, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Self-organized reactivation maintains and reinforces memories despite synaptic turnover
Long-term memories are believed to be stored in the synapses of cortical neuronal networks. However, recent experiments report continuous creation and removal of cortical synapses, which raises the question how memories can survive on such a variable substrate. Here, we study the formation and retention of associative memory in a computational model based on Hebbian cell assemblies in the presence of both synaptic and structural plasticity. During rest periods, such as may occur during sleep, the assemblies reactivate spontaneously, reinforcing memories against ongoing synapse removal and replacement. Brief daily reactivat...
Source: eLife - May 10, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Computational mechanisms of curiosity and goal-directed exploration
We present two distinct mechanisms for goal-directed exploration that express separable profiles of active sampling to reduce uncertainty. ‘Hidden state’ exploration motivates agents to sample unambiguous observations to accurately infer the (hidden) state of the world. Conversely, ‘model parameter’ exploration, compels agents to sample outcomes associated with high uncertainty, if they are informative for their representation of the task structure. We illustrate the emergence of these types of information-gain, termed active inference and active learning, and show how these forms of exploration ind...
Source: eLife - May 10, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Sensory perception drives food avoidance through excitatory basal forebrain circuits
Appetite is driven by nutritional state, environmental cues, mood, and reward pathways. Environmental cues strongly influence feeding behavior, as they can dramatically induce or diminish the drive to consume food despite homeostatic state. Here, we have uncovered an excitatory neuronal population in the basal forebrain that is activated by food-odor related stimuli, and potently drives hypophagia. Notably, we found that the basal forebrain directly integrates environmental sensory cues to govern feeding behavior, and that basal forebrain signaling, mediated through projections to the lateral hypothalamus, promotes selecti...
Source: eLife - May 10, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus
The restricted host tropism of hepatitis C virus (HCV) remains incompletely understood, especially post-entry, and has hindered developing an immunocompetent, small animal model. HCV replication in non-permissive species may be limited by incompatibilities between the viral replication machinery and orthologs of essential host factors, like cyclophilin A (CypA). We thus compared the ability of CypA from mouse, tree shrew, and seven non-human primate species to support HCV replication, finding that murine CypA only partially rescued viral replication in Huh7.5-shRNA CypA cells. We determined the specific amino acid differen...
Source: eLife - May 10, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Critical role for piccolo in synaptic vesicle retrieval
Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to in...
Source: eLife - May 10, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Circulating transforming growth factor- β1 facilitates remyelination in the adult central nervous system
Oligodendrocyte maturation is necessary for functional regeneration in the CNS; however, the mechanisms by which the systemic environment regulates oligodendrocyte maturation is unclear. We found that Transforming growth factor (TGF)- β1, which is present in higher levels in the systemic environment, promotes oligodendrocyte maturation. Oligodendrocyte maturation was enhanced by adult mouse serum treatment via TGF-β type I receptor. Decrease in circulating TGF-β1 level prevented remyelination in the spinal cord after toxin-ind uced demyelination. TGF-β1 administration promoted remyelination and restored...
Source: eLife - May 9, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Regulatory switch at the cytoplasmic interface controls TRPV channel gating
Temperature-sensitive transient receptor potential vanilloid (thermoTRPV) channels are activated by ligands and heat, and are involved in various physiological processes. ThermoTRPV channels possess a large cytoplasmic ring consisting of N-terminal ankyrin repeat domains (ARD) and C-terminal domains (CTD). The cytoplasmic inter-protomer interface is unique and consists of a CTD coiled around a b-sheet which makes contacts with the neighboring ARD. Despite much existing evidence that the cytoplasmic ring is important for thermoTRPV function, the mechanism by which this unique structure is involved in thermoTRPV gating has n...
Source: eLife - May 9, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis
Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes...
Source: eLife - May 9, 2019 Category: Biomedical Science Tags: Genetics and Genomics Human Biology and Medicine Source Type: research

The relationship between spatial configuration and functional connectivity of brain regions revisited
In our previous paper (Bijsterbosch et al., 2018), we showed that network-based modelling of brain connectivity interacts strongly with the shape and exact location of brain regions, such that cross-subject variations in the spatial configuration of functional brain regions are being interpreted as changes in functional connectivity. Here we show that these spatial effects on connectivity estimates actually occur as a result of spatial overlap between brain networks. This is shown to systematically bias connectivity estimates obtained from group spatial ICA followed by dual regression. We introduce an extended method that ...
Source: eLife - May 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Dlg1 activates beta-catenin signaling to regulate retinal angiogenesis and the blood-retina and blood-brain barriers
Beta-catenin (i.e., canonical Wnt) signaling controls CNS angiogenesis and the blood-brain and blood-retina barriers. To explore the role of the Discs large/membrane-associated guanylate kinase (Dlg/MAGUK) family of scaffolding proteins in beta-catenin signaling, we studied vascular endothelial cell (EC)-specific knockout of Dlg1/SAP97. EC-specific loss of Dlg1 produces a retinal vascular phenotype that closely matches the phenotype associated with reduced beta-catenin signaling, synergizes with genetically-directed reductions in beta-catenin signaling components, and can be rescued by stabilizing beta-catenin in ECs. In r...
Source: eLife - May 8, 2019 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Asymmetric recruitment and actin dependent cortical flows drive the neuroblast polarity cycle
During the asymmetric divisions ofDrosophilaneuroblasts, the Par polarity complex cycles between the cytoplasm and an apical cortical domain that restricts differentiation factors to the basal cortex. We used rapid imaging of the full cell volume to uncover the dynamic steps that underlie transitions between neuroblast polarity states. Initially the Par proteins aPKC and Bazooka form discrete foci at the apical cortex. Foci grow into patches that together comprise a discontinuous, unorganized structure. Coordinated cortical flows that begin near metaphase and are dependent on the actin cytoskeleton rapidly transform the pa...
Source: eLife - May 8, 2019 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research