bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases
Authors: Davis Kaitlin A. , Morelli Marco , Patton John T. 
Published: August 2017

ABSTRACT
The rotavirus nonstructural protein NSP1 repurposes cullin-RING E3 ubiquitin ligases (CRLs) to antagonize innate immune responses. By functioning as substrate adaptors of hijacked CRLs, NSP1 causes ubiquitination and proteasomal degradation of host proteins that are essential for expression of interferon (IFN) and IFN-stimulated gene products. The target of most human and porcine rotaviruses is the β-transducin repeat-containing protein (β-TrCP), a regulator of NF-κB activation. β-TrCP recognizes a phosphorylated degron (DSGΦXS) present in the inhibitor of NF-κB (IκB); phosphorylation of the IκB degron is mediated by IκB kinase (IKK). Because NSP1 contains a C-terminal IκB-like degron (ILD; DSGXS) that recruits β-TrCP, we investigated whether the NSP1 ILD is similarly activated by phosphorylation and whether this modification is required to trigger the incorporation of NSP1 into CRLs. Based on mutagenesis and phosphatase treatment studies, we found that both serine residues of the NSP1 ILD are phosphorylated, a pattern mimicking phosphorylation of IκB. A three-pronged approach using small-molecule inhibitors, small interfering RNAs, and mutagenesis demonstrated that NSP1 phosphorylation is mediated by the constitutively active casein kinase II (CKII), rather than IKK. In coimmunoprecipitation assays, we found that this modification was essential for NSP1 recruitment of β-TrCP and induced changes involving the NSP1 N-terminal RING motif that allowed formation of Cul3-NSP1 complexes. Taken together, our results indicate a highly regulated stepwise process in the formation of NSP1-Cul3 CRLs that is initiated by CKII phosphorylation of NSP1, followed by NSP1 recruitment of β-TrCP and ending with incorporation of the NSP1–β-TrCP complex into the CRL via interactions dependent on the highly conserved NSP1 RING motif.

IMPORTANCE
Rotavirus is a segmented double-stranded RNA virus that causes severe diarrhea in young children. A primary mechanism used by the virus to inhibit host innate immune responses is to hijack cellular cullin-RING E3 ubiquitin ligases (CRLs) and redirect their targeting activity to the degradation of cellular proteins crucial for interferon expression. This task is accomplished through the rotavirus nonstructural protein NSP1, which incorporates itself into a CRL and serves as a substrate recognition subunit. The substrate recognized by the NSP1 of many human and porcine rotaviruses is β-TrCP, a protein that regulates the transcription factor NF-κB. In this study, we show that formation of NSP1 CRLs is a highly regulated stepwise process initiated by CKII phosphorylation of the β-TrCP recognition motif in NSP1. This modification triggers recruitment of the β-TrCP substrate and induces subsequent changes in a highly conserved NSP1 RING domain that allow anchoring of the NSP1–β-TrCP complex to a cullin scaffold.
Translational Repression of the RpoS Antiadapter IraD by CsrA Is Mediated via Translational Coupling to a Short Upstream Open Reading Frame
Authors: Park Hongmarn , McGibbon Louise C. , Potts Anastasia H. , Yakhnin Helen , Romeo Tony , Babitzke Paul 
Published: August 2017

ABSTRACT

CsrA is a global regulatory RNA binding protein that has important roles in regulating carbon metabolism, motility, biofilm formation, and numerous other cellular processes. IraD functions as an antiadapter protein that inhibits RssB-mediated degradation of RpoS, the general stress response and stationary-phase sigma factor of
Escherichia coli
. Here we identified a novel mechanism in which CsrA represses
iraD
translation via translational coupling. Expression studies with quantitative reverse transcriptase PCR, Western blotting, and
lacZ
fusions demonstrated that CsrA represses
iraD
expression. Gel mobility shift, footprint, and toeprint studies identified four CsrA binding sites in the
iraD
leader transcript, all of which are far upstream of the
iraD
ribosome binding site. Computational modeling and RNA structure mapping identified an RNA structure that sequesters the
iraD
Shine-Dalgarno (SD) sequence. Three open reading frames (ORFs), all of which are translated, were identified in the
iraD
leader region. Two of these ORFs do not affect
iraD
expression. However, the translation initiation region of the third ORF contains three of the CsrA binding sites, one of which overlaps its SD sequence. Furthermore, the ORF stop codon overlaps the
iraD
start codon, a sequence arrangement indicative of translational coupling.
In vivo
expression and
in vitro
translation studies with wild-type and mutant reporter fusions demonstrated that bound CsrA directly represses translation initiation of this ORF. We further established that CsrA-dependent repression of
iraD
translation occurs entirely via translational coupling with this ORF, leading to accelerated
iraD
mRNA decay.

IMPORTANCE
CsrA posttranscriptionally represses gene expression associated with stationary-phase bacterial growth, often in opposition to the transcriptional effects of the stationary-phase sigma factor RpoS. We show that CsrA employs a novel regulatory mechanism to repress translation of
iraD
, which encodes an antiadapter protein that protects RpoS against proteolysis. CsrA binds to four sites in the
iraD
leader transcript but does not directly occlude ribosome binding to the
iraD
SD sequence. Instead, CsrA represses translation of a short open reading frame encoded upstream of
iraD
, causing repression of
iraD
translation via translational coupling. This finding offers a novel mechanism of gene regulation by the global regulator CsrA, and since RpoS can activate
csrA
transcription, this also highlights a new negative-feedback loop within the complex Csr and RpoS circuitry.
Higher health literacy is associated with better glycemic control in adults with type 1 diabetes: a cohort study among 1399 Danes
Authors: Olesen Kasper , F Reynheim Anne Louise , Joensen Lene , Ridderstråle Martin , Kayser Lars , Maindal Helle T , Osborne Richard H , Skinner Timothy , Willaing Ingrid 
Published: August 2017

AimSelf-management of diabetes is influenced by a range of factors including the ability to access, understand, appraise, and use of health information in everyday life, which can collectively be called health literacy. We investigated associations between nine domains of health literacy and HbA1c level in people with type 1 diabetes.MethodsA cross-sectional study was conducted with 1399 people with type 1 diabetes attending a Danish specialist diabetes clinic. Health literacy was assessed using the nine-domain Health Literacy Questionnaire. The association between health literacy and HbA1c was analyzed using linear regression with adjustment for age, sex, educational attainment and diabetes duration.ResultsOf the 1399 participants, 50% were women, mean age was 54 years, and mean HbA1c was 61 mmol/mol (7.8%). Higher health literacy scores were associated with lower HbA1c levels across eight of nine health literacy domains. This association remained significant after adjusting for educational attainment. Among the domains, ‘Actively managing my health’ had the strongest impact on HbA1c. This was in turn predicted by ‘Appraising health information’, ‘Having sufficient information to manage health’, and ‘Social support for health’.ConclusionsHigher health literacy levels are associated with lower HbA1c regardless of educational background. This study highlights the importance of healthcare provision to respond to the health literacy levels of people with diabetes and to the possible need to provide program designed to enhance health literacy.
A qualitative study exploring the factors influencing admission to hospital from the emergency department
Authors: Pope Ian , Burn Helen , Ismail Sharif A , Harris Tim , McCoy David 
Published: August 2017

ObjectiveThe number of emergency admissions to hospital in England and Wales has risen sharply in recent years and is a matter of concern to clinicians, policy makers and patients alike. However, the factors that influence this decision are poorly understood. We aimed to ascertain how non-clinical factors can affect hospital admission rates.MethodWe conducted semistructured interviews with 21 participants from three acute hospital trusts. Participants included 11 emergency department (ED) doctors, 3 ED nurses, 3 managers and 4 inpatient doctors. A range of seniority was represented among these roles. Interview questions were developed from key themes identified in a theoretical framework developed by the authors to explain admission decision-making. Interviews were recorded, transcribed and analysed by two independent researchers using framework analysis.FindingsDepartmental factors such as busyness, time of day and levels of senior support were identified as non-clinical influences on a decision to admit rather than discharge patients. The 4-hour waiting time target, while overall seen as positive, was described as influencing decisions around patient admission, independent of clinical need. Factors external to the hospital such as a patient’s social support and community follow-up were universally considered powerful influences on admission. Lastly, the culture within the ED was described as having a strong influence (either negatively or positively) on the decision to admit patients.ConclusionMultiple factors were identified which go some way to explaining marked variation in admission rates observed between different EDs. Many of these factors require further inquiry through quantitative research in order to understand their influence further.
Regional transarterial hypothermic infusion in combination with endovascular thrombectomy in acute ischaemic stroke with cerebral main arterial occlusion: protocol to investigate safety of the clinical trial
Authors: Tokairin Kikutaro , Osanai Toshiya , Abumiya Takeo , Kazumata Ken , Ono Kota , Houkin Kiyohiro 
Published: August 2017

IntroductionAcute cerebral ischaemia with main cerebral artery occlusion requires treatment with intravenous tissue plasminogen activator administration and/or endovascular thrombectomy. However, some patients fail to recover even after recanalisation because of ischaemia/reperfusion (I/R) injury. We hypothesised that regional transarterial hypothermic infusion would be effective for patients with I/R injury. The aim of this study is to validate the safety of this procedure.Methods and analysisThis is a clinical exploratory study to evaluate safety of regional transarterial hypothermic infusion in combination with endovascular thrombectomy. Patients with acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 5–29 who require endovascular thrombectomy are eligible for the study. When no improvement in NIHSS score after the recanalisation is achieved by thrombectomy, cold saline (15°C) will be administered through a microcatheter located in the ipsilateral internal carotid artery. The primary endpoints of this study are mortality and morbidity. The secondary endpoint is deleterious effects on clinical data such as symptoms, radiographic findings and physiological data. The primary and secondary endpoints will be accumulated as case series because this study will be conducted on a small sample of seven patients.Ethics and disseminationAll protocols and the informed consent form comply with the Ethics Guideline for Clinical Research (Japanese Ministry of Health, Labour and Welfare). Ethics review committees at the Hokkaido University Hospital approved the study protocols. The results of the study will be disseminated at several research conferences and also contributed to peer-reviewed journals. The study will be implemented and reported in line with the SPIRIT statement.Trial registration numberUMIN Clinical Trails Registry (UMIN000018255); pre-results
Antenatal antiarrhythmic treatment for fetal tachyarrhythmias: a study protocol for a prospective multicentre trial
Authors: Miyoshi Takekazu , Maeno Yasuki , Sago Haruhiko , Inamura Noboru , Yasukochi Satoshi , Kawataki Motoyoshi , Horigome Hitoshi , Yoda Hitoshi , Taketazu Mio , Shozu Makio , Nii Masaki , Hagiwara Akiko , Kato Hitoshi , Shimizu Wataru , Shiraishi Isao , Sakaguchi Heima , Ueda Keiko , Katsuragi Shinji , Ikeda Tomoaki , Yamamoto Haruko , Hamasaki Toshimitsu 
Published: August 2017

IntroductionSeveral retrospective or single-centre studies demonstrated the efficacy of transplacental treatment of fetal tachyarrhythmias. Our retrospective nationwide survey showed that the fetal therapy will be successful at an overall rate of 90%. For fetuses with hydrops, the treatment success rate will be 80%. However, standard protocol has not been established. The objective of this study is to evaluate the efficacy and safety of the protocol-defined transplacental treatment of fetal tachyarrhythmias. Participant recruitment began in October 2010.Methods and analysisThe current study is a multicentre, single-arm interventional study. A total of 50 fetuses will be enrolled from 15 Japanese institutions. The protocol-defined transplacental treatment is performed for singletons with sustained fetal tachyarrhythmia ≥180 bpm, with a diagnosis of supraventricular tachycardia or atrial flutter. Digoxin, sotalol, flecainide or a combination is used for transplacental treatment. The primary endpoint is disappearance of fetal tachyarrhythmias. The secondary endpoints are fetal death related to tachyarrhythmia, proportion of preterm birth, rate of caesarean section attributable to fetal arrhythmia, improvement in fetal hydrops, neonatal arrhythmia, neonatal central nervous system disorders and neonatal survival. Maternal, fetal and neonatal adverse events are evaluated at 1 month after birth. Growth and development are also evaluated at 18 and 36 months of corrected age.Ethics and disseminationThe Institutional Review Board of the National Cerebral and Cardiovascular Center of Japan has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications.Trial registration numberUMIN Clinical Trials Registry UMIN000004270.
Organ damage in sickle cell disease study (ORDISS): protocol for a longitudinal cohort study based in Ghana
Authors: Anie Kofi A , Paintsil Vivian , Owusu-Dabo Ellis , Ansong Daniel , Osei-Akoto Alex , Ohene-Frempong Kwaku , Amissah Kofi Aikins , Addofoh Nicholas , Ackah Ezekiel Bonwin , Owusu-Ansah Amma Twumwa , Ofori-Acquah Solomon Fiifi 
Published: August 2017

IntroductionSickle cell disease is highly prevalent in Africa with a significant public health burden. Nonetheless, morbidity and mortality in sickle cell disease that result from the progression of organ damage is not well understood. The Organ Damage in Sickle Cell Disease Study (ORDISS) is designed as a longitudinal cohort study to provide critical insight into cellular and molecular pathogenesis of chronic organ damage for the development of future innovative treatment.Methods and analysisORDISS aims to recruit children aged 0–15 years who attend the Kumasi Centre for Sickle Cell Disease based at the Komfo Anokye Teaching Hospital in Kumasi, Ghana. Consent is obtained to collect blood and urine samples from the children during specified clinic visits and hospitalisations for acute events, to identify candidate and genetic markers of specific organ dysfunction and end-organ damage, over a 3 year period. In addition, data concerning clinical history and complications associated with sickle cell disease are collected. Samples are stored in biorepositories and analysed at the Kumasi Centre for Collaborative Research in Tropical Medicine, Ghana and the Centre for Translational and International Haematology, University of Pittsburgh, USA. Appropriate statistical analyses will be performed on the data acquired.Ethics and disseminationResearch ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals, and the key findings presented at national and international conferences.
Trends in disability of instrumental activities of daily living among older Chinese adults, 1997-2006: population based study
Authors: Liang Yajun , Welmer Anna-Karin , Möller Jette , Qiu Chengxuan 
Published: August 2017

BackgroundData on trends for disability in instrumental activity of daily living (IADL) are sparse in older Chinese adults.ObjectivesTo assess trends in prevalence and incidence of IADL disability among older Chinese adults and to explore contributing factors.DesignPopulation based study.Setting15 provinces and municipalities in China.SubjectsParticipants (age ≥60) were from four waves of the China Health and Nutrition Survey, conducted in 1997 (n=1533), 2000 (n=1581), 2004 (n=2028) and 2006 (n=2256), and from two cohorts constructed within the national survey: cohort 1997–2004 (n=712) and cohort 2000–2006 (n=823).MeasurementsIADL disability was defined as inability to perform one or more of the following: shopping, cooking, using transportation, financing and telephoning. Data were analysed with logistic regression and generalised estimating equation models.ResultsThe prevalence of IADL disability significantly decreased from 1997 to 2006 in the total sample and in all of the subgroups by age, sex, living region and IADL items (all ptrend<0.05). The incidence of IADL disability remained stable from cohort 1997-2004 to cohort 2000-2006 in the total sample and in all of the subgroups (all p>0.10). The recovery rate from IADL disability significantly increased over time in those aged 60–69 years (p=0.03). Living in a rural area or access to local clinics for healthcare was less disabling over time (ptrend<0.02).ConclusionsThe prevalence of IADL disability decreased among older Chinese adults during 1997–2006, whereas the incidence remained stable. The declining prevalence of IADL disability might be partly due to the decreased duration of IADL disability, and to improvements in living conditions and healthcare facilities over time.
Determinants of severe acute malnutrition among children under 5 years of age in Nepal: a community-based case–control study
Authors: Pravana Nilesh Kumar , Piryani Suneel , Chaurasiya Surendra Prasad , Kawan Rasmila , Thapa Ram Krishna , Shrestha Sumina 
Published: August 2017

BackgroundMalnutrition is one of the leading causes of morbidity and mortality among children under the age of 5 years in low and middle income countries like Nepal. Children with severe acute malnutrition (SAM) are nine times more likely to die than children without malnutrition. The prevalence of SAM has increased in Nepal over the past 15 years; however, the determinants of SAM have not been clearly assessed in the country.ObjectiveTo assess the determinants of SAM among children aged 6–59 months in the Bara district of Nepal.SettingA community-based case–control study was conducted in 12 randomly selected Village Development Committees (VDCs) of the Bara district of Nepal.ParticipantsA random sample of 292 children aged 6–59 months (146 as cases and 146 as controls) from 12 VDCs were included in this study.ResultsThe prevalence of SAM among children under the age of 5 years was 4.14%. The following factors were significantly associated with SAM: low socioeconomic status (adjusted odds ratio (AOR) 17.13, 95% CI 5.85 to 50.13); mother’s age at birth <20 or >35 years (AOR 3.21, 95% CI 1.30 to 7.94); birth interval <24 months (AOR 4.09, 95% CI 1.87 to 8.97); illiterate father (AOR 3.65, 95% CI 1.62 to 8.20); bottle feeding (AOR 2.19, 95% CI 1.73 to 12.03); and not initiating complementary feeding at the age of 6 months (AOR 2.91, 95% CI 1.73 to 12.03). Mother’s educational level, initiation of breastfeeding, colostrum feeding, and exclusive breastfeeding were not significantly associated with SAM.ConclusionThe mother's age at birth, birth interval, socioeconomic status, father’s educational level and initiation of complementary feeding at the age of 6 months were important determinants of SAM among children. A multi-sector approach is essential to address SAM. There is a need for further studies not only focusing on SAM but also moderate acute malnutrition.
The Chinese version of the Severe Respiratory Insufficiency questionnaire for patients with chronic hypercapnic chronic obstructive pulmonary disease receiving non-invasive positive pressure ventilation
Authors: Chen Rongchang , Guan Lili , Wu Weiliang , Yang Zhicong , Li Xiaoying , Luo Qun , Liang Zhenyu , Wang Fengyan , Guo Bingpeng , Huo Yating , Yang Yuqiong , Zhou Luqian 
Published: August 2017

ObjectivesThe Severe Respiratory Insufficiency (SRI) questionnaire is the best assessment tool for health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) receiving non-invasive positive pressure ventilation (NIPPV). This study aimed to translate the SRI Questionnaire into Chinese and to validate it.DesignProspective validation study.Setting and participantsA total of 149 participants with chronic hypercapnic COPD receiving NIPPV completed the study.MethodsThe SRI questionnaire was translated into Chinese using translation and back-translation. Reliability was gauged using Cronbach’s α coefficient. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to assess construct validity. Content validity was confirmed by evaluating the relationship between the score of each item and the total score of the relevant subscale.ResultsCronbach’s α coefficients for each subscale and summary scale were above 0.7. Using EFA, one factor was extracted from the anxiety and summary scales and two factors were extracted from the remaining six subscales. Based on the EFA results, subsequent CFA revealed a good model fit for each subscale, but the extracted factors of each subscale were correlated. Content validity was confirmed by the good relationship between the score of each item and the total score of the relevant subscale.ConclusionThe Chinese version of the SRI questionnaire is valid and reliable for patients with chronic hypercapnic COPD receiving NIPPV in China.Trial registration numberNCT02499718.