bluuebunny/crossref_metadata_2025_split huggingface dataset:
The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores
Authors: Wu Zhenyong , Dharan Nadiv , McDargh Zachary A. , Thiyagarajan Sathish , O’Shaughnessy Ben , Karatekin Erdem 
Published: May 2019

ABSTRACTAll membrane fusion reactions proceed through an initial fusion pore, including calcium-triggered release of neurotransmitters and hormones. Expansion of this small pore to release cargo is energetically costly and regulated by cells, but the mechanisms are poorly understood. Here we show that the neuronal/exocytic calcium sensor Synaptotagmin-1 (Syt1) promotes expansion of fusion pores induced by SNARE proteins. Pore dilation relied on calcium-induced insertion of the tandem C2 domain hydrophobic loops of Syt1 into the membrane, previously shown to reorient the C2 domain. Mathematical modelling suggests that C2B reorientation rotates a bound SNARE complex so that it exerts force on the membranes in a mechanical lever action that increases the height of the fusion pore, provoking pore dilation to offset the bending energy penalty. We conclude that Syt1 exerts novel non-local calcium-dependent mechanical forces on fusion pores that dilate pores and assist neurotransmitter and hormone release.SIGNIFICANCE STATEMENTDuring neurotransmitter release, calcium-induced membrane insertion of the C2B domain of Synaptotagmin re-orients the bound SNARE complex which dilates the fusion pore in a mechanical lever action.
The Catalytic Core of DEMETER Guides Active DNA Demethylation in Arabidopsis
Authors: Zhang Changqing , Hung Yu-Hung , Zhang Xiang-Qian , Zhang Dapeng , Frost Jennifer M. , Liu Fang , Xiao Wenyan , Iyer Lakshminarayan M. , Aravind L. , Huh Jin Hoe , Fischer Robert L. , Hsieh Tzung-Fu 
Published: May 2019

AbstractThe Arabidopsis DEMETER (DME) DNA glycosylase demethylates the maternal genome in the central cell prior to fertilization, and is essential for seed viability. DME preferentially targets small transposons that flank coding genes, influencing their expression and initiating plant gene imprinting. DME also targets intergenic and heterochromatic regions, and how it is recruited to these differing chromatin landscapes is unknown. The C-terminal DME catalytic core consists of three conserved regions required for catalysis in vitro. We show that the catalytic core of DME guides active demethylation at endogenous targets, rescuing the developmental and genomic hypermethylation phenotypes of DME mutants. However, without the N-terminus, heterochromatin demethylation is significantly impeded, and abundant CG-methylated genic sequences are ectopically demethylated. We used comparative analysis to reveal that the conserved DME N-terminal domains are only present in the flowering plants, whereas the domain architecture of DME-like proteins in non-vascular plants mainly resembles the catalytic core, suggesting that it might represent the ancestral form of the 5mC DNA glycosylase found in all plant lineages. We propose a bipartite model for DME protein action and suggest that the DME N-terminus was acquired late during land plant evolution to improve specificity and facilitate demethylation at heterochromatin targets.
Tractostorm: Rater reproducibility assessment in tractography dissection of the pyramidal tract
Authors: Rheault Francois , De Benedictis Alessandro , Daducci Alessandro , Maffei Chiara , Tax Chantal M.W , Romascano David , Caverzasi Eduardo , Morency Felix C. , Corrivetti Francesco , Pestilli Franco , Girard Gabriel , Theaud Guillaume , Zemmoura Ilyess , Hau Janice , Glavin Kelly , Jordan Kesshi M. , Pomiecko Kristofer , Chamberland Maxime , Barakovic Muhamed , Goyette Nil , Poulin Philippe , Chenot Quentin , Panesar Sandip S. , Sarubbo Silvio , Petit Laurent , Descoteaux Maxime 
Published: May 2019

AbstractInvestigative studies of white matter (WM) brain structures using diffusion MRI (dMRI) tractography frequently require manual WM bundle segmentation, often called “virtual dissection”. Human errors and personal decisions make these manual segmentations hard to reproduce, which have not yet been quantified by the dMRI community. The contribution of this study is to provide the first large-scale, international, multi-center variability assessment of the “virtual dissection” of the pyramidal tract (PyT). Eleven (11) experts and thirteen (13) non-experts in neuroanatomy and “virtual dissection” were asked to perform 30 PyT segmentation and their results were compared using various voxel-wise and streamline-wise measures. Overall the voxel representation is always more reproducible than streamlines (≈70% and ≈35% overlap respectively) and distances between segmentations are also lower for voxel-wise than streamline-wise measures (¾3mm and ¾ûmm respectively). This needs to be seriously considered before using tract-based measures (e.g. bundle volume versus streamline count) for an analysis. We show and argue that future bundle segmentation protocols need to be designed to be more robust to human subjectivity. Coordinated efforts by the diffusion MRI tractography community are needed to quantify and account for reproducibility of WM bundle extraction techniques in this era of open and collaborative science.
Developmental exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) selectively decreases brain dopamine levels in northern leopard frogs
Authors: Foguth Rachel M. , Flynn R. Wesley , de Perre Chloe , Iacchetta Michael , Lee Linda S. , Sepúlveda Maria S. , Cannon Jason R. 
Published: May 2019

AbstractPer- and polyfluoroalkyl substances (PFAS) are synthetic compounds that are a major public health concern due to widespread use, long environmental and biological half-lives, detection in most human plasma samples, and links to multiple adverse health outcomes. The literature suggests that some PFAS may be neurotoxic. However, there are major gaps in the literature with respect to how environmentally-relevant doses during development may influence the nervous system. To address this gap, we utilized a sentinel species, Northern leopard frogs (Lithobates pipiens) to determine the effects of developmental exposure to environmentally relevant perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on major neurotransmitter systems. Frog larvae at Gosner stage 25 were exposed to 10, 100, or 1000 ppb PFOS or PFOA for 30 days before neurochemical analysis. High performance liquid chromatography (HPLC) with electrochemical detection or fluorescent detection assays was used to measure neurotransmitter levels, which were normalized to protein levels in each sample. Dopamine (DA) decreased significantly in the brains of frogs treated with PFOA (1000 ppb) and PFOS (100 and 1000 ppb). Significant increases in DA turnover also resulted from PFOA and PFOS treatment. Neither PFOS, nor PFOA produced detectable alterations in serotonin (nor its metabolite), norepinephrine, gamma-amino butyric acid (GABA), glutamate, or acetylcholine. PFAS body burdens showed that PFOS accumulated relative to dose, while PFOA did not. These data suggest that DArgic neurotransmission is selectively affected in developmentally exposed amphibians and that PFAS should be evaluated for a potential role in diseases that target the DA system.
Comparison of vibrotactile and joint-torque feedback in a myoelectric upper-limb prosthesis
Authors: Thomas Neha , Ung Garrett , McGarvey Colette , Brown Jeremy D. 
Published: May 2019

AbstractBackgroundDespite the technological advancements in myoelectric prostheses, body-powered prostheses remain a popular choice for amputees, in part due to the natural sensory advantage they provide. Research on haptic feedback in myoelectric prostheses has delivered mixed results. Furthermore, there is limited research comparing various haptic feedback modalities in myoelectric prostheses. In this paper, we present a comparison of the feedback intrinsically present in body-powered prostheses (joint-torque feedback) to a commonly proposed feedback modality for myoelectric prostheses (vibrotactile feedback). In so doing, we seek to understand whether the advantages of kinesthetic feedback present in body-powered prostheses translate to myoelectric prostheses, and whether there are differences between kinesthetic and cutaneous feedback in prosthetic applications.MethodsWe developed an experimental testbed that features a cable-driven, voluntary-closing 1-DoF prosthesis, a capstan-driven elbow exoskeleton, and a vibrotactile actuation unit. The system can present grip force to users as either a flexion moment about the elbow or vibration on the wrist. To provide an equal comparison of joint-torque and vibrotactile feedback, a stimulus intensity matching scheme was utilized. Non-amputee participants (n=12) were asked to discriminate objects of varying stiffness with the prosthesis in three conditions: no haptic feedback, vibrotactile feedback, and joint-torque feedback.ResultsResults indicate that haptic feedback increased discrimination accuracy over no haptic feedback, but the difference between joint-torque feedback and vibrotactile feedback was not significant. In addition, our results highlight nuanced differences in performance depending on the objects’ stiffness, and suggest that participants likely pay less attention to incidental cues with the addition of haptic feedback.ConclusionEven when haptic feedback is not modality matched to the task, such as in the case of vibrotactile feedback, performance with a myoelectric prosthesis can improve significantly. This implies it is possible to achieve the same benefits with vibrotactile feedback, which is cheaper and easier to implement than other forms of feedback.
Direct monitoring of cAMP at the cardiac ryanodine receptor using a novel targeted fluorescence biosensor mouse
Authors: Berisha Filip , Götz Konrad R. , Wegener Jörg W. , Jungen Christiane , Pape Ulrike , Kraft Axel E. , Warnke Svenja , Lindner Diana , Westermann Dirk , Blankenberg Stefan , Meyer Christian , Hasenfuß Gerd , Lehnart Stephan E. , Nikolaev Viacheslav O. 
Published: May 2019

AbstractRationaleCyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which, upon β-adrenergic receptor (β-AR) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating the cAMP-dependent protein kinase (PKA) phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac ryanodine receptor type 2 (RyR2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum (SR) often occurring upon RyR2 hyperphosphorylation by PKA and calcium/calmodulin-dependent kinase.ObjectiveWe sought to establish a real time approach capable of directly visualizing cAMP and its pathological changes in the vicinity of RyR2 by generating a proper targeted biosensor and transgenic mouse model to express it in adult cardiomyocytes.Methods and ResultsWe generated transgenic mice expressing a novel targeted fluorescent biosensor for RyR2-associated cAMP in adult mouse cardiomyocytes. In healthy cardiomyocytes, β1-AR but not β2-AR stimulation strongly increased local RyR2-associated cAMP levels. However, in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of phosphodiesterases (PDEs) 2, 3 and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurable β2-AR-induced cAMP signals, increased SR calcium leak and arrhythmia susceptibility.ConclusionsOur new targeted biosensor expressed in transgenic mice can visualize cAMP levels in the vicinity of cardiac RyR2 in healthy and diseased cardiomyocytes. In the future, this novel biosensor can be used to better understand alterations of RyR2-associated cAMP in cardiovascular diseases and local actions of new therapies.
The effect of phosphatidylserine on the membrane insertion of the cancer-targeting ATRAM peptide is defined by the non-inserting end
Authors: Nguyen V. P. , Dixson A. C. , Barrera F. N. 
Published: May 2019

AbstractThe acidity-triggered rational membrane (ATRAM) peptide was designed to target acidic diseases such as cancer. An acidic extracellular medium, such as that found in aggressive tumors, drives the protonation of the glutamic acids in ATRAM, leading to the membrane translocation of its C-terminus and the formation of a transmembrane helix. Compared to healthy cells, cancerous cells often increase exposure of the negatively charged phosphatidylserine (PS) on the outer leaflet of the plasma membrane. Here we use a reconstituted vesicle system to explore how phosphatidylserine influences the interaction of ATRAM with membranes. To explore this, we used two new variants of ATRAM, termed K2-ATRAM and Y-ATRAM, with small modifications at the non-inserting N-terminus. We observed that the effect of PS on the membrane insertion pK and lipid partitioning hinged on the sequence of the non-inserting end. Our data additionally indicate that the effect of PS on the insertion pK does not merely depend on electrostatics, but it is multifactorial. Here we show how small sequence changes can impact the interaction of a peptide with membranes of mixed lipid composition. These data illustrate how model studies using neutral bilayers, which do not mimic the negative charge found in the plasma membrane of cancer cells, may fail to capture important aspects of the interaction of anticancer peptides with tumor cells. This information can guide the design of therapeutic peptides that target the acidic environments of different diseased tissues.Statement of SignificanceCurrent targeted therapies for cancer have limited success due to drug resistance. Resistance often arises after mutation of the receptor being targeted. A more general target is needed to prevent drug resistance. Most aggressive solid tumors have an extracellular medium. We propose that extracellular acidity is promising for improved targeted therapies. The acidity-triggered rational membrane (ATRAM) inserts in membranes only under acidic conditions. However, it is now known how the lipid changes that occur in the plasma membrane of cancer cells impact the membrane insertion of ATRAM. Here we perform biophysical experiments that show that PS, a lipid exposed in the cancer cell, can impact the membrane insertion of ATRAM. We also uncovered a region of the peptide important for insertion.
Genome-scale comparative analysis for host resistance against sea lice between Atlantic salmon and rainbow trout
Authors: Cáceres Pablo , Barría Agustín , Christensen Kris A. , Bassini Liane N. , Correa Katharina , Lhorente Jean P. , Yáñez José M. 
Published: May 2019

AbstractSea lice (Caligus rogercresseyi) are ectoparasites that cause major production losses in the salmon aquaculture industry worldwide. Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) are two of the most susceptible salmonid species to sea lice infestation. The goal of this study was to identify common candidate genes involved in resistance against sea lice. For this, 2,626 Atlantic salmon and 2,643 rainbow trout from breeding populations were challenged with sea lice and genotyped with a 50k and 57k SNP panel. We ran two independent genome-wide association studies for sea lice resistance on each species and identified 7 and 13 windows explaining 3% and 2.7% respectively the genetic variance. Heritabilities were observed with values of 0.19 for salmon and 0.08 for trout. We identified genes associated with immune responses, cytoskeletal factors and cell migration. We found 15 orthogroups which allowed us to identifydust8anddust10as candidate genes in orthogroup 13. This suggests that similar mechanisms can regulate resistance in different species; however, they most likely do not share the same standing variation within the genomic regions and genes that regulate resistance. Our results provide further knowledge and may help establish better control for sea lice in fish populations.
Reconstructing Phylogenetic Relationships Based on Repeat Sequence Similarities
Authors: Vitales Daniel , Garcia Sònia , Dodsworth Steven 
Published: May 2019

AbstractA recent phylogenetic method based on genome-wide abundance of different repeat types proved to be useful in reconstructing the evolutionary history of several plant and animal groups. Here, we demonstrate that an alternative information source from the repeatome can also be employed to infer phylogenetic relationships among taxa. Specifically, this novel approach makes use of the repeat sequence similarity matrices obtained from the comparative clustering analyses of RepeatExplorer 2, which are subsequently transformed to between-taxa distance matrices. These pairwise matrices are used to construct neighbour-joining trees for each of the top most-abundant clusters and they are finally summarized in a consensus network. This methodology was tested on three groups of angiosperms and one group of insects, resulting in congruent evolutionary hypotheses compared to more standard systematic analyses based on commonly used DNA markers. We propose that the combined application of these phylogenetic approaches based on repeat abundances and repeat sequence similarities could be helpful to understand mechanisms governing genome and repeatome evolution.
Introgressed Manihot glaziovii Alleles in Modern Cassava Germplasm Benefit Important Traits and Are Under Balancing Selection
Authors: Wolfe Marnin D. , Bauchet Guillaume J. , Chan Ariel W. , Lozano Roberto , Ramu Punna , Egesi Chiedozie , Kawuki Robert , Kulakow Peter , Rabbi Ismail , Jannink Jean-Luc 
Published: May 2019

1.AbstractIntrogression of alleles from wild relatives has often been adaptive, usually for disease resistance, in plant breeding. However, the significance of historical hybridization events in modern breeding is often not clear. Cassava (Manihot esculenta) is among the most important staple foods in the world, sustaining hundreds of millions of people in the tropics, especially in sub-Saharan Africa. Widespread genotyping makes cassava a model for clonally-propagated root and tuber crops in the developing world and provides an opportunity to study the modern benefits and consequences of historical introgression. We detected large introgressed M. glaziovii genome-segments in a collection of 2742 modern cassava landraces and elite germplasm, the legacy of 1930’s era breeding to combat epidemics disease. African landraces and improved varieties were on average 3.8% (max 13.6%) introgressed. Introgressions accounted for significant (mean 20%, max 56%) portion of the heritability of tested traits M. glaziovii alleles on the distal 10Mb of chr. 1 increased dry matter and root number. On chr. 4, introgressed alleles in a 20Mb region improved harvest index and brown streak disease tolerance. Three cycles of selection initially doubled the introgression frequency on chr. 1. Later stage variety trials selectively excluded homozygotes which indicates a heterozygous advantage. We show that maintaining large recombination-suppressed introgressions in the heterozygous state allows the accumulation of deleterious mutations. We conclude that targeted recombination of introgression segments would therefore increase the efficiency of cassava breeding by allowing simultaneous fixation of beneficial alleles and purging of genetic load.Significance StatementCrosses to wild relatives have often been adaptive for crop breeding, but their modern importance is usually poorly understood. Cassava (Manihot esculenta) is an important staple crop, feeding hundreds of millions in the developing world, and is a model for vegetatively-propagated non-inbred crops. In the 1930’s, crossing to M. glaziovii averted mosaic disease epidemic in Africa. We reveal that large genome segments, the legacy of those crosses, benefit a number of traits including yield in modern cassava and are consistently favored during selection. Elite cultivars are almost exclusively heterozygous for wild alleles; homozygotes are rejected during early stage trials, suggesting inbreeding depression. More recombination around beneficial wild alleles will allow purging of genetic load and increase genetic gain in cassava.
A role for phagocytosis in inducing cell death during thymocyte negative selection
Authors: Kurd Nadia S. , Lutes Lydia K. , Yoon Jaewon , Dzhagalov Ivan L. , Hoover Ashley , Robey Ellen A. 
Published: May 2019

AbstractAutoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, we demonstrate that phagocytosis promotes negative selection, and that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a two-step model for negative selection in which thymocytes initiate the death process following strong TCR signaling, but ultimately depend upon phagocytosis for their timely death. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.
F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes
Authors: van Bommel Bas , Konietzny Anja , Kobler Oliver , Bär Julia , Mikhaylova Marina 
Published: May 2019

AbstractOrganelle positioning within neurites is required for proper neuronal function. In dendrites with their complex cytoskeletal organization, transport of organelles is guided by local specializations of the microtubule and actin cytoskeleton, and by coordinated activity of different motor proteins. Here, we focus on the actin cytoskeleton in the dendritic shaft and describe dense structures consisting of longitudinal and branched actin filaments. These actin patches are devoid of microtubules and are frequently located at the base of spines, or form an actin mesh around excitatory shaft synapses. Using lysosomes as an example, we demonstrate that the presence of actin patches has a strong impact on dendritic organelle transport, as lysosomes frequently stall at these locations. We provide mechanistic insights on this pausing behavior, demonstrating that actin patches form a physical barrier for kinesin-driven cargo. In addition, we identify myosin Va as an active tether which mediates long-term stalling. This correlation between the presence of actin meshes and halting of organelles could be a generalized principle by which synapses control organelle trafficking.