bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism
Authors: Chong Stephen Jun Fei , Iskandar Kartini , Lai Jolin Xiao Hui , Qu Jianhua , Raman Deepika , Valentin Rebecca , Herbaux Charles , Collins Mary , Low Ivan Cherh Chiet , Loh Thomas , Davids Matthew , Pervaiz Shazib 
Published: October 2020

Abstract
Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications.
Synthetic rewiring and boosting type I interferon responses for visualization and counteracting viral infections
Authors: Gödecke Natascha , Riedel Jan , Herrmann Sabrina , Behme Sara , Rand Ulfert , Kubsch Tobias , Cicin-Sain Luka , Hauser Hansjörg , Köster Mario , Wirth Dagmar 
Published: October 2020

AbstractMammalian first line of defense against viruses is accomplished by the interferon (IFN) system. Viruses have evolved numerous mechanisms to reduce the IFN action allowing them to invade the host and/or to establish latency. We generated an IFN responsive intracellular hub by integrating the synthetic transactivator tTA into the chromosomal Mx2 locus for IFN-based activation of tTA dependent expression modules. The additional implementation of a synthetic amplifier module with positive feedback even allowed for monitoring and reacting to infections of viruses that can antagonize the IFN system. Low and transient IFN amounts are sufficient to trigger these amplifier cells. This gives rise to higher and sustained—but optionally de-activatable—expression even when the initial stimulus has faded out. Amplification of the IFN response induced by IFN suppressing viruses is sufficient to protect cells from infection. Together, this interfaced sensor/actuator system provides a toolbox for robust sensing and counteracting viral infections.
Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment
Authors: Miyai Masafumi , Kanayama Tomohiro , Hyodo Fuminori , Kinoshita Takamasa , Ishihara Takuma , Okada Hideshi , Suzuki Hiroki , Takashima Shigeo , Wu Zhiliang , Hatano Yuichiro , Egashira Yusuke , Enomoto Yukiko , Nakayama Noriyuki , Soeda Akio , Yano Hirohito , Hirata Akihiro , Niwa Masayuki , Sugie Shigeyuki , Mori Takashi , Maekawa Yoichi , Iwama Toru , Matsuo Masayuki , Hara Akira , Tomita Hiroyuki 
Published: October 2020

Abstract

Background
Gliomas typically escape surgical resection and recur due to their “diffuse invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the “diffuse invasion” phenotype, designated the Scherer’s secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown.

Methods
We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients.

Results
Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients.

Conclusions
Targeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
BSR guideline on the management of adults with systemic lupus erythematosus (SLE) 2018: baseline multi-centre audit in the UK
Authors: Pearce Fiona A , Rutter Megan , Sandhu Ravinder , Batten Rebecca L , Garner Rozeena , Little Jayne , Narayan Nehal , Sharp Charlotte A , Bruce Ian N , Erb Nicola , Griffiths Bridget , Guest Hannah , Macphie Elizabeth , Packham Jon , Hiley Chris , Obrenovic Karen , Rivett Ali , Gordon Caroline , Lanyon Peter C 
Published: October 2020

Abstract

Objectives
To assess the baseline care provided to patients with SLE attending UK Rheumatology units, audited against standards derived from the recently published BSR guideline for the management of adults with SLE, the NICE technology appraisal for belimumab, and NHS England’s clinical commissioning policy for rituximab.

Methods
SLE cases attending outpatient clinics during any 4-week period between February and June 2018 were retrospectively audited to assess care at the preceding visit. The effect of clinical environment (general vs dedicated CTD/vasculitis clinic and specialized vs non-specialized centre) were tested. Bonferroni’s correction was applied to the significance level.

Results
Fifty-one units participated. We audited 1021 episodes of care in 1003 patients (median age 48 years, 74% diagnosed &gt;5 years ago). Despite this disease duration, 286 (28.5%) patients had active disease. Overall in 497 (49%) clinic visits, it was recorded that the patient was receiving prednisolone, including in 28.5% of visits where disease was assessed as inactive. Low documented compliance (&lt;60% clinic visits) was identified for audit standards relating to formal disease-activity assessment, reduction of drug-related toxicity and protection against comorbidities and damage. Compared with general clinics, dedicated clinics had higher compliance with standards for appropriate urine protein quantification (85.1% vs 78.1%, P ≤ 0.001). Specialized centres had higher compliance with BILAG Biologics Register recruitment (89.4% vs 44.4%, P ≤ 0.001) and blood pressure recording (95.3% vs 84.1%).

Conclusions
This audit highlights significant unmet need for better disease control and reduction in corticosteroid toxicity and is an opportunity to improve compliance with national guidelines. Higher performance with nephritis screening in dedicated clinics supports wider adoption of this service-delivery model.
Sleep and high-risk behavior in military service members: a mega-analysis of four diverse U.S. Army units
Authors: Mantua Janna , Bessey Alexxa F , Mickelson Carolyn A , Choynowski Jake J , Noble Jeremy J , Burke Tina M , McKeon Ashlee B , Sowden Walter J 
Published: October 2020

AbstractExperimental sleep restriction and deprivation lead to risky decision-making. Further, in naturalistic settings, short sleep duration and poor sleep quality have been linked to real-world high-risk behaviors (HRB), such as reckless driving or substance use. Military populations, in general, tend to sleep less and have poorer sleep quality than nonmilitary populations due to a number of occupational, cultural, and psychosocial factors (e.g. continuous operations, stress, and trauma). Consequently, it is possible that insufficient sleep in this population is linked to HRB. To investigate this question, we combined data from four diverse United States Army samples and conducted a mega-analysis by aggregating raw, individual-level data (n = 2,296, age 24.7 ± 5.3). A negative binomial regression and a logistic regression were used to determine whether subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI], Insomnia Severity Index [ISI], and duration [h]) predicted instances of military-specific HRB and the commission of any HRB (yes/no), respectively. Poor sleep quality slightly elevated the risk for committing HRBs (PSQI Exp(B): 1.12 and ISI Exp(B): 1.07), and longer duration reduced the risk for HRBs to a greater extent (Exp(B): 0.78), even when controlling for a number of relevant demographic factors. Longer sleep duration also predicted a decreased risk for commission of any HRB behaviors (Exp(B): 0.71). These findings demonstrate that sleep quality and duration (the latter factor, in particular) could be targets for reducing excessive HRB in military populations. These findings could therefore lead to unit-wide or military-wide policy changes regarding sleep and HRB.
Leave against Medical Advice in Children: Rural Indian Perspective
Authors: Datta Debadyuti , Mondal Tanushree , Sarkar Mihir , Chel Soumita , Das Sankar Kumar , Nandy Arnab , M Ivan Divyoshanu , Mondal Rakesh 
Published: October 2020

Abstract

Objectives
To determine the burden and etiological factors of leave against medical advice (LAMA) in Indian children.

Methodology
In this prospective study, legal guardians of 528 patients who took the decision of LAMA were interviewed (using structured question answers based multi-option) and data were captured over a period of 16 months. The resultant database was analyzed using standard statistical methods.

Results
About 6.12% of childhood LAMA cases were dealt out of total pediatric admission including newborns. Neonatal preponderance noted in cases of LAMA from intensive care unit (ICU; 57.14%, p &lt; 0.05). The overall male (n = 293) to female (n = 235) ratio in this study was 1.25:1. Number of LAMA patients was higher from rural area (83.33%), mostly admitted in ICU (93.65%, Pearson’s chi-squared test, p &lt; 0.05). Higher proportion (29.47%) of patients with infection availed LAMA from neonatal age group but overall LAMA patients fall under category of respiratory disorders (22.35%). Interest of the domestics issues other than suffering child was considered primary during LAMA for those admitted in ward as compared with ICU patients [odds ratio (OR): 1.73, CI: 1.02–2.94, p &lt; 0.05]. ICU patients were reportedly to be taken to private health care facility (OR: 1.93, CI: 1.06–3.49, p &lt; 0.05). Duration of stay before taking LAMA from ward was &lt;7 days (85.59%, OR: 0.19, CI: 0.11–0.35, p &lt; 0.05). Upper-lower socio-economic class attributed financial constraint as the main reason for LAMA (Pearson’s chi-squared test, Chi-square value: 152.23, p &lt; 0.05).

Conclusions
This study tried to elucidate the determinants of childhood LAMA in rural Indian setting.
Leveraging big data for classification of children who stutter from fluent peers
Authors: Rutherford Saige , Angstadt Mike , Sripada Chandra , Chang Soo-Eun 
Published: October 2020

AbstractIntroductionLarge datasets, consisting of hundreds or thousands of subjects, are becoming the new data standard within the neuroimaging community. While big data creates numerous benefits, such as detecting smaller effects, many of these big datasets have focused on non-clinical populations. The heterogeneity of clinical populations makes creating datasets of equal size and quality more challenging. There is a need for methods to connect these robust large datasets with the carefully curated clinical datasets collected over the past decades.MethodsIn this study, resting-state fMRI data from the Adolescent Brain Cognitive Development study (N=1509) and the Human Connectome Project (N=910) is used to discover generalizable brain features for use in an out-of-sample (N=121) multivariate predictive model to classify young (3-10yrs) children who stutter from fluent peers.ResultsAccuracy up to 72% classification is achieved using 10-fold cross validation. This study suggests that big data has the potential to yield generalizable biomarkers that are clinically meaningful. Specifically, this is the first study to demonstrate that big data-derived brain features can differentiate children who stutter from their fluent peers and provide novel information on brain networks relevant to stuttering pathophysiology.DiscussionThe results provide a significant expansion to previous understanding of the neural bases of stuttering. In addition to auditory, somatomotor, and subcortical networks, the big data-based models highlight the importance of considering large scale brain networks supporting error sensitivity, attention, cognitive control, and emotion regulation/self-inspection in the neural bases of stuttering.
FANCM regulates repair pathway choice at stalled replication forks
Authors: Panday Arvind , Willis Nicholas A. , Elango Rajula , Menghi Francesca , Duffey Erin E. , Liu Edison T. , Scully Ralph 
Published: October 2020

SummaryConservative repair of stalled replication forks is important for the maintenance of a stable genome. However, the mechanisms that regulate repair pathway “choice” at stalled mammalian forks remain poorly understood. The Fanconi anemia complementation group M gene,FANCM, encodes a multi-domain scaffolding and motor protein that interacts with several distinct repair protein complexes at stalled forks. Here we use a chromosomally integrated reporter of stalled fork repair, in combination with defined mutations engineered within the endogenousFancmgene in primary mammalian cells, to study howFancmregulates stalled fork repair. We identify separation-of-functionFancmmutants, which reveal that distinct repair functions of FANCM are enacted by modular, molecularly separable scaffolding domains. These findings define FANCM as a key mediator of repair pathway choice at stalled replication forks and reveal its molecular mechanism. Notably, a mutation that inactivates the ATPase function of FANCM disables all FANCM-mediated repair functions and appears to “trap” FANCM at stalled forks. We find thatFancmnull cells do not survive genetic inactivation ofBrca1. This synthetic lethal interaction is recapitulated inFancmATPase-defective mutants. The ATPase function of FANCM may therefore represent a promising “druggable” target for therapy ofBRCA1mutant cancers.
Regulation of intracellular signaling and neuron function by Bardet-Biedl Syndrome proteins in patient-specific iPSC-derived neurons
Authors: Wang Liheng , Liu Yang , Stratigopoulos George , Panigrahi Sunil , Sui Lina , Leduc Charles A. , Glover Hannah J. , De Rosa Maria Caterina , Burnett Lisa C. , Williams Damian J. , Shang Linshan , Goland Robin , Tsang Stephen H. , Wardlaw Sharon , Egli Dieter , Zheng Deyou , Doege Claudia A. , Leibel Rudolph L. 
Published: October 2020

AbstractBardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and characterized by hyperphagic obesity. We developed a cellular model of BBS using induced pluripotent stem cell (iPSCs)-derived hypothalamic arcuate-like neurons. BBS mutationsBBS1M390RandBBS10C91fsX95did not affect neuron differentiation efficiency but caused morphological defects including impaired neurite outgrowth and longer primary cilia. Expression of intactBBS10normalized cilia length. Single-cell RNA sequencing (scRNA-seq) of BBS1M390Rhypothalamic neurons identified several down regulated pathways including insulin and cAMP signaling, and axon guidance. In agreement with scRNA-seq data, insulin-induced AKT phosphorylation at Thr308 was reduced inBBS1M390RandBBS10c91fsX95human fibroblasts and iPSC-derived neurons, as well as inBBS10knockdown iPSC-derived neurons. Overexpression of intactBBS10fully restored insulin receptor tyrosine phosphorylation inBBS10c91fsX95neurons. Mutations inBBS1andBBS10impaired leptin-mediated p-STAT3 activation in both human primary fibroblasts and iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling.POMCexpression inBBS1M390RandBBS10C91fsX95iPSC-derived hypothalamic neurons was downregulated, as was hypothalamicPomcin BBS1M390Rknockin (KI) mice. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBsome in CNS primary cilia mediate effects on energy homeostasis.
Global population structure and genotyping framework for genomic surveillance of the major dysentery pathogen,Shigella sonnei
Authors: Hawkey Jane , Paranagama Kalani , Baker Kate S. , Bengtsson Rebecca J. , Weill François-Xavier , Thomson Nicholas R. , Baker Stephen , Cerdeira Louise , Iqbal Zamin , Hunt Martin , Ingle Danielle J. , Dallman Timothy J. , Jenkins Claire , Williamson Deborah A. , Holt Kathryn E. 
Published: October 2020

AbstractShigella sonneiis the most common agent of shigellosis in high-income countries, and causes a significant disease burden in low- and middle-income countries. Antimicrobial resistance is increasingly common in all settings. Whole genome sequencing (WGS) is increasingly utilised forS. sonneioutbreak investigation and surveillance, but comparison of data between studies and labs is challenging. Here, we present a genomic framework and genotyping scheme forS. sonneito efficiently identify genotype and resistance determinants from WGS data. The scheme is implemented in the software package Mykrobe and tested on thousands of genomes. Applying this approach to analyse >4,000S. sonneiisolates sequenced in public health labs in three countries identified several common genotypes associated with increased rates of ciprofloxacin resistance and azithromycin resistance, confirming intercontinental spread of highly-resistantS. sonneiclones and demonstrating the genomic framework can facilitate monitoring of the emergence and spread of resistant clones at local and global scales.
CuBlock: A cross-platform normalization method for gene-expression microarrays
Authors: Junet Valentin , Farrés Judith , Mas José M. , Daura Xavier 
Published: October 2020

AbstractMotivationCross-(multi)platform normalization of gene-expression microarray data remains an unresolved issue. Despite the existence of several algorithms, they are either constrained by the need to normalize all samples of all platforms together, compromising scalability and reuse, by adherence to the platforms of a specific provider, or simply by poor performance. In addition, many of the methods presented in the literature have not been specifically tested against multi-platform data and/or other methods applicable in this context. Thus, we set out to develop a normalization algorithm appropriate for gene-expression studies based on multiple, potentially large microarray sets collected along multiple platforms and at different times, applicable in systematic studies aimed at extracting knowledge from the wealth of microarray data available in public repositories; for example, for the extraction of Real-World Data to complement data from Randomized Controlled Trials. Our main focus or criterion for performance was on the capacity of the algorithm to properly separate samples from different biological groups.ResultsWe present CuBlock, an algorithm addressing this objective, together with a strategy to validate cross-platform normalization methods. To validate the algorithm and benchmark it against existing methods, we used two distinct data sets, one specifically generated for testing and standardization purposes and one from an actual experimental study. Using these data sets, we benchmarked CuBlock against ComBat (Johnsonet al., 2007), YuGene (Lê Caoet al., 2014), DBNorm (Menget al., 2017), Shambhala (Borisovet al., 2019) and a simple log2transform as reference. We note that many other popular normalization methods are not applicable in this context. CuBlock was the only algorithm in this group that could always and clearly differentiate the underlying biological groups after mixing the data, from up to six different platforms in this study.AvailabilityCuBlock can be downloaded fromhttps://www.mathworks.com/matlabcentral/fileexchange/77882-cublockContactxouse@anaxomics.com,xavier.daura@uab.catSupplementary informationSupplementary data are available atbioRxivonline.
Amyloid ß Impacts Future Freezing of Gait in Parkinson’s Disease Via White Matter Hyperintensities
Authors: Dadar Mahsa , Miyasaki Janis , Duchesne Simon , Camicioli Richard 
Published: October 2020

AbstractBackgroundFreezing of gait (FOG) is a common symptom in Parkinson’s Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage.ObjectivesTo assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other.MethodsWe used baseline MRI and longitudinal gait data from the Parkinson’s Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG.ResultsSN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid β levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels.ConclusionsAmyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.