bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central processing of leg proprioception inDrosophila
Authors: Agrawal Sweta , Dickinson Evyn S , Sustar Anne , Gurung Pralaksha , Shepherd David , Truman Jim , Tuthill John C 
Published: June 2020

AbstractProprioception, the sense of self-movement and position, is mediated by mechanosensory neurons that detect diverse features of body kinematics. Although proprioceptive feedback is crucial for accurate motor control, little is known about how downstream circuits transform limb sensory information to guide motor output. Here, we investigate neural circuits inDrosophilathat process proprioceptive information from the fly leg. We identify three cell-types from distinct developmental lineages that are positioned to receive input from proprioceptor subtypes encoding tibia position, movement, and vibration. 13Bα neurons encode femur-tibia joint angle and mediate postural changes in tibia position. 9Aα neurons also drive changes in leg posture, but encode a combination of directional movement, high frequency vibration, and joint angle. Activating 10Bα neurons, which encode tibia vibration at specific joint angles, elicits pausing in walking flies. Altogether, our results reveal that central circuits integrate information across proprioceptor subtypes to construct complex sensorimotor representations that mediate diverse behaviors, including reflexive control of limb posture and detection of leg vibration.
Fructose Metabolism Contributes to the Warburg effect
Authors: Han Bing , Wang Lu , Zhang Jingyu , Wei Meilin , Rajani Cynthia , Wei Runming , Wang Jingye , Yang Haining , Carbone Michele , Xie Guoxiang , Zhou Wen , Jia Wei 
Published: June 2020

SUMMARYFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, it remains unclear why cancer cells favor fructose metabolism and how they acquire a sufficient amount of fructose. Here we report that cancer cells convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and promotes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancer. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study suggests that the Warburg effect is achieved by means of fructose metabolism, instead of glucose metabolism alone.
Unveiling inter individual variability of human fibroblast innate immune response using robust cell-based protocols
Authors: Chansard A. , Dubrulle N. , Poujol de Mollens M. , Falanga P. B. , Stephen T. , Hasan M. , van Zandbergen G. , Aulner N. , Shorte S. L. , David-Watine B. ,   for the Milieu Intérieur Consortium
Published: June 2020

ABSTRACTThe LabEx Milieu Interieur (MI) project is a clinical study centered on the detailed characterization of the baseline and induced immune responses in blood samples from 1000 healthy donors. Analyses of these samples has lay ground for seminal studies on the genetic and environmental determinants of immunologic variance in a healthy cohort population. In the current study we developed in vitro methods enabling standardized quantification of MI-cohort-derived primary fibroblasts responses. Our results show that in vitro human donor cohort fibroblast responses to stimulation by different MAMPs analogs allows to characterize individual donor immune-phenotype variability. The results provide proof-of-concept foundation to a new experimental framework for such studies.A bio-bank of primary fibroblast lines was generated from 323 out of 1,000 healthy individuals selected from the MI-study cohort. To study inter-donor variability of innate immune response in primary human dermal fibroblasts we chose to measure the TLR3 and TLR4 response pathways, both receptors being expressed and previously studied in fibroblasts. We established high-throughput automation compatible methods for standardized primary fibroblast cell activation, using purified MAMPS analogs, poly I:C and LPS that stimulate TLR3 and TLR4 pathways respectively. These results were in turn compared with a stimulation method using infection by HSV-1 virus. Our “Add-only” protocol minimizes high-throughput automation system variability facilitating whole process automation from cell plating through stimulation to recovery of cell supernatants, and fluorescent labeling. Images were acquired automatically by high-throughput acquisition on an automated high-content imaging microscope. Under these methodological conditions standardized image acquisition provided for quantification of cellular responses allowing biological variability to be measured with low system noise and high biological signal fidelity. Optimal for automated analysis of immuno-phenotype of primary human cell responses our method and experimental framework as reported here is highly compatible to high-throughput screening protocols like those necessary for chemo-genomic screening. In context of primary fibroblasts derived from donors enrolled to the MI-clinical-study our results open the way to assert the utility of studying immune-phenotype characteristics relevant to a human clinical cohort.
The evolution of Sox gene repertoires and regulation of segmentation in arachnids
Authors: Baudouin-Gonzalez Luis , Schoenauer Anna , Harper Amber , Blakeley Grace , Seiter Michael , Arif Saad , Sumner-Rooney Lauren , Russell Steven , Sharma Prashant P. , McGregor Alistair P. 
Published: June 2020

AbstractThe Sox family of transcription factors regulate many processes during metazoan development, including stem cell maintenance and nervous system specification. Characterising the repertoires and roles of these genes can therefore provide important insights into animal evolution and development. We further characterised the Sox repertoires of several arachnid species with and without an ancestral whole genome duplication (WGD), and compared their expression between the spiderParasteatoda tepidariorumand the harvestmanPhalangium opilio. We also found that most Sox families have been retained as ohnologs after WGD and evidence for potential subfunctionalisation and/or neofunctionalization events. Our results also suggest thatSox21b-1likely regulated segmentation ancestrally in arachnids, playing a similar role to the closely related SoxB gene,Dichaete, in insects. We previously showed thatSox21b-1is required for the simultaneous formation of prosomal segments and sequential addition of opisthosomal segments inP. tepidariorum. We studied the expression and function ofSox21b-1further in this spider and found that while this gene regulates the generation of both prosomal and opisthosomal segments, it plays different roles in the formation of these tagmata reflecting their contrasting modes of segmentation and deployment of gene regulatory networks with different architectures.
SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
Authors: Martinat Charlotte , Cormier Arthur , Tobaly-Tapiero Joёlle , Palmic Noé , Casartelli Nicoletta , Coggins Si’Ana A. , Buchrieser Julian , Persaud Mirjana , Diaz-Griffero Felipe , Espert Lucile , Bossis Guillaume , Lesage Pascale , Schwartz Olivier , Kim Baek , Margottin-Goguet Florence , Saïb Ali , Zamborlini Alessia 
Published: June 2020

AbstractSAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function. These observations clearly establish that the absence of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that concomitant SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity.
A RIF1/KAP1-based toggle switch stabilises the identities of the inactive and active X chromosomes during X inactivation
Authors: Enervald Elin , Powell Lynn Marie , Boteva Lora , Foti Rossana , Ruiz Nerea Blanes , Kibar Gözde , Piszczek Agnieszka , Cavaleri Fatima , Vingron Martin , Cerase Andrea , Buonomo Sara B.C. 
Published: June 2020

ABSTRACTThe onset of random X inactivation in mouse requires the switch from a symmetric to an asymmetric state, where the identities of the future inactive and active X chromosomes are assigned. Here we show that RIF1 and KAP1 are two fundamental factors for the definition of the asymmetry. Our data show that at the onset of mESC differentiation, upregulation of the long non-coding RNA Tsix weakens the symmetric RIF1 association with theXistpromoter, and opens a window of opportunity for a more stable association of KAP1. KAP1 is required to sustain high levels of Tsix, thus reinforcing and propagating the asymmetry, and, as a result, marking the future active X chromosome. Furthermore, we show that RIF1 association with the future inactive X chromosome is essential for Xist upregulation. This double-bookmarking system, based on the mutually exclusive relationships of Tsix and RIF1, and RIF1 and KAP1, thus coordinates the identification of the inactive and active X chromosomes and initiates a self-sustaining loop that transforms an initially stochastic event into a stably inherited asymmetric X chromosome state.
Sleeping While Awake: The Intrusion of Neural Activity Associated with Sleep Onset in the Awake Human Brain
Authors: Hawes Stephanie , Innes Carrie R. H. , Parsons Nicholas , Drummond Sean P.A. , Caeyensberghs Karen , Jones Richard D. , Poudel Govinda R. 
Published: June 2020

AbstractSleep can intrude into the awake human brain when sleep deprived or fatigued, even while performing cognitive tasks. However, how the brain activity associated with sleep onset can co-exist with the activity associated with cognition in the awake humans remains unexplored. Here, we used simultaneous fMRI and EEG to generate fMRI activity maps associated with EEG theta (4-7 Hz) activity associated with sleep onset. We implemented a method to track these fMRI activity maps in individuals performing a cognitive task after well-rested and sleep-deprived nights. We found frequent intrusions of the fMRI maps associated with sleep-onset in the task-related fMRI data. These sleep events elicited a pattern of transient fMRI activity, which was spatially distinct from the task-related activity in the frontal and parietal areas of the brain. They were concomitant with reduced arousal as indicated by decreased pupil size and increased response time. Graph theoretical modelling showed that the activity associated with sleep onset emerges from the basal forebrain and spreads anterior-posteriorly via the brain’s structural connectome. We replicated the key findings in an independent dataset, which suggests that the approach can be reliably used in understanding the neuro-behavioural consequences of sleep and circadian disturbances in humans.
RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site
Authors: Haza Katarzyna Z , Martin Heather L , Rao Ajinkya , Turner Amy L , Saunders Sophie E , Petersen Britta , Tiede Christian , Tipping Kevin , Tang Anna A , Ajayi Modupe , Taylor Thomas , Fishwick Keri M , Adams Thomas L , Gaule Thembaninkosi G. , Trinh Chi H , Johnson Matthew , Breeze Alexander L , Edwards Thomas A , McPherson Michael J , Tomlinson Darren C 
Published: June 2020

ABSTRACTRAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. We have identified two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signalling pathways with distinct isoform and mutant profiles. Affimer K6 is the first biologic to bind in the SI/SII pocket, whilst Affimer K3 is the first non-covalent inhibitor of the SII region, revealing a novel RAS conformer with a large, druggable SII/α3 pocket. This work demonstrates the potential of using biologics with small interface surfaces to select novel druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins.
Grazing pressure-induced shift in planktonic bacterial communities with the dominance of acIII-A1 actinobacterial lineage in soda pans
Authors: Szabó Attila , Korponai Kristóf , Somogyi Boglárka , Vajna Balázs , Vörös Lajos , Horváth Zsófia , Boros Emil , Szabó-Tugyi Nóra , Márialigeti Károly , Felföldi Tamás 
Published: June 2020

AbstractAstatic soda pans of the Pannonian Steppe are unique environments with respect to their multiple extreme physical and chemical characteristics (high daily water temperature fluctuation, high turbidity, alkaline pH, salinity, polyhumic organic carbon concentration, hypertrophic state and special ionic composition). However, little is known about the seasonal dynamics of the bacterial communities inhabiting these lakes and the role of environmental factors that have the main impact on their structure. Therefore, two soda pans were sampled monthly between April 2013 and July 2014 to reveal changes in the planktonic community. By late spring in both years, a sudden shift in the community structure was observed, the previous algae-associated bacterial communities had collapsed, resulting the highest ratio of actinobacteria within the bacterioplankton (89%, with the dominance of acIII-A1 lineage) ever reported in the literature. Before these peaks, an extremely high abundance (>10,000 individuum l−1) of microcrustaceans (MoinaandArctodiaptomus) was observed. OTU-based statistical approaches showed that in addition to algal blooms and water-level fluctuations, zooplankton densities had the strongest effect on the composition of bacterial communities. In these extreme environments, this implies a surprisingly strong, community-shaping top-down role of microcrustacean grazers.
Linear-Nonlinear Cascades Capture Synaptic Dynamics
Authors: Rossbroich Julian , Trotter Daniel , Beninger John , Tóth Katalin , Naud Richard 
Published: June 2020

AbstractShort-term synaptic dynamics differ markedly across connections and strongly regulate how action potentials communicate information. To model the range of synaptic dynamics observed in experiments, we have developed a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show that it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks.Author summaryUnderstanding how information is transmitted relies heavily on knowledge of the underlying regulatory synaptic dynamics. Existing computational models for capturing such dynamics are often either very complex or too restrictive. As a result, effectively capturing the different types of dynamics observed experimentally remains a challenging problem. Here, we propose a mathematically flexible linear-nonlinear model that is capable of efficiently characterizing synaptic dynamics. We demonstrate the ability of this model to capture different features of experimentally observed data.
PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning
Authors: Wei Hai , Lambie Eric J. , Osório Daniel S. , Carvalho Ana X. , Conradt Barbara 
Published: June 2020

AbstractThe mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that theC. elegansorthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. TheC. elegansNSM neuroblast divides to produce a larger cell that differentiates into a neuron and a smaller cell that dies. We find that in this context, PIG-1 is required for partitioning of CES-1 Snail, a transcriptional repressor of the pro-apoptotic geneegl-1BH3-only.pig-1MELK is controlled by both aces-1Snail- andpar-4LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose thatpig-1MELK-induced local contractility of the actomyosin network plays a conserved role in the acquisition of the apoptotic fate. Our work also uncovers an auto-regulatory loop through whichces-1Snail controls its own activity through the formation of a gradient of CES-1 Snail protein.Significance StatementApoptosis is critical for the elimination of ‘unwanted’ cells. What distinguishes wanted from unwanted cells in developing animals is poorly understood. We report that in theC. elegansNSM neuroblast lineage, the level of CES-1, a Snail-family member and transcriptional repressor of the pro-apoptotic geneegl-1, contributes to this process. In addition, we demonstrate thatC. elegansPIG-1, the orthologue of mammalian proto-oncoprotein MELK, plays a critical role in controlling CES-1Snaillevels. Specifically, during NSM neuroblast division, PIG-1MELKcontrols partitioning of CES-1Snailinto one but not the other daughter cell thereby promoting the making of one wanted and one unwanted cell. Furthermore, we present evidence that PIG-1MELKacts prior to NSM neuroblast division by locally activating the actomyosin network.
In silico analysis of imprinted gene expression in the mouse skin
Authors: Marr Alexandra K. , Boughorbel Sabri , Toufiq Mohammed , Anbari Mohammed El , Chouchane Aouatef I. , Kino Tomoshige 
Published: June 2020

1.AbstractImprinted genes help mediate embryonic cell proliferation and differentiation, but their roles after birth are far less well understood. A subset of 16 imprinted gene network (IGN) genes is expressed at higher levels in stem cell progenitor cells of adult skeletal muscle and epidermis compared to their differentiated counterparts. While these genes function in muscle regeneration, their role in the skin is poorly understood. We assessed the expression profiles of these 16 IGN genes in publicly available datasets and revealed elevated expression of IGN genes in the telogen and early anagen phases in mouse skin. We also identified IGN genes among a list of previously identified hair cycle-associated genes. Furthermore, our results suggest that IGN genes form part of a larger network and function predominantly as upstream regulators of hair cycle-regulated genes. Based on thesein silicodata, we propose a potential novel role of these 16 IGN genes as upstream regulators of hair cycle-associated genes. We speculate that IGN gene dysregulation participates in syndromes characterized by an impaired hair cycle. Thus, IGN gene expression might serve as a point of therapeutic intervention for patients suffering from cutaneous pathologies such as common hair-loss disorders.
Goats Given Transdermal Flunixin Meglumine Displayed Less Pain Behavior After Castration
Authors: Lee Amanda , Graves Meggan , Lear Andrea , Cox Sherry , Caldwell Marc , Krawczel Peter 
Published: June 2020

AbstractPain management should be utilized with castration to reduce physiological and behavioral changes. Transdermal application of drugs require less animal management and fewer labor risks, which can occur with oral administration or injections. The objective was to determine the effects of transdermal flunixin meglumine on meat goats’ behavior post-castration. Male goats (N = 18; mean body weight ± standard deviation: 26.4 ± 1.6 kg) were housed individually in pens and randomly assigned to 1 of 3 treatments: (1) castrated, dosed with transdermal flunixin meglumine; (2) castrated, dosed with transdermal placebo; and (3) sham castrated, dosed with transdermal flunixin meglumine. Body position, rumination, and head- pressing were observed for 1 h ± 10 minutes twice daily on days −1, 0, 1, 2, and 5 around castration. Each goat was observed once every 5-minutes (scan samples) and reported as percentage of observations. Accelerometers were used to measure standing, lying, and laterality (total time, bouts, and bout duration). A linear mixed model was conducted using GLIMMIX. Fixed effects of treatment, day relative to castration, and treatment*day relative to castration and random effect of date and goat nested within treatment were included. Treatment 1 goats (32.7 ± 2.8%) and treatment 2 goats (32.5 ± 2.8%) ruminated less than treatment 3 goats (47.4 ± 2.8%,P= 0.0012). Head pressing was greater on day of castration in treatment 2 goats (P< 0.001). Standing bout duration was greatest in treatment 2 goats on day 1 post-castration (P< 0.001). Lying bout duration was greatest in treatment 2 goats on day 1 post-castration compared to treatment 1 and treatment 3 goats(P< 0.001). Transdermal flunixin meglumine improved goats’ fluidity of movement post-castration and decreased head pressing, indicating a mitigation of pain behavior.
Locus coeruleus spiking differently correlates with somatosensory cortex activity and pupil diameter
Authors: Yang Hongdian , Bari Bilal A. , Cohen Jeremiah Y. , O’Connor Daniel H. 
Published: June 2020

ABSTRACTWe examined the relationships between activity in the locus coeruleus (LC), activity in the primary somatosensory cortex (S1), and pupil diameter in mice performing a tactile detection task. While LC spiking consistently preceded S1 membrane potential depolarization and pupil dilation, the correlation between S1 and pupil was more heterogeneous. Furthermore, the relationships between LC, S1 and pupil varied on timescales of sub-seconds to seconds within trials. Our data suggest that pupil diameter can be dissociated from LC spiking and cannot be used as a stationary index of LC activity.