bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frameshift and frame-preserving mutations in zebrafishpresenilin 2affect different cellular functions in young adult brains
Authors: Barthelson Karissa , Pederson Stephen Martin , Newman Morgan , Jiang Haowei , Lardelli Michael 
Published: November 2020

AbstractBackgroundMutations inPRESENILIN 2(PSEN2) cause early disease onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for allPRESENILINgene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon – the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated.MethodsA frameshift mutation (psen2N140fs) and a reading frame-preserving mutation (psen2T141_L142delinsMISLISV) were previously isolated during genome editing directed at the N140 codon of zebrafishpsen2(equivalent to N141 of humanPSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analysed. Bioinformatics techniques were used to predict cellular functions affected by heterozygosity for each mutation.ResultsThe reading frame preserving mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signalling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions.ConclusionA frameshift and frame-preserving mutation at the same position in zebrafishpsen2cause discrete effects. Changes in oxidative phosphorylation, long term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.
Salicylate, Bile Acids and Extreme Acid Cause Fitness Tradeoffs for Multidrug Pumps inEscherichia coliK-12
Authors: Schaffner Samantha H. , Lee Abigail V. , Pham Minh T. N. , Kassaye Beimnet B. , Li Haofan , Tallada Sheetal , Lis Cassandra , Lang Mark , Liu Yangyang , Ahmed Nafeez , Galbraith Logan G. , Moore Jeremy P. , Bischof Katarina M. , Slonczewski Joan L. 
Published: November 2020

ABSTRACTThe aspirin derivative salicylate selects against bacterial multidrug efflux pumps ofEscherichia coliK-12 such as MdtEF-TolC and EmrAB-TolC, and acid stress regulators such as GadE. Salicylate uptake is driven by the transmembrane pH gradient (ΔpH) and the proton motive force (PMF) which drives many efflux pumps. We used flow cytometry to measure the fitness tradeoffs of salicylate, bile acids, and extreme low pH forE. colicultured with pump deletants. The AcrAB-TolC efflux pump conferred a fitness advantage in the presence of bile acids, an efflux substrate. Without bile acids, AcrA incurred a small fitness cost. The fitness advantage with bile acids was eliminated by the PMF uncoupler CCCP. The Gad acid fitness island encodes components of MdtEF-TolC (an acid-adapted efflux pump) as well as acid regulator GadE. The fitness advantage ofE. colicocultured with a Gad deletant (Δslp-gadX) was lost in the presence of salicylate. Salicylate caused an even larger fitness cost for GadE. MdtE incurred negative or neutral fitness under all media conditions, as did EmrA. But when the competition cycle included two hours at pH 2, MdtE conferred a fitness advantage. The MdtE advantage required the presence of bile acids. Thus, the MdtEF-TolC pump is useful toE. colifor transient extreme acid exposure comparable to passage through the acidic stomach. Salicylate selects against some multidrug efflux pumps, whereas bile acids selects for them; and these fitness tradeoffs are amplified by extreme acid.IMPORTANCEControl of drug resistance in gut microbial communities is a compelling problem for human health. Growth of gut bacteria is limited by host-produced acids such as bile acids, and may be modulated by plant-derived acids such as salicylic acid. Membrane-soluble organic acids can control bacterial growth by disrupting membranes, decreasing cell pH, and depleting PMF. Our flow cytometry assay measures the fitness effects of exposure to membrane-soluble organic acids, with growth cycles that may include a period of extreme acid. We find that extreme-acid exposure leads to a fitness advantage for a multidrug pump, MdtEF-TolC, which otherwise incurs a large fitness cost. Thus, organic acids and stomach acid may play important roles in controlling multidrug resistance in the gut microbiome. Therapeutic acids might be developed to limit the prevalence of multidrug resistance pumps in environmental and host-associated communities.
STAT3 inhibits Myocardin induced cardiac hypertrophy
Authors: Liao Xing-Hua , Xiang Yuan , Li Jia-Peng , Li Hui , Huang You , Shen Chao , Zhang Hui-Min , Zhang Tong-Cun 
Published: November 2020

AbstractBackgroundIn order to explore the molecular mechanism of cardiomyocyte-dependent myocardial gene expression and cardiomyocyte differentiation in cardiac hypertrophy, and to provide new insights for cardiac hypertrophy.MethodsCardiac myocytes were isolated from day 1-3 Sprague-Dawley rat pups. Real time quantitative PCR, western blot and immunocytochemistry Assay were used to detect the expression and localization of related genes. CO-IP was used to detect direct protein interactions between Myocardin and STAT3. Luciferase reporter assay and chromatin immunoprecipitation were used to detect the binding of Myocardin to the promoter of a downstream target gene. Microinjection of zebrafish embryos was used to examine the effects of STAT3 and Myocardin interactions on cardiac development in vivoResultsThe N-terminus of STAT3 directly binds to the basic domain of myocardin and inhibits the transcriptional activity of Myocardin-mediated cardiac-specific genes ANF and α-actinin, thereby inhibiting their expression, and further inhibit myocardin-mediated cardiac hypertrophy in vivo.ConclusionsIn summary, our report states that signal transduction and transcriptional activation factor 3 (STAT3) are inhibitors of the major cardiac hypertrophic transcription factor Myocardiin, which is required for cardiomyocyte differentiation. The STAT3-cardiacin interaction identified nuclear hormone receptor-mediated and cardiac-specific gene-regulated convergence sites and suggested a possible mechanism for cardioprotective effects.
Dynamic integration and segregation of amygdala subregional functional circuits linking to physiological arousal
Authors: Zeng Yimeng , Tao Fuxiang , Cui Zaixu , Wu Liyun , Xu Jiahua , Dong Wenshan , Liu Chao , Yang Zhi , Qin Shaozheng 
Published: November 2020

AbstractThe dynamical organization of brain networks is essential to support human cognition and emotion for rapid adaption to ever-changing environment. As the core nodes of emotion-related brain circuitry, the basolateral amygdala (BLA) and centromedial amygdala (CMA) as two major amygdalar nuclei, are recognized to play distinct roles in affective functions and internal states, via their unique connections with cortical and subcortical structures in rodents. However, little is known how the dynamical organization of emotion-related brain circuitry reflects internal autonomic responses in humans. Using resting-state functional magnetic resonance imaging (fMRI) with K-means clustering approach in a total of 79 young healthy individuals (cohort 1: 42; cohort 2: 37), we identified two distinct states of BLA- and CMA-based intrinsic connectivity patterns, with one state (integration) showing generally stronger BLA- and CMA-based intrinsic connectivity with multiple brain networks, while the other (segregation) exhibiting weaker yet dissociable connectivity patterns. In an independent cohort 2 of fMRI data with concurrent recording of skin conductance, we replicated two similar dynamic states and further found higher skin conductance level in the integration than segregation state. Moreover, machine learning-based Elastic-net regression analyses revealed that time-varying BLA and CMA intrinsic connectivity with distinct network configurations yield higher predictive values for spontaneous fluctuations of skin conductance level in the integration than segregation state. Our findings highlight dynamic functional organization of emotion-related amygdala nuclei circuits and networks and its links to spontaneous autonomic arousal in humans.
English rural policing: job stress and psychological distress
Authors: Houdmont Jonathan , Jachens Liza , Randall Raymond , Colwell Jim 
Published: November 2020

PurposeJob stressor exposure is associated with mental health in police officers. Police stress research rarely draws a distinction between urban and rural policing, raising the possibility that stressors specific to the rural context remain unidentified and their implications unknown. This may hinder actions to protect the mental health of those involved in policing rural communities.Design/methodology/approachAmong rural policing teams in an English county police force this study used an exploratory sequential mixed method design to (1) identify and quantify exposure to rural policing stressors and (2) examine links between job stressor exposure and psychological distress.FindingsInterviews (N = 34) identified three rural policing job stressor themes: (1) job demands, (2) isolation and (3) critical decisions. Survey data (N = 229) indicated significant differences in exposure by rank to demand and critical decision stressors, with police community support officers (PCSOs) reporting lower exposure than officers of constable and sergeant rank. Overall, 44% of respondents reported symptoms of psychological distress indicative of likely minor psychiatric disorder; higher levels of psychological distress were associated with higher stressor exposure across all three job stressor themes for PCSOs and constables and within the job demand theme for sergeants.Originality/valueFindings point towards practical actions focussed on resource provision for officers and a research strategy to ameliorate the impact of stressors in English rural policing.
Novel mutations in Chinese hypotrichosis simplex patients associated with LSS gene
Authors: Hua Shengyuan , Ding Yu , Zhang Jia , Qian Qiufang , Li Ming 
Published: November 2020

AbstractHypotrichosis simplex (HS) is a rare form of hereditary alopecia caused by a variety of genetic mutations. Currently, only four studies regarding LSS‐related HS have been reported. In this study, we try to make a definite diagnosis in two unrelated Chinese families with three pediatric patients clinically suspected of HS. Whole‐exome sequencing (WES) was performed for these two families to reveal the pathogenic mutation. WES revealed two different compound heterozygous mutations in LSS in two probands that confirmed the diagnosis, including three novel mutations. In this paper, we describe a new accompanying phenotype of teeth dysplasia in a HS patient. Moreover, we provide a review of all reported LSS mutation‐related patients and infer some potential genotype–phenotype correlations for the first time.
Health inequalities, fundamental causes and power: towards the practice of good theory
Authors: McCartney Gerry , Dickie Elinor , Escobar Oliver , Collins Chik 
Published: November 2020

AbstractReducing health inequalities remains a challenge for policy makers across the world. Beginning from Lewin’s famous dictum that “there is nothing as practical as a good theory”, this paper begins from an appreciative discussion of ‘fundamental cause theory’, emphasizing the elegance of its theoretical encapsulation of the challenge, the relevance of its critical focus for action, and its potential to support the practical mobilisation of knowledge in generating change. Moreover, it is argued that recent developments in the theory, provide an opportunity for further theoretical development focused more clearly on the concept of power (Dickie et al. 2015). A critical focus on power as the essential element in maintaining, increasing or reducing social and economic inequalities – including health inequalities – can both enhance the coherence of the theory, and also enhance the capacity to challenge the roots of health inequalities at different levels and scales. This paper provides an initial contribution by proposing a framework to help to identify the most important sources, forms and positions of power, as well as the social spaces in which they operate. Subsequent work could usefully test, elaborate and adapt this framework, or indeed ultimately replace it with something better, to help focus actions to reduce inequalities.
Community pharmacy and public health: preserving professionalism by extending the pharmacy gaze?
Authors: Atkin Karl , Madden Mary , Morris Stephanie , Gough Brendan , McCambridge Jim 
Published: November 2020

AbstractCommunity pharmacy faces ongoing challenges to its economic and social standing. A concern to legitimate professional status explains the attraction of public health. Interventions currently advocated by UK State‐sponsored health care seek to reconcile the autonomous ‘entrepreneurial’ patient with market‐driven solutions. Engaging critically with recent Foucauldian sociological work on pharmacy as a conduit for disciplinary power, we explore how professional ambiguity is exploited to ‘manage’ the subjectivities of community pharmacists. Locating our discussion in the observed empirical realities of pharmacy practice (the inclusion of alcohol and other ‘healthy living’ advice in the Medicines Use Review), we connect unresolved historical debates in community pharmacy with current ongoing (neoliberal) changes in policy and pharmacy business practices, drawing attention to the poor evidence base underpinning healthy living activities in community pharmacy. Our findings show how community pharmacists struggle to provide meaningful advice, valued by patients. Instead of enhancing professional status, ‘add‐on’ public health roles created the risk of offering little more than an essentialised enactment of consumerist health care. Understanding how patients conceptualise drinking and ‘healthy living’ in relation to their long‐term health, using more open discussions, including the negotiation (rather than provision) of information, could help community pharmacists challenge the current professional vulnerabilities they face.
G6PD overexpression protects from oxidative stress and age‐related hearing loss
Authors: Bermúdez‐Muñoz Jose M. , Celaya Adelaida M. , Hijazo‐Pechero Sara , Wang Jing , Serrano Manuel , Varela‐Nieto Isabel 
Published: November 2020

AbstractAging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose‐6‐phosphate dehydrogenase (G6PD), which catalyzes the rate‐limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD‐Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild‐type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3‐month‐old G6PD‐Tg mice than in wild‐type counterparts, whereas the levels of pro‐apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL+ apoptotic cells were all lower in 9‐month‐old G6PD‐Tg than in wild‐type counterparts. Unexpectedly, G6PD overexpression triggered low‐grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.
Genes Associated with Calcium Signaling are Involved in Alcohol‐Induced Breast Cancer Growth
Authors: Ho Charles , Lin Chin‐Yo 
Published: November 2020

BackgroundAlcohol consumption is a risk factor for breast cancer, contributing to up to nearly 23,000 new cases each year. Mechanistic studies show that alcohol increases tumor aggressiveness and metastatic potential, promotes angiogenesis, induces chronic inflammation, and dysregulates RNA polymerase III–related genes. Alcohol has also been shown to affect estrogen signaling in breast cancer, including in our study of the transcriptomic effects of alcohol in breast cancer cells.MethodsTo elucidate mechanisms of action of alcohol in breast cancer, we carried out secondary analyses of our alcohol‐responsive transcriptome data using gene ontology and pathway databases and analysis tools and cistromic data analysis of candidate transcription factors which may mediate the transcriptomic alterations. Predicted alcohol‐responsive pathways and mechanisms were perturbed and examined experimentally in breast cancer cells. The clinical relevance of identified genes was determined by expression profiles in patient samples and correlation with disease outcomes and alcohol consumption in previously published study cohorts.ResultsGene ontology analysis showed that alcohol alters the expression of many metabolism‐related genes, and cistromic data of differentially expressed genes revealed the potential involvement of nuclear factor of activated T cells 3 (NFATC3) in mediating the transcriptomic effects of alcohol. Pathway analysis also predicted regulation of calcium signaling by alcohol in breast cancer cells. Chemical perturbation of this pathway reversed the effect of alcohol on breast cancer cell growth and reduced the elevated cytosolic Ca2+ levels induced by alcohol. Expression levels of alcohol‐responsive genes in tumor samples from breast cancer patients are associated with poor disease outcomes. Moreover, expression of some of these genes was altered in breast cancer patients who consumed alcohol previously as compared to those who did not drink.ConclusionAlcohol alters expression of genes that regulate intracellular calcium levels and downstream signaling pathways which drive breast cancer cell proliferation and disease progression.
Are emotionally intelligent people happier? A meta‐analysis of the relationship between emotional intelligence and subjective well‐being using Chinese samples
Authors: Xu Xiaobo , Pang Weiguo , Xia Mengya 
Published: November 2020

To assess an overall correlation between emotional intelligence (EI) and subjective well‐being (SWB) within Chinese culture, accounting for possible moderating factors, we conducted a meta‐analysis of 119 correlations obtained from 62 studies with a total sample size of 29,922. The results uncovered a moderately positive correlation,r = .32, 95% CI [0.29, 0.36],p < .001, between EI and SWB. The strength of the correlation was moderated by EI stream, SWB component, participant’s age, and participant’s employment status. Specifically, this association was stronger when EI was measured as self‐report mixed EI,r = .49, and self‐report ability EI,r = .32, than when it was measured as performance‐based ability EI,r = .08. In addition, EI was more strongly associated with the cognitive components of SWB,r = .32, than with the affective component of SWB,r = .29, and the EI–SWB association was stronger in adults,r = .33, than in adolescents,r = .25. Furthermore, EI was more closely related to SWB in working adults,r = .43, compared to students,r = .29, and EI was almost equally associated with SWB across males and females, β = −.08,p = .55. The results, as well as their theoretical and practical implications, are discussed in detail with reference to relevant cross‐cultural theories and comparative empirical findings.
The effect of blood‐flow‐restricted interval training on lactate and H+ dynamics during dynamic exercise in man
Authors: Christiansen Danny , Eibye Kasper , Hostrup Morten , Bangsbo Jens 
Published: November 2020

AbstractAimTo assess how blood‐flow‐restricted (BFR) interval‐training affects the capacity of the leg muscles for pH regulation during dynamic exercise in physically trained men.MethodsTen men (age: 25 ± 4y; : 50 ± 5 mL∙kg−1∙min−1) completed a 6‐wk interval‐cycling intervention (INT) with one leg under BFR (BFR‐leg; ~180 mmHg) and the other without BFR (CON‐leg). Before and after INT, thigh net H+‐release (lactate‐dependent, lactate‐independent and sum) and blood acid/base variables were measured during knee‐extensor exercise at 25% (Ex25) and 90% (Ex90) of incremental peak power output. A muscle biopsy was collected before and after Ex90 to determine pH, lactate and density of H+‐transport/buffering systems.ResultsAfter INT, net H+ release (BFR‐leg: 15 ± 2; CON‐leg: 13 ± 3; mmol·min−1; Mean ± 95% CI), net lactate‐independent H+ release (BFR‐leg: 8 ± 1; CON‐leg: 4 ± 1; mmol·min−1) and net lactate‐dependent H+ release (BFR‐leg: 9 ± 3; CON‐leg: 10 ± 3; mmol·min−1) were similar between legs during Ex90 (P > .05), despite a ~142% lower muscle intracellular‐to‐interstitial lactate gradient in BFR‐leg (−3 ± 4 vs 6 ± 6 mmol·L−1; P < .05). In recovery from Ex90, net lactate‐dependent H+ efflux decreased in BFR‐leg with INT (P < .05 vs CON‐leg) owing to lowered muscle lactate production (~58% vs CON‐leg, P < .05). Net H+ gradient was not different between legs (~19%, P > .05; BFR‐leg: 48 ± 30; CON‐leg: 44 ± 23; mmol·L−1). In BFR‐leg, NHE1 density was higher than in CON‐leg (~45%; P < .05) and correlated with total‐net H+‐release (r = 0.71; P = .031) and lactate‐independent H+ release (r = 0.74; P = .023) after INT, where arterial [] and standard base excess in Ex25 were higher in BFR‐leg than CON‐leg.ConclusionCompared to a training control, BFR‐interval training increases the capacity for pH regulation during dynamic exercise mainly via enhancement of muscle lactate‐dependent H+‐transport function and blood H+‐buffering capacity.
Influence of blood haemoglobin concentration on renal haemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep
Authors: Lankadeva Yugeesh R. , May Clive N. , Cochrane Andrew D. , Marino Bruno , Hood Sally G. , McCall Peter R. , Okazaki Nobuki , Bellomo Rinaldo , Evans Roger G. 
Published: November 2020

AbstractAimBlood transfusion may improve renal oxygenation during cardiopulmonary bypass (CPB). In an ovine model of experimental CPB, we tested whether increasing blood haemoglobin concentration [Hb] from ~7 g dL−1 to ~9 g dL−1 improves renal tissue oxygenation.MethodsTen sheep were studied while conscious, under stable isoflurane anaesthesia, and during 3 hours of CPB. In a randomized cross‐over design, 5 sheep commenced bypass at a high target [Hb], achieved by adding 600 mL donor blood to the priming solution. After 90 minutes of CPB, PlasmaLyte® was added to the blood reservoir to achieve low target [Hb]. For the other 5 sheep, no blood was added to the prime, but after 90 minutes of CPB, 800‐900 mL of donor blood was given to achieve a high target [Hb].ResultsOverall, CPB was associated with marked reductions in renal oxygen delivery (−50 ± 12%, mean ± 95% confidence interval) and medullary tissue oxygen tension (PO2, −54 ± 29%). Renal fractional oxygen extraction was 17 ± 10% less during CPB at high [Hb] than low [Hb] (P = .04). Nevertheless, no increase in tissue PO2 in either the renal medulla (0 ± 6 mmHg change, P > .99) or cortex (−19 ± 13 mmHg change, P = .08) was detected with high [Hb].ConclusionsIn experimental CPB blood transfusion to increase Hb concentration from ~7 g dL−1 to ~9 g dL−1 did not improve renal cortical or medullary tissue PO2 even though it decreased whole kidney oxygen extraction.