bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental perception and epigenetic memory: mechanistic insight through FLC
Authors: Berry Scott , Dean Caroline 
Published: April 2015

SummaryChromatin plays a central role in orchestrating gene regulation at the transcriptional level. However, our understanding of how chromatin states are altered in response to environmental and developmental cues, and then maintained epigenetically over many cell divisions, remains poor. The floral repressor gene FLOWERING LOCUS C (FLC) in Arabidopsis thaliana is a useful system to address these questions. FLC is transcriptionally repressed during exposure to cold temperatures, allowing studies of how environmental conditions alter expression states at the chromatin level. FLC repression is also epigenetically maintained during subsequent development in warm conditions, so that exposure to cold may be remembered. This memory depends on molecular complexes that are highly conserved among eukaryotes, making FLC not only interesting as a paradigm for understanding biological decision‐making in plants, but also an important system for elucidating chromatin‐based gene regulation more generally. In this review, we summarize our understanding of how cold temperature induces a switch in the FLC chromatin state, and how this state is epigenetically remembered. We also discuss how the epigenetic state of FLC is reprogrammed in the seed to ensure a requirement for cold exposure in the next generation.
Development of Disease‐specific, Context‐specific Surveillance Models: Avian Influenza (H5N1)‐Related Risks and Behaviours in African Countries
Authors: Fasina F. O. , Njage P. M. K. , Ali A. M. M. , Yilma J. M. , Bwala D. G. , Rivas A. L. , Stegeman A. J. 
Published: April 2015

SummaryAvian influenza virus (H5N1) is a rapidly disseminating infection that affects poultry and, potentially, humans. Because the avian virus has already adapted to several mammalian species, decreasing the rate of avian–mammalian contacts is critical to diminish the chances of a total adaptation of H5N1 to humans. To prevent the pandemic such adaptation could facilitate, a biology‐specific disease surveillance model is needed, which should also consider geographical and socio‐cultural factors. Here, we conceptualized a surveillance model meant to capture H5N1‐related biological and cultural aspects, which included food processing, trade and cooking‐related practices, as well as incentives (or disincentives) for desirable behaviours. This proof of concept was tested with data collected from 378 Egyptian and Nigerian sites (local [backyard] producers/live bird markets/village abattoirs/commercial abattoirs and veterinary agencies). Findings revealed numerous opportunities for pathogens to disseminate, as well as lack of incentives to adopt preventive measures, and factors that promoted epidemic dissemination. Supporting such observations, the estimated risk for H5N1‐related human mortality was higher than previously reported. The need for multidimensional disease surveillance models, which may detect risks at higher levels than models that only measure one factor or outcome, was supported. To develop efficient surveillance systems, interactions should be captured, which include but exceed biological factors. This low‐cost and easily implementable model, if conducted over time, may identify focal instances where tailored policies may diminish both endemicity and the total adaptation of H5N1 to the human species.
Angiotensin‐dependent autonomic dysregulation precedes dilated cardiomyopathy in a mouse model of muscular dystrophy
Authors: Sabharwal Rasna , Weiss Robert M. , Zimmerman Kathy , Domenig Oliver , Cicha Michael Z. , Chapleau Mark W. 
Published: April 2015

New Findings

What is the central question of this study?
Is autonomic dysregulation in a mouse model of muscular dystrophy dependent on left ventricular systolic dysfunction and/or activation of the renin–angiotensin system (RAS) and does it predict development of dilated cardiomyopathy (DCM)?

What is the main finding and its importance?
The results demonstrate that autonomic dysregulation precedes and predicts left ventricular dysfunction and DCM in sarcoglycan‐δ‐deficient (Sgcd−/−) mice. The autonomic dysregulation is prevented by treatment of young Sgcd−/− mice with the angiotensin II type 1 receptor blocker losartan. Measurements of RAS activation and autonomic dysregulation may predict risk of DCM, and therapies targeting the RAS and autonomic dysregulation at a young age may slow disease progression in patients.

Sarcoglycan mutations cause muscular dystrophy. Patients with muscular dystrophy develop autonomic dysregulation and dilated cardiomyopathy (DCM), but the temporal relationship and mechanism of autonomic dysregulation are not well understood. We hypothesized that activation of the renin–angiotensin system (RAS) causes autonomic dysregulation prior to development of DCM in sarcoglycan‐δ‐deficient (Sgcd−/−) mice and that the severity of autonomic dysfunction at a young age predicts the severity of DCM at older ages. At 10–12 weeks of age, when left ventricular function assessed by echocardiography remained normal, Sgcd−/− mice exhibited decreases in arterial pressure, locomotor activity, baroreflex sensitivity and cardiovagal tone and increased sympathetic tone compared with age‐matched C57BL/6 control mice (P < 0.05). Systemic and skeletal muscle RAS were activated, and angiotensin II type 1 receptor (AT1R) expression, superoxide and fibrosis were increased in dystrophic skeletal muscle (P < 0.05). Treatment with the AT1R blocker losartan for 7–9 weeks beginning at 3 weeks of age prevented or strongly attenuated the abnormalities in Sgcd−/− mice (P < 0.05). Repeated assessment of phenotypes between 10 and 75 weeks of age demonstrated worsening of autonomic function, progressive cardiac dysfunction and DCM and increased mortality in Sgcd−/− mice. High sympathetic tone predicted subsequent left ventricular dysfunction. We conclude that activation of the RAS causes severe autonomic dysregulation in young Sgcd−/− mice, which portends a worse long‐term prognosis. Therapeutic targeting of the RAS at a young age may improve autonomic function and slow disease progression in muscular dystrophy.
Chromosomal “Stress-Response” Domains Govern the Spatiotemporal Expression of the Bacterial Virulence Program
Authors: Jiang Xuejiao , Sobetzko Patrick , Nasser William , Reverchon Sylvie , Muskhelishvili Georgi 
Published: April 2015

ABSTRACT

Recent studies strongly suggest that the gene expression sustaining both normal and pathogenic bacterial growth is governed by the structural dynamics of the chromosome. However, the mechanistic device coordinating the chromosomal configuration with selective expression of the adaptive traits remains largely unknown. We used a holistic approach exploring the inherent relationships between the physicochemical properties of the DNA and the expression of adaptive traits, including virulence factors, in the pathogen
Dickeya dadantii
(formerly
Erwinia chrysanthemi
). In the transcriptomes obtained under adverse conditions encountered during bacterial infection, we explored the patterns of chromosomal DNA sequence organization, supercoil dynamics, and gene expression densities, together with the long-range regulatory impacts of the abundant DNA architectural proteins implicated in pathogenicity control. By integrating these data, we identified transient chromosomal domains of coherent gene expression featuring distinct couplings between DNA thermodynamic stability, supercoil dynamics, and virulence traits.

IMPORTANCE
We infer that the organization of transient chromosomal domains serving specific functions acts as a fundamental device for versatile adjustment of the pathogen to environmental stress. We believe that the identification of chromosomal “stress-response” domains harboring distinct virulence traits and mediating the cellular adaptive behavior provides a breakthrough in understanding the control mechanisms of bacterial pathogenicity.
Single Nucleoprotein Residue Modulates Arenavirus Replication Complex Formation
Authors: Knopp Kristeene A. , Ngo Tuan , Gershon Paul D. , Buchmeier Michael J. 
Published: April 2015

ABSTRACT

The
Arenaviridae
are enveloped, negative-sense RNA viruses with several family members that cause hemorrhagic fevers. This work provides immunofluorescence evidence that, unlike those of New World arenaviruses, the replication and transcription complexes (RTC) of lymphocytic choriomeningitis virus (LCMV) colocalize with eukaryotic initiation factor 4E (eIF4E) and that eIF4E may participate in the translation of LCMV mRNA. Additionally, we identify two residues in the LCMV nucleoprotein (NP) that are conserved in every mammalian arenavirus and are required for recombinant LCMV recovery. One of these sites, Y125, was confirmed to be phosphorylated by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). NP Y125 is located in the N-terminal region of NP that is disordered when RNA is bound. The other site, NP T206, was predicted to be a phosphorylation site. Immunofluorescence analysis demonstrated that NP T206 is required for the formation of the punctate RTC that are typically observed during LCMV infection. A minigenome reporter assay using NP mutants, as well as Northern blot analysis, demonstrated that although NP T206A does not form punctate RTC, it can transcribe and replicate a minigenome. However, in the presence of matrix protein (Z) and glycoprotein (GP), translation of the minigenome message with NP T206A was inhibited, suggesting that punctate RTC formation is required to regulate viral replication. Together, these results highlight a significant difference between New and Old World arenaviruses and demonstrate the importance of RTC formation and translation priming in RTC for Old World arenaviruses.

IMPORTANCE
Several members of the
Arenaviridae
cause hemorrhagic fevers and are classified as category A pathogens. Arenavirus replication-transcription complexes (RTC) are nucleated by the viral nucleoprotein. This study demonstrates that the formation of these complexes is required for virus viability and suggests that RTC nucleation is regulated by the phosphorylation of a single nucleoprotein residue. This work adds to the body of knowledge about how these key viral structures are formed and participate in virus replication. Additionally, the fact that Old World arenavirus complexes colocalize with the eukaryotic initiation factor 4E, while New World arenaviruses do not, is only the second notable difference observed between New and Old World arenaviruses, the first being the difference in the glycoprotein receptor.
Implementation of the partograph in India's JSY cash transfer programme for facility births: a mixed methods study in Madhya Pradesh province
Authors: Chaturvedi Sarika , Upadhyay Sourabh , De Costa Ayesha , Raven Joanna 
Published: April 2015

ObjectivesTo study implementation of partograph use to monitor labour in facilities providing the JSY (Janani Suraksha Yojana) cash transfer programme for facility births in India by determining (1) adherence to partograph use, (2) staff abilities at partograph use and (3) staff responsiveness to the policy on partograph use.DesignA mixed methods study using Carroll's framework for implementation fidelity. Methods include (1) obstetric case record review, (2) a vignette-based survey among nurse midwives and (3) interviews with staff.SettingRoutine use of the partograph is recommended to monitor progress of labour in most low-and middle-income countries (LMICs), including India, although currently available evidence in this regard is insufficient. This study was conducted in the context of the highly successful JSY programme in three districts of Madhya Pradesh province.Participants73 different level JSY programme facilities participated in the record review, 233 nurse midwives at these facilities participated in the vignette survey and a total of 11 doctors and midwives participated in the interviews.ResultsThe partograph was used in 6% of the 1466 records reviewed. The staff obtained a median score of 1.08 (maximum of 10) at competence in plotting a partograph. Three themes emerged from the qualitative data: (1) partographs are used rarely and retrospectively; (2) training does not support correct use of the partograph; and (3) partographs can be useful but are not feasible.ConclusionsImplementation fidelity of partograph use in the JSY programme is low. Successful implementation of the partograph can result in improved quality of care in the JSY programme only if potential moderators to its adherence, such as training, supervision, staff ‘buy in’ and practice environment are addressed so that staff find a conducive practice environment in which to use the partograph and women find it beneficial to present early in labour.
Acupuncture for treating sciatica: a systematic review protocol
Authors: Qin Zongshi , Liu Xiaoxu , Yao Qin , Zhai Yanbing , Liu Zhishun 
Published: April 2015

IntroductionThis systematic review aims to assess the effectiveness and safety of acupuncture for treating sciatica.MethodsThe following nine databases will be searched from their inception to 30 October 2014: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese Biomedical Literature Database (CBM), the Chinese Medical Current Content (CMCC), the Chinese Scientific Journal Database (VIP database), the Wan-Fang Database, the China National Knowledge Infrastructure (CNKI) and Citation Information by National Institute of Informatics (CiNii). Randomised controlled trials (RCTs) of acupuncture for sciatica in English, Chinese or Japanese without restriction of publication status will be included. Two researchers will independently undertake study selection, extraction of data and assessment of study quality. Meta-analysis will be conducted after screening of studies. Data will be analysed using risk ratio for dichotomous data, and standardised mean difference or weighted mean difference for continuous data.DisseminationThis systematic review will be disseminated electronically through a peer-reviewed publication or conference presentations.Trial registration numberPROSPERO CRD42014015001.
Thalassaemia and risk of cancer: a population-based cohort study
Authors: Chung Wei-Sheng , Lin Chun-Liang , Lin Cheng-Li , Kao Chia-Hung 
Published: April 2015

BackgroundStudies that have investigated the epidemiological relationship between thalassaemia and cancers are scarce. Therefore, we conducted a longitudinal nationwide cohort study to determine whether patients with thalassaemia are at an increased risk of cancer.MethodsWe investigated the incidence and risk of cancer in 2655 patients diagnosed with thalassaemia between 1998 and 2010 by using data from the Taiwan Longitudinal Health Insurance Database. The comparison cohort comprised 10 620 people from the general population without thalassaemia. The follow-up period extended from the diagnostic date for thalassaemia to the date of a cancer diagnosis, censoring or 31 December 2011. We used Cox proportional hazard regression models to analyse the risks of cancer.ResultsThe incidences of cancer were 3.96 and 2.60/1000 person-years for the thalassaemia and comparison cohorts, respectively. The overall incidence of cancer was 52% higher in the thalassaemia cohort than in the comparison cohort, with an adjusted HR (aHR) of 1.54 (95% CI 1.15 to 2.07). Patients with thalassaemia had a considerably higher risk of haematological malignancy (aHR=5.32, 95% CI 2.18 to 13.0) and abdominal cancer (aHR=1.96, 95% CI 1.22 to 3.15) than did the comparison cohort. Furthermore, patients with thalassaemia with transfusion exhibited a 9.31-fold risk for developing haematological malignancy and a 9.12-fold risk for developing abdominal cancer compared with those who did not receive transfusion.ConclusionsThis nationwide retrospective cohort study indicates that patients with thalassaemia carried substantial risks of haematological malignancy and abdominal cancer compared with those of the general population.
A healed strike-slip plate boundary in North Greenland indicated through associated pull-apart basins
Authors: Håkansson Eckart , Schack Pedersen Stig A. 
Published: April 2015

Abstract
In the North Atlantic, Laurentia–Eurasia break-up commenced in the Late Carboniferous, largely following the structural grain of the Caledonian Fold Belt. However, in the Arctic region, a 45° offset in the plate boundary between North Greenland and Svalbard was determined by a number of pre-Caledonian fundamental faults in North Greenland. As a result, this segment of the plate boundary experienced significant episodes of combined transtension and transpression, in part controlled by the movement of a temporarily independent Greenland Plate. Late Permian–Mesozoic deposits in the North Greenland Wandel Sea Basin record the plate-boundary history along this offset, in our view in a series of at least 20, variously disturbed, pull-apart basins, most of which can be assigned to four major episodes of pull-apart basin formation. The direction of the pre-existing fundamental faults, in combination with the regional variation in rock properties of both the basin floor and basin fill, explains the marked differences in tectonic style recorded along the plate boundary.
Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non–Small Cell Lung Cancer Patients (SAKK 19/05 trial)
Authors: Franzini Anca , Baty Florent , Macovei Ina I. , Dürr Oliver , Droege Cornelia , Betticher Daniel , Grigoriu Bogdan D. , Klingbiel Dirk , Zappa Francesco , Brutsche Martin H. 
Published: April 2015

Abstract
Purpose: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non–small cell lung cancer (NSCLC) patients.
Experimental Design: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome.
Results: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001).
Conclusions: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response. Clin Cancer Res; 21(23); 5253–63. ©2015 AACR.
See related commentary by Cascone and Heymach, p. 5188
Validation of the 2014 European Society of Cardiology Guidelines Risk Prediction Model for the Primary Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy
Authors: Vriesendorp Pieter A. , Schinkel Arend F.L. , Liebregts Max , Theuns Dominic A.M.J. , van Cleemput Johan , ten Cate Folkert J. , Willems Rik , Michels Michelle 
Published: April 2015

Background—
The recently released 2014 European Society of Cardiology guidelines of hypertrophic cardiomyopathy (HCM) use a new clinical risk prediction model for sudden cardiac death (SCD), based on the HCM Risk-SCD study. Our study is the first external and independent validation of this new risk prediction model.

Methods and Results—

The study population consisted of a consecutive cohort of 706 patients with HCM without prior SCD event, from 2 tertiary referral centers. The primary end point was a composite of SCD and appropriate implantable cardioverter-defibrillator therapy, identical to the HCM Risk-SCD end point. The 5-year SCD risk was calculated using the HCM Risk-SCD formula. Receiver operating characteristic curves and C-statistics were calculated for the 2014 European Society of Cardiology guidelines, and risk stratification methods of the 2003 American College of Cardiology/European Society of Cardiology guidelines and 2011 American College of Cardiology Foundation/American Heart Association guidelines. During follow-up of 7.7±5.3 years, SCD occurred in 42 (5.9%) of 706 patients (ages 49±16 years; 34% women). The C-statistic of the new model was 0.69 (95% CI, 0.57–0.82;
P
=0.008), which performed significantly better than the conventional risk factor models based on the 2003 guidelines (C-statistic of 0.55: 95% CI, 0.47–0.63;
P
=0.3), and 2011 guidelines (C-statistic of 0.60: 95% CI, 0.50–0.70;
P
=0.07).

Conclusions—
The HCM Risk-SCD model improves the risk stratification of patients with HCM for primary prevention of SCD, and calculating an individual risk estimate contributes to the clinical decision-making process. Improved risk stratification is important for the decision making before implantable cardioverter-defibrillator implantation for the primary prevention of SCD.
Underutilization of Radial Access in Patients Undergoing Percutaneous Coronary Intervention for ST-Segment–Elevation Myocardial Infarction
Authors: Howe Michael J. , Seth Milan , Riba Arthur , Hanzel George , Zainea Mark , Gurm Hitinder S. 
Published: April 2015

Background—
The purpose of this study was to evaluate the frequency and temporal trends in use of transradial access (TRA) for percutaneous coronary intervention (PCI) in ST-segment–elevation myocardial infarction (STEMI). The use of TRA has been associated with less bleeding and improved clinical outcomes in patients undergoing PCI for STEMI.

Methods and Results—

The frequency of TRA compared with transfemoral access for patients undergoing PCI for STEMI or other indications (non–ST-segment–elevation myocardial infarction, unstable angina, and non–acute coronary syndrome) in The Blue Cross Blue Shield of Michigan Cardiovascular Consortium database between 2010 and 2013 was evaluated. Propensity matching was used to assess the relationship of TRA with in-hospital clinical end points of major bleeding, transfusion, and death. The TRA cohort of patients was stratified into deciles based on their predicted bleeding risk and compared with PCI indication. Of 122 728 PCI procedures, 17 912 (14.6%) were via TRA. Among patients with STEMI cases, 8.3% of the PCI cases were performed via TRA. The use of TRA increased over the study period although the growth was slower for STEMI than for other indications,
P
<0.001. The use of TRA for PCI in STEMI was associated with a lower rate of bleeding (11.7% versus 20.0%;
P
<0.001) and vascular complications (0.7% versus 2.6%;
P
=0.001), but no mortality difference (1.25% versus 2.33%;
P
=0.175). There was a strong negative association between the predicted risk of bleeding and the use of TRA (
P
<0.001).

Conclusions—
The use of radial access for PCI in STEMI is increasing but at a slower pace than for patients with other indications. TRA was associated with a reduction in bleeding and transfusion, but there is a strong negative correlation between the predicted risk of bleeding and actual use of TRA in STEMI.