bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus
Authors: Chan Liana C. , Chaili Siyang , Filler Scott G. , Barr Kevin , Wang Huiyuan , Kupferwasser Deborah , Edwards John E. , Xiong Yan Q. , Ibrahim Ashraf S. , Miller Lloyd S. , Schmidt Clint S. , Hennessey John P. , Yeaman Michael R. 
Published: September 2015

ABSTRACT

Staphylococcus aureus
is the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due to
S. aureus
, particularly methicillin-resistant
S. aureus
(MRSA) strains, suggests that infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA, after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 reduced T cell and neutrophil infiltration and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability, and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses but did increase gamma interferon (IFN-γ) expression at these sites. The inhibition of IL-22 led to a reduction in IL-17A expression, but not vice versa. These results suggest that the expression of IL-17A is at least partially dependent on IL-22 in this model. Inhibition of IL-17A but not IL-22 led to hematogenous dissemination to kidneys, which correlated with decreased T cell infiltration in renal tissue. Collectively, these findings indicate that IL-17A and IL-22 have complementary but nonredundant roles in host defense against cutaneous versus hematogenous infection. These insights may support targeted immune enhancement or other novel approaches to address the challenge of MRSA infection.
Y-Box Binding Protein 1 Stabilizes Hepatitis C Virus NS5A via Phosphorylation-Mediated Interaction with NS5A To Regulate Viral Propagation
Authors: Wang Wei-Ting , Tsai Tsung-Yuan , Chao Chi-Hong , Lai Bo-Ying , Wu Lee Yan-Hwa 
Published: September 2015

ABSTRACT
Replication of hepatitis C virus (HCV) is dependent on virus-encoded proteins and numerous cellular factors. DDX3 is a well-known host cofactor of HCV replication. In this study, we investigated the role of a DDX3-interacting protein, Y-box binding protein 1 (YB-1), in the HCV life cycle. Both YB-1 and DDX3 interacted with the viral nonstructural protein NS5A. During HCV infection, YB-1 partially colocalized with NS5A and the HCV replication intermediate double-stranded RNA (dsRNA) in HCV-infected Huh-7.5.1 cells. Despite sharing the same interacting partners, YB-1 participated in HCV RNA replication but was dispensable in steady-state HCV RNA replication, different from the action of DDX3. Moreover, knockdown of YB-1 in HCV-infected cells prevented infectious virus production and reduced the ratio of hyperphosphorylated (p58) to hypophosphorylated (p56) forms of NS5A, whereas DDX3 silencing did not affect the ratio of the p58 and p56 phosphoforms of NS5A. Interestingly, silencing of YB-1 severely reduced NS5A protein stability in NS5A-ectopically expressing, replicon-containing, and HCV-infected cells. Furthermore, mutations of serine 102 of YB-1 affected both YB-1–NS5A interaction and NS5A-stabilizing activity of YB-1, indicating that this Akt phosphorylation site of YB-1 plays an important role in stabilizing NS5A. Collectively, our results support a model in which the event of YB-1 phosphorylation-mediated interaction with NS5A results in stabilizing NS5A to sustain HCV RNA replication and infectious HCV production. Overall, our study may reveal a new aspect for the development of novel anti-HCV drugs.

IMPORTANCE
Chronic hepatitis C virus (HCV) infection induces liver cirrhosis and hepatocellular carcinoma. The viral nonstructural protein NS5A co-opting various cellular signaling pathways and cofactors to support viral genome replication and virion assembly is a new strategy for anti-HCV drug development. NS5A phosphorylation is believed to modulate switches between different stages of the HCV life cycle. In this study, we identified the cellular protein YB-1 as a novel NS5A-interacting protein. YB-1 is a multifunctional protein participating in oncogenesis and is an oncomarker of hepatocellular carcinoma (HCC). We found that YB-1 protects NS5A from degradation and likely regulates NS5A phosphorylation through its phosphorylation-dependent interaction with NS5A, which might be controlled by HCV-induced signaling pathways. Our observations suggest a model in which HCV modulates NS5A level and the ratio of the p58 and p56 phosphoforms for efficient viral propagation via regulation of cellular signaling inducing YB-1 phosphorylation. Our finding may provide new aspects for developing novel anti-HCV drugs.
Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes
Authors: Kwon Young-Chan , Bose Sandip K. , Steele Robert , Meyer Keith , Di Bisceglie Adrian M. , Ray Ratna B. , Ray Ranjit 
Published: September 2015

ABSTRACT

We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH) induces the epithelial mesenchymal transition (EMT) state and extends hepatocyte life span (S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, J Virol 86:13621–13628, 2012,
http://dx.doi.org/10.1128/JVI.02016-12
). These hepatocytes displayed sphere formation on ultralow binding plates and survived for more than 12 weeks. The sphere-forming hepatocytes expressed a number of cancer stem-like cell (CSC) markers, including high levels of the stem cell factor receptor c-Kit. The c-Kit receptor is regarded as one of the CSC markers in hepatocellular carcinoma (HCC). Analysis of c-Kit mRNA displayed a significant increase in the liver biopsy specimens of chronically HCV-infected patients. We also found c-Kit is highly expressed in transformed human hepatocytes (THH) infected
in vitro
with cell culture-grown HCV genotype 2a. Further studies suggested that HCV core protein significantly upregulates c-Kit expression at the transcriptional level. HCV infection of THH led to a significant increase in the number of spheres displayed on ultralow binding plates and in enhanced EMT and CSC markers and tumor growth in immunodeficient mice. The use of imatinib or dasatinib as a c-Kit inhibitor reduced the level of sphere-forming cells in culture. The sphere-forming cells were sensitive to treatment with sorafenib, a multikinase inhibitor, that is used for HCC treatment. Further, stattic, an inhibitor of the Stat3 molecule, induced sphere-forming cell death. A combination of sorafenib and stattic had a significantly stronger effect, leading to cell death. These results suggested that HCV infection potentiates CSC generation, and selected drugs can be targeted to efficiently inhibit cell growth.

IMPORTANCE
HCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies.
Sexually Transmitted Diseases and Travel: From Boudoir to Bordello
Authors: Avery Ann K. , Zenilman Jonathan M. 
Published: September 2015

ABSTRACT
Travel has historically been an important risk factor for acquisition of sexually transmitted infections (STIs). Travel is often associated with a sense of adventure, periods of loneliness, and exploration away from one’s home environment—which often form a milieu in which sexual activity can occur with new partners. Survey data clearly demonstrate that out-of-country travel is associated with recruitment of new sex partners and increased STI risk. Pretravel counseling to prevent STI risk is variable, and there is little evidence that it modifies risk behavior. Some travel occurs specifically for sexual purposes, such as the sexual tourism junkets to Southeast Asian destinations which became popular during the 1980s or the more recent rise in the popularity of circuit parties for men who have sex with men. Some travel situations pose particularly high risks. For example, military deployments and assignments to work camps such as those for oil extraction occur in the context of large groups of individuals of reproductive age, often predominantly males, exposed to high levels of stress in unfamiliar environments. Additionally, over the past decade, the Internet has dramatically changed the ability to identify sexual partners while traveling.
Development and validation of risk prediction equations to estimate future risk of heart failure in patients with diabetes: a prospective cohort study
Authors: Hippisley-Cox Julia , Coupland Carol 
Published: September 2015

ObjectiveTo develop and externally validate risk prediction equations to estimate the 10-year risk of heart failure in patients with diabetes, aged 25–84 years.DesignCohort study using routinely collected data from general practices in England between 1998 and 2014 contributing to the QResearch and Clinical Research Practice Datalink (CPRD) databases.SettingWe used 763 QResearch practices to develop the equations. We validated it in 254 different QResearch practices and 357 CPRD practices.Participants437 806 patients in the derivation cohort; 137 028 in the QResearch validation cohort, and 197 905 in the CPRD validation cohort.MeasurementIncident diagnosis of heart failure recorded on the patients’ linked electronic General Practitioner (GP), mortality, or hospital record. Risk factors included age, body mass index (BMI), systolic blood pressure, cholesterol/ high-density lipoprotein (HDL) ratio, glycosylated haemoglobin (HbA1c), material deprivation, ethnicity, smoking, diabetes duration, type of diabetes, atrial fibrillation, cardiovascular disease, chronic renal disease, and family history of premature coronary heart disease.MethodsWe used Cox proportional hazards models to derive separate risk equations in men and women for evaluation at 10 years. Measures of calibration, discrimination, and sensitivity were determined in 2 external validation cohorts.ResultsWe identified 25 480 cases of heart failure in the derivation cohort, 8189 in the QResearch validation cohort, and 11 311 in the CPRD cohort. The equations included: age, BMI, systolic blood pressure, cholesterol/HDL ratio, HbA1c, material deprivation, ethnicity, smoking, duration and type of diabetes, atrial fibrillation, cardiovascular disease, and chronic renal disease. The equations had good performance in CPRD for women (R2of 41.2%; D statistic 1.71; and receiver operating characteristic curve (ROC) statistic 0.78) and men (38.7%, 1.63; and 0.77 respectively).ConclusionsWe have developed and externally validated risk prediction equations to quantify absolute risk of heart failure in men and women with diabetes. These can be used to identify patients at high risk of heart failure for prevention or assessment of the disease.
A protocol for developing early warning score models from vital signs data in hospitals using ensembles of decision trees
Authors: Xu Michael , Tam Benjamin , Thabane Lehana , Fox-Robichaud Alison 
Published: September 2015

IntroductionMultiple early warning scores (EWS) have been developed and implemented to reduce cardiac arrests on hospital wards. Case–control observational studies that generate an area under the receiver operator curve (AUROC) are the usual validation method, but investigators have also generated EWS with algorithms with no prior clinical knowledge. We present a protocol for the validation and comparison of our local Hamilton Early Warning Score (HEWS) with that generated using decision tree (DT) methods.Methods and analysisA database of electronically recorded vital signs from 4 medical and 4 surgical wards will be used to generate DT EWS (DT-HEWS). A third EWS will be generated using ensemble-based methods. Missing data will be multiple imputed. For a relative risk reduction of 50% in our composite outcome (cardiac or respiratory arrest, unanticipated intensive care unit (ICU) admission or hospital death) with a power of 80%, we calculated a sample size of 17 151 patient days based on our cardiac arrest rates in 2012. The performance of the National EWS, DT-HEWS and the ensemble EWS will be compared using AUROC.Ethics and disseminationEthics approval was received from the Hamilton Integrated Research Ethics Board (#13-724-C). The vital signs and associated outcomes are stored in a database on our secure hospital server. Preliminary dissemination of this protocol was presented in abstract form at an international critical care meeting. Final results of this analysis will be used to improve on the existing HEWS and will be shared through publication and presentation at critical care meetings.
Efficient computation of limit spectra of sample covariance matrices
Authors: Dobriban Edgar 
Published: September 2015

Models from random matrix theory (RMT) are increasingly used to gain insights into the behavior of statistical methods under high-dimensional asymptotics. However, the applicability of the framework is limited by numerical problems. Consider the usual model of multivariate statistics where the data is a sample from a multivariate distribution with a given covariance matrix. Under high-dimensional asymptotics, there is a deterministic map from the distribution of eigenvalues of the population covariance matrix (the population spectral distribution or PSD), to the of empirical spectral distribution (ESD). The current methods for computing this map are inefficient, and this limits the applicability of the theory. We propose a new method to compute numerically the ESD from an arbitrary input PSD. Our method, called SPECTRODE, finds the support and the density of the ESD to high precision; we prove this for finite discrete distributions. In computational experiments SPECTRODE outperforms existing methods by orders of magnitude in speed and accuracy. We apply it to compute expectations and contour integrals of the ESD, which are often central in applications. We also illustrate that SPECTRODE is directly useful in statistical problems, such as estimation and hypothesis testing for covariance matrices. Our proposal, implemented in open source software, may broaden the use of RMT in high-dimensional data analysis.
Young Hispanic Women Experience Higher In‐Hospital Mortality Following an Acute Myocardial Infarction
Authors: Rodriguez Fátima , Foody JoAnne M. , Wang Yun , López Lenny 
Published: September 2015

Background

Although mortality rates for acute myocardial infarction (
AMI
) have declined for men and women, prior studies have reported a sex gap in mortality such that younger women were most likely to die after an
AMI
.

Methods and Results

We sought to explore the impact of race and ethnicity on the sex gap in
AMI
patterns of care and mortality for younger women in a contemporary patient cohort. We constructed multivariable hierarchical logistic regression models to examine trends in
AMI
hospitalizations, procedures, and in‐hospital mortality by sex, age (<65 and ≥65 years), and race/ethnicity (white, black, and Hispanic). Analyses were derived from 194 071 patients who were hospitalized for an
AMI
with available race and ethnicity data from the 2009–2010 National Inpatient Sample. Hospitalization rates, procedures (coronary angiography, percutaneous coronary interventions, and cardiac bypass surgery), and inpatient mortality were analyzed across age, sex, and race/ethnic groups. There was significant variation in hospitalization rates by age and race/ethnicity. All racial/ethnic groups were less likely to undergo invasive procedures compared with white men (
P
<0.001). After adjustment for comorbidities, younger Hispanic women experienced higher in‐hospital mortality compared with younger white men, with an odds ratio of 1.5 (95%
CI
1.2 to 1.9), adjusted for age and comorbidities.

Conclusion

We found significant racial and sex disparities in
AMI
hospitalizations, care patterns, and mortality, with higher in‐hospital mortality experienced by younger Hispanic women. Future studies are necessary to explore determinants of these significant racial and sex disparities in outcomes for
AMI
.
On the Mass-Flux Representation of Vertical Transport in Moist Convection
Authors: Zhu Ping 
Published: September 2015

Abstract
This study investigates to what extent the convective fluxes formulated within the mass-flux framework can represent the total vertical transport of heat and moisture in the cloud layer and whether the same approach can be extended to represent the vertical momentum transport using large-eddy simulations (LESs) of six well-documented cloud cases, including both deep and shallow convection. Two methods are used to decompose the LES-resolved vertical fluxes: decompositions based on the coherent convective features using the mass-flux top-hat profile and by two-dimensional fast Fourier transform (2D-FFT) in terms of wavenumbers. The analyses show that the convective fluxes computed using the mass-flux formula can account for most of the total fluxes of conservative thermodynamic variables in the cloud layer of both deep and shallow convection for an appropriately defined convective updraft fraction, a result consistent with the mass-flux dynamic view of moist convection and previous studies. However, the mass-flux approach fails to represent the vertical momentum transport in the cloud layer of both deep and shallow convection. The 2D-FFT and other analyses suggest that such a failure results from a number of reasons: 1) the complicated momentum distribution in the cloud layer cannot be well described by the simple top-hat profile; 2) shear-driven small-scale eddies are more efficient momentum carriers than coherent convective plumes; 3) the phase relationship between vertical velocity and horizontal momentum components is substantially different from that between vertical velocity and conservative thermodynamic variables; and 4) the structure of horizontal momentum can change substantially from case to case even in the same climate regime.
The Connection between Southern Ocean Winds, the Atlantic Meridional Overturning Circulation, and Indo-Pacific Upwelling
Authors: Jochum M. , Eden Carsten 
Published: September 2015

Abstract
Coupled GCM simulations are analyzed to quantify the dynamic effect of Southern Ocean (SO) winds on transports in the ocean. It is found that the closure for skew diffusivity in the non-eddy-resolving ocean model does not allow for a realistic eddy saturation of the zonal transports in the SO in response to the wind changes and that eddy compensation of the meridional transports in the SO is underestimated too. Despite this underestimated eddy compensation in the SO, however, and in contrast to previous suggestions, the Atlantic meridional overturning circulation (AMOC) strength is almost insensitive to SO winds. In the limit of weak SO winds the AMOC waters upwell not in the SO but rather in the tropical Indo-Pacific. Through their effect on sea ice, weaker SO winds also lead to less production of Antarctic Bottom Water and therefore a deeper and stronger AMOC.
The French politics of retrenchment (2007–2012): Institutions and blame avoidance strategies
Authors: Bezes Philippe , Le Lidec Patrick 
Published: September 2015

While the semi-presidential French regime and the reinforcement of ‘presidentialization’ under Nicolas Sarkozy have often been associated with the idea of disruptive and heroic changes, France’s post-crisis budgetary policy appeared strongly embedded in the previous commitments made by President Sarkozy and relied largely on measures of a gradual and low-profile nature without significant U-turns. In order to explain this result, the article emphasizes the effects of French institutions on government capabilities and on the potential allocation of blame and the related political strategies connected with the electoral cycle and timing. In addition, it also explores the specific characteristics of the French national crisis and its perceptions by top bureaucrats, as well as the nature of the external macro-constraints that influenced French budgetary policy, whether originating with markets, international organizations or the European Union. Points for practitioners This article emphasizes the importance of institutions and political strategies in cutback management. The main argument is that budget reduction policies are embedded in political and electoral constraints that strongly affect their design and choices. The article provides many empirical elements about the specific characteristics of the French national crisis and how French governments reacted to the 2008 crisis. It puts emphasis on the specificities of French political institutions and the strong exposure to blame. The French political strategies of blame avoidance are described between 2008 and 2012, as well as the nature of the external macro-constraints that influenced French budgetary policy, whether originating with markets, international organizations or the European Union.
Activated clotting time test alone is inadequate to optimize therapeutic heparin dosage adjustment during post-cardiopulmonary resuscitational extracorporeal membrane oxygenation (e-CPR)
Authors: Yie Kilsoo , Chon Soon-Ho Daniel , Na Chan-Young 
Published: September 2015

Background: We conducted an observational study to evaluate the relationship between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) tests, anticipating the possibility that the ACT will become a substitute test for the aPTT in post-CPR extracorporeal membrane oxygenation (e-CPR). Patients and Methods: Three hundred and fifteen paired ACT and aPTT samples were derived from 60 in-hospital e-CPR patients and were divided into three groups according to the observed ACT value: low level (ACT<170 s, Group A), intended target level (ACT 170–210 s Group B) and high level (ACT>210 s, Group C). The relationship of aPTT in each group was analyzed. Results: The mean ACT and aPTT values were 189.39 ± 48.27 s (IQR, 163–202) and 71.85 ± 45.32 s (IQR, 44.5–81.8), respectively. Although the observed mean ACT value of 189.39 s was similar to the intended mean target value of 190 s (p=0.823), the observed mean aPTT value (71.85 s) was significantly lower than the predicted mean target value (77.5 s, p=0.027). Despite the mean ACT values being significantly different in each group (p<0.0001), the mean aPTT values were not statistically different between Groups A and B (p = 0.317). Of the Group B samples (n = 139), only 31 samples (22.3%) met the optimal therapeutic aPTT range. Pearson’s correlation coefficient for Group B showed only a weak correlation between ACT and aPTT (r=0.177; p=0.037). Conclusions: Our study demonstrates that the ACT test alone does not seem to be enough to optimize therapeutic heparin dosage adjustment during e-CPR.