bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collective versus Individual Effects in Survival Analysis of Multiple Failures
Authors: Li Jialiang , Huang Zhipeng , Ma Shuangge , Lee Mei‐Ling Ting 
Published: October 2015

AbstractIn survival analysis, we sometimes encounter data with multiple censored outcomes. Under certain scenarios, partial or even all covariates have ‘similar’ relative risks on the multiple outcomes in the Cox regression analysis. The similarity in covariate effects can be quantified using the proportionality of regression coefficients. Identifying the proportionality structure, or equivalently whether covariates have individual or collective effects, may have important scientific implications. In addition, it can lead to a smaller set of unknown parameters, which in turn results in more accurate estimation. In this article, we develop a novel approach for identifying the proportionality structure. Simulation shows the satisfactory performance of the proposed approach and its advantage over estimation under no assumed structure. We analyse three datasets to demonstrate the practical application of the proposed approach.
Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high‐fat diet
Authors: Shah Amin , Reyes Laura M. , Morton Jude S. , Fung David , Schneider Jillian , Davidge Sandra T. 
Published: October 2015

Key points
Prenatal hypoxia, a common outcome of many pregnancy complications, predisposes offspring to chronic diseases in later life.
We investigated the effect of prenatal hypoxia, on a background of a high‐fat diet, on metabolic and cardiac function in adult male and female rat offspring. We also examined the therapeutic role of resveratrol supplementation in preventing metabolic and cardiac dysfunction.
Prenatal hypoxia impaired both metabolic and cardiac function in male and only cardiac function in female rat offspring. We also observed that male rat offspring were more susceptible to metabolic and cardiac dysfunction as compared with their female counterparts; this provides evidence of sexual dichotomy in the fetal programming of diseases due to prenatal hypoxia.
Resveratrol supplementation in the diet improved metabolic and cardiac function independent of sex; this provides evidence of a possible therapeutic role of resveratrol in susceptible male and female rat offspring exposed to prenatal hypoxia.
AbstractPrenatal hypoxia, a common outcome of pregnancy complications, predisposes offspring to the development of metabolic and cardiovascular disorders in later life. We have previously observed that resveratrol improved cardiovascular and metabolic health in adult male rat offspring exposed to prenatal hypoxia and a postnatal high‐fat (HF) diet; however, the effects of resveratrol in female rat offspring are not known. Our aim was to identify the mechanism(s) by which resveratrol may prevent metabolic and cardiac dysfunction in both male and female rat offspring exposed to prenatal hypoxia and a postnatal HF diet. Offspring that experienced normoxia or hypoxia in utero were fed a HF diet or a HF diet supplemented with resveratrol for 9 weeks following weaning. Body composition, metabolic function, in vivo cardiac function and ex vivo cardiac susceptibility to ischaemia–reperfusion (I/R) injury were assessed at 12 weeks of age. Prenatal hypoxia impaired metabolic function in male, but not female, rat offspring fed a HF diet and this was improved by resveratrol supplementation. Prenatal hypoxia also led to reduced recovery from cardiac I/R injury in male, and to a lesser extent in female, rat offspring fed a HF diet. Indices of cardiac oxidative stress after I/R were enhanced in both male and female rat offspring exposed to prenatal hypoxia. Resveratrol improved cardiac recovery from I/R injury and attenuated superoxide levels in both male and female rat offspring. In conclusion, prenatal hypoxia impaired metabolic and cardiac function in a sex‐specific manner. Resveratrol supplementation may improve metabolic and cardiovascular health in adult male and female rat offspring exposed to prenatal hypoxia.
Degradation of proton depth dose distributions attributable to microstructures in lung‐equivalent material
Authors: Titt Uwe , Sell Martin , Unkelbach Jan , Bangert Mark , Mirkovic Dragan , Oelfke Uwe , Mohan Radhe 
Published: October 2015

Purpose:The purpose of the work reported here was to investigate the influence of sub‐millimeter size heterogeneities on the degradation of the distal edges of proton beams and to validate Monte Carlo (MC) methods’ ability to correctly predict such degradation.Methods:A custom‐designed high‐resolution plastic phantom approximating highly heterogeneous, lung‐like structures was employed in measurements and in Monte Carlo simulations to evaluate the degradation of proton Bragg curves penetrating heterogeneous media.Results:Significant differences in distal falloff widths and in peak dose values were observed in the measured and the Monte Carlo simulated curves compared to pristine proton Bragg curves. Furthermore, differences between simulations of beams penetrating CT images of the phantom did not agree well with the corresponding experimental differences. The distal falloff widths in CT image‐based geometries were underestimated by up to 0.2 cm in water (corresponding to 0.8–1.4 cm in lung tissue), and the peak dose values of pristine proton beams were overestimated by as much as ˜35% compared to measured curves or depth‐dose curves simulated on the basis of true geometry. The authors demonstrate that these discrepancies were caused by the limited spatial resolution of CT images that served as a basis for dose calculations and lead to underestimation of the impact of the fine structure of tissue heterogeneities. A convolution model was successfully applied to mitigate the underestimation.Conclusions:The results of this study justify further development of models to better represent heterogeneity effects in soft‐tissue geometries, such as lung, and to correct systematic underestimation of the degradation of the distal edge of proton doses.
Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2
Authors: Jiao Lianying , Liu Xin 
Published: October 2015

A tripartite gene silencing complex
The formation of specialized cell types during development involves the silencing of genes not required in those cell types. An important player in this silencing process is the polycomb repressive complex 2 (PRC2), which methylates histone H3 on lysine residue 27 (H3K27me). Jiao and Liu determined the x-ray crystal structure of a functional PRC2 complex from a thermophilic yeast species (see the Perspective by Schapira). The intimate association of the three subunits confers stability to PRC2. The structure also reveals how the reaction product, H3K27me, stimulates PRC2 allosterically and how a cancer-associated histone mutation blocks the PRC2 active site.

Science
, this issue p.
10.1126/science.aac4383
; see also p.
278
Sequence Variation in Amplification Target Genes and Standards Influences Interlaboratory Comparison of BK Virus DNA Load Measurement
Authors: Solis Morgane , Meddeb Mariam , Sueur Charlotte , Domingo-Calap Pilar , Soulier Eric , Chabaud Angeline , Perrin Peggy , Moulin Bruno , Bahram Seiamak , Stoll-Keller Françoise , Caillard Sophie , Barth Heidi , Fafi-Kremer Samira 
Published: October 2015

ABSTRACT

International guidelines define a BK virus (BKV) load of ≥4 log
10
copies/ml as presumptive of BKV-associated nephropathy (BKVN) and a cutoff for therapeutic intervention. To investigate whether BKV DNA loads (BKVL) are comparable between laboratories, 2 panels of 15 and 8 clinical specimens (urine, whole blood, and plasma) harboring different BKV genotypes were distributed to 20 and 27 French hospital centers in 2013 and 2014, respectively. Although 68% of the reported results fell within the acceptable range of the expected result ±0.5 log
10
, the interlaboratory variation ranged from 1.32 to 5.55 log
10
. Polymorphisms specific to BKV genotypes II and IV, namely, the number and position of mutations in amplification target genes and/or deletion in standards, arose as major sources of interlaboratory disagreements. The diversity of DNA purification methods also contributed to the interlaboratory variability, in particular for urine samples. Our data strongly suggest that (i) commercial external quality controls for BKVL assessment should include all major BKV genotypes to allow a correct evaluation of BKV assays, and (ii) the BKV sequence of commercial standards should be provided to users to verify the absence of mismatches with the primers and probes of their BKV assays. Finally, the optimization of primer and probe design and standardization of DNA extraction methods may substantially decrease interlaboratory variability and allow interinstitutional studies to define a universal cutoff for presumptive BKVN and, ultimately, ensure adequate patient care.
Standardization of Operator-Dependent Variables Affecting Precision and Accuracy of the Disk Diffusion Method for Antibiotic Susceptibility Testing
Authors: Hombach Michael , Maurer Florian P. , Pfiffner Tamara , Böttger Erik C. , Furrer Reinhard 
Published: October 2015

ABSTRACT

Parameters like zone reading, inoculum density, and plate streaking influence the precision and accuracy of disk diffusion antibiotic susceptibility testing (AST). While improved reading precision has been demonstrated using automated imaging systems, standardization of the inoculum and of plate streaking have not been systematically investigated yet. This study analyzed whether photometrically controlled inoculum preparation and/or automated inoculation could further improve the standardization of disk diffusion. Suspensions of
Escherichia coli
ATCC 25922 and
Staphylococcus aureus
ATCC 29213 of 0.5 McFarland standard were prepared by 10 operators using both visual comparison to turbidity standards and a Densichek photometer (bioMérieux), and the resulting CFU counts were determined. Furthermore, eight experienced operators each inoculated 10 Mueller-Hinton agar plates using a single 0.5 McFarland standard bacterial suspension of
E. coli
ATCC 25922 using regular cotton swabs, dry flocked swabs (Copan, Brescia, Italy), or an automated streaking device (BD-Kiestra, Drachten, Netherlands). The mean CFU counts obtained from 0.5 McFarland standard
E. coli
ATCC 25922 suspensions were significantly different for suspensions prepared by eye and by Densichek (
P
< 0.001). Preparation by eye resulted in counts that were closer to the CLSI/EUCAST target of 10
8
CFU/ml than those resulting from Densichek preparation. No significant differences in the standard deviations of the CFU counts were observed. The interoperator differences in standard deviations when dry flocked swabs were used decreased significantly compared to the differences when regular cotton swabs were used, whereas the mean of the standard deviations of all operators together was not significantly altered. In contrast, automated streaking significantly reduced both interoperator differences, i.e., the individual standard deviations, compared to the standard deviations for the manual method, and the mean of the standard deviations of all operators together, i.e., total methodological variation.
Proton Channel Activity of Influenza A Virus Matrix Protein 2 Contributes to Autophagy Arrest
Authors: Ren Yizhong , Li Chufang , Feng Liqiang , Pan Weiqi , Li Liang , Wang Qian , Li Jiashun , Li Na , Han Ling , Zheng Xuehua , Niu Xuefeng , Sun Caijun , Chen Ling 
Published: October 2015

ABSTRACT
Influenza A virus infection can arrest autophagy, as evidenced by autophagosome accumulation in infected cells. Here, we report that this autophagosome accumulation can be inhibited by amantadine, an antiviral proton channel inhibitor, in amantadine-sensitive virus infected cells or cells expressing influenza A virus matrix protein 2 (M2). Thus, M2 proton channel activity plays a role in blocking the fusion of autophagosomes with lysosomes, which might be a key mechanism for arresting autophagy.
The C-type Lectin Langerin Functions as a Receptor for Attachment and Infectious Entry of Influenza A Virus
Authors: Ng Wy Ching , Londrigan Sarah L. , Nasr Najla , Cunningham Anthony L. , Turville Stuart , Brooks Andrew G. , Reading Patrick C. 
Published: October 2015

ABSTRACT

It is well established that influenza A virus (IAV) attachment to and infection of epithelial cells is dependent on sialic acid (SIA) at the cell surface, although the specific receptors that mediate IAV entry have not been defined and multiple receptors may exist. Lec2 Chinese hamster ovary (CHO) cells are SIA deficient and resistant to IAV infection. Here we demonstrate that the expression of the C-type lectin receptor langerin in Lec2 cells (Lec2-Lg) rendered them permissive to IAV infection, as measured by replication of the viral genome, transcription of viral mRNA, and synthesis of viral proteins. Unlike SIA-dependent infection of parental CHO cells, IAV attachment and infection of Lec2-Lg cells was mediated via lectin-mediated recognition of mannose-rich glycans expressed by the viral hemagglutinin glycoprotein. Lec2 cells expressing endocytosis-defective langerin bound IAV efficiently but remained resistant to IAV infection, confirming that internalization via langerin was essential for infectious entry. Langerin-mediated infection of Lec2-Lg cells was pH and dynamin dependent, occurred via clathrin- and caveolin-mediated endocytic pathways, and utilized early (Rab5
+
) but not late (Rab7
+
) endosomes. This study is the first to demonstrate that langerin represents an authentic receptor that binds and internalizes IAV to facilitate infection. Moreover, it describes a unique experimental system to probe specific pathways and compartments involved in infectious entry following recognition of IAV by a single cell surface receptor.

IMPORTANCE
On the surface of host cells, sialic acid (SIA) functions as the major attachment factor for influenza A viruses (IAV). However, few studies have identified specific transmembrane receptors that bind and internalize IAV to facilitate infection. Here we identify human langerin as a transmembrane glycoprotein that can act as an attachment factor and a
bone fide
endocytic receptor for IAV infection. Expression of langerin by an SIA-deficient cell line resistant to IAV rendered cells permissive to infection. As langerin represented the sole receptor for IAV infection in this system, we have defined the pathways and compartments involved in infectious entry of IAV into cells following recognition by langerin.
Identification of
MEF2B
,
EBF1
, and
IL6R
as Direct Gene Targets of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Critical for EBV-Infected B-Lymphocyte Survival
Authors: Tempera Italo , De Leo Alessandra , Kossenkov Andrew V. , Cesaroni Matteo , Song Hui , Dawany Noor , Showe Louise , Lu Fang , Wikramasinghe Priyankara , Lieberman Paul M. 
Published: October 2015

ABSTRACT

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the EBV-encoded nuclear antigen and sequence-specific DNA binding protein required for viral origin binding and episome maintenance during latency. EBNA1 can also bind to numerous sites in the cellular genome and can provide a host cell survival function, but it is not yet known how EBNA1 sequence-specific binding is responsible for host cell survival. Here, we integrate EBNA1 chromatin immunoprecipitation sequencing (ChIP-Seq) with transcriptome sequencing (RNA-Seq) after EBNA1 depletion to identify cellular genes directly regulated by EBNA1 that are also essential for B-cell survival. We first compared EBNA1 ChIP-Seq patterns in four different EBV-positive cell types, including Burkitt lymphoma (BL) cells, nasopharyngeal carcinoma (NPC) cells, and lymphoblastoid cell lines (LCLs). EBNA1 binds to ∼1,000 sites that are mostly invariant among cell types and share a consensus recognition motif. We found that a large subset of EBNA1 binding sites are located proximal to transcription start sites and correlate genome-wide with transcription activity. EBNA1 bound to genes of high significance for B-cell growth and function, including
MEF2B
,
IL6R
, and
EBF1
. EBNA1 depletion from latently infected LCLs results in the loss of cell proliferation and the loss of gene expression for some EBNA1-bound genes, including
MEF2B
,
EBF1
, and
IL6R
. Depletion of MEF2B, EBF1, or IL6R partially phenocopies EBNA1 depletion by decreasing the cell growth and viability of cells latently infected with EBV. These findings suggest that EBNA1 binds to a large cohort of cellular genes important for cell viability and implicates EBNA1 as a critical regulator of transcription of host cell genes important for enhanced survival of latently infected cells.

IMPORTANCE
Epstein-Barr virus (EBV) latent infection is responsible for a variety of lymphoid and epithelial cell malignancies. EBNA1 is the EBV-encoded nuclear antigen that is consistently expressed in all EBV-associated cancers. EBNA1 is known to provide a host cell survival function, but the mechanism is not known. EBNA1 is a sequence-specific binding protein important for viral genome maintenance during latency. Here, by integrating ChIP-Seq and RNA-Seq, we demonstrate that EBNA1 binds directly to the promoter regulatory regions and upregulates the transcription of host genes that are important for the survival of EBV-infected cells. Identification of EBNA1 target genes provides potential new targets for therapeutic intervention in EBV-associated disease.
Comparative
In Vitro
and
In Vivo
Studies of Porcine Rotavirus G9P[13] and Human Rotavirus Wa G1P[8]
Authors: Shao Lulu , Fischer David D. , Kandasamy Sukumar , Rauf Abdul , Langel Stephanie N. , Wentworth David E. , Stucker Karla M. , Halpin Rebecca A. , Lam Ham Ching , Marthaler Douglas , Saif Linda J. , Vlasova Anastasia N. 
Published: October 2015

ABSTRACT
The changing epidemiology of group A rotavirus (RV) strains in humans and swine, including emerging G9 strains, poses new challenges to current vaccines. In this study, we comparatively assessed the pathogenesis of porcine RV (PRV) G9P[13] and evaluated the short-term cross-protection between this strain and human RV (HRV) Wa G1P[8] in gnotobiotic pigs. Complete genome sequencing demonstrated that PRV G9P[13] possessed a human-like G9 VP7 genotype but shared higher overall nucleotide identity with historic PRV strains. PRV G9P[13] induced longer rectal virus shedding and RV RNAemia in pigs than HRV Wa G1P[8] and generated complete short-term cross-protection in pigs challenged with HRV or PRV, whereas HRV Wa G1P[8] induced only partial protection against PRV challenge. Moreover, PRV G9P[13] replicated more extensively in porcine monocyte-derived dendritic cells (MoDCs) than did HRV Wa G1P[8]. Cross-protection was likely not dependent on serum virus-neutralizing (VN) antibodies, as the heterologous VN antibody titers in the sera of G9P[13]-inoculated pigs were low. Thus, our results suggest that heterologous protection by the current monovalent G1P[8] HRV vaccine against emerging G9 strains should be evaluated in clinical and experimental studies to prevent further dissemination of G9 strains. Differences in the pathogenesis of these two strains may be partially attributable to their variable abilities to replicate and persist in porcine immune cells, including dendritic cells (DCs). Additional studies are needed to evaluate the emerging G9 strains as potential vaccine candidates and to test the susceptibility of various immune cells to infection by G9 and other common HRV/PRV genotypes.

IMPORTANCE
The changing epidemiology of porcine and human group A rotaviruses (RVs), including emerging G9 strains, may compromise the efficacy of current vaccines. An understanding of the pathogenesis and genetic, immunological, and biological features of the new emerging RV strains will contribute to the development of new surveillance and prevention tools. Additionally, studies of cross-protection between the newly identified emerging G9 porcine RV strains and a human G1 RV vaccine strain in a susceptible host (swine) will allow evaluation of G9 strains as potential novel vaccine candidates to be included in porcine or human vaccines.
Differing perceptions of safety culture across job roles in the ambulatory setting: analysis of the AHRQ Medical Office Survey on Patient Safety Culture
Authors: Hickner John , Smith Scott A , Yount Naomi , Sorra Joann 
Published: October 2015

BackgroundExperts in patient safety stress the importance of a shared culture of safety. Lack of consensus may be detrimental to patient safety. This study examines differences in patient safety culture perceptions among providers, management and staff in a large national survey of safety culture in ambulatory practices in the USA.MethodsThe US Agency for Healthcare Research and Quality Medical Office Survey on Patient Safety Culture (SOPS) assesses perceptions about patient safety issues and event reporting in medical offices (ie, ambulatory practices). Using the 2014 data, we analysed responses from medical offices with at least five respondents. We calculated differences in perceptions of patient safety culture across six job positions (physicians, management, nurse practitioners (NPs)/physician assistants (PAs), nurses, clinical support staff and administrative/clerical staff) for 10 survey composites, the average of the 10 composites and an overall patient safety rating using multivariate hierarchical linear regressions.ResultsWe analysed data from 828 medical offices with responses from 15 523 providers and staff, with an average 20 completed surveys per medical office (range: 5–367) and an average medical office response rate of 65% (range: 3%–100%). Management had significantly more positive patient safety culture perceptions on nine of 10 composite scores compared with all other job positions, including physicians. The composite that showed the largest difference was Communication Openness; Management (85% positive) was 22% points more positive than other clinical and support staff and administrative/clerical staff. Physicians were significantly more positive than PAs/NPs, nursing staff, other clinical and support staff and administrative/clerical staff on four composites: Communication About Error, Communication Openness, Staff Training and Teamwork, ranging from 3% to 20% points more positive.ConclusionsThese findings suggest that managers need to pay attention to the training needs of office staff, since this was an area with one of the greatest gaps in perceptions. In addition, both office managers and physicians need to encourage more open communication. As medical offices innovate to improve value, efficiency and patient-centred care, it is important that they continue to foster shared perceptions about what organisational members need, understanding that those perceptions may differ systematically by job position.