bluuebunny/crossref_metadata_2025_split huggingface dataset:
ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain
Authors: Bulla M. , Gyimesi G. , Kim J.H. , Bhardwaj R. , Hediger M.A. , Frieden M. , Demaurex N. 
Published: November 2018

Key points
Gain‐of‐function mutations in the highly selective Ca2+ channel ORAI1 cause tubular aggregate myopathy (TAM) characterized by muscular pain, weakness and cramping.
TAM‐associated mutations in ORAI1 first and third transmembrane domain facilitate channel opening by STIM1, causing constitutive Ca2+ influx and increasing the currents evoked by Ca2+ store depletion.
Mutation V107M additionally decreases the channel selectivity for Ca2+ ions and its inhibition by acidic pH, while mutation T184M does not alter the channel sensitivity to pH or to reactive oxygen species.
The ORAI blocker GSK‐7975A prevents the constitutive activity of TAM‐associated channels and might be used in therapy for patients suffering from TAM.
AbstractSkeletal muscle differentiation relies on store‐operated Ca2+ entry (SOCE) mediated by STIM proteins linking the depletion of endoplasmic/sarcoplasmic reticulum Ca2+ stores to the activation of membrane Ca2+‐permeable ORAI channels. Gain‐of‐function mutations in STIM1 or ORAI1 isoforms cause tubular aggregate myopathy (TAM), a skeletal muscle disorder with muscular pain, weakness and cramping. Here, we characterize two overactive ORAI1 mutants from patients with TAM: V107M and T184M, located in the first and third transmembrane domain of the channel. When ectopically expressed in HEK‐293T cells or human primary myoblasts, the mutated channels increased basal and store‐operated Ca2+ entry. The constitutive activity of V107M, L138F, T184M and P245L mutants was prevented by low concentrations of GSK‐7975A while the G98S mutant was resistant to inhibition. Electrophysiological recordings confirmed ORAI1‐V107M constitutive activity and revealed larger STIM1‐gated V107M‐ and T184M‐mediated currents with conserved fast and slow Ca2+‐dependent inactivation. Mutation V107M altered the channel selectivity for Ca2+ ions and conferred resistance to acidic inhibition. Ca2+ imaging and molecular dynamics simulations showed a preserved sensitivity of T184M to the negative regulation by reactive oxygen species. Both mutants were able to mediate SOCE in Stim1−/−/Stim2−/− mouse embryonic fibroblasts expressing the binding‐deficient STIM1‐F394H mutant, indicating a higher sensitivity for STIM1‐mediated gating, with ORAI1‐T184M gain‐of‐function being strictly dependent on STIM1. These findings provide new insights into the permeation and regulatory properties of ORAI1 mutants that might translate into therapies against diseases with gain‐of‐function mutations in ORAI1.
Predicting reservoir hosts and arthropod vectors from evolutionary signatures in RNA virus genomes
Authors: Babayan Simon A. , Orton Richard J. , Streicker Daniel G. 
Published: November 2018

Predicting hosts and vectorsDuring outbreaks of mysterious infections, events can rapidly become dangerous and confusing. A combination of increasing experience with outbreaks and genome-sequencing technology now means the pathogen can often be identified within days. But for some of the most frightening viral pathogens, the originating hosts and possible vectors often remain obscure. Babayanet al.took sequence data from more than 500 single-stranded RNA viruses (see the Perspective by Woolhouse) and used machine-learning algorithms to extract evolutionary signals imprinted in the virus sequence that offer information about its original hosts and if an arthropod vector, and what type, plays a part in the virus's natural ecology.Science, this issue p.577; see also p.524
Atrial Fibrillation Screen, Management And Guideline Recommended Therapy (AF SMART II) in the rural primary care setting: an implementation study protocol
Authors: Orchard Jessica J , Neubeck Lis , Freedman Ben , Webster Ruth , Patel Anushka , Gallagher Robyn , Li Jialin , Hespe Charlotte Mary , Ferguson Caleb , Zwar Nicholas , Lowres Nicole 
Published: November 2018

IntroductionScreening for atrial fibrillation (AF) in people ≥65 years is now recommended by guidelines and expert consensus. While AF is often asymptomatic, it is the most common heart arrhythmia and is associated with increased risk of stroke. Early identification and treatment with oral anticoagulants can substantially reduce stroke risk. The general practice setting is ideal for opportunistic screening and provides a natural pathway for treatment for those identified.This study aims to investigate the feasibility of implementing screening for AF in rural general practice using novel electronic tools. It will assess whether screening will fit within an existing workflow to quickly and accurately identify AF, and will potentially inform a generalisable, scalable approach.Methods and analysisScreening with a smartphone ECG will be conducted by general practitioners and practice nurses in rural general practices in New South Wales, Australia for 3–4 months during 2018–2019. Up to 10 practices will be recruited, and we aim to screen 2000 patients aged ≥65 years. Practices will be given an electronic screening prompt and electronic decision support to guide evidence-based treatment for those with AF. De-identified data will be collected using a clinical audit tool and qualitative interviews will be conducted with selected practice staff. A process evaluation and cost-effectiveness analysis will also be undertaken. Outcomes include implementation success (proportion of eligible patients screened, fidelity to protocol), proportion of people screened identified with new AF and rates of treatment with anticoagulants and antiplatelets at baseline and completion. Results will be compared against an earlier metropolitan study and a ‘control’ dataset of practices.Ethics and disseminationEthics approval was received from the University of Sydney Human Research Ethics Committee on 27 February 2018 (Project no.: 2017/1017). Results will be disseminated through various forums, including peer-reviewed publication and conference presentations.Trial registration numberACTRN12618000004268; Pre-results.
Diagnosis of intrathyroidal ectopic thymus in thyroid fine needle aspiration samples
Authors: Li Weijie , Dim Daniel , Paulson Lorien , Rivard Douglas 
Published: November 2018

AimsIntrathyroidal ectopic thymus (ITET) is a rare cause of paediatric thyroid nodules. Although ultrasonography of ITET demonstrates a characteristic appearance similar to that of normal thymus, accurate differentiation from other thyroid nodule etiologies by ultrasonography is difficult, and so that fine needle aspiration (FNA) is usually performed for further analysis. The aim of this study was to evaluate the utility of flow cytometry (FCM) in confirming the diagnosis of ITET in thyroid FNA samples.MethodsFive cases of ITET were retrieved from our thyroid FNA database within a 3-year period. Their clinical information, ultrasonographic features, cytology and FCM findings were retrospectively reviewed. The FCM results were compared with those of 22 T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma (T-ALL/LBL) cases.ResultsThe FNA smears of all five ITET cases demonstrated abundant lymphocytes of variable sizes, which included some immature lymphoid cells. No Hassall’s bodies or atypical epithelioid cells were recognised. By multicolour FCM analysis including antibodies against CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD34, TDT and TCR, all ITET cases showed antigen expression patterns consistent with normal thymocyte maturation. All T-ALL/LBL cases exhibited significant immunophenotypic aberrancy.ConclusionsThe diagnosis of ITET based on FNA cytology is often inconclusive. The presence of immature lymphocytes often raises the concern for LBL. FCM with adequate antigen coverage can reliably distinguish ITET from T-ALL/LBL and make the diagnosis of ITET in FNA samples. Avoiding unnecessary further invasive procedures, providing reassurance to clinician and patient, the accurate diagnosis of ITET by FCM in FNA samples is clinically important.
Intergenerational social mobility and allostatic load in Great Britain
Authors: Präg Patrick , Richards Lindsay 
Published: November 2018

BackgroundIntergenerational social mobility is hypothesised to be a stressful process that has a negative effect on health. By examining the relationship between own socioeconomic position, parental socioeconomic position and allostatic load (AL) in a representative sample of the British population, we test this hypothesis.MethodsOur study uses cross-sectional data from 9851 adult participants of waves 2 and 3 of Understanding Society. The relationship between parental occupational class at age 14 years, respondents’ social class at the time of the interview and AL is explored by means of diagonal reference models, which allow us to disentangle the effects of parental social class, own social class and the mobility process. The AL score comprises the following biomarkers: (1) total cholesterol, (2) high-density lipoprotein cholesterol, (3) triglycerides, (4) glycated haemoglobin, (5) C-reactive protein, (6) fibrinogen, (7) systolic blood pressure, (8) diastolic blood pressure, (9) resting heart rate, (10) body mass index and (11) waist circumference.ResultsAL is particularly high among the stable working class and low among the stable upper class. On average, current class and origin class exert about equal weight on current AL. However, social mobility—regardless of whether upwards or downwards—is not detrimental for AL. Furthermore, we find evidence that class of origin may be less important among those outside the labour market for reasons other than retirement.ConclusionBoth own social class and parental social class influence AL to a similar extent. However, we find no evidence that mobility trajectories exert any effects, good or bad, on AL.
Correlates of support for a nicotine-reduction policy in smokers with 6-week exposure to very low nicotine cigarettes
Authors: Denlinger-Apte Rachel L , Tidey Jennifer W , Koopmeiners Joseph S , Hatsukami Dorothy K , Smith Tracy T , Pacek Lauren R , McClernon F Joseph , Donny Eric C 
Published: November 2018

BackgroundThe US Food and Drug Administration recently issued an advanced notice of proposed rule-making for reducing the nicotine content in cigarettes to a minimally addictive level. Very little is known about whether use of very low nicotine content (VLNC) cigarettes affects support for a nicotine reduction policy.ObjectiveThis study examined the effects of using VLNC versus usual brand (UB) cigarettes on support for a nicotine reduction policy and determined whether participant characteristics and responses to VLNC cigarettes were associated with policy support.MethodsParticipants from a cigarette trial who were assigned to either 0.4 mg nicotine/g tobacco research cigarettes or their UB for 6 weeks were asked about their support for the policy. χ2tests were used to compare support for the policy between cigarette conditions and logistic regression analyses were conducted to assess covariates associated with policy support.FindingsPolicy support did not differ by condition. After 6 weeks of using VLNC cigarettes, 50% of participants supported the policy, 26% opposed and 24% responded ‘Don’t Know’. Support was higher among those adherent to smoking only VLNC cigarettes (65%) compared with those who were non-adherent (44%). Older participants and those interested in quitting had increased odds of support. Cigarette satisfaction, perceived harm and perceived nicotine content were not significantly associated with support.ConclusionsSmoking VLNC cigarettes did not affect support for a nicotine reduction policy. Understanding predictors of policy support and opposition will help public health officials to maximise the public health acceptance and impact of this policy (ClinicalTrials.gov Identifier:NCT01681875Post-Results).
Exertional myopathy and hyoid luxation in a greyhound
Authors: Marsh Oliver James Richard , De Risio Luisa 
Published: November 2018

A four‐year‐old female neutered greyhound was presented for investigation of back pain and cough one week after an episode of extreme exertion. Investigations revealed severely elevated creatine kinase (CK), but no other haematological, biochemical or urinary abnormalities. MRI of the thoracolumbar spine showed diffuse, bilaterally symmetrical signal changes of the longissimus and iliocostalis muscles. These muscles were mildly hyperintense on T1W and markedly hyperintense on T2W and short tau inversion recovery (STIR) images, with strong contrast enhancement. The signal changes were consistent with muscle oedema, which was attributed to exertional myopathy. MRI of the pharynx demonstrated ceratohyoid‐epihyoid subluxation. This dog made a complete recovery with two weeks of conservative management, which consisted of strict rest and analgesia (carprofen and gabapentin).
DIDACache
Authors: Shen Zhaoyan , Chen Feng , Jia Yichen , Shao Zili 
Published: November 2018

Key-value caching is crucial to today’s low-latency Internet services. Conventional key-value cache systems, such as Memcached, heavily rely on expensive DRAM memory. To lower Total Cost of Ownership, the industry recently is moving toward more cost-efficient flash-based solutions, such as Facebook’s McDipper [14] and Twitter’s Fatcache [56]. These cache systems typically take commercial SSDs and adopt a Memcached-like scheme to store and manage key-value cache data in flash. Such a practice, though simple, is inefficient due to the huge
semantic gap
between the key-value cache manager and the underlying flash devices.

In this article, we advocate to reconsider the cache system design and directly open device-level details of the underlying flash storage for key-value caching. We propose an enhanced flash-aware key-value cache manager, which consists of a novel unified address mapping module, an integrated garbage collection policy, a dynamic over-provisioning space management, and a customized wear-leveling policy, to directly drive the flash management. A thin intermediate library layer provides a slab-based abstraction of low-level flash memory space and an API interface for directly and easily operating flash devices. A special flash memory SSD hardware that exposes flash physical details is adopted to store key-value items. This co-design approach bridges the semantic gap and well connects the two layers together, which allows us to leverage both the domain knowledge of key-value caches and the unique device properties. In this way, we can maximize the efficiency of key-value caching on flash devices while minimizing its weakness. We implemented a prototype, called DIDACache, based on the Open-Channel SSD platform. Our experiments on real hardware show that we can significantly increase the throughput by 35.5%, reduce the latency by 23.6%, and remove unnecessary erase operations by 28%.
Absence of the sulfate transporter SAT-1 has no impact on oxalate handling by mouse intestine and does not cause hyperoxaluria or hyperoxalemia
Authors: Whittamore Jonathan M. , Stephens Christine E. , Hatch Marguerite 
Published: November 2018

The anion exchanger SAT-1 [sulfate anion transporter 1 (Slc26a1)] is considered an important regulator of oxalate and sulfate homeostasis, but the mechanistic basis of these critical roles remain undetermined. Previously, characterization of the SAT-1-knockout (KO) mouse suggested that the loss of SAT-1-mediated oxalate secretion by the intestine was responsible for the hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis reportedly displayed by this model. To test this hypothesis, we compared the transepithelial fluxes of14C-oxalate,35[Formula: see text], and36Cl−across isolated, short-circuited segments of the distal ileum, cecum, and distal colon from wild-type (WT) and SAT-1-KO mice. The absence of SAT-1 did not impact the transport of these anions by any part of the intestine examined. Additionally, SAT-1-KO mice were neither hyperoxaluric nor hyperoxalemic. Instead, 24-h urinary oxalate excretion was almost 50% lower than in WT mice. With no contribution from the intestine, we suggest that this may reflect the loss of SAT-1-mediated oxalate efflux from the liver. SAT-1-KO mice were, however, profoundly hyposulfatemic, even though there were no changes to intestinal sulfate handling, and the renal clearances of sulfate and creatinine indicated diminished rates of sulfate reabsorption by the proximal tubule. Aside from this distinct sulfate phenotype, we were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO model. In conclusion, oxalate and sulfate transport by the intestine were not dependent on SAT-1, and we found no evidence supporting the long-standing hypothesis that intestinal SAT-1 contributes to oxalate and sulfate homeostasis.NEW & NOTEWORTHY SAT-1 is a membrane-bound transport protein expressed in the intestine, liver, and kidney, where it is widely considered essential for the excretion of oxalate, a potentially toxic waste metabolite. Previously, calcium oxalate kidney stone formation by the SAT-1-knockout mouse generated the hypothesis that SAT-1 has a major role in oxalate excretion via the intestine. We definitively tested this proposal and found no evidence for SAT-1 as an intestinal anion transporter contributing to oxalate homeostasis.
Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease
Authors: Xiao Heng , Deng Sheng , Deng Xiong , Gu Shaojuan , Yang Zhijian , Yin Hang , Deng Hao 
Published: November 2018

Background: Wilson’s disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu2+ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD. Methods: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation. Results: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val. Conclusion: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.
Proteome and Transcriptome Reveal Involvement of Heat Shock Proteins and Indoleacetic Acid Metabolism Process in Lentinula Edodes Thermotolerance
Authors: Wang Gang-Zheng , Ma Chao-Jun , Luo Yi , Zhou Sha-Sha , Zhou Yan , Ma Xiao-Long , Cai Ying-Li , Yu Jing-Jing , Bian Yin-Bing , Gong Yu-Hua 
Published: November 2018

Background/Aims: Heat stress could cause huge losses for Lentinula edodes in China and other Asian cultivation areas. Yet our understanding of mechanism how to defend to heat stress is incomplete. Methods: Using heat-tolerant and heat-sensitive strains of L. edodes, we reported a combined proteome and transcriptome analysis of L. edodes response to 40 °C heat stress for 24 h. Meanwhile, the effect of LeDnaJ on the thermotolerance and IAA (indoleacetic acid) biosynthesis in L. edodes was analyzed via the over-expression method. Results: The proteome results revealed that HSPs (heat shock proteins) such as Hsp40 (DnaJ), Hsp70, Hsp90 and key enzymes involved in tryptophan and IAA metabolism process LeTrpE, LeTrpD, LeTam-1, LeYUCCA were more highly expressed in S606 than in YS3357, demonstrating that HSPs and tryptophan as well as IAA metabolism pathway should play an important role in thermotolerance. Over-expression of LeDnaJ gene in S606 strains showed better tolerance to heat stress. It was also documented that intracellular IAA accumulation of S606 (8-fold up) was more than YS3357 (2-fold up), and exogenous IAA enhanced L. edodes tolerance to heat stress. Conclusion: Our data support the interest of LeTrpE, LeDnaJ, tryptophan and IAA could play a pivotal role in enhancing organism thermotolerance.
Покази до планового хірургічного лікування вагітних при первинному симптомному хронічному захворюванню вен нижніх кінцівок, зовнішніх статевих органів, промежини або в їх поєднанні в умовах короткотермінового перебування в стаціонарі
Authors: Аntonyuk-Кysil V. M. , Dziubanovskyi I. Ya. , Yenikeeva V. M. , Lichner S. I. , Lypnyi V. M. , Semeniuk M. V. 
Published: November 2018

Мета роботи: розробити і впровадити суворо індивідуальні показання до безпечного як для матері, так і дитини, ефективного патогенетичного планового хірургічного лікування вагітних із первинним симптомним хронічним захворюванням вен (ПСХЗВ) в умовах короткотермінового перебування в акушерському стаціонарі (до 72 год за термінологією IAAS).
Матеріали і методи. На базі комунального закладу «Обласний перинатальний центр» Рівненської обласної ради за період з початку 2013р.по перший квартал 2018р. прооперовано 356 вагітних з ПСХЗВ С2s-C4s,Еp,Аs,p.Pr (basis СЕАР,2002). Показанями до планового оперативного втручання у 246 вагітних (69,1 %) – були наростання явищ хронічної венозної недостатності нижніх кінцівок, зовнішніх статевих органів, промежини не зважаючи на проведену консервативну терапію; у 84 пацієнток (23,6 %) з метою підготовки пологових шляхів до природних пологів при варикозному розширенні вен зовнішніх статевих органів та промежини, для зменшення ризиків кровотеч при можливому розриві варикозних вузлів та звужуючи покази до хірургічних пологів; у 26 хворих (7,3 %) за їх побажанням зменшення косметичних проблем, які зумовлені варикозним розширенням вен зовнішніх статевих органів і/або на відкритих частинах нижніх кінцівок. Всім оперованим вагітним виконано дуплексне сканування вен із картографуванням патологічних зон (рефлюкси, варикозні конгломерати), оцінку біофізичного профілю плода (БПП), кардіотокографію (КТГ), вивчення згортаючої системи крові, кровотік у маткових, пуповинній, середньомозковій артеріях як до, так і після операції.
Результати досліджень та їх обговорення. Оперативні втручання виконували тільки при згоді вагітних, при відсутності протипоказань до оперативного втручання як з боку соматичного, так і акушерського статусів в умовах акушерського стаціонару. Всі оперативні втручання виконували без премедикації, для знеболення використовували тумесцентну анестезію і хірургічну методику за типом CHIVA при низхідному розвитку ПСХЗВ, а при висхідному – поєднання методик CHIVA і ASVAL. У 100 % вагітних під час оперативного втручання в післяопераційному періоді порушень соматичного статусу, тонусу матки у вагітних, серцебиття плода (дані КТГ, БПП) не зафіксовано. За суб’єктивною оцінкою вагітними, порушень кількості та якості рухів плода не зазначено, і вони у 98 % випадків вказали на позитивний клінічний результат хірургічного втручання. Оперовані у ІІ та на початку ІІІ триместрів у 85 % знаходились протягом 24 год, 10 % – на протягом 48 год в умовах стаціонару, після виписувались під спостереження акушера-гінеколога за місцем проживання, 5 % оперованих в кінці ІІІ триместру залишались в стаціонарі до пологів.