bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silicoanalysis of SNPs in human phosphofructokinase, Muscle (PFKM) gene: An apparent therapeutic target of aerobic glycolysis and cancer
Authors: Rani Yogita , kaur Kamaljit , Sharma Madhvi , Kalia Namarta 
Published: May 2020

ABSTRACTPhosphofructokinase, muscle (PFKM), a key glycolytic regulatory enzyme is a potential target for cancer therapeutic studies accredited to the employed inefficient phenomenon known as Warburg effect. PFKM is encoded byPFKMgene located at chromosome 12q13.11. Single nucleotide polymorphisms (SNPs) are known to profoundly affect gene expression and protein function. Therefore, the first attempt was made to computationally identify putative functional PFKM variants. These SNPs were further explored to find their probable association with different cancer types. A total of 9694 SNPs were retrieved from dbSNP database. Of which, only 85 validated SNPs with ≥10% minor allele frequency (MAF) were subjected to analysis by softwares including Ensembl Genome browser, FuncPred (SNPinfo), regulomeDB (v 2.0), SIFT and PolyPhen-2. The relative analysis of output obtained classified the selected-SNPs into 11 highly prioritized (HP), 20 moderately prioritized and 54 not/poorly prioritized SNPs. The 11 HP-SNPs were found to have the highest likelihood of being functionally important, evidenced by previous association of rs2269935, rs11168417, rs11609399 and rs2228500 HP-SNPs with cachexia, lung and breast cancer. The study warrants further experiments to confirm the predictive role of prioritized SNPs in cancer etiology and also provides directions to fellow researchers.
Ablation of MYB-dependent leukaemia phenotype in MLL-driven AML correlates with increased expression of MAFB
Authors: Ward C , Cauchy P , Walton DS , Clarke ML , Blakemore D , Grebien F , Garcia P , Frampton J , Volpe G 
Published: May 2020

ABSTRACTThe transcription factor MYB plays a pivotal role in haematopoietic homeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). Our previous work has demonstrated that not all AML types display the same dependency onMYBexpression and that MYB dependence is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML still remains to be further elucidated. In this study, we investigate the importance ofMYBin human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-fusion-driven leukaemia uponMYBsuppression is not seen in AML cells with a complex karyotype. By performing transcriptome analysis, we demonstrate that a strong activation ofMAFBexpression driven byMYBablation is restricted to MYB-dependent cells. In line with these observations, stratification of publicly available patient data reveals a reciprocal relationship between the expression ofMYBandMAFB, highlighting a novel connection between those two factors in AML.
A mathematical model for storage and recovery of motor actions in the spinal cord
Authors: Parker David J , Srivastava Vipin 
Published: May 2020

AbstractMotor outputs are generated by the spinal cord in response to de-scending inputs from the brain. While particular descending commands generate specific outputs, how descending inputs interact with spinal cord circuitry to generate these outputs remains unclear. Here, we suggest that during development particular motor programmes are stored in premotor spinal circuitry, and that these can subsequently be retrieved when the associated descending input is received. We propose that different motor patterns are not stored in the spinal cord as a library of separate programmes, but that the spinal cord orthogonalises and normalises the various inputs, identifies the similarities and differences between them, and stores only the differences: similarities between patterns are recognised and used as a common basis that subsequent input patterns are built upon. By removing redundancy this can greatly increase the storage capacity of a system composed of a finite number of processing units, thus overcoming the problems associated with the storage limits of conventional artificial networks (e.g. ‘catastrophic interference’). Where possible we relate the various stages of the processing to the known circuitry and synaptic properties of spinal cord locomotor networks, and suggest experimental approaches that could test unknown aspects.
LRRK2 regulates AP2M1 phosphorylation cycles to mediate endocytosis and dopaminergic neurodegeneration
Authors: Liu Qinfang , Bautista-Gomez Judith , Higgins Daniel A. , Yu Jianzhong , Xiong Yulan 
Published: May 2020

AbstractRecent genetic evidence revealed endocytic pathway plays a major role in Parkinson’s disease (PD). However, the molecular mechanism is poorly understood. Here we report that LRRK2, the most genetic cause of PD, binds to and phosphorylates AP2M1, the core component of endocytosis recently implicated in PD risk. Both knockout and overexpression of LRRK2 cause abnormal AP2M1 phosphorylation cycle and in turn endocytic defects. Mechanistically, knockout of LRRK2 decreases AP2M1 phosphorylation required for the initial clathrin coated vesicle (CCV) formation while LRRK2 overexpression inhibits AP2M1 uncoating for entering into a new cycle of CCV formation. Our study also uncovered a novel tissue-specific regulation of AP2M1 phosphorylation by LRRK2. Further, we found LRRK2 phosphorylation on AP2M1 mediates LRRK2-induced neuronal toxicity bothin vitroandin vivo. Importantly, AP2M1 phosphorylation levels are elevated in PD patient fibroblasts. Together, our study provides a direct mechanistic link between LRRK2, AP2 and endocytosis in PD pathogenesis.
HAP40 is a conserved central regulator of Huntingtin and a specific modulator of mutant Huntingtin toxicity
Authors: Xu Shiyu , Li Gang , Ye Xin , Chen Dongsheng , Chen Zhihua , Xu Zhen , Ye Lili , Stimming Erin F. , Marchionini Deanna , Zhang Sheng 
Published: May 2020

AbstractPerturbation of Huntingtin (HTT)’s physiological function is one postulated pathogenic factor in Huntington’s disease (HD). However, little is known how HTT is regulatedin vivo. In a proteomic study, we isolated a novel ∼40kDa protein as a strong binding partner ofDrosophilaHTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT’s conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT, loss of HAP40 resulted in similar phenotypes as HTT knockout, including animal viability and autophagy, and more strikingly, HAP40 depletion significantly reduced the levels of endogenous HTT, while HAP40 was mostly degraded via the proteasome in the absence of HTT. Interestingly, polyglutamine expansion in HTT did not affect its affinity for HAP40. However, HAP40 modulated HD pathogenesis inDrosophilamodel by regulating the overall protein levels and the toxicity of full-length mutant HTT. Together, our study uncovers a conserved mechanism governing the stability andin vivofunctions of HTT, and demonstrates that HAP40 is a central and positive regulator of HTT, a potential modulator of HD pathogenesis and a promising candidate for “HTT-lowering” strategy against HD.
An analog to digital converter controls bistable transfer competence development of a widespread bacterial integrative and conjugative element
Authors: Carraro Nicolas , Richard Xavier , Sulser Sandra , Delavat François , Mazza Christian , van der Meer Jan Roelof 
Published: May 2020

AbstractConjugative transfer of the integrative and conjugative element ICEclcinPseudomonasrequires development of a transfer competence state in stationary phase, which arises only in 3-5% of individual cells. The mechanisms controlling this bistable switch between non-active and transfer competent cells have long remained enigmatic. Using a variety of genetic tools and epistasis experiments inP. putida, we uncovered an ‘upstream’ cascade of three consecutive transcription factor-nodes, which controls transfer competence initiation. Initiation activates a feedback loop, which stochastic modeling and experimental data demonstrated acts as a scalable converter of unimodal input to bistable output. The feedback loop further enables prolonged production of a transcription factor that ensures ‘downstream’ transfer competence formation in activated cells. Phylogenetic analyses showed that the ICEclcregulatory factors are widespread amongGamma-andBeta-proteobacteria, highlighting its evolutionary conservation and prime importance to control the behaviour of this wide family of conjugative elements.
Estrogen receptors in human bladder cells regulate innate cytokine responses to differentially modulate uropathogenicE. colicolonization
Authors: Sen Ayantika , Kaul Anil , Kaul Rashmi 
Published: May 2020

AbstractThe bladder epithelial cells elicit robust innate immune responses against urinary tract infections (UTIs) for preventing the bacterial colonization. Physiological fluctuations in circulating estrogen levels in women increase the susceptibility to UTI pathogenesis, often resulting in adverse health outcomes. Dr adhesin bearingEscherichia coli(DrE. coli) cause recurrent UTIs in menopausal women and acute pyelonephritis in pregnant women. DrE. colibind to epithelial cells via host innate immune receptor CD55, under hormonal influence. The role of estrogens or estrogen receptors (ERs) in regulating the innate immune responses in the bladder are poorly understood. In the current study, we investigated the role of ERα, ERβ and GPR30 in modulating the innate immune responses against DrE. coliinduced UTI using human bladder epithelial carcinoma 5637 cells (HBEC). Both ERα and ERβ agonist treatment in bladder cells induced a protection against DrE. coliinvasion via upregulation of TNFα and downregulation of CD55 and IL10, and these effects were reversed by action of ERα and ERβ antagoinsts. In contrast, the agonist-mediated activation of GPR30 led to an increased bacterial colonization due to suppression of innate immune factors in the bladder cells, and these effects were reversed by the antagonist-mediated suppression of GPR30. Further, siRNA-mediated ERα knockdown in the bladder cells reversed the protection against bacterial invasion observed in the ERα positive bladder cells, by modulating the gene expression of TNFα, CD55 and IL10, thus confirming the protective role of ERα. We demonstrate for the first time a protective role of nuclear ERs, ERα and ERβ but not of membrane ER, GPR30 against DrE. coliinvasion in HBEC 5637 cells. These findings have many clinical implications and suggest that ERs may serve as potential drug targets towards developing novel therapeutics for regulating local innate immunity and treating UTIs.HighlightsEstrogen receptor (ER) subtypes regulate the gene expression of innate immune molecules, CD55, TNFα and IL10 in human bladder epithelial cells impacting the bacterial colonization by DrE. coli.Activation of nuclear ER subtypes, ERα and ERβ, upregulate the gene expression of proinflammatory cytokine, TNFα, but downregulate the gene expression of anti-inflammatory cytokine, IL10, and DrE. colicolonization receptor, CD55, thus leading to efficient bacterial clearance in human bladder cells.In contrast, activation of the membrane ER subtype, GPR30, shows opposite effects to ERα and ERβ that were mediated on TNFα, IL10 and CD55 gene expression, thus leading to impaired bacterial clearance of DrE. coliin human bladder cells.ER subtypes can serve as potential drug candidates for designing new therapies to boost or modulate the local immunity in the human bladder preventing the establishment ofE. coliinfections.
Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells
Authors: Reed Megan R. , Maddukuri Leena , Ketkar Amit , Byrum Stephanie D. , Zafar Maroof K. , Bostian April C. L. , Tackett Alan J. , Eoff Robert L. 
Published: May 2020

ABSTRACTAberrant expression of tryptophan 2,3-dioxygenase (TDO) is a determinant of malignancy and immune response in gliomas in part through kynurenine (KYN)-mediated activation of the aryl hydrocarbon receptor (AhR). In the current study, we investigated the hypothesis that TDO activation in gliomas has a broad impact upon genome maintenance - promoting tolerance of replication stress (RS) and repair of DNA damage. We report that inhibition of TDO activity attenuated recovery from hydroxyurea (HU)-induced RS and increased the genotoxic effects of bis-chloroethylnitrosourea (BCNU), as fork progress was impeded when TDO-deficient glioma cells were treated with BCNU. Activation of the Chk1 arm of the replication stress response (RSR) was reduced when TDO activity was blocked prior to treatment with BCNU, whereas phosphorylation of serine 33 (pS33) on replication protein A (RPA) was enhanced – indicative of increased fork collapse. Restoration of KYN levels protected against some replication-associated effects of BCNU. Inhibition of TDO activity had a strong anti-proliferative effect on glioma-derived cells – enhancing the cytotoxic effects of BCNU. Analysis of results obtained using quantitative proteomics revealed TDO-dependent changes in several signaling pathways – including down-regulation of DNA repair factors and sirtuin signaling. Consistent with these observations, inhibition of TDO diminished SIRT7 recruitment to chromatin, which increased histone H3K18 acetylation – a key mark involved in 53BP1 recruitment to sites of DNA damage. Cells lacking TDO activity exhibited defective recruitment of 53BP1 to gH2AX foci, which corresponded with delayed repair of BCNU-induced DNA breaks. Addition of exogenous KYN increased the rate of break repair. The discovery that TDO activity modulates sensitivity to DNA damage by fueling SIRT7/53BP1 localization to chromatin and repair of BCNU-induced DNA damage highlights the potential for tumor-specific metabolic changes to influence genome stability and may have implications for glioma biology and treatment strategies.
Playing a P300-based BCI VR game leads to changes in cognitive functions of healthy adults
Authors: Bulat Matvey , Karpman Alexandra , Samokhina Alina , Panov Alexander 
Published: May 2020

In this paper, we present the results of a study to determine the effect of the P300-based brain-computer interface (BCI) virtual reality game on the cognitive functions of healthy human subjects. This study is a part of on-going research related to evaluation of the the long-term effect of P300 training in Virtual Reality surrounding (VR game) on the cognitive performance of the young healthy population. A comparison of results between 3 groups of participants (15 people each) revealed the progressing difference in cognitive assessment for experimental group played P300 BCI VR game, showing the positive increase in flanker and conjunction visual search task performance associated with selective attention and mental inhibition. We show that the effect is due to the use of P300 BCI paradigm. Our results suggest that P300 BCI games combined with virtual reality can not only be used for rehabilitation in patients with slight mental disorders or elderly, but for increasing some cognitive functions in healthy subjects, giving an additional improvement in learning in case of combination with possible educational tasks or used for attention trainingGRAPHICAL ABSTRACTPlease check the journal’s author guildines for whether a graphical abstract, key points, new findings, or other items are required for display in the Table of Contents.
Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity
Authors: Leyrer-Jackson Jonna M. , Holter Michael , Overby Paula F. , Newbern Jason M. , Scofield Michael D. , Olive M. Foster , Gipson Cassandra D. 
Published: May 2020

AbstractNicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cue-induced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens α4β2- and α7-containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement. Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.
𝓲-SATA: A MATLAB based toolbox to estimate Current Density generated by Transcranial Direct Current Stimulation in an Individual Brain
Authors: Kashyap Rajan , Bhattacharjee Sagarika , Arumugam Ramaswamy , Oishi Kenichi , Desmond John E. , Chen SH Annabel 
Published: May 2020

AbstractBackgroundTranscranial Direct Current Stimulation (tDCS) is a technique where a weak current is passed through the electrodes placed on the scalp. The distribution of the electric current induced in the brain due to tDCS is provided by simulation toolbox like Realistic-volumetric-Approach-based-Simulator-for-Transcranial-electric-stimulation (ROAST). However, the procedure to estimate the total current density induced at the target and the intermediary region of the cortex is complex. The Systematic-Approach-for-tDCS-Analysis (SATA) was developed to overcome this problem. However, SATA is limited to standardized headspace only. Here we developindividual-SATA (𝓲-SATA) to extend it to individual head.MethodT1-weighted images of 15 subjects were taken from two Magnetic Resonance Imaging (MRI) scanners of different strengths. Across the subjects, the montages were simulated in ROAST. 𝓲-SATA converts the ROAST output to Talairach space. The x, y and z coordinates of the anterior commissure (AC), posterior commissure (PC), and Mid-Sagittal (MS) points are necessary for the conversion. AC and PC are detected using the acpcdetect toolbox. We developed a method to determine the MS in the image and cross-verified its location manually using BrainSight®.ResultDetermination of points with 𝓲-SATA is fast and accurate. The 𝓲-SATA provided estimates of the current-density induced across an individual’s cortical lobes and gyri as tested on images from two different scanners.ConclusionResearchers can use 𝓲-SATA for customizing tDCS-montages. With 𝓲-SATA it is also easier to compute the inter-individual variation in current-density across the target and intermediary regions of the brain. The software is publicly available.
Do M-cells contribute significantly in T-wave morphology during normal and arrhythmogenesis conditions like short QT Syndrome?
Authors: Priya Ponnuraj Kirthi , Jayaraman Srinivasan 
Published: May 2020

AbstractAimsThis paper proposes to explain the mechanism of M-cells, particularly its role in the T-wave generation and its contribution to arrhythmogenesis in short QT syndrome 2 (SQTS2).MethodsA 2D transmural anisotropic ventricular model made up of three principal cell types were developed. Different setups in which: a) entire column of mid-myocardial (mid) cells, b) single island of cells c) two island of cells within the mid-layer d) single island of cells in endocardial (endo)-mid layer were considered as M-cells. These setups are stimulated to explain i) contribution of M-cells in T-wave morphology ii) arrhythmia generation phenomena under SQTS2 heterozygous gene mutation by creating pseudo ECGs from the tissue.ResultsFindings infer that setups with an entire layer of M-cells and a higher percentage of epicardial (epi) cells exhibit positive T-waves. Increasing the size of the island in M-cell island setups results in an increased positive T-peak. Placing the M-cell island in the bottom of the mid-layer produced low amplitude T-waves. Further, in two M-cell islands setup, a higher T-wave amplitude was observed when the islands are placed closer than far apart. Moving the M-cell island slightly into the endo layer increases the amplitude of the T-wave. Lastly, on including SQTS2 conditions and pacing with premature beats, an arrhythmia occurs only in those setups containing a layer of M-cells compared to M-cells island setup.ConclusionThese simulation findings paved the way for a better understanding of the M-cells functionality in T-wave morphology as well as promoting arrhythmogenesis under SQTS2 condition.
Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies
Authors: Barnes Christopher O. , West Anthony P. , Huey-Tubman Kathryn E. , Hoffmann Magnus A.G. , Sharaf Naima G. , Hoffman Pauline R. , Koranda Nicholas , Gristick Harry B. , Gaebler Christian , Muecksch Frauke , Cetrulo Lorenzi Julio C. , Finkin Shlomo , Hagglof Thomas , Hurley Arlene , Millard Katrina G. , Weisblum Yiska , Schmidt Fabian , Hatziioannou Theodora , Bieniasz Paul D. , Caskey Marina , Robbiani Davide F. , Nussenzweig Michel C. , Bjorkman Pamela J. 
Published: May 2020

SummaryNeutralizing antibody responses to coronaviruses focus on the trimeric spike, with most against the receptor-binding domain (RBD). Here we characterized polyclonal IgGs and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their degree of focus on RBD epitopes, recognition of SARS-CoV, MERS-CoV, and mild coronaviruses, and how avidity effects contributed to increased binding/neutralization of IgGs over Fabs. Electron microscopy reconstructions of polyclonal plasma Fab-spike complexes showed recognition of both S1Aand RBD epitopes. A 3.4Å cryo-EM structure of a neutralizing monoclonal Fab-S complex revealed an epitope that blocks ACE2 receptor-binding on “up” RBDs. Modeling suggested that IgGs targeting these sites have different potentials for inter-spike crosslinking on viruses and would not be greatly affected by identified SARS-CoV-2 spike mutations. These studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived fromVH3-53/VH3-66and similarity to a SARS-CoVVH3-30antibody, providing criteria for evaluating vaccine-elicited antibodies.