bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porcine Epidemic Diarrhea Virus 3C-Like Protease Regulates Its Interferon Antagonism by Cleaving NEMO
Authors: Wang Dang , Fang Liurong , Shi Yanling , Zhang Huan , Gao Li , Peng Guiqing , Chen Huanchun , Li Kui , Xiao Shaobo 
Published: December 2015

ABSTRACT
Porcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus causing lethal watery diarrhea in piglets. Since 2010, a PEDV variant has spread rapidly in China, and it emerged in the United States in 2013, posing significant economic and public health concerns. The ability to circumvent the interferon (IFN) antiviral response, as suggested for PEDV, promotes viral survival and regulates pathogenesis of PEDV infections, but the underlying mechanisms remain obscure. Here, we show that PEDV-encoded 3C-like protease, nsp5, is an IFN antagonist that proteolytically cleaves the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), an essential adaptor bridging interferon-regulatory factor and NF-κB activation. NEMO is cleaved at glutamine 231 (Q231) by PEDV, and this cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of PEDV nsp5 abrogated NEMO cleavage and the inhibition of IFN induction. Structural analysis suggests that several key residues outside the catalytic sites of PEDV nsp5 probably impact NEMO cleavage by modulating potential interactions of nsp5 with their substrates. These data show that PEDV nsp5 disrupts type I IFN signaling by cleaving NEMO. Previously, we and others demonstrated that NEMO is also cleaved by 3C or 3C-like proteinases of picornavirus and artertivirus. Thus, NEMO probably represents a prime target for 3C or 3C-like proteinases of different viruses.

IMPORTANCE
The continued emergence and reemergence of porcine epidemic diarrhea virus (PEDV) underscore the importance of studying how this virus manipulates the immune responses of its hosts. During coevolution with its hosts, PEDV has acquired mechanisms to subvert host innate immune responses for its survival advantage. At least two proteins encoded by PEDV have been identified as interferon (IFN) antagonists, papain-like protease (PLP) and N protein. Here, we report that the PEDV nsp5 gene, which encodes the 3C-like protease of PEDV, is another IFN antagonist. Mechanistically, the cysteine protease activity of PEDV nsp5 mediates proteolysis of NEMO, the key adaptor for IFN synthesis, and NEMO is cleaved at glutamine 231 (Q231). The new molecular details and determinants impacting NEMO scission by PEDV nsp5 delineated in this study are fundamental to our understanding of critical virus-host interactions that determine PEDV pathogenesis.
Suppression of NYVAC Infection in HeLa Cells Requires RNase L but Is Independent of Protein Kinase R Activity
Authors: Fernández-Escobar Mercedes , Nájera José Luis , Baldanta Sara , Rodriguez Dolores , Way Michael , Esteban Mariano , Guerra Susana 
Published: December 2015

ABSTRACT

Protein kinase R (PKR) and RNase L are host cell components that function to contain viral spread after infections. In this study, we analyzed the role of both proteins in the abortive infection of human HeLa cells with the poxvirus strain NYVAC, for which an inhibition of viral
A27L
and
B5R
gene expression is described. Specifically, the translation of these viral genes is independent of PKR activation, but their expression is dependent on the RNase L activity.
Mutations of Conserved Residues in the Major Homology Region Arrest Assembling HIV-1 Gag as a Membrane-Targeted Intermediate Containing Genomic RNA and Cellular Proteins
Authors: Tanaka Motoko , Robinson Bridget A. , Chutiraka Kasana , Geary Clair D. , Reed Jonathan C. , Lingappa Jaisri R. 
Published: December 2015

ABSTRACT
The major homology region (MHR) is a highly conserved motif that is found within the Gag protein of all orthoretroviruses and some retrotransposons. While it is widely accepted that the MHR is critical for assembly of HIV-1 and other retroviruses, how the MHR functions and why it is so highly conserved are not understood. Moreover, consensus is lacking on when HIV-1 MHR residues function during assembly. Here, we first addressed previous conflicting reports by confirming that MHR deletion, like conserved MHR residue substitution, leads to a dramatic reduction in particle production in human and nonhuman primate cells expressing HIV-1 proviruses. Next, we used biochemical analyses and immunoelectron microscopy to demonstrate that conserved residues in the MHR are required after assembling Gag has associated with genomic RNA, recruited critical host factors involved in assembly, and targeted to the plasma membrane. The exact point of inhibition at the plasma membrane differed depending on the specific mutation, with one MHR mutant arrested as a membrane-associated intermediate that is stable upon high-salt treatment and other MHR mutants arrested as labile, membrane-associated intermediates. Finally, we observed the same assembly-defective phenotypes when the MHR deletion or conserved MHR residue substitutions were engineered into Gag from a subtype B, lab-adapted provirus or Gag from a subtype C primary isolate that was codon optimized. Together, our data support a model in which MHR residues act just after membrane targeting, with some MHR residues promoting stability and another promoting multimerization of the membrane-targeted assembling Gag oligomer.

IMPORTANCE
The retroviral Gag protein exhibits extensive amino acid sequence variation overall; however, one region of Gag, termed the major homology region, is conserved among all retroviruses and even some yeast retrotransposons, although the reason for this conservation remains poorly understood. Highly conserved residues in the major homology region are required for assembly of retroviruses; however, when these residues are required during assembly is not clear. Here, we used biochemical and electron microscopic analyses to demonstrate that these conserved residues function after assembling HIV-1 Gag has associated with genomic RNA, recruited critical host factors involved in assembly, and targeted to the plasma membrane but before Gag has completed the assembly process. By revealing precisely when conserved residues in the major homology region are required during assembly, these studies resolve existing controversies and set the stage for future experiments aimed at a more complete understanding of how the major homology region functions.
Qingdao Port Cardiovascular Health Study: a prospective cohort study
Authors: Spatz Erica S , Jiang Xianyan , Lu Jiapeng , Masoudi Frederick A , Spertus John A , Wang Yongfei , Li Xi , Downing Nicholas S , Nasir Khurram , Du Xue , Li Jing , Krumholz Harlan M , Liu Xiancheng , Jiang Lixin 
Published: December 2015

PurposeIn China, efforts are underway to respond to rapidly increasing rates of heart disease and stroke. Yet the epidemiology of cardiovascular disease in China may be different from that of other populations. Thus, there is a critical need for population-based studies that provide insight into the risk factors, incidence and outcomes of cardiovascular disease in China. The Qingdao Port Cardiovascular Health Study is designed to investigate the burden of cardiovascular disease and the sociodemographic, biological, environmental and clinical risk factors associated with disease onset and outcomes.ParticipantsFor this study, from 2000 through 2013, 32 404 employees aged 18 years or older were recruited from the Qingdao Port Group in China, contributing 221 923 annual health assessments. The mean age at recruitment was 43.4 (SD=12.9); 79% were male. In this ongoing study, annual health assessments, governed by extensive quality control mechanisms, include a questionnaire (capturing demographic and employment information, medical history, medication use, health behaviours and health outcomes), physical examination, ECG, and blood and urine analysis. Additional non-annual assessments include an X-ray, echocardiogram and carotid ultrasound; bio-samples will be collected for future genetic and proteomic analyses. Cardiovascular outcomes are accessed via self-report and are actively being verified with medical insurance claims; efforts are underway to adjudicate outcomes with hospital medical records.Findings to dateEarly findings reveal a significant increase in cardiovascular risk factors from 2000 to 2010 (hypertension: 26.4–39.4%; diabetes: 3.3–8.9%; hyperlipidaemia: 5.0–33.6%; body mass index >28 m/kg2: 14.1–18.6%).Future PlansWe aim to generate novel insights about the epidemiology and outcomes of cardiovascular disease in China, with specific emphasis on the potentially unique risk factor profiles of this Chinese population. Knowledge generated will be disseminated in the peer-reviewed literature, and will inform population-based strategies to improve cardiovascular health in China.Trial registration numberNCT02329886.
Discordance between presumed standard of care and actual clinical practice: the example of rubber dam use during root canal treatment in the National Dental Practice-Based Research Network
Authors: Gilbert Gregg H , Riley Joseph L , Eleazer Paul D , Benjamin Paul L , Funkhouser Ellen 
Published: December 2015

ObjectivesUse of a rubber dam during root canal treatment is considered the standard of care because it enhances patient safety and optimises the odds of successful treatment. Nonetheless, not all dentists use a rubber dam, creating disconnect between presumed standard of care and what is actually done in clinical practice. Little is known about dentists’ attitudes towards use of the rubber dam in their practices. The objectives were to: (1) quantify these attitudes and (2) test the hypothesis that specific attitudes are significantly associated with rubber dam use.SettingNational Dental Practice-Based Research Network (NationalDentalPBRN.org).Participants1490 network dentists.Outcome measuresDentists completed a questionnaire about their attitudes towards rubber dam use during root canal treatment. Three attitude scales comprised 33 items that used a 5-point ordinal scale to measure beliefs about effectiveness, inconvenience, ease of placement, comparison to other isolation techniques and patient factors. Factor analysis, cluster analysis and multivariable logistic regression analysed the relationship between attitudes and rubber dam use.ResultsAll items had responses at each point on the 5-point scale, with an overall pattern of substantial variation across dentists. Five attitudinal factors (rubber dam effectiveness; inconvenient/time-consuming; ease of placement; effectiveness compared to Isolite; patient factors) and 4 clusters of practitioners were identified. Each factor and cluster was independently and strongly associated with rubber dam use.ConclusionsGeneral dentists have substantial variation in attitudes about rubber dam use. Beliefs that rubber dam use is not effective, inconvenient, time-consuming, not easy to place or affected by patient factors, were independently and significantly associated with lower rubber dam use. These attitudes explain why there is substantial discordance between presumed standard of care and actual practice.
A New View of Ras Isoforms in Cancers
Authors: Nussinov Ruth , Tsai Chung-Jung , Chakrabarti Mayukh , Jang Hyunbum 
Published: December 2015

Abstract
Does small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras? A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl, K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1, K-Ras4A is only farnesylated, like K-Ras4B; in state 2, farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region sequence is positively charged, in between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and pancreatic ductal adenocarcinoma. On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia. Importantly, H-Ras has two, singly and doubly, palmitoylated states that may also serve distinct functional roles. The multiple signaling states of palmitoylated Ras isoforms question the completeness of small GTPase Ras isoform statistics in different cancer types and call for reevaluation of concepts and protocols. They may also call for reconsideration of oncogenic Ras therapeutics. Cancer Res; 76(1); 18–23. ©2015 AACR.
Regulator of G-Protein Signaling 5 Prevents Smooth Muscle Cell Proliferation and Attenuates Neointima Formation
Authors: Daniel Jan-Marcus , Prock André , Dutzmann Jochen , Sonnenschein Kristina , Thum Thomas , Bauersachs Johann , Sedding Daniel G. 
Published: December 2015

Objective—
Regulator of G-protein signaling 5 (RGS5) is abundantly expressed in vascular smooth muscle cells (SMCs) and inhibits G-protein signaling by enhancing the guanosine triphosphate–hydrolyzing activity of Gα-subunits. In the present study, we investigated the effects of RGS5 on vascular SMC function in vitro and neointima formation after wire-induced injury in mice and determined the underlying mechanisms.

Approach and Results—
We found a robust expression of RGS5 in native arteries of C57BL/6 mice and a highly significant downregulation within neointimal lesions 10 and 21 days after vascular injury as assessed by quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. In vitro, RGS5 was found significantly downregulated after mitogenic stimulation of human coronary artery SMCs. To restore RGS5 levels, SMCs were transduced with adenoviral vectors encoding wild-type RGS5 or a nondegradable mutant. RGS5-WT and, even more prominently, the C2A-RGS5 mutant prevented SMC proliferation and migration. In contrast, the siRNA-mediated knockdown of RGS5 significantly augmented SMC proliferation. Following overexpression of RGS5, fluorescence-activated cell sorting analysis of propidium iodide–stained cells indicated cell cycle arrest in G0/G1 phase. Mechanistically, inhibition of the phosphorylation of the extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase downstream signaling was shown to be responsible for the anti-proliferative effect of RGS5. Following wire-induced injury of the femoral artery in C57BL/6 mice, adenoviral-mediated overexpression of RGS5-WT or C2A-RGS5 significantly reduced SMC proliferation and neointima formation in vivo.

Conclusions—
Downregulation of RGS5 is an important prerequisite for SMC proliferation in vitro and in vivo. Therefore, reconstitution of RGS5 levels represents a promising therapeutic option to prevent vascular remodeling processes.
Evaluation of NASA’s MERRA Precipitation Product in Reproducing the Observed Trend and Distribution of Extreme Precipitation Events in the United States
Authors: Ashouri Hamed , Sorooshian Soroosh , Hsu Kuo-Lin , Bosilovich Michael G. , Lee Jaechoul , Wehner Michael F. , Collow Allison 
Published: December 2015

Abstract
This study evaluates the performance of NASA’s Modern-Era Retrospective Analysis for Research and Applications (MERRA) precipitation product in reproducing the trend and distribution of extreme precipitation events. Utilizing the extreme value theory, time-invariant and time-variant extreme value distributions are developed to model the trends and changes in the patterns of extreme precipitation events over the contiguous United States during 1979–2010. The Climate Prediction Center (CPC) U.S. Unified gridded observation data are used as the observational dataset. The CPC analysis shows that the eastern and western parts of the United States are experiencing positive and negative trends in annual maxima, respectively. The continental-scale patterns of change found in MERRA seem to reasonably mirror the observed patterns of change found in CPC. This is not previously expected, given the difficulty in constraining precipitation in reanalysis products. MERRA tends to overestimate the frequency at which the 99th percentile of precipitation is exceeded because this threshold tends to be lower in MERRA, making it easier to be exceeded. This feature is dominant during the summer months. MERRA tends to reproduce spatial patterns of the scale and location parameters of the generalized extreme value and generalized Pareto distributions. However, MERRA underestimates these parameters, particularly over the Gulf Coast states, leading to lower magnitudes in extreme precipitation events. Two issues in MERRA are identified: 1) MERRA shows a spurious negative trend in Nebraska and Kansas, which is most likely related to the changes in the satellite observing system over time that has apparently affected the water cycle in the central United States, and 2) the patterns of positive trend over the Gulf Coast states and along the East Coast seem to be correlated with the tropical cyclones in these regions. The analysis of the trends in the seasonal precipitation extremes indicates that the hurricane and winter seasons are contributing the most to these trend patterns in the southeastern United States. In addition, the increasing annual trend simulated by MERRA in the Gulf Coast region is due to an incorrect trend in winter precipitation extremes.
Selection into Street Gangs
Authors: Pyrooz David C. , Densley James A. 
Published: December 2015

Objective: The mechanisms underlying selection into street gangs remain elusive in the current inventory of theory and research on gangs, raising continued questions about not who or why, but how youth enter gangs and the attendant criminological implications. This study provides a suggestive analysis of an alternative framing of the selection process, one that is rooted in signaling theory. Methods: A signaling scale was constructed using a mixed graded response model and national longitudinal data to explore the thesis that (1) gang prospects select into gangs using hard-to-fake signals of quality and gangs, in turn, receive and interpret these signals to select high-quality over low-quality prospects and (2) the selection process in a signaling framework conditions the well-established relationship between gang membership and criminal offending. Results: Respondents scoring higher on a signaling scale were more likely to select into gangs prospectively and see greater, although nonlinear, increases in criminal offending upon entering gangs, net of adjusting for alternative explanations for these relationships. Conclusions: By further extending and analyzing signaling theory within the study of gang selection and criminal offending, the results of this study reveal that signaling theory has much to offer the study of gangs particularly and criminology generally.
The migraine–stroke connection: A genetic perspective
Authors: Malik Rainer , Winsvold Bendik , Auffenberg Eva , Dichgans Martin , Freilinger Tobias 
Published: December 2015

Background A complex relationship between migraine and vascular disease has long been recognized. The pathophysiological basis underlying this correlation is incompletely understood. Aim The aim of this review is to focus on the migraine–vascular disorders connection from a genetic perspective, illustrating potentially shared (molecular) mechanisms. Results We first summarize the clinical presentation and genetic basis of CADASIL and other monogenic vascular syndromes with migraine as a prominent disease manifestation. Based on data from transgenic mouse models for familial hemiplegic migraine, we then discuss cortical spreading depression as a potential mechanistic link between migraine and ischemic stroke. Finally, we review data from genome-wide association studies, with a focus on overlapping findings with cervical artery dissection, ischemic stroke in general and cardiovascular disease. Conclusion A wealth of data supports a genetic link between migraine and vascular disease. Based on growing high-throughput data-sets, new genotyping techniques and in-depth phenotyping, further insights are expected for the future.
Menarche and Menstruation in Rural Adolescent Girls in Maharashtra, India
Authors: Behera Deepanjali , Sivakami Muthusamy , Behera Manas Ranjan 
Published: December 2015

Background: Menarche and menstrual experiences play a critical role in adolescent girls’ life. These not only significantly influence their sexual and reproductive health but also possess much social and educational impact. This study qualitatively explores the perceptions, practices and experiences related to menarche and menstruation among rural Indian adolescent girls which has been less studied in the past literature. Methods: A convenience sampling method was used to select 32 adolescent girls (eight girls who did not reach menarche and 24 girls who attained menarche) from rural Maharashtra in India. Information about the perceptions, practices and experiences of menarche and menstruation among the participants was obtained through focus group discussions and was analyzed using thematic analysis. Findings: Most of the participants, especially girls without menarche lacked adequate knowledge about menstruation and its processes. All communications regarding menstruation were between friends, whereas mothers were found to be playing a limited role. Some of the girls were using sanitary pads, while most girls still use old cloths. Financial concerns and difficulty in obtaining sanitary pads were major obstructions for their use. Lack of awareness and appropriate care for menstrual morbidities were reported among these girls, which put impact on their educational attainment. Conclusions: Suitable strategy needs to be developed for providing correct knowledge about menstruation among adolescent girls, such as inclusion of adolescent friendly services in school curriculum and training of mothers and teachers to provide friendly counselling to the girls. Further, menstrual pad vending machines could be installed in schools and colleges, for easy access of sanitary pads at subsidized rate. Special care and support during menstruation can prevent several adverse events from occurring in adolescent girls’ lives.
Ethical use of the media by psychiatrists: towards an antipodean formulation of the “Goldwater Rule”
Authors: Robertson Michael , Walter Garry , Bloch Sidney 
Published: December 2015

Objectives: To review the ethical problems posed by the participation of psychiatrists in various forms of lay media and propose a method of resolving quandaries in this area. Conclusions: We review the potential ethical problems that arise when psychiatrists make contributions to the lay media, particularly when commentary and opinion reflects the views of the individual rather than the profession. The issues raised by the North American injunction known as the “Goldwater Rule” are pertinent to Australasia, particularly when media statements made by psychiatrists may seem to diminish the profession through politicisation, polemic, or bringing the profession and the field into disrepute. We propose a series of reflective questions to assist psychiatrists in Australasia to deliberate on the potential ethical problems arising from their participation in media activities. We conclude that it is for the Royal Australian and New Zealand College of Psychiatrists to formulate an approach to situations where the media activities of Fellows raise such problems.