bluuebunny/crossref_metadata_2025_split huggingface dataset:
How thermophilic Gram-positive organisms perform extracellular electron transfer: characterization of the cell surface terminal reductase OcwA
Authors: Costa N.L. , Hermann B. , Fourmond V. , Faustino M. , Teixeira M. , Einsle O. , Paquete C.M. , Louro R.O. 
Published: May 2019

AbstractExtracellular electron transfer is the key process underpinning the development of bioelectrochemical systems for the production of energy or added-value compounds. Thermincola potens JR is a promising Gram-positive bacterium to be used in these systems because it is thermophilic. In this paper we describe the structural and functional properties of the nonaheme cytochrome OcwA, which is the terminal reductase of this organism. The structure of OcwA, determined at 2.2Å resolution shows that the overall-fold and organization of the hemes are not related to other metal reductases and instead are similar to that of multiheme cytochromes involved in the biogeochemical cycles of nitrogen and sulfur. We show that, in addition to solid electron acceptors, OcwA can also reduce soluble electron shuttles and oxyanions. These data reveal that OcwA can take the role of a respiratory ‘swiss-army knife’ allowing this organism to grow in environments with rapidly changing availability of terminal electron acceptors without the need for transcriptional regulation and protein synthesis.ImportanceThermophilic Gram-positive organisms were recently shown to be a promising class of organisms to be used in bioelectrochemical systems for the production of electrical energy. These organisms present a thick peptidoglycan layer that was thought to preclude them to perform extracellular electron transfer (i.e. exchange catabolic electrons with solid electron acceptors outside of the cell). In this manuscript we describe the structure and functional mechanisms of the multiheme cytochrome OcwA, the terminal reductase of the Gram-positive bacterium Thermincola potens JR found at the cell surface of this organism. The results presented here show that this protein is unrelated with terminal reductases found at the cell surface of other electroactive organisms. Instead, OcwA is similar to terminal reductases of soluble electron acceptors. Our data reveals that terminal oxidoreductases of soluble and insoluble substrates are evolutionarily related, providing novel insights into the evolutionary pathway of multiheme cytochromes.
Aversive Learning Increases Release Probability of Olfactory Sensory Neurons
Authors: Bhattarai Janardhan P. , Schreck Mary , Moberly Andrew H. , Luo Wenqin , Ma Minghong 
Published: May 2019

AbstractPredicting danger from previously associated sensory stimuli is essential for survival. Contributions from altered peripheral sensory inputs are implicated in this process, but the underlying mechanisms remain elusive. Here we use the mammalian olfactory system to investigate such mechanisms. Primary olfactory sensory neurons (OSNs) project their axons directly to the olfactory bulb (OB) glomeruli where their synaptic release is subject to local and cortical influence and neuromodulation. Pairing optogenetic activation of a single glomerulus with foot shock in mice induces freezing to the light stimulation alone during fear retrieval. This is accompanied by an increase in OSN release probability and a reduction in GABAB receptor expression in the conditioned glomerulus. Furthermore, freezing time is positively correlated with the release probability of OSNs in fear conditioned mice. These results suggest that aversive learning increases peripheral olfactory inputs at the first synapse, which may contribute to the behavioral outcome.
Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
Authors: Psaila Bethan , Wang Guanlin , Meira Alba Rodriguez , Heuston Elisabeth F. , Li Rong , O’Sullivan Jennifer , Sousos Nikolaos , Anderson Stacie , Senis Yotis , Weinberg Olga K. , Calicchio Monica L. ,   NIH Intramural Sequencing Center, Iskander Deena , Royston Daniel , Milojkovic Dragana , Roberts Irene , Bodine David M. , Thongjuea Supat , Mead Adam J. 
Published: May 2019

SummaryMyelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,538 hematopoietic stem/progenitor cells (HSPCs), single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed byJAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the immunoglobulin receptor G6B as a promisingJAK2-mutant clone-specific antigen warranting further development as an immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
Categorical Assignment of Pulmonary Embolism is a Simple and More Accurate Indicator of Right Ventricular Dysfunction and Short Team Mortality
Authors: Chen Yu Lin , Wright Colin , Pietropaoli Anthony P. , Elbadawi Ayman , Delehanty Joseph , Barrus Bryan , Gosev Igor , Trawick David , Patel Dhwani , Cameron Scott J. 
Published: May 2019

AbstractSeveral risk stratification tools are available to predict short-term mortality in patients with acute pulmonary embolism (PE). Right ventricular (RV) dysfunction, which is common to intermediate and high risk PE, is an independent predictor of mortality and may be a faster and simpler way to assess patient risk in acute care settings. We evaluated 571 patients presenting with acute PE as the primary diagnosis, stratifying them by the Pulmonary Embolism Severity Index (PESI), by the BOVA score, orcategoricallyas low risk (no RV dysfunction by imaging), intermediate risk (RV dysfunction by imaging), or high risk PE (RV dysfunction by imaging with sustained hypotension). Using imaging data to firstly define the presence of RV dysfunction, and plasma cardiac troponin T (cTnT) and NT-proBNP as additional evidence for myocardial strain, we evaluated the PESI and BOVA scoring systems compared to categorical assignment of PE as low risk, submassive, and massive PE. Cardiac biomarkers poorly distinguished between PESI classes and BOVA stages in patients with acute PE. Cardiac TnT and NT-proBNP easily distinguished low risk from submassive PE with an area under the curve (AUC) of 0.84 (95% C.I. 0.73 – 0.95, p< 0.0001), and 0.88 (95% C.I. 0.79-0.97, p< 0.0001), respectively, and low risk from massive PE with an area under the curve (AUC) of 0.89 (95% C.I. 0.78 – 1.00, p< 0.0001), and 0.89 (95% C.I. 0.82-0.95, p< 0.0001), respectively. Predicted short-term mortality by PESI score or BOVA stage was lower than the observed mortality for submassive PE by a two-fold order of magnitude. These data suggest the presence of RV dysfunction in the context of acute PE is sufficient for the purposes of risk stratification, while more complicated risk stratification algorithms may under-estimate short-term mortality risk.
TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain
Authors: Nguyen Huynh TH , Wood Rhiannon J , Prawdiuk Alexa R , Furness Sebastian GB , Xiao Junhua , Murray Simon S , Fletcher Jessica L 
Published: May 2019

AbstractThe neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in the cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after one-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.
Interactions between motor thalamic field potentials and single unit spiking predict behavior in rats
Authors: Gaidica Matt , Hurst Amy , Cyr Christopher , Leventhal Daniel K. 
Published: May 2019

AbstractThe thalamus plays a central role in generating circuit-level neural oscillations believed to coordinate brain activity over large spatiotemporal scales. Such thalamic influences are well-documented for sleep rhythms and in sensory systems, but the relationship between thalamic activity, motor circuit local field potential (LFP) oscillations, and behavior is unknown. We recorded wideband motor thalamic (Mthal) electrophysiology as healthy rats performed a two-alternative forced choice task. The power of delta (1−4 Hz), beta (13−30 Hz), low gamma (30−70 Hz), and high gamma (70−200 Hz) oscillations were strongly modulated by task performance. As in cortex, delta phase predicted beta/low gamma power and reaction time. Furthermore, delta phase differentially predicted spike timing in functionally distinct populations of Mthal neurons, which also predicted task performance and beta power. These complex relationships suggest mechanisms for commonly observed LFP-LFP and spike-LFP interactions, as well as subcortical influences on motor output.
Unique spatial integration in mouse primary visual cortex and higher visual areas
Authors: Murgas Kevin A. , Wilson Ashley M. , Michael Valerie , Glickfeld Lindsey L. 
Published: May 2019

AbstractNeurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields in primary visual cortex (V1) and three downstream higher visual areas (HVAs): LM (lateromedial), AL (anterolateral) and PM (posteromedial). We find significantly larger receptive field sizes and less surround suppression in PM than in V1 or the other HVAs. Unlike other visual features studied in this system, specialization of spatial integration in PM cannot be explained by specific projections from V1 to the HVAs. Instead, our data suggests that distinct connectivity within PM may support the area’s unique ability to encode global features of the visual scene, whereas V1, LM and AL may be more specialized for processing local features.
In vivoimaging of myonuclei during spontaneous muscle contraction reveals non-uniform nuclear mechanical dynamics inNesprin/klarmutants
Authors: Lorber Dana , Rotkopf Ron , Volk Talila 
Published: May 2019

AbstractMuscle contractions produce reiterated cytoplasmic mechanical variations, which impact the nuclear membrane and potentially influence nuclear mechanotransduction. It is unclear, however, whether the mechanical dynamics of individual myonuclei changes during each contractile wave, and whether mutants whose connection to the cytoskeleton is impaired are subjected to different mechanical input.To monitor nuclear mechanical dynamicsin vivo, we imaged myonuclei along muscles during multiple spontaneous muscle contractile events, within live and intactDrosophilawild-type orNesprin/klarmutant larvae. The data were subsequently analyzed and quantified aiming to reveal potential changes in the mechanical parameters of nuclear dynamics during muscle contraction in theNesprin/klarmutant. Our results show that all myonuclei in control larvae exhibited comparable dynamics in the course of multiple contractile events. In contrast, myonuclei of homozygous mutant larvae lacking the Nesprin-like geneklardisplayed differential dynamics relative to wild type, and higher variability between myonuclei at distinct positions along individual myofibers. Estimation of the drag force applied on individual myonuclei revealed that force fluctuations in time were considerably higher in theNesprin/klarmutant myonuclei relative to control, reflecting a significant variability in the mechanical dynamics of individual myonuclei during contractile waves. The variable mechanical dynamics along the muscle fiber and the higher variance ofNesprin/klarmutant myonuclei may lead to altered nuclear mechanotransduction. Since mutations inNespringenes lead to devastating muscle and cardiac human diseases, our findings may provide new insight into the mechanism underlying these pathologies.
Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer’s disease
Authors: Walsh D.A. , Brown J.T. , Randall A.D. 
Published: May 2019

AbstractTransgenic mice that overproduce beta-amyloid (Aβ) peptides exhibit neurophysiological alterations at the cellular, synaptic and network levels. Recently, increased neuronal activity in nucleus reuniens (Re), has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether alterations to the intrinsic electrophysiological properties of Re neurons could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons displayed a hyperpolarised membrane potential in J20 mice without changes to the incidence or frequency of spontaneous action potential (AP) generation. Passive membrane properties were independent of transgene expression. Re neurons recorded from J20 mice did not exhibit increased AP generation in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increase in rebound firing does not appear to result from alterations to T-type calcium channels. Finally, in J20 mice there was an ∼8% reduction in spike width, similar to what we and others have reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to the hyperexcitability observed in hippocampal-thalmo-cortical circuits under pathological Aβ load.Key PointsAlterations in the neurophysiology of hippocampal and cortical neurons has been linked to network hyperexcitability in mouse models of amyloidopathy.The nucleus reuniens (Re) is part of a cognitive network involving the hippocampal formation and prefrontal cortex. Increased cellular activity in Re has been linked to the generation of hippocampal-thalamo-cortical seizure activity in J20 mice.Re neurons display hyperpolarised resting membrane potentials in J20 mice. Passive membrane properties are unaffected by transgene expression. Re neurons recorded from J20 mice did not exhibit increased excitability in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increased rebound firing was not a result of changes in T-type Ca2+ conductances. Finally we observed a decrease in AP width.These results help us understand how altered Re cellular neurophysiology may contribute to hippocampal-thalamo-cortical hyperexcitability in J20 mice.
Context-Aware Seeds for Read Mapping
Authors: Xin Hongyi , Shao Mingfu , Kingsford Carl 
Published: May 2019

AbstractMotivationMost modern seed-and-extend NGS read mappers employ a seeding scheme that requires extracting t non-overlapping seeds in each read in order to find all valid mappings under an edit distance threshold of t. As t grows (such as in long reads with high error rate), this seeding scheme forces mappers to use more and shorter seeds, which increases the seed hits (seed frequencies) and therefore reduces the efficiency of mappers.ResultsWe propose a novel seeding framework, context-aware seeds (CAS). CAS guarantees finding all valid mapping but uses fewer (and longer) seeds, which reduces seed frequencies and increases efficiency of mappers. CAS achieves this improvement by attaching a confidence radius to each seed. We prove that all valid mappings can be found if the sum of confidence radii of seeds are greater than t. CAS generalizes the existing pigeonhole-principle-based seeding scheme in which this confidence radius is implicitly always 1. Moreover, we design an efficient algorithm that constructs the confidence radius database in linear time. We experiment CAS with E. coli genome and show that CAS reduces seed frequencies by up to 25.4% when compared with the state-of-the-art pigeonhole-principle-based seeding algorithm, the Optimal Seed Solver.Availabilityhttps://github.com/Kingsford-Group/CAS_code
Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth
Authors: Suff Natalie , Karda Rajvinder , Antinao Diaz Juan , Ng Joanne , Baruteau Julien , Perocheau Dany , Taylor Peter W. , Alber Dagmar , Buckley Suzanne M.K. , Bajaj-Elliott Mona , Waddington Simon N. , Peebles Donald 
Published: May 2019

AbstractApproximately 40% of preterm births are preceded by microbial invasion of the intrauterine space: ascent from the vagina is the most common pathway. Within the cervical canal, antimicrobial peptides and proteins (AMPs) help to constitute a barrier which prevents ascending infection. We investigated whether expression of the AMP, human β-defensin-3 (HBD3), in the cervical mucosa prevented bacterial ascent from the vagina into the uterine cavity of pregnant mice. An adeno-associated virus vector containing both the HBD3 gene and GFP transgene (AAV8 HBD3.GFP) or control (AAV8 GFP), was administered intravaginally into E13.5 pregnant mice. Ascending infection was induced at E16.5 using bioluminescent E.coli (E.coli K1 A192PP-lux2). Bioluminescence imaging showed bacterial ascent into the uterine cavity, cellular events that led to premature delivery and a reduction in pups born alive, compared with uninfected controls. In addition, a significant reduction in uterine bioluminescence in the AAV8 HBD3.GFP-treated mice was observed 24 hours post-E.coli infection, compared to AAV8 GFP treated mice, signifying reduced bacterial ascent in AAV8 HBD3.GFP-treated mice. There was also an increase in the number of living pups in AAV HBD3.GFP-treated mice. We propose that HBD3 may be considered a possible candidate for augmenting cervical innate immunity to prevent ascending infection-related preterm birth.
HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons
Authors: Byczkowicz Niklas , Eshra Abdelmoneim , Montanaro Jacqueline , Trevisiol Andrea , Hirrlinger Johannes , Kole Maarten H. P. , Shigemoto Ryuichi , Hallermann Stefan 
Published: May 2019

AbstractHyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can bidirectionally be modulated by HCN channel blockers, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mice cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 µM; estimated endogenous cAMP concentration 13 µM). In accord, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily via altering the resting membrane potential and was associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators an opportunity to finely tune energy consumption and temporal delays across axons in the brain.
Area 2 of primary somatosensory cortex encodes kinematics of the whole arm
Authors: Chowdhury Raeed H , Glaser Joshua I , Miller Lee E 
Published: May 2019

AbstractProprioception, the sense of body position, movement, and associated forces, remains poorly understood, despite its critical role in movement. Most studies of area 2, a proprioceptive area of somatosensory cortex, have simply compared neurons’ activities to the movement of the hand through space. By using motion tracking, we sought to elaborate this relationship by characterizing how area 2 activity relates to whole arm movements. We found that a whole-arm model, unlike classic models, successfully predicted how features of neural activity changed as monkeys reached to targets in two workspaces. However, when we then evaluated this whole-arm model across active and passive movements, we found that many neurons did not consistently represent the whole arm over both conditions. These results suggest that 1) neural activity in area 2 includes representation of the whole arm during reaching and 2) many of these neurons represented limb state differently during active and passive movements.
Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice
Authors: Ehinger Yann , Bruyère Julie , Panayotis Nicolas , Abada Yah-Se , Borloz Emilie , Matagne Valérie , Scaramuzzino Chiara , Vitet Hélène , Delatour Benoit , Saidi Lydia , Villard Laurent , Saudou Frédéric , Roux Jean-Christophe 
Published: May 2019

AbstractMutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain-derived neurotrophic factor (BDNF) levels, but non-specific overexpression of BDNF only partially improves the phenotype of Mecp2-deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in Mecp2 knock-out brains. Here we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho-mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice—even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.