Δευτέρα, 6 Φεβρουαρίου 2017

Biosensing of DNA oxidative damage: a model of using glucose meter for non-glucose biomarker detection

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Light-triggered liposomal cargo delivery platform incorporating photosensitizers and gold nanoparticles for enhanced singlet oxygen generation and increased cytotoxicity

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Image-guided adaptive brachytherapy dose escalation for cervix cancer via fractionation compensation

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Publication date: Available online 6 February 2017
Source:Brachytherapy
Author(s): William Shaw, William I.D. Rae, Markus L. Alber
PurposeIn image-guided adaptive brachytherapy (IGABT), dose distributions are optimized for each fraction. Optimum fractional dose can be constant or adapted to previous fractions and a conjecture about the future ones. We evaluate the efficacy of different fraction size schemes, derived from total IGABT dose constraints, against constant per-fraction constraints.Methods and MaterialsThis retrospective planning study included 20 IGABT patients where four different fractionation schedules were compared based on modern planning recommendations. A total high-risk–clinical target volume D90 (minimum dose in 90% of the volume) dose aim of 90.0 Gy with constant per-fraction organs at risk (OARs) dose constraint planning (CONST) was compared with conservative and aggressive fractionation compensation (COMP) techniques. COMP allows variations in the per-fraction dose constraints. Dose accumulation was performed through dose summation at a given volume and equivalent uniform dose (EUD) worst-case dose estimates.ResultsNo significant differences were identifiable between dose metrics of CONST and COMP in the total patient population. However, a subgroup of patients with alternating dose-limiting OARs had significant benefit from COMP. Median high-risk–clinical target volume dose escalation ranged from 5% to 12%, whereas OAR dose increases were lower and ranged from 3% to 8%. EUD-based planning delivered similar tumor doses, although slightly lower OAR doses. By distributing the treatment aim over an increased number of treatment fractions, median tumor dose could be increased by a further 8% per additional treatment fraction at the same OAR dose levels for both CONST and COMP.ConclusionsCOMP is effective in patients with alternating dose-limiting OARs and is enhanced using more treatment fractions and EUD constraints.



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Toothache

Toothache: Pain in the tooth or gum. The most common cause of a toothache is a cavity or an injury to a tooth that exposes the pulp, which is heavily supplied by nerves.



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Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis

Summary

Hypoxia and HIF1α signaling direct tissue-specific gene responses regulating tumor progression, invasion and metastasis. By integrating HIF1α knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1α-dependent / hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP-Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for ten of the HIF1α direct targets – GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 – are significantly correlated with reduced time of Disease Free Status (DFS) in melanoma by logistic regression (P-value =0.0013) and ROC curve analysis (AUC= 0.826, P-value<0.0001). This HIF1α-regulated profile defines a melanocyte-specific response under hypoxia, and demonstrates the role of HIF1α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization and invasion.

This article is protected by copyright. All rights reserved.



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Expression, purification and functionality of bioactive recombinant human vascular endothelial growth factor VEGF165 in E. coli

Vascular endothelial growth factor (VEGF) is associated with tumour growth and metastasis. Because VEGF is the major player in both angiogenesis and vascular permeability and the most explored factor in angio-...

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Increasing cocoa butter-like lipid production of Saccharomyces cerevisiae by expression of selected cocoa genes

Cocoa butter (CB) extracted from cocoa beans mainly consists of three different kinds of triacylglycerols (TAGs), 1,3-dipalmitoyl-2-oleoyl-glycerol (POP, C16:0–C18:1–C16:0), 1-palmitoyl-3-stearoyl-2-oleoyl-gly...

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A maternal Western diet during gestation and lactation modifies offsprings microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs [Research]

A suboptimal early nutritional environment (i.e., excess of energy, sugar, and fat intake) can increase susceptibility to diseases and neurocognitive disorders. The purpose of this study was to investigate in nonobese Yucatan minipigs (Sus scrofa) the impact of maternal diet [standard (SD) vs. Western (WD) diet] during gestation and 25 d of lactation on milk composition, blood metabolism, and microbiota activity of sows (n = 17) and their piglets (n = 65), and on spatial cognition (n = 51), hippocampal plasticity (n = 17), and food preferences/motivation (n = 51) in the progeny. Milk dry matter and lipid content, as well as plasma total cholesterol and free fatty acid (FFA) concentrations (P < 0.05) were higher in WD than in SD sows. Microbiota activity decreased in both WD sows and 100-d-old piglets (P < 0.05 or P < 0.10, depending on short-chain FAs [SCFAs]). At weaning [postnatal day (PND) 25], WD piglets had increased blood triglyceride and FFA levels (P < 0.01). Both SD and WD piglets consumed more of a known SD than an unknown high-fat/-sucrose (HFS) diet (P < 0.0001), but were quicker to obtain HFS rewards compared with SD rewards (P < 0.01). WD piglets had higher working memory (P = 0.015) and reference memory (P < 0.001) scores, which may reflect better cognitive abilities in the task context and a higher motivation for the food rewards. WD piglets had a smaller hippocampal granular cell layer (P = 0.03) and decreased neurogenesis (P < 0.005), but increased cell proliferation (P < 0.001). A maternal WD during gestation and lactation, even in the absence of obesity, has significant consequences for piglets’ blood lipid levels, microbiota activity, gut–brain axis, and neurocognitive abilities after weaning.—Val-Laillet, D., Besson, M., Guérin, S., Coquery, N., Randuineau, G., Kanzari, A., Quesnel, H., Bonhomme, N., Bolhuis, J. E., Kemp, B., Blat, S., Le Huërou-Luron, I., Clouard, C. A maternal Western diet during gestation and lactation modifies offspring’s microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs.



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Adopting and sustaining a Virtual Fracture Clinic model in the District Hospital setting - a quality improvement approach

Virtual Fracture Clinics (VFCs) are an alternative to the conventional fracture clinics, to manage certain musculoskeletal injuries. This has recently been reported as a safe, cost-effective and efficient care model. As demonstrated at vanguard sites in the United Kingdom, VFCs can enhance patient care by standardising treatment and reducing outpatient appointments.

This project demonstrates how a Quality Improvement approach was applied to introduce VFCs in the District General Hospital setting. We demonstrate how undertaking Process Mapping, Driver Diagrams, and Stakeholder Analysis can assist implementation. We discuss Whole Systems Measures applicable to VFCs, to consider how robust and specific data collection can progress this care model.

Three Plan-Do-Study-Act cycles led to a change in practice over a 21-month period. Our target for uptake of new patients seen in VFCs within 6 months of starting was set at 50%. It increased from 0% to 56.1% soon after introduction, and plateaued at an average of 56.4% in the six-months before the end of the study period.

Careful planning, frequent monitoring, and gathering feedback from a multidisciplinary team of varying seniority, were the important factors in transitioning to, and sustaining, a successful VFC model.



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Correction

van Fessem J, Willems J, Kruip M, et al. Making safer preoperative arrangements for patients using vitamin K antagonists. BMJ Qual Improv Report 2017;6:u212617.w5031 doi:10.1136/bmjquality.u212617.w5031

Table 2a in this article has been amended.



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Erratum to: A feasibility study of the clinical effectiveness and cost-effectiveness of individual cognitive behavioral therapy for panic disorder in a Japanese clinical setting: an uncontrolled pilot study



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Prognostic factors and survival according to tumour subtype in women presenting with breast cancer brain metastases at initial diagnosis

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Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): José Pablo Leone, Julieta Leone, Ariel Osvaldo Zwenger, Julián Iturbe, Bernardo Amadeo Leone, Carlos Teodoro Vallejo
BackgroundThe presence of brain metastases at the time of initial breast cancer diagnosis (BMIBCD) is uncommon. Hence, the prognostic assessment and management of these patients is very challenging. The aim of this study was to analyse the influence of tumour subtype compared with other prognostic factors in the survival of patients with BMIBCD.MethodsWe evaluated women with BMIBCD, reported to Surveillance, Epidemiology and End Results program from 2010 to 2013. Patients with other primary malignancy were excluded. Univariate and multivariate analyses were performed to determine the effects of each variable on overall survival (OS).ResultsWe included 740 patients. Median OS for the whole population was 10 months, and 20.7% of patients were alive at 36 months. Tumour subtype distribution was: 46.6% hormone receptor (HR)+/HER2−, 17% HR+/HER2+, 14.1% HR−/HER2+ and 22.3% triple-negative. Univariate analysis showed that the presence of liver metastases, lung metastases and triple-negative patients (median OS 6 months) had worse prognosis. The HR+/HER2+ subtype had the longest OS with a median of 22 months. In multivariate analysis, older age (hazard ratio 1.8), lobular histology (hazard ratio 2.08), triple-negative subtype (hazard ratio 2.25), liver metastases (hazard ratio 1.6) and unmarried patients (hazard ratio 1.39) had significantly shorter OS.ConclusionsAlthough the prognosis of patients with BMIBCD is generally poor, 20.7% were still alive 3 years after the diagnosis. There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS are age at diagnosis, marital status, histology and liver metastases.



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Policy and priorities for national cancer control planning in low- and middle-income countries: Lessons from the Association of Southeast Asian Nations (ASEAN) Costs in Oncology prospective cohort study

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Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): The ACTION Study GroupWriting committeNirmalaBhoo-PathyCheng-HarYipSanne A.E.PetersMerelKimmanRichardSullivanStephenJanMarkWoodwardChiu-WanNg: Julius Centre University of Malaya Department of Social and Preventive Medicine Faculty of Medicine University of Malaya 50603 Lembah Pantai Kuala Lumpur Malaysia. Fax: +60 3 7967 4975.Principal investigatorsPhetsamoneArounlangsySoeAungSoledad L.BaleteNirmalaBhoo-PathyBounthaphanyBounxoueiDieuBuiJayDatukanAgnes E.GorospeCheng HarYipPrasitKhopaibulThanutKhuayjarernpanishkThiravudKhuhapremaMyoKhinTawinKlinwimolSomkietLalitwongsaDhanooLawbundisConradoLolaGloriaCristal-LunaLeoMarbellaKhoa MaiTrongSoe OoMaungShuMonWin PaPa NaingCorazon A.NgelangelHtun LwinNyeinAnnielyn BerylOng-CornelKhin MayOoIrisylOrolfo-RealDung PhamXuanSeangPharinPujiantoOudayvoneRattanavongKouySamnangSomphobSangkittipaiboonSuleepornSangrajrangCherelinaSantiago-FerrerasPrihSarniantoSanShweEavSokhaThanadejSinthusakeDaruneeSuanpluJitrapornTanabodeeHasbullahThabranyKitisakThepsuwanYin YinHtunHengViroathLeLe WinSwe SweWinTin MoeWinOther contributorsAmiAshariatiDjumhanaAtmakusumaI.MadeBaktaLoan DangThi KimPhung DangThi NgocTuan DiepBaoArioDjatmikoAndiFachruddinPik-PinGohJohanKurniandaHelenMonaghanAbdulMuthalibTrang NgoThuyThao NguyenHoangNga NguyenThi HoaiSonar S.PanigoroHuy PhạmQuangKhanh QuachThanhDradjat R.SuardiShriDeviSubramaniamAru W.SudoyoKhoa TranDangHa TranDinhCatharinaSuhartiSuyatno
BackgroundEvidence to guide policymakers in developing affordable and equitable cancer control plans are scarce in low- and middle-income countries (LMIC).MethodsThe 2012–2014 ASEAN Costs in Oncology Study prospectively followed-up 9513 newly diagnosed cancer patients from eight LMIC in Southeast Asia for 12 months. Overall and country-specific incidence of financial catastrophe (out-of-pocket health costs ≥ 30% of annual household income), economic hardship (inability to make necessary household payments), poverty (living below national poverty line), and all-cause mortality were determined. Stepwise multinomial regression was used to estimate the extent to which health insurance, cancer stage and treatment explained these outcomes.ResultsThe one-year incidence of mortality (12% in Malaysia to 45% in Myanmar) and financial catastrophe (24% in Thailand to 68% in Vietnam) were high. Economic hardship was reported by a third of families, including inability to pay for medicines (45%), mortgages (18%) and utilities (12%), with 28% taking personal loans, and 20% selling assets (not mutually exclusive). Out of households that initially reported incomes above the national poverty levels, 4·9% were pushed into poverty at one year. The adverse economic outcomes in this study were mainly attributed to medical costs for inpatient/outpatient care, and purchase of drugs and medical supplies. In all the countries, cancer stage largely explained the risk of adverse outcomes. Stage-stratified analysis however showed that low-income patients remained vulnerable to adverse outcomes even when diagnosed with earlier cancer stages.ConclusionThe LMIC need to realign their focus on early detection of cancer and provision of affordable cancer care, while ensuring adequate financial risk protection, particularly for the poor.



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Randomised controlled trial examining the effect of an outpatient exercise training programme on haemodynamics and cardiac MR parameters of right ventricular function in patients with pulmonary arterial hypertension: the ExPAH study protocol

Introduction

Pulmonary hypertension (PH) is a potentially life-threatening condition characterised by elevated pulmonary artery pressure. Early stage PH patients are often asymptomatic. Disease progression is associated with impairment of right ventricular function and progressive dyspnoea. Current guidelines recommend exercise training (grade IIa, level B). However, many questions remain regarding the mechanisms of improvement, intensity of supervision and optimal frequency, duration and intensity of exercise. This study will assess the effect of an outpatient rehabilitation programme on haemodynamics and cardiac right ventricular function in patients with pulmonary arterial hypertension (PAH), a subgroup of PH.

Methods and analysis

This randomised controlled trial involves both a major urban tertiary and smaller regional hospital in New South Wales, Australia. The intervention will compare an outpatient rehabilitation programme with a control group (home exercise programme). Participants will be stable on oral PAH-specific therapy. The primary outcome measure will be right ventricular ejection fraction measured by cardiac MRI. Secondary outcomes will include haemodynamics measured by right heart catheterisation, endurance, functional capacity, health-related quality of life questionnaires and biomarkers of cardiac function and inflammation.

Ethics approval and dissemination

Ethical approval has been granted by St Vincent's Hospital, Sydney (HREC/14/SVH/341). Results of this study will be disseminated through presentation at scientific conferences and in scientific journals.

Trial registration number

ACTRN12615001041549; pre-results.



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Systematic review and meta-analysis: Tai Chi for preventing falls in older adults

Objective

It remains unclear whether Tai Chi is effective for preventing falls in older adults. We undertook this systematic review to evaluate the preventive effect of Tai Chi by updating the latest trial evidence.

Design

Systematic review and meta-analysis.

Methods

The Cochrane Library, MEDLINE and EMBASE were searched up to February 2016 to identify randomised trials evaluating Tai Chi for preventing falls in older adults. We evaluated the risk of bias of included trials using the Cochrane Collaboration's tool. Results were combined using random effects meta-analysis.

Outcome measures

Number of fallers and rate of falls.

Results

18 trials with 3824 participants were included. The Tai Chi group was associated with significantly lower chance of falling at least once (risk ratio (RR) 0.80, 95% CI 0.72 to 0.88) and rate of falls (incidence rate ratio (IRR) 0.69, 95% CI 0.60 to 0.80) than the control group. Subgroup analyses suggested that the preventive effect was likely to increase with exercise frequency (number of fallers: p=0.001; rate of falls: p=0.007) and Yang style Tai Chi was likely to be more effective than Sun style Tai Chi (number of fallers: p=0.01; rate of falls: p=0.001). The results might be influenced by publication bias as the funnel plots showed asymmetry. Sensitivity analyses by sample size, risk of bias and comorbidity showed no major influence on the primary results.

Conclusions

Tai Chi is effective for preventing falls in older adults. The preventive effect is likely to increase with exercise frequency and Yang style Tai Chi seems to be more effective than Sun style Tai Chi.



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Does achieving the best practice tariff improve outcomes in hip fracture patients? An observational cohort study

Objectives

To determine if the introduction of the best practice tariff (BPT) has improved survival of the elderly hip fracture population, or if achieving BPT results in improved survival for an individual.

Setting

A single university-affiliated teaching hospital.

Participants

2541 patients aged over 60 admitted with a neck of femur fracture between 2008 and 2010 and from 2012 to 2014 were included, to create two cohorts of patients, before and after the introduction of BPT. The post-BPT cohort was divided into two groups, those who achieved the criteria and those who did not.

Primary and secondary outcome measures

Primary outcomes of interest were differences in mortality across cohorts. Secondary analysis was performed to identify associations between individual BPT criteria and mortality.

Results

The introduction of BPT did not significantly alter overall 30-mortality in the hip fracture population (8.3% pre-BPT vs 10.0% post-BPT; p=0.128). Neither was there a significant reduction in length of stay (15 days (IQR 9–21) pre-BPT vs 14 days (IQR 11–22); p=0.236). However, the introduction of BPT was associated with a reduction in the time from admission to theatre (median 44 hours pre-BPT (IQR 24–44) vs 23 hours post-BPT (IQR 17–30); p<0.005). 30-day mortality in those who achieved BPT was significantly lower (6.0% vs 21.0% in those who did not achieve-BPT; p<0.005). There was a survival benefit at 1 year for those who achieved BPT (28.6% vs 42.0% did not achieve-BPT; p<0.005). Multivariate logistic regression revealed that of the BPT criteria, AMT monitoring and expedited surgery were the only BPT criteria that significantly influenced survival.

Conclusions

The introduction of the BPT has not led to a demonstrable improvement in outcomes at organisational level, though other factors may have confounded any benefits. However, patients where BPT criteria are met appear to have improved outcomes.



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Standardisation of delivery and assessment of research training for specialty trainees based on curriculum requirements: recommendations based on a scoping review

Objectives

(1) To conduct a scoping review of postgraduate specialty training (ST) curricula for doctors within Health Education England in order to identify common themes and variations in requirements for training and assessment of research competencies. (2) To make recommendations on standardisation of training for clinical research across ST programmes.

Setting

Health Education England North East and National Institute for Health Research Clinical Research Network (CRN)—North East and North Cumbria.

Methods

Annual Review of Competence Progression (ARCP); Certificate of Completion of Training (CCT) checklists and curricula for ST were obtained from Health Education England North East and reviewed between June and September 2015. Research competence requirements based on knowledge, skills or behaviour-based domains were identified and entered onto a spreadsheet for analysis. Common themes with levels of competence required were identified. This information was used to construct and propose a model for delivery of training in clinical research across ST programmes.

Results

Sixty-two ST curricula were reviewed and seven common themes for research training were found in up to 97% of the curricula. Requirement for good clinical practice (GCP) in research training was included in 15% of curricula. One of the common themes involved knowledge-based competency, and three each of the remaining seven involved skills or behaviour-based competencies. There was less clarity and larger variation between specialties in how research competencies were assessed; and what evidence was required for ARCP and CCT to assure competence. 63% (19/30) of curricula from medical specialties had no mention of research requirements within their ARCP guidelines.

Conclusions

Given that the majority of specialty curricula contain consistent themes around core research knowledge, consideration should be given to standardising the delivery and assessment of generic research competencies within ST. Our recommendations from this review could form the basis for developing structured research training for specialty trainees involving: (1) a taught course for knowledge-based competencies; (2) clinical placements with CRN teams for practical workplace-based experience and (3) developing research tutors to help support placements and assessment of these competencies.



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Integrated collaborative care teams to enhance service delivery to youth with mental health and substance use challenges: protocol for a pragmatic randomised controlled trial

Introduction

Among youth, the prevalence of mental health and addiction (MHA) disorders is roughly 20%, yet youth are challenged to access evidence-based services in a timely fashion. To address MHA system gaps, this study tests the benefits of an Integrated Collaborative Care Team (ICCT) model for youth with MHA challenges. A rapid, stepped-care approach geared to need in a youth-friendly environment is expected to result in better youth MHA outcomes. Moreover, the ICCT approach is expected to decrease service wait-times, be more youth-friendly and family-friendly, and be more cost-effective, providing substantial public health benefits.

Methods and analysis

In partnership with four community agencies, four adolescent psychiatry hospital departments, youth and family members with lived experience of MHA service use, and other stakeholders, we have developed an innovative model of collaborative, community-based service provision involving rapid access to needs-based MHA services. A total of 500 youth presenting for hospital-based, outpatient psychiatric service will be randomised to ICCT services or hospital-based treatment as usual, following a pragmatic randomised controlled trial design. The primary outcome variable will be the youth's functioning, assessed at intake, 6 months and 12 months. Secondary outcomes will include clinical change, youth/family satisfaction and perception of care, empowerment, engagement and the incremental cost-effectiveness ratio (ICER). Intent-to-treat analyses will be used on repeated-measures data, along with cost-effectiveness and cost-utility analyses, to determine intervention effectiveness.

Ethics and dissemination

Research Ethics Board approval has been received from the Centre for Addiction and Mental Health, as well as institutional ethical approval from participating community sites. This study will be conducted according to Good Clinical Practice guidelines. Participants will provide informed consent prior to study participation and data confidentiality will be ensured. A data safety monitoring panel will monitor the study. Results will be disseminated through community and peer-reviewed academic channels.

Trial registration number

Clinicaltrials.gov NCT02836080.



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Evaluation of demands, usage and unmet needs for emergency care in Yaounde, Cameroon: a cross-sectional study

Objectives

To assess the burden of emergent illnesses and emergency care system usage by Yaoundé residents and to evaluate unmet needs for emergency care and associated barriers.

Design

A cross-sectional study using a community-based survey.

Setting

Yaoundé, Cameroon.

Participants

All residents living in Yaoundé were selected as the target population to investigate the needs and usage of emergency care in Yaoundé. 14 households in every health area (47 in total) were selected using 2-stage sampling.

Primary outcome measures

Unmet needs for emergency care.

Results

Among the 3201 participants from 619 households who completed the survey, 1113 (34.8%) with median age of 22 experienced 1 or more emergency conditions in the previous year. Respondents who experienced emergency conditions used emergency units (7.0%), outpatient clinics (46.5%) or hospitalisation (13.0%), and in overall, 68.8% of them reported unmet needs for emergency care. The primary reasons for not seeking healthcare were economic issues (37.2%) and use of complementary medicine (22.2%). Young age (adjusted OR (95% CI) 1.80 (1.23 to 2.62)), rental housing (1.50 (1.11 to 2.03)) and moderate household income (0.60 (0.36 to 0.99)) were associated with unmet needs for emergency care.

Conclusions

Residents of Yaoundé had a high demand for emergency care, and high unmet needs were observed due to low emergency care usage. Development of a cost-effective, universal emergency care system is urgently needed in Cameroon.



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Validation of a risk stratification tool for fall-related injury in a state-wide cohort

Objective

A major preventable contributor to healthcare costs among older individuals is fall-related injury. We sought to validate a tool to stratify such risk based on readily available clinical data, including projected medication adverse effects, using state-wide medical claims data.

Design

Sociodemographic and clinical features were drawn from health claims paid in the state of Massachusetts for individuals aged 35–65 with a hospital admission for a period spanning January–December 2012. Previously developed logistic regression models of hospital readmission for fall-related injury were refit in a testing set including a randomly selected 70% of individuals, and examined in a training set comprised of the remaining 30%. Medications at admission were summarised based on reported adverse effect frequencies in published medication labelling.

Setting

The Massachusetts health system.

Participants

A total of 68 764 hospitalised individuals aged 35–65 years.

Primary Measures

Hospital readmission for fall-related injury defined by claims code.

Results

A total of 2052 individuals (3.0%) were hospitalised for fall-related injury within 90 days of discharge, and 3391 (4.9%) within 180 days. After recalibrating the model in a training data set comprised of 48 136 individuals (70%), model discrimination in the remaining 30% test set yielded an area under the receiver operating characteristic curve (AUC) of 0.74 (95% CI 0.72 to 0.76). AUCs were similar across age decades (0.71 to 0.78) and sex (0.72 male, 0.76 female), and across most common diagnostic categories other than psychiatry. For individuals in the highest risk quartile, 11.4% experienced fall within 180 days versus 1.2% in the lowest risk quartile; 57.6% of falls occurred in the highest risk quartile.

Conclusions

This analysis of state-wide claims data demonstrates the feasibility of predicting fall-related injury requiring hospitalisation using readily available sociodemographic and clinical details. This translatable approach to stratification allows for identification of high-risk individuals in whom interventions are likely to be cost-effective.



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Occupational Therapy Students’ Perceptions of the Role of Robots in the Care for Older People Living in the Community

Background. The question arises how recent developments in robotics can contribute to the care for older people. The study is part of the EU-funded ENRICHME project. Objectives of Study. The aim of the study was to investigate opinions of occupational therapy students (OTS), as future professional caregivers, on the use of robots in care for older people. Methods. It included 26 OTS from Poznan University of Medical Sciences. To collect data, the Users’ Needs, Requirements, and Abilities Questionnaire (UNRAQ) was developed. Findings. OTS perceived the robot as “a useful device” and “an assistant” rather than “a companion” (). In their opinion, the most important functions of the robot were related to health aspects (emergency alarms, health parameters monitoring, physical activity and memory training, and reminders about medication, drinks, etc.), scored positively by 23–26 OTS. Functions such as mood detection, encouraging to contact with friends, and monitoring of food consumption were accepted by 16-17 OTS. Two statements concerning social functions (accompanying in everyday activities and decreasing the sense of loneliness) were rated positively by less the than half of the participants. Limitations and Recommendations for Further Research. A module concerning technology use, including robotics, should constitute an important part of the curricula of both academic and continuous education of OTS.

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Are the Pathological Characteristics of Prostate Cancer More Aggressive or More Indolent Depending upon the Patient Age?

Purpose. To identify pathological characteristics of prostate cancer according to patient age at diagnosis. Methods. A retrospective review of 2,929 men diagnosed with prostate cancer was performed. Pathological characteristics were compared across age groups: ≤55, 56–75, and >75 years. Results. The study cohort included 133 patients (4.5%), 2,033 patients (69.5%), and 763 patients (26.0%) in the three age groups, respectively. The median pathological Gleason sums in the three age groups were 8, 7, and 8, respectively. The Gleason sum, primary Gleason score, and second primary Gleason score were significantly different among the three age groups (, ; , ; , , resp.). The percentages of Gleason pattern 5 tumors for the three age groups were 44.4%, 32.3%, and 36.8%, respectively; they were significantly different (, ). The percentages of tumors with Gleason score grade groups 3–5 for the three age groups were 66.9%, 60.5%, and 66.3%, respectively; they were significantly different (, ). Conclusions. The present study indicated that men aged ≤55 years or >75 years show higher levels of clinically significant prostate cancer compared to patients between the ages of 55 and 75 years. Younger and more elderly male patients are more likely to have a more aggressive disease.

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Unconventional Role of Caspase-6 in Spinal Microglia Activation and Chronic Pain

Chronic pain affects ~20% of the worldwide population. The clinical management of chronic pain is mostly palliative and results in limited success. Current treatments mostly target the symptoms or neuronal signaling of chronic pain. It has been increasingly recognized that glial cells, such as microglia, and inflammatory signaling play a major role in the pathogenesis of chronic pain. Caspases (CASPs) are a family of protease enzymes involved in apoptosis and inflammation. They are pivotal components in a variety of neurological diseases. However, little is known about the role of CASPs in microglial modulation as to chronic pain. In particular, our recent studies have shown that CASP6 regulates chronic pain via microglial inflammatory signaling. Inhibition of microglia and CASP signaling might provide a new strategy for the prevention and treatment of chronic pain.

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Functional Roles and Therapeutic Applications of Exosomes in Hepatocellular Carcinoma

Exosomes are important in intercellular communication. They assure the horizontal transfer of specific functional contents (i.e., proteins, lipids, RNA molecules, and circulating DNA) from donor to recipient cells. Notably, tumor-derived exosomes (TDEs) appear to be an important vehicle of specific signals in cancer, impacting on tumor growth and metastasis. Recent researches point to the characterization of exosomes in Hepatocellular Carcinoma (HCC), the major adult liver malignancy. In this review, we summarize current findings on HCC exosomes, focusing on the identification of noncoding RNAs as exosome-enriched functional regulators and new potential biomarkers. The great potential of exosomes in future HCC diagnostic and therapeutic approaches is underlined.

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Primary Tumor Characteristics Are Important Prognostic Factors for Sorafenib-Treated Patients with Metastatic Renal Cell Carcinoma: A Retrospective Multicenter Study

We aimed to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with sorafenib. We investigated 177 patients, including 116 who received sorafenib as first-line therapy, using the Cox regression model. During a median follow-up period of 19.2 months, the PFS and OS were 6.4 and 32.6 months among all patients and 7.4 months and undetermined for first-line sorafenib-treated patients, respectively. Clinical T3-4 stage (hazard ratio [HR] 2.56) and a primary tumor size >7 cm (HR 0.34) were significant prognostic factors for PFS among all patients, as were tumor size >7 cm (HR 0.12), collecting system invasion (HR 5.67), and tumor necrosis (HR 4.11) for OS (). In first-line sorafenib-treated patients, ≥4 metastatic lesions (HR 28.57), clinical T3-4 stage (HR 4.34), collecting system invasion (univariate analysis HR 2.11; multivariate analysis HR 0.07), lymphovascular invasion (HR 13.35), and tumor necrosis (HR 6.69) were significant prognosticators of PFS, as were bone metastasis (HR 5.49) and clinical T3-4 stages (HR 4.1) for OS (). Our study thus identified a number of primary tumor-related characteristics as important prognostic factors in sorafenib-treated mRCC patients.

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Capacity Allocation and Revenue Sharing in Airline Alliances: A Combinatorial Auction-Based Modeling

This paper attempts to establish a framework to help airline alliances effectively allocate their seat capacity with the purpose of maximizing alliances’ revenue. By assuming the airline alliance as the auctioneer and seat capacity in an itinerary as lots, the combinatorial auction model is constructed to optimize the allocation of the seat, and the revenue sharing method is established to share revenue between partners by Vickrey-Clarke-Groves (VCG) mechanism. The result of the numerical study shows that the seat capacity allocation is effective even without information exchanging completely and the twofold revenue shares method shows more excitation for the airlines.

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Long-Term Use and Perceived Benefits of Goal-Oriented Attentional Self-Regulation Training in Chronic Brain Injury

Primary Objective. To investigate the long-term use and perceived benefit(s) of strategies included in Goal-Oriented Attentional Self-Regulation (GOALS) training (Novakovic-Agopian et al., 2011) by individuals with acquired brain injury (ABI) and chronic executive dysfunction. Research Design. Longitudinal follow-up of training. Methods and Procedures. Sixteen participants with chronic ABI participated in structured telephone interviews 20 months (range 11 to 31 months) following completion of GOALS training. Participants responded to questions regarding the range of strategies they continued to utilize, perceived benefit(s) of strategy use, situations in which strategy use was found helpful, and functional changes attributed to training. Results. Nearly all participants (94%) reported continued use of at least one trained strategy in their daily lives, with 75% of participants also reporting improved functioning resulting from training. However, there was considerable variability with respect to the specific strategies individuals found helpful as well as the perceived impact of training on overall functioning. Conclusions. GOALS training shows promising long-term benefits for individuals in the chronic phase of brain injury. Identifying individual- and injury-level factors that account for variability in continued strategy use and the perceived long-term benefits of training will help with ongoing intervention development.

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Astronomical Tasks for Tests of X-Ray Optics in VZLUSAT-1 Nanosatellite

VZLUSAT-1 nanosatellite (scheduled launch in spring 2017 from India) is a CubeSat mission which, besides other instrumentation, contains X-ray desk to perform efficiency tests of the X-ray optics. In this article the analysis of potential observational candidates for VZLUSAT-1 X-ray board is presented together with the suggestion of observational modes, laboratory measurements, and estimations of exposure settings.

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Objective Ventricle Segmentation in Brain CT with Ischemic Stroke Based on Anatomical Knowledge

Ventricle segmentation is a challenging technique for the development of detection system of ischemic stroke in computed tomography (CT), as ischemic stroke regions are adjacent to the brain ventricle with similar intensity. To address this problem, we developed an objective segmentation system of brain ventricle in CT. The intensity distribution of the ventricle was estimated based on clustering technique, connectivity, and domain knowledge, and the initial ventricle segmentation results were then obtained. To exclude the stroke regions from initial segmentation, a combined segmentation strategy was proposed, which is composed of three different schemes: (1) the largest three-dimensional (3D) connected component was considered as the ventricular region; (2) the big stroke areas were removed by the image difference methods based on searching optimal threshold values; (3) the small stroke regions were excluded by the adaptive template algorithm. The proposed method was evaluated on 50 cases of patients with ischemic stroke. The mean Dice, sensitivity, specificity, and root mean squared error were 0.9447, 0.969, 0.998, and 0.219 mm, respectively. This system can offer a desirable performance. Therefore, the proposed system is expected to bring insights into clinic research and the development of detection system of ischemic stroke in CT.

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Effects of Honey on Oral Mucositis among Pediatric Cancer Patients Undergoing Chemo/Radiotherapy Treatment at King Abdulaziz University Hospital in Jeddah, Kingdom of Saudi Arabia

One of the most common complications of cancer chemotherapy is oral mucositis. This study evaluates the therapeutic effects of honey with the focus on grade III and IV oral mucositis, reduction of bacterial and fungal infections, duration of episodes of oral mucositis, and body weight in pediatric leukemic patients undergoing chemo/radiotherapy. This is an open labeled randomized controlled study conducted at our hospital on 40 pediatric cancer patients undergoing chemo/radiotherapy. All the 40 patients included in this study experienced a sum total of 390 episodes of fever and neutropenia associated with oral mucositis. A significant reduction of oral mucositis, associated Candida, and aerobic pathogenic bacterial infections was noted in patients in the honey treatment group. Also, there is a significant decrease in the duration of hospitalization for all those in the treatment group combined with a significant increase of body weight, delayed onset, and decreased severity of pain related to oral mucositis. Complications of oral mucositis can be tremendously reduced by the topical application of local Saudi honey and honey should be used as an integrative approach in prophylaxis and treatment of chemo/radiotherapy-induced oral mucositis in pediatric cancer patients. Further research is needed to elucidate and better understand the underlying mechanism.

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Detection of Intermittent Fault for Discrete-Time Systems with Output Dead-Zone: A Variant Tobit Kalman Filtering Approach

This paper is concerned with the intermittent fault detection problem for a class of discrete-time linear systems with output dead-zone. Dead-zone phenomenon exists in many real practical systems due to the employment of low-cost commercial off-the-shelf sensors. Two Bernoulli random variables are utilized to model the dead-zone effect and a variant formation of Tobit Kalman filter is brought forward to generate a residual that can indicate the occurrence of an intermittent fault. A numerical example is presented to demonstrate the effectiveness and applicability of the proposed technique. The statistical performance of the technique is illustrated as well.

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Obfuscated RSUs Vector Based Signature Scheme for Detecting Conspiracy Sybil Attack in VANETs

Given the popularity of vehicular Ad hoc networks (VANETs) in traffic management, a new challenging issue comes into traffic safety, that is, security of the networks, especially when the adversary breaks defence. Sybil attack, for example, is a potential security threat through forging several identities to carry out attacks in VANETs. At this point, the paper proposed a solution named DMON that is a Sybil attack detection method with obfuscated neighbor relationship of Road Side Units (RSUs). DMON presents a ring signature based identification scheme and replaces vehicles’ identities with their trajectory for the purpose of anonymity. Furthermore, the neighbor relationship of RSUs is obfuscated to achieve privacy preserving of locations. The proposed scheme has been formally proved in the views of security and performance. Simulation has also been implemented to validate the scheme, in which the findings reveal the lower computational overhead and higher detection rate comparing with other related solutions.

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Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Specific immunotherapies, including vaccines with autologous tumor cells and tumor antigen-specific monoclonal antibodies, are important treatments for PC patients. To evaluate the clinical outcomes of PC-specific immunotherapy, we performed a systematic review and meta-analysis of the relevant published clinical trials. The effects of specific immunotherapy were compared with those of nonspecific immunotherapy and the meta-analysis was executed with results regarding the overall survival (OS), immune responses data, and serum cancer markers data. The pooled analysis was performed by using the random-effects model. We found that significantly improved OS was noted for PC patients utilizing specific immunotherapy and an improved immune response was also observed. In conclusion, specific immunotherapy was superior in prolonging the survival time and enhancing immunological responses in PC patients.

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Impact of Physical Activity on Cognitive Decline, Dementia, and Its Subtypes: Meta-Analysis of Prospective Studies

The association of physical activity with dementia and its subtypes has remained controversial in the literature and has continued to be a subject of debate among researchers. A systematic review and meta-analysis of longitudinal studies on the relationship between physical activity and the risk of cognitive decline, all-cause dementia, Alzheimer’s disease, and vascular dementia among nondemented subjects are considered. A comprehensive literature search in all available databases was conducted up until April 2016. Well-defined inclusion and exclusion criteria were developed with focus on prospective studies ≥ 12 months. The overall sample from all studies is 117410 with the highest follow-up of 28 years. The analyses are performed with both Bayesian parametric and nonparametric models. Our analysis reveals a protective effect for high physical activity on all-cause dementia, odds ratio of 0.79, 95% CI (0.69, 0.88), a higher and better protective effect for Alzheimer’s disease, odds ratio of 0.62, 95% CI (0.49, 0.75), cognitive decline odds ratio of 0.67, 95% CI (0.55, 0.78), and a nonprotective effect for vascular dementia of 0.92, 95% CI (0.62, 1.30). Our findings suggest that physical activity is more protective against Alzheimer’s disease than it is for all-cause dementia, vascular dementia, and cognitive decline.

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Accuracy of Colon Capsule Endoscopy in Detecting Colorectal Polyps in Individuals with Familial Colorectal Cancer: Could We Avoid Colonoscopies?

Background. Individuals with a family history of colorectal cancer (CRC) have an increased risk of CRC. We evaluated the diagnostic yield of CCE in the detection of lesions and also two different colon preparations. Methods. A prospective multicenter study was designed to assess CCE diagnostic yield in a cohort of asymptomatic individuals with a family history of CRC. CCE and colonoscopy were performed on the same day by 2 endoscopists who were blinded to the results of the other procedure. Results. Fifty-three participants were enrolled. The sensitivity, specificity, PPV, and NPV of CCE for detecting advanced adenomas were 100%, 98%, 67%, and 100%. Sensitivity, specificity, PPV, and NPV of CCE for the diagnosis of individuals with polyps were 87%, 97%, 93%, and 88%, respectively. CCE identify 100% of individuals with significant or advanced lesions. Overall cleanliness was adequate by 60.7% of them. The PEG-ascorbic boost seems to improve colon cleanliness, with similar colonic transit time. Conclusion. CCE is a promising tool, but it has to be considered as an alternative technique in this population in order to reduce the number of colonoscopies performed. More studies are needed to understand appropriate screening follow-up intervals and optimize the bowel preparation regimen.

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Safety and Efficacy of Two Trabecular Micro-Bypass Stents as the Sole Procedure in Japanese Patients with Medically Uncontrolled Primary Open-Angle Glaucoma: A Pilot Case Series

Purpose. To evaluate efficacy and safety of a trabecular micro-bypass stent system when used as the sole procedure in Japanese patients with medically uncontrolled primary open-angle glaucoma (POAG). Design. Prospective nonrandomized interventional pilot study. Methods. Ten eyes of 10 Japanese patients with medically uncontrolled POAG taking three ocular hypotensive medications were treated using only the implantation of two iStent trabecular micro-bypass stents. Each patient continued to take the same ocular hypotensive medications used preoperatively throughout the study. Intraocular pressure (IOP) and endothelial cell density (ECD) were determined at baseline and at 1, 3, and 6 months postoperatively. Best-corrected visual acuity (BCVA) was measured at baseline and 6 months after surgery. Results. Mean IOP was  mmHg at baseline and  mmHg at 6 months, which represented a mean reduction of 5.1 mmHg or 23.2%. No significant changes were observed in the ECD and BCVA. Complications that occurred during the early postoperative period included hyphema, peripheral anterior synechiae, and occlusion of the stent by the iris. Conclusion. Implantation of two trabecular micro-bypass stents as the sole procedure in Japanese POAG patients effectively reduced IOP and exhibited a favorable safety profile. Clinical Trials Registration number is UMIN000004002.

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Outcomes of Using Otoendoscopy During Surgery for Cholesteatoma

Abstract

To determine the impact of using otoendoscopy at the time of primary surgery of cholesteatoma in identifying hidden “cholesteatoma remnant”. Study was prospective study. Setting was University tertiary care hospital. One hundred fifty, patients diagnosed clinically and by CT as having cholesteatoma, have been operated. 64 patients operated by using canal up technique and 86 patients operated by using canal down technique. Once all visible cholesteatoma was removed with standard microscopic techniques, otoendoscopy was utilized in every patient to identify any hidden “cholesteatoma remnant”. Despite apparent total microscopic eradication of cholesteatoma of the operated cases, otoendoscopy at time of primary surgery revealed an overall incidence of hidden cholesteatoma remnants of 18%. The incidence of hidden cholesteatoma remnants identified by otoendoscopy was 23% in the canal up group and 14% in the canal down group. Otoendoscopy should be used as an adjunct with standard microscopic technique to identify hidden cholesteatoma remnants during surgery of cholesteatoma.



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The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monoxygenase Complexed with Octane Discloses Several Structural Adaptations for {omega}-Hydroxylation [Enzymology]

P450 family 4 fatty acid ω-hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for ω-hydroxylation. The structure indicated that octane is bound in a narrow active site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for ω-hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized E310 contributes to substrate positioning. The preference for ω-hydroxylation was decreased in a E310A mutant having a shorter side-chain, but overall rates of metabolism were retained. E310D and E310Q substitutions having longer side-chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane ω-hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for ω-hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for ω-hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of un-activated primary C-H bonds.

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Identification of a Membrane Protein Required for Lipomannan Maturation and Lipoarabinomannan Synthesis in Corynebacterineae [Microbiology]

Mycobacterium tuberculosis and related Corynebacterineae synthesize a family of lipomannans (LM) and lipoarabinomannans (LAM) that are abundant components of the multilaminate cell wall and essential virulence factors in pathogenic species. Here we describe a new membrane protein, highly conserved in all Corynebacterineae, that is required for synthesis of full length LM and LAM. Deletion of the Corynebacterium glutamicum NCgl2760 gene resulted in a complete loss of mature LM/LAM, and the appearance of a truncated LM (t-LM). Complementation of the mutant with the NCgl2760 gene fully restored LM/LAM synthesis. Structural studies, including monosaccharide analysis, methylation linkage analysis and mass spectrometry of native LM species, indicated that the ∆NCgl2760 t-LM comprised a series of short LM species (8-27 residues long) containing an α1-6 linked mannose backbone with greatly reduced α1-2 mannose side chains and no arabinose caps. The structure of the ∆NCgl2760 t-LM was similar to the t-LM produced by a C. glutamicum mutant lacking the mptA gene, encoding a membrane α1-6 mannosyltransferase involved in extending the α1-6 mannan backbone of LM intermediates. Interestingly, NCgl2760 lacks any motifs or homology to other proteins of known function. Attempts to delete the NCgl2760 orthologue in Mycobacterium smegmatis were unsuccessful, consistent with previous studies indicating that the M. tuberculosis orthologue, Rv0227c, is an essential gene. Together, these data suggest that NCgl2760/Rv0227c plays a critical role in the elongation of the mannan backbone of mycobacterial and corynebacterial LM, further highlighting the complexity of lipoglycan pathways of Corynebacterineae.

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Adaptation of a genetic screen reveals an inhibitor for mitochondrial protein import component Tim44 [Cell Biology]

Diverse protein import pathways into mitochondria use translocons on the outer membrane (TOM) and inner membrane (TIM). We adapted a genetic screen, based on Ura3 mistargeting from mitochondria to the cytosol, to identify small molecules that attenuated protein import. Small molecule Mitochondrial import Blockers of the Carla Koehler laboratory (MitoBloCK, MB)-10 inhibited import of substrates that require the TIM23 translocon. Mutational analysis coupled with molecular docking and molecular dynamics modeling revealed that MB-10 binds to a specific pocket in the C-terminal domain of Tim44 of the Protein Associated Motor (PAM) complex. This region was proposed to anchor Tim44 to the membrane but biochemical studies with MB-10 show this region is required for binding to the translocating precursor and binding to mtHsp70 in low ATP conditions. This study also supports a direct role for the PAM complex in the import of substrates that are laterally sorted to the inner membrane as well as the mitochondrial matrix. Thus, MB-10 is the first small molecule modulator to attenuate PAM complex activity, likely through binding to the C-terminal region of Tim44.

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Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma [Gene Regulation]

RNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, GRIA2, modifies a codon replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site of GRIA2 is essential and reduced editing of GRIA2 transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify ADAR3 as an important regulator of Q/R site editing, investigate its mode of action and detect elevated ADAR3 expression in glioblastoma tumors compared to adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site of GRIA2. Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site of GRIA2 is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding to GRIA2 transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to the GRIA2 pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contribute to the relative level of GRIA2 editing in tumors from patients suffering from glioblastoma.

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Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Aggregation Causes Mitochondrial Dysfunction During Oxidative Stress-Induced Cell Death [Cell Biology]

Glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that also mediates cell death under oxidative stress. We previously reported that the active-site cysteine (Cys-152) of GAPDH plays an essential role in oxidative stress-induced aggregation of GAPDH associated with cell death, and a C152A-GAPDH mutant rescues nitric oxide (NO)-induced cell death by interfering with aggregation of wild type (WT)-GAPDH. However, the detailed mechanism underlying GAPDH-aggregate-induced cell death remains elusive. Here we report that NO-induced GAPDH aggregation specifically causes mitochondrial dysfunction. First, we observed a correlation between NO-induced GAPDH aggregation and mitochondrial dysfunction, and GAPDH aggregation occurred at mitochondria in SH-SY5Y cells. In isolated mitochondria, aggregates of WT-GAPDH directly induced mitochondrial swelling and depolarization, whereas mixtures containing aggregates of C152A-GAPDH reduced mitochondrial dysfunction. Additionally, treatment with cyclosporin A improved WT-GAPDH aggregate-induced swelling and depolarization. In doxycycline-inducible SH-SY5Y cells, overexpression of WT-GAPDH augmented NO-induced mitochondrial dysfunction and increased mitochondrial GAPDH aggregation, whereas induced overexpression of C152A-GAPDH significantly suppressed mitochondrial impairment. Further, NO-induced cytochrome c release into the cytosol and nuclear translocation of apoptosis-inducing factor from mitochondria were both augmented in cells overexpressing WT-GAPDH but ameliorated in C152A-GAPDH-overexpressing cells. Interestingly, GAPDH aggregates induced necrotic cell death via permeability transition pore (PTP) opening. The expression of either WT- or C152A-GAPDH did not affect other cell-death pathways associated with protein aggregation, such as proteasome inhibition, gene expression induced by endoplasmic reticulum stress, or autophagy. Collectively, these results suggest that NO-induced GAPDH aggregation specifically induces mitochondrial dysfunction via PTP opening, and leading to cell death.

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Detection of Lipid Induced Structural Changes of the Marburg Virus Matrix Protein VP40 Using Hydrogen/Deuterium Exchange Mass Spectrometry [Microbiology]

Marburg virus (MARV) is a lipid-enveloped virus from the Filoviridae family containing a negative sense RNA genome. One of the seven MARV genes encodes the matrix protein VP40, which forms a matrix layer beneath the plasma membrane inner leaflet to facilitate budding from the host cell. MARV VP40 (mVP40) has been shown to be a dimeric peripheral protein with a broad and flat basic surface that can associate with anionic phospholipids such as phosphatidylserine. While a number of mVP40 cationic residues have been shown to facilitate binding to membranes containing anionic lipids, much less is known on how mVP40 assembles to form the matrix layer following membrane binding. Here we have used hydrogen-deuterium exchange (H/DX) mass spectrometry to determine the solvent accessibility of mVP40 residues in the absence and presence of phosphatidylserine and phosphatidylinositol-4,5-bisphosphate. H/DX analysis demonstrates two basic loops in the mVP40 C-terminal domain make important contributions to anionic membrane binding and also revealed a potential oligomerization interface in the C-terminal domain as well as a conserved oligomerization interface in the mVP40 N-terminal domain. Lipid binding assays confirm the role of the two basic patches elucidated with HD/X measurements while molecular dynamics simulations and membrane insertion measurements complement these studies to demonstrate mVP40 doesn't appreciably insert into the hydrocarbon region of anionic membranes in contrast to the matrix protein from Ebola virus. Taken together, we propose a model by which association of the mVP40 dimer with the anionic plasma membrane facilitates assembly of mVP40 oligomers.

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Adherence to acute otitis media diagnosis and treatment guidelines among Israeli otolaryngologists

The recent Israeli acute otitis media (AOM) guidelines, drafted mainly by pediatricians and family physicians in 2013, addressed diagnostic and therapeutic issues, in order to reduce over-diagnosis and treatment. These guidelines are considered as the 'standard of care' for AOM management. While the adherence rate of pediatricians to previous Israeli AOM guidelines (2004) was reported to be high (>85%), the compliance of otolaryngologists has not been studied.

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Influence of nasal septum deformity on nasal obstruction, disease severity, and medical treatment response among children and adolescents with persistent allergic rhinitis

To evaluate the impact of different types of nasal septum deformity (NSD) on nasal obstruction, rhinitis severity and response to medical treatment among pediatric persistent allergic rhinitis (PER) patients.

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Do post-tonsillectomy patients who report bleeding require observation if no bleeding is present on exam?

Three to ten percent of tonsillectomy patients experience post-tonsillectomy hemorrhage. Examination of those patients who return to the Emergency Department (ED) with a history of hemorrhage are found to have active bleeding, a coagulum within the fossa, or a normal post-operative exam. It is not known if those with a normal postoperative exam require inpatient observation.

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Using click-evoked auditory brainstem response thresholds in infants to estimate the corresponding pure-tone audiometry thresholds in children referred from UNHS

To examine whether behavioral pure-tone audiometry (PTA) thresholds in children can be accurately estimated from the corresponding infants' click-evoked auditory brainstem response (ABR) thresholds through a retrospective review of data from a universal newborn hearing screening (UNHS) program in Taiwan.

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Bilateral Cochlear Implantation in a Child with Johanson Blizzard Syndrome

Sensorineural hearing loss (SNHL) occurs in more than 80% of cases of Johanson Blizzard Syndrome (JBS). However, limited knowledge exists in medical literature of cochlear implantation (CI) outcomes in children with JBS. We report the case of a 5 year-old male with JBS and bilateral CI. While minimal progress in spoken language scores was noted after 4 years of bilateral CI use, substantial improvements in discrimination of speech sounds and audibility of spoken language and environmental sounds were documented.

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Could HPV screening replace Pap smear for cevical cancer testing?

For many years, cytology has been the established method used for cervical cancer screening. Commonly known as the Pap test, cytology and its regular use in yearly exams has been credited with significantly reducing the number of deaths from cervical...

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CTLA4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky SCID

CTLA4-Ig controls immune dysregulation in an Artemis deficient mouse model that recapitulates leaky SCID/ Omenn Syndrome clinical manifestations.

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Identification and expression profile analysis of odorant binding protein and chemosensory protein genes in Bemisia tabaci MED by head transcriptome

by Ran Wang, Fengqi Li, Wei Zhang, Xiaoman Zhang, Cheng Qu, Guillaume Tetreau, Lujuan Sun, Chen Luo, Jingjiang Zhou

Odorant binding proteins (OBPs) and chemosensory proteins (CSPs) of arthropods are thought to be involved in chemical recognition which regulates pivotal behaviors including host choice, copulation and reproduction. In insects, OBPs and CSPs located mainly in the antenna but they have not been systematically characterized yet in Bemisia tabaci which is a cryptic species complex and could damage more than 600 plant species. In this study, among the 106,893 transcripts in the head assembly, 8 OBPs and 13 CSPs were identified in B. tabaci MED based on head transcriptomes of adults. Phylogenetic analyses were conducted to investigate the relationships of B. tabaci OBPs and CSPs with those from several other important Hemipteran species, and the motif-patterns between Hemiptera OBPs and CSPs were also compared by MEME. The expression profiles of the OBP and CSP genes in different tissues of B. tabaci MED adults were analyzed by real-time qPCR. Seven out of the 8 OBPs found in B. tabaci MED were highly expressed in the head. Conversely, only 4 CSPs were enriched in the head, while the other nine CSPs were specifically expressed in other tissues. Our findings pave the way for future research on chemical recognition of B. tabaci at the molecular level.

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Pollen gene flow, male reproductive success, and genetic correlations among offspring in a northern red oak (Quercus rubra L.) seed orchard

by Lisa Alexander, Keith Woeste

Northern red oak is a high-value hardwood used for lumber, furniture and veneer. Intensively managed northern red oak seed orchards are required to obtain genetic gain for trait improvement. Data from conifer seed orchards and natural and managed stands of hardwood trees have shed light on the distance over which pollen can move, and underscore the need for managerial attention to seed orchard design, placement, and maintenance. We used eleven microsatellite markers to investigate pollen gene flow, female mate choice, and male reproductive success in a clonal seed orchard of northern red oak based on paternity analysis of seed orchard offspring in progeny tests. Nearly all (93%) offspring were sired by a male parent within the seed orchard. The mean number of male parents per year was 69.5, or 47.6% of all clones in the seed orchard. Female clones in the early phenology group had more offspring sired from extra-orchard pollen (13%) than clones in the intermediate (5%) and late (1%) phenology groups. Distance was the largest influence on pollination success, and pollination occurred most often by male trees in the same subline as the maternal tree. Males in the early phenology group sired more offspring overall in the progeny pool and more offspring per mother tree than males in the intermediate or late phenology groups. Average genetic correlations among all OP progeny ranged between 0.2557 and 0.3529 with a mean of 0.28±0.01. The importance of progeny test genotyping for northern red oak improvement likely is increasing with the demand for improved varieties. The current study demonstrated the feasibility of post hoc assembly of full-sib families for genetic analysis.

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Ankylosis of Temporomandibular Joints After Mandibular Distraction Osteogenesis in the Patients of Nager Syndrome: Report of Two Cases and Literature Review

Nager syndrome, also known as Nager acrofacial dysostosis, was first described by Nager and deReynier in 1948. The patients are commonly presented with micrognathia and a preventive tracheostomy is necessary when there are symptoms of upper airway obstruction. Mandibular distraction osteogenesis is considered as an effective procedure, which not only improves micrognathia but also minimizes the chance of the tracheostomy. However, mandibular distraction osteogenesis has some complications, such as relapse, teeth injury, infection and injury of the temporomandibular joints.

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Mothers’ pupillary responses to infant facial expressions

Human parental care relies heavily on the ability to monitor and respond to a child’s affective states. The current study examined pupil diameter as a potential physiological index of mothers’ affective respon...

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Lipoma of Columella with septal extension in Pai syndrome: report of a rare case

Lipoma in nasal region in a case of Pai syndrome is very rare. Very few cases of Pai syndrome with columellar lipoma with extension to septum and tip have been reported till date.

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Switching from smoking to vaping does reduce your carcinogens

Many smokers believe e-cigarettes are just as bad for you, but now a study has shown that switching to e-cigarettes reduces cancer-causing chemicals in the body

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Switching from smoking to vaping does reduce your carcinogens

gettyimages-528424254.jpg

Many smokers believe e-cigarettes are just as bad for you, but now a study has shown that switching to e-cigarettes reduces cancer-causing chemicals in the body

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Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis

Publication date: Available online 6 February 2017
Source:Cellular Signalling
Author(s): Colin Niaudet, Stéphanie Bonnaud, Maëva Guillonneau, Sébastien Gouard, Marie-Hélène Gaugler, Soizic Dutoit, Natacha Ripoche, Nolwenn Dubois, Valérie Trichet, Isabelle Corre, François Paris
The p38 MAPK signaling pathway is essential in the cellular response to stress stimuli, in particular in the endothelial cells that are major target of external stress. The importance of the bioactive sphingolipid ceramide generated by acid sphingomyelinase is also firmly established in stress-induced endothelial apoptotic cell death. Despite a suggested link between the p38 MAPK and ceramide pathways, the exact molecular events of this connection remain elusive. In the present study, by using two different activators of p38 MAPK, namely anisomycin and ionizing radiation, we depicted how ceramide generated by acid sphingomyelinase was involved in p38 MAPK-dependent apoptosis of endothelial cells. We first proved that both anisomycin and ionizing radiation conducted to apoptosis through activation of p38 MAPK in human microvascular endothelial cells HMEC-1. We then found that both treatments induced activation of acid sphingomyelinase and the generation of ceramide. This step was required for p38 MAPK activation and apoptosis. We finally showed that irradiation, as well as treatment with exogenous C16-ceramide or bacterial sphingomyelinase, induced in endothelial cells a deep reorganization of the plasma membrane with formation of large lipid platforms at the cell surface, leading to p38 MAPK activation and apoptosis in endothelial cells. Altogether, our results proved that the plasma membrane reorganization leading to ceramide production is essential for stress-induced activation of p38 MAPK and apoptosis in endothelial cells and established the link between the acid sphingomyelinase/ceramide and p38 MAPK pathways.

Graphical abstract

image


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Mutational Analysis of the QRRQ Motif in the Yeast Hig1-type 2 Protein, Rcf1, Reveals a Regulatory Role for the Cytochrome c Oxidase Complex [Metabolism]

The yeast Rcf1 protein is a member of the conserved family of proteins termed the hypoxia induced gene (domain) 1 (Hig1 or HIGD1) family. Rcf1 interacts with components of the mitochondrial oxidative phosphorylation system in particular the cytochrome bc1 (complex III)-cytochrome c oxidase (complex IV) supercomplex (termed III-IV) and the ADP/ATP carrier proteins (AAC). Rcf1 plays a role in the assembly and modulation of the activity of complex IV, however, the molecular basis for how Rcf1 influences the activity of complex IV is currently unknown. Hig1-type 2 isoforms, which include the Rcf1 protein, are characterized in part by the presence of a conserved motif, (Q/I)-X3-(R/H)-X-R-X3-Q, termed here the QRRQ motif. We show that mutation of conserved residues within the Rcf1 QRRQ motif alters the interactions between Rcf1 and partner proteins and results in the destabilization of complex IV and an alteration of its enzymatic properties. Our findings indicate that Rcf1 does not serve as a stoichiometric component, i.e. as a subunit of complex IV, to support its activity. Rather, we propose that Rcf1 serves to dynamically interact with complex IV during its assembly process and in doing so regulates a late maturation step of complex IV. We speculate that the Rcf1/Hig1 proteins play a role in the incorporation and/or remodeling of lipids, in particular cardiolipin, into complex IV and possibly other mitochondrial proteins, such as AAC.

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Histone Deacetylase (HDAC) Inhibition Induces I{kappa}B Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells [Immunology]

Overexpression of the pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) is associated with poor prognosis in several solid tumors, including epithelial ovarian cancer (EOC). Even though histone deacetylase (HDAC) inhibition has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in solid tumors, including EOC. Here, we report results that may explain the decreased efficiency of HDAC inhibition in EOC, based on our data demonstrating that HDAC inhibition specifically induces expression of IL-8/CXCL8 in SKOV3, CAOV3, and OVCAR3 cells. Suppression or neutralization of the vorinostat-induced IL-8/CXCL8 potentiates the vorinostat inhibitory effect on cell viability and proliferation. The IL-8/CXCL8 expression induced by vorinostat in EOC cells is dependent on IκB kinase (IKK) activity, and associated with a gene-specific recruitment of IKKβ and IKK-dependent recruitment of p65 NFκB to IL-8/CXCL8 promoter. In addition, HDAC inhibition induces acetylation of p65 and histone H3, and their IL-8/CXCL8 promoter occupancy. In vivo results demonstrate that combining vorinostat and the IKK inhibitor Bay 117085 significantly reduces tumor growth in nude mice when compared to control untreated mice or either drug alone. Mice in the combination group had the lowest IL-8/CXCL8 tumor levels, and the lowest tumor expression of the murine neutrophil [7/4] antigen, indicating a reduced neutrophil infiltration. Together, our results demonstrate that HDAC inhibition specifically induces IL-8/CXCL8 expression in EOC cells, and that the mechanism involves IKK, suggesting that using IKK inhibitors may increase effectiveness of HDAC inhibitors in treating ovarian cancer and other solid tumors characterized by increased IL-8/CXCL8 expression.

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Heat Shock Induced Phosphorylation of TAR DNA Binding Protein 43 (TDP-43) by MAPK/ERK Kinase Regulates TDP-43 Function [Neurobiology]

TAR DNA binding protein (TDP-43) is a highly conserved and essential DNA- and RNA-binding protein that controls gene expression through RNA processing, in particular, regulation of splicing. Intracellular aggregation of TDP-43 is a hallmark of amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. This TDP-43 pathology is also present in other types of neurodegeneration including Alzheimer's disease. We report here that TDP-43 is a substrate of MEK, a central kinase in the MAPK/ERK signaling pathway. TDP-43 dual phosphorylation by MEK, at threonine-153 and tyrosine-155 (p-T153/Y155), was dramatically increased by the heat shock response (HSR) in human cells. HSR promotes cell survival under proteotoxic conditions by maintaining protein homeostasis and preventing protein misfolding. MEK is activated by HSR and contributes to the regulation of proteome stability. Phosphorylated TDP-43 was not associated with TDP-43 aggregation, and p-T153/Y155 remained soluble under conditions that promote protein misfolding. We found that active MEK significantly alters TDP-43-regulated splicing and that phosphomimetic substitutions at these two residues reduce binding to GU-rich RNA. Cellular imaging using a phospho-specific p-T153/Y155 antibody showed that phosphorylated TDP-43 was specifically recruited to the nucleoli, suggesting that p-T153/Y155 regulates a previously unappreciated function of TDP-43 in the processing of nucleolar-associated RNA. These findings highlight a new mechanism that regulates TDP-43 function and homeostasis through phosphorylation and, therefore, may contribute to the development of strategies to prevent TDP-43 aggregation and to uncover previously unexplored roles of TDP-43 in cell metabolism.

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Characterization of H type 1 and type 1 N-acetyllactosamine glycan epitopes on ovarian cancer specifically recognized by the anti-glycan monoclonal antibody mAb-A4 [Molecular Bases of Disease]

Cancer-specific glycans of ovarian cancer are promising epitopes for targeting with monoclonal antibodies (mAb). Despite their potential, structural characterization of these glycan epitopes remains a significant challenge in mAb preclinical development. Our group generated the monoclonal antibody mAb-A4 against human embryonic stem cells (hESC), which also bound specifically to N-glycans present on 11 out of 19 ovarian cancer (OC) and 8 out of 14 breast cancer cell lines tested. Normal cell lines and tissue were unstained by mAb-A4. To characterize the N-linked glycan epitopes on OC cell lines targeted by mAb-A4, we used glycosidases, glycan microarray, siRNA and advanced high-sensitivity matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The mAb-A4 epitopes were found to be Fuc α1-2Galβ1-3GlcNAcβ (H Type 1) and Galβ1-3GlcNAcβ (Type 1 LacNAc). These structures were found to be present on multiple proteins from hESC and OC. Importantly, endo-β-galactosidase coupled with MALDI-MS allowed these two epitopes, for the first time, to be directly identified on the polylactosamines of N-glycans of SKOV3, IGROV1, OV90 and OVCA433. Furthermore, siRNA knockdown of B3GALT5 expression in SKOV3 demonstrated that mAb-A4 binding was dependent on B3GALT5, providing orthogonal evidence of the epitopes' structures. The recognition of oncofetal H Type 1 and Type 1 LacNAc on OC by mAb-A4 is a novel and promising way to target OC and supports the theory that cancer can acquire stem-like phenotypes. We propose that the orthogonal framework used in this work could be the basis for advancing anti-glycan mAb characterization.

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Site-specific O-glycosylation by Polypeptide GalNAc-transferase T2 Co-regulates Beta1-adrenergic Receptor N-terminal Cleavage [Glycobiology and Extracellular Matrices]

The β1-adrenergic receptor (β1AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for β-adrenergic antagonists, such as beta-blockers, relatively little is still known about its regulation. We have previously shown that β1AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation, and moreover that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates β1AR at five residues in the extracellular N-terminus, including the Ser49 residue at a location of the common Ser49Gly single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T edited cell line model systems, and a GalNAc-T2 knockout rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of β1AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis leads to attenuated receptor signaling, as the maximal response elicited by the βAR agonist isoproterenol and it potency in a cAMP accumulation assay was decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of β1AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases.

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Mechanism of action of trabectedin in desmoplastic small round cell tumor cells

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11...

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Correction: Broncho Alveolar Dendritic Cells and Macrophages Are Highly Similar to Their Interstitial Counterparts

by The PLOS ONE Staff



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Correction: Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

by Olallo Sanchez, Oscar Campuzano, Anna Fernández-Falgueras, Georgia Sarquella-Brugada, Sergi Cesar, Irene Mademont, Jesus Mates, Alexandra Pérez-Serra, Monica Coll, Ferran Pico, Anna Iglesias, Coloma Tirón, Catarina Allegue, Esther Carro, María Ángeles Gallego, Carles Ferrer-Costa, Anna Hospital, Narcís Bardalet, Juan Carlos Borondo, Albert Vingut, Elena Arbelo, Josep Brugada, Josep Castellà, Jordi Medallo, Ramon Brugada



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Correction: Cardiosphere-Derived Cells Facilitate Heart Repair by Modulating M1/M2 Macrophage Polarization and Neutrophil Recruitment

by Al Shaimaa Hasan, Lan Luo, Chen Yan, Tian-Xia Zhang, Yoshishige Urata, Shinji Goto, Safwat A. Mangoura, Mahmoud H. Abdel-Raheem, Shouhua Zhang, Tao-Sheng Li



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Correction: Genomic Regions Associated with Feed Efficiency Indicator Traits in an Experimental Nellore Cattle Population

by Bianca Ferreira Olivieri, Maria Eugênia Zerlotti Mercadante, Joslaine Noely dos Santos Gonçalves Cyrillo, Renata Helena Branco, Sarah Figueiredo Martins Bonilha, Lucia Galvão de Albuquerque, Rafael Medeiros de Oliveira Silva, Fernando Baldi



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Correction: Time-Course of Changes in Choroidal Thickness after Complete Mydriasis Induced by Compound Tropicamide in Children

by The PLOS ONE Staff



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Being friendly puts monkeys at risk in times of revolution

The young of sociable female capuchin monkeys survive better in times of peace, but are more likely to be killed when the group is going through a change of leadership

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Proteomics Tracing the Footsteps of Infectious Disease [Perspective]

Every year, a major cause of human disease and death worldwide is infection with the various pathogens - viruses, bacteria, fungi, and protozoa - that are intrinsic to our ecosystem. In efforts to control the prevalence of infectious disease and develop improved therapies, the scientific community has focused on building a molecular picture of pathogen infection and spread. These studies have been aimed at defining the cellular mechanisms that allow pathogen entry into hosts cells, their replication and transmission, as well as the core mechanisms of host defense against pathogens. The past two decades have demonstrated the valuable implementation of proteomic methods in all these areas of infectious disease research. Here, we provide a perspective on the contributions of mass spectrometry and other proteomics approaches to understanding the molecular details of pathogen infection. Specifically, we highlight methods used for defining the composition of viral and bacterial pathogens and the dynamic interaction with their hosts in space and time. We discuss the promise of MS-based proteomics in supporting the development of diagnostics and therapies, and the growing need for multi-omics strategies for gaining a systems view of pathogen infection.



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Being friendly puts monkeys at risk in times of revolution

01441940.jpg

The young of sociable female capuchin monkeys survive better in times of peace, but are more likely to be killed when the group is going through a change of leadership

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Low-dose chemotherapy protocol relies on normalisation of tumour blood supply

The effects of a promising new approach to chemotherapy that involves frequent administration of dosage levels much lower than traditionally used appears to rely on the "normalisation" of blood vessels within and around a tumour. In their report...

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Antimicrobial Stewardship: The Role of the Patient

Opinion Statement

The aim of this article is to describe the current state of the patient role in antimicrobial stewardship efforts. There is a global crisis in antimicrobial resistance (AR) for which antimicrobial use is the main driver. Antimicrobial stewardship (AS) is a critical ally in the battle against AR. The extent to which specific AS initiatives are implemented across settings varies considerably; many acute care settings have a formal antimicrobial stewardship program (ASP), but other patient care settings such as outpatient clinics or long-term care facilities are generally in the early phases of developing AS efforts which may include a regional approach encompassing transitions of care. In recognizing that a coordinated care approach across the spectrum of healthcare is essential to improve patient outcomes, there is a renewed and increased push to broaden AS implementation across multiple settings. In the acute care setting, a common characteristic of an ASP is a multidisciplinary team to guide antibiotic decision-making at an individual and a facility level. Efforts often target appropriate use of antimicrobials via formulary restrictions, prescribing decision-support models, education, and audit and feedback of prescribing practices. Patients are not usually included in stewardship efforts. Stewardship literature which includes a patient-role component is limited and focuses primarily on physician-patient communication or educational campaigns to raise public awareness of AS. There is little research exploring direct patient involvement in AS efforts, although there is some evidence that patients are aware of the implications of AR, its link to antimicrobial use, and its impact on health at the population level. Recent work has shown that patients believe there is a role for them in AS efforts; however, there is no guidance on the best approach to achieve patient involvement in AS initiatives and no evidence of the effect of such patient involvement on clinical outcomes. In order to fill the gap in knowledge related to the patient role in AS, we recommend the following for clinicians and researchers:

• Increase patient awareness and understanding of AS and the impact on their care. This may be the first step in successfully involving patients in AS endeavors.

• Identify situations in which patients can realistically become part of the AS movement across the healthcare spectrum. This would call for studying the process of patient recruitment and engagement and impact of adding the patient voice. This could also include studying patient perspectives about being involved in AS, along with clinician and researcher perspectives of involving patients.

• Undertake research studies to examine different implementation strategies for involving patients and evaluate the effect of engagement on clinical outcomes relevant to AS such as decreased antibiotic usage and antibiotic resistance.



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Case report: clinical and postmortem findings in four cows with rib fracture

Published reports of rib fractures in adult cattle are limited to the occurrence of chronic rib swellings caused by calluses, which are unremarkable from a clinical standpoint, whereas studies identifying clin...

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Pre-flight evaluation of adult patients with cystic fibrosis: a cross-sectional study

Air travel may imply a health hazard for patients with cystic fibrosis (CF) due to hypobaric environment in the aircraft cabin. The objective was to identify pre-flight variables, which might predict severe hy...

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New title will be launched on J-STAGE.Time Studies



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New title will be launched on J-STAGE.Shinrin Kagaku



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New title will be launched on J-STAGE.Dental Journal of Iwate Medical University



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newly available online.PROGRAMME AND ABSTRACTS THE VOLCANOLOGICAL SOCIETY OF JAPAN



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The new issue is now available.Taxa, Proceedings of the Japanese Society of Systematic Zoology

Vol.41

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The new issue is now available.Japanese Journal of Social Psychology

Vol.21 No.3

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The new issue is now available.Japanese Journal of Social Psychology

Vol.21 No.2

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The new issue is now available.Japanese Journal of Nursing Art and Science

Vol.15 No.3

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The new issue is now available.Japanese Journal of Farm Work Research

Vol.51 No.2

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The new issue is now available.Journal of Epidemiology

Vol.27 No.1

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The new issue is now available.Industrial Health

Vol.55 No.1

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The new issue is now available.International Heart Journal

Vol.58 No.1

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The new issue is now available.Journal of Life Cycle Assessment, Japan

Vol.13 No.1

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The new issue is now available.PROGRAMME AND ABSTRACTS THE VOLCANOLOGICAL SOCIETY OF JAPAN

Vol.2016

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The new issue is now available.Japanese Journal of Social Psychology

Vol.21 No.1

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The new issue is now available.SUGAKU

Vol.65 No.3

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The new issue is now available.Journal of Life Cycle Assessment, Japan

Vol.12 No.4

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The new issue is now available.Honyurui Kagaku (Mammalian Science)

Vol.56 No.2

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Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes

by Elisabetta Groppelli, Hazel C. Levy, Eileen Sun, Mike Strauss, Clare Nicol, Sarah Gold, Xiaowei Zhuang, Tobias J. Tuthill, James M. Hogle, David J. Rowlands

Picornaviruses are non-enveloped RNA viruses that enter cells via receptor-mediated endocytosis. Because they lack an envelope, picornaviruses face the challenge of delivering their RNA genomes across the membrane of the endocytic vesicle into the cytoplasm to initiate infection. Currently, the mechanism of genome release and translocation across membranes remains poorly understood. Within the enterovirus genus, poliovirus, rhinovirus 2, and rhinovirus 16 have been proposed to release their genomes across intact endosomal membranes through virally induced pores, whereas one study has proposed that rhinovirus 14 releases its RNA following disruption of endosomal membranes. For the more distantly related aphthovirus genus (e.g. foot-and-mouth disease viruses and equine rhinitis A virus) acidification of endosomes results in the disassembly of the virion into pentamers and in the release of the viral RNA into the lumen of the endosome, but no details have been elucidated as how the RNA crosses the vesicle membrane. However, more recent studies suggest aphthovirus RNA is released from intact particles and the dissociation to pentamers may be a late event. In this study we have investigated the RNase A sensitivity of genome translocation of poliovirus using a receptor-decorated-liposome model and the sensitivity of infection of poliovirus and equine-rhinitis A virus to co-internalized RNase A. We show that poliovirus genome translocation is insensitive to RNase A and results in little or no release into the medium in the liposome model. We also show that infectivity is not reduced by co-internalized RNase A for poliovirus and equine rhinitis A virus. Additionally, we show that all poliovirus genomes that are internalized into cells, not just those resulting in infection, are protected from RNase A. These results support a finely coordinated, directional model of viral RNA delivery that involves viral proteins and cellular membranes.

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Correction: Evaluation of Direct Colorimetric MTT Assay for Rapid Detection of Rifampicin and Isoniazid Resistance in Mycobacterium tuberculosis

by Gadissa Bedada Hundie, Dawit Woldemeskel, Amare Gessesse



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Compliant flooring to prevent fall-related injuries in older adults: A scoping review of biomechanical efficacy, clinical effectiveness, cost-effectiveness, and workplace safety

by Chantelle C. Lachance, Michal P. Jurkowski, Ania C. Dymarz, Stephen N. Robinovitch, Fabio Feldman, Andrew C. Laing, Dawn C. Mackey

Background

Compliant flooring, broadly defined as flooring systems or floor coverings with some level of shock absorbency, may reduce the incidence and severity of fall-related injuries in older adults; however, a lack of synthesized evidence may be limiting widespread uptake.

Methods

Informed by the Arksey and O’Malley framework and guided by a Research Advisory Panel of knowledge users, we conducted a scoping review to answer: what is presented about the biomechanical efficacy, clinical effectiveness, cost-effectiveness, and workplace safety associated with compliant flooring systems that aim to prevent fall-related injuries in healthcare settings? We searched academic and grey literature databases. Any record that discussed a compliant flooring system and at least one of biomechanical efficacy, clinical effectiveness, cost-effectiveness, or workplace safety was eligible for inclusion. Two independent reviewers screened and abstracted records, charted data, and summarized results.

Results

After screening 3611 titles and abstracts and 166 full-text articles, we included 84 records plus 56 companion (supplementary) reports. Biomechanical efficacy records (n = 50) demonstrate compliant flooring can reduce fall-related impact forces with minimal effects on standing and walking balance. Clinical effectiveness records (n = 20) suggest that compliant flooring may reduce injuries, but may increase risk for falls. Preliminary evidence suggests that compliant flooring may be a cost-effective strategy (n = 12), but may also result in increased physical demands for healthcare workers (n = 17).

Conclusions

In summary, compliant flooring is a promising strategy for preventing fall-related injuries from a biomechanical perspective. Additional research is warranted to confirm whether compliant flooring (i) prevents fall-related injuries in real-world settings, (ii) is a cost-effective intervention strategy, and (iii) can be installed without negatively impacting workplace safety. Avenues for future research are provided, which will help to determine whether compliant flooring is recommended in healthcare environments.



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