bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vinexin β Interacts with Hepatitis C Virus NS5A, Modulating Its Hyperphosphorylation To Regulate Viral Propagation
Authors: Xiong Wei , Yang Jie , Wang Mingzhen , Wang Hailong , Rao Zhipeng , Zhong Cheng , Xin Xiu , Mo Lin , Yu Shujuan , Shen Chao , Zheng Congyi 
Published: May 2015

ABSTRACT
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is essential for HCV genome replication and virion production and is involved in the regulation of multiple host signaling pathways. As a proline-rich protein, NS5A is capable of interacting with various host proteins containing Src homology 3 (SH3) domains. Previous studies have suggested that vinexin, a member of the sorbin homology (SoHo) adaptor family, might be a potential binding partner of NS5A by yeast two-hybrid screening. However, firm evidence for this interaction is lacking, and the significance of vinexin in the HCV life cycle remains unclear. In this study, we demonstrated that endogenously and exogenously expressed vinexin β coimmunoprecipitated with NS5A derived from different HCV genotypes. Two residues, tryptophan (W307) and tyrosine (Y325), in the third SH3 domain of vinexin β and conserved Pro-X-X-Pro-X-Arg motifs at the C terminus of NS5A were indispensable for the vinexin-NS5A interaction. Furthermore, downregulation of endogenous vinexin β significantly suppressed NS5A hyperphosphorylation and decreased HCV replication, which could be rescued by expressing a vinexin β short hairpin RNA-resistant mutant. We also found that vinexin β modulated the hyperphosphorylation of NS5A in a casein kinase 1α-dependent on manner. Taken together, our findings suggest that vinexin β modulates NS5A phosphorylation via its interaction with NS5A, thereby regulating HCV replication, implicating vinexin β in the viral life cycle.

IMPORTANCE
Hepatitis C virus (HCV) nonstructural protein NS5A is a phosphoprotein, and its phosphorylation states are usually modulated by host kinases and other viral nonstructural elements. Additionally, cellular factors containing Src homology 3 (SH3) domains have been reported to interact with proline-rich regions of NS5A. However, it is unclear whether there are any relationships between NS5A phosphorylation and the NS5A-SH3 interaction, and little is known about the significance of this interaction in the HCV life cycle. In this work, we demonstrate that vinexin β modulates NS5A hyperphosphorylation through the NS5A-vinexin β interaction. Hyperphosphorylated NS5A induced by vinexin β is casein kinase 1α dependent and is also crucial for HCV propagation. Overall, our findings not only elucidate the relationships between NS5A phosphorylation and the NS5A-SH3 interaction but also shed new mechanistic insight on
Flaviviridae
NS5A (NS5) phosphorylation. We believe that our results may afford the potential to offer an antiviral therapeutic strategy.
Hepatitis B Virus-Infected HepG2hNTCPCells Serve as a Novel Immunological Tool To Analyze the Antiviral Efficacy of CD8+T CellsIn Vitro
Authors: Hoh Alexander , Heeg Maximilian , Ni Yi , Schuch Anita , Binder Benedikt , Hennecke Nadine , Blum Hubert E. , Nassal Michael , Protzer Ulrike , Hofmann Maike , Urban Stephan , Thimme Robert 
Published: May 2015

ABSTRACTCD8+T cells are the main effector lymphocytes in the control of hepatitis B virus (HBV) infection. However, limitations of model systems, such as low infection rates, restrict mechanistic studies of HBV-specific CD8+T cells. Here, we established a novel immunological cell culture model based on HBV-infected HepG2hNTCPcells that endogenously processed viral antigens and presented them to HBV-specific CD8+T cells. This induced cytolytic and noncytolytic CD8+T-cell effector functions and reduction of viral loads.
Bacterial Swarms Recruit Cargo Bacteria To Pave the Way in Toxic Environments
Authors: Finkelshtein Alin , Roth Dalit , Ben Jacob Eshel , Ingham Colin J. 
Published: May 2015

ABSTRACT

Swarming bacteria are challenged by the need to invade hostile environments. Swarms of the flagellated bacterium
Paenibacillus vortex
can collectively transport other microorganisms. Here we show that
P. vortex
can invade toxic environments by carrying antibiotic-degrading bacteria; this transport is mediated by a specialized, phenotypic subpopulation utilizing a process not dependent on cargo motility. Swarms of beta-lactam antibiotic (BLA)-sensitive
P. vortex
used beta-lactamase-producing, resistant, cargo bacteria to detoxify BLAs in their path. In the presence of BLAs, both transporter and cargo bacteria gained from this temporary cooperation; there was a positive correlation between BLA resistance and dispersal.
P. vortex
transported only the most beneficial antibiotic-resistant cargo (including environmental and clinical isolates) in a sustained way.
P. vortex
displayed a bet-hedging strategy that promoted the colonization of nontoxic niches by
P. vortex
alone; when detoxifying cargo bacteria were not needed, they were lost. This work has relevance for the dispersal of antibiotic-resistant microorganisms and for strategies for asymmetric cooperation with agricultural and medical implications.

IMPORTANCE
Antibiotic resistance is a major health threat. We show a novel mechanism for the local spread of antibiotic resistance. This involves interactions between different bacteria: one species provides an enzyme that detoxifies the antibiotic (a sessile cargo bacterium carrying a resistance gene), while the other (
Paenibacillus vortex
) moves itself and transports the cargo.
P. vortex
used a bet-hedging strategy, colonizing new environments alone when the cargo added no benefit, but cooperating when the cargo was needed. This work is of interest in an evolutionary context and sheds light on fundamental questions, such as how environmental antibiotic resistance may lead to clinical resistance and also microbial social organization, as well as the costs, benefits, and risks of dispersal in the environment.
Dengue Virus NS Proteins Inhibit RIG-I/MAVS Signaling by Blocking TBK1/IRF3 Phosphorylation: Dengue Virus Serotype 1 NS4A Is a Unique Interferon-Regulating Virulence Determinant
Authors: Dalrymple Nadine A. , Cimica Velasco , Mackow Erich R. 
Published: May 2015

ABSTRACT
Dengue virus (DENV) replication is inhibited by the prior addition of type I interferon or by RIG-I agonists that elicit RIG-I/MAVS/TBK1/IRF3-dependent protective responses. DENV infection of primary human endothelial cells (ECs) results in a rapid increase in viral titer, which suggests that DENV inhibits replication-restrictive RIG-I/interferon beta (IFN-β) induction pathways within ECs. Our findings demonstrate that DENV serotype 4 (DENV4) nonstructural (NS) proteins NS2A and NS4B inhibited RIG-I-, MDA5-, MAVS-, and TBK1/IKKε-directed IFN-β transcription (>80%) but failed to inhibit IFN-β induction directed by STING or constitutively active IRF3-5D. Expression of NS2A and NS4B dose dependently inhibited the phosphorylation of TBK1 and IRF3, which suggests that they function at the level of TBK1 complex activation. NS2A and NS4B from DENV1/2/4, as well as the West Nile virus NS4B protein, commonly inhibited TBK1 phosphorylation and IFN-β induction. A comparative analysis of NS4A proteins across DENVs demonstrated that DENV1, but not DENV2 or DENV4, NS4A proteins uniquely inhibited TBK1. These findings indicate that DENVs contain conserved (NS2A/NS4B) and DENV1-specific (NS4A) mechanisms for inhibiting RIG-I/TBK1-directed IFN responses. Collectively, our results define DENV NS proteins that restrict IRF3 and IFN responses and thereby facilitate DENV replication and virulence. Unique DENV1-specific NS4A regulation of IFN induction has the potential to be a virulence determinant that contributes to the increased severity of DENV1 infections and the immunodominance of DENV1 responses during tetravalent DENV1-4 vaccination.

IMPORTANCE
Our findings demonstrate that NS2A and NS4B proteins from dengue virus serotypes 1, 2, and 4 are inhibitors of RIG-I/MDA5-directed interferon beta (IFN-β) induction and that they accomplish this by blocking TBK1 activation. We determined that IFN inhibition is functionally conserved across NS4B proteins from West Nile virus and DENV1, -2, and -4 viruses. In contrast, DENV1 uniquely encodes an extra IFN regulating protein, NS4A, that inhibits TBK1-directed IFN induction. DENV1 is associated with an increase in severe patient disease, and added IFN regulation by the DENV1 NS4A protein may contribute to increased DENV1 replication, immunodominance, and virulence. The regulation of IFN induction by nonstructural (NS) proteins suggests their potential roles in enhancing viral replication and spread and as potential protein targets for viral attenuation. DENV1-specific IFN regulation needs to be considered in vaccine strategies where enhanced DENV1 replication may interfere with DENV2-4 seroconversion within coadministered tetravalent DENV1-4 vaccines.
A population-based study comparing patterns of care delivery on the quality of care for persons living with HIV in Ontario
Authors: Kendall Claire E , Taljaard Monica , Younger Jaime , Hogg William , Glazier Richard H , Manuel Douglas G 
Published: May 2015

ObjectivesPhysician specialty is often positively associated with disease-specific outcomes and negatively associated with primary care outcomes for people with chronic conditions. People with HIV have increasing comorbidity arising from antiretroviral therapy (ART) related longevity, making HIV a useful condition to examine shared care models. We used a previously described, theoretically developed shared care framework to assess the impact of care delivery on the quality of care provided.DesignRetrospective population-based observational study from 1 April 2009 to 31 March 2012.Participants13 480 patients with HIV and receiving publicly funded healthcare in Ontario were assigned to one of five patterns of care.Outcome measuresCancer screening, ART prescribing and healthcare utilisation across models using adjusted multivariable hierarchical logistic regression analyses.ResultsModels in which patients had an assigned family physician had higher odds of cancer screening than those in exclusively specialist care (colorectal cancer screening, exclusively primary care adjusted OR (AOR)=3.12, 95% CI (1.90 to 5.13), family physician-dominant co-management AOR=3.39, 95% CI (1.94 to 5.93), specialist-dominant co-management AOR=2.01, 95% CI (1.23 to 3.26)). The odds of having one emergency department visit did not differ among models, although the odds of hospitalisation and HIV-specific hospitalisation were lower among patients who saw exclusively family physicians (AOR=0.23, 95% CI (0.14 to 0.35) and AOR=0.15, 95% CI (0.12 to 0.21)). The odds of antiretroviral prescriptions were lower among models in which patients’ HIV care was provided predominantly by family physicians (exclusively primary care AOR=0.15, 95% CI (0.12 to 0.21), family physician-dominant co-management AOR=0.45, 95% CI (0.32 to 0.64)).ConclusionsHow care is provided had a potentially important influence on the quality of care delivered. Our key limitation is potential confounding due to the absence of HIV stage measures.
Republished: Importance of carcinoma-associated fibroblast-derived proteins in clinical oncology
Authors: Valcz Gabor , Sipos Ferenc , Tulassay Zsolt , Molnar Bela , Yagi Yukako 
Published: May 2015

ABSTRACTCarcinoma-associated fibroblast (CAF) as prominent cell type of the tumour microenvironment has complex interaction with both the cancer cells and other non-neoplastic surrounding cells. The CAF-derived regulators and extracellular matrix proteins can support cancer progression by providing a protective microenvironment for the cancer cells via reduction of chemotherapy sensitivity. On the other hand, these proteins may act as powerful prognostic markers as well as potential targets of anticancer therapy. In this review, we summarise the clinical importance of the major CAF-derived signals influencing tumour behaviour and determining the outcome of chemotherapy.
TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor–Binding Sites in Chronic Myelomonocytic Leukemia
Authors: Yamazaki Jumpei , Jelinek Jaroslav , Lu Yue , Cesaroni Matteo , Madzo Jozef , Neumann Frank , He Rong , Taby Rodolphe , Vasanthakumar Aparna , Macrae Trisha , Ostler Kelly R. , Kantarjian Hagop M. , Liang Shoudan , Estecio Marcos R. , Godley Lucy A. , Issa Jean-Pierre J. 
Published: May 2015

Abstract
TET2 enzymatically converts 5-methylcytosine to 5-hydroxymethylcytosine as well as other covalently modified cytosines and its mutations are common in myeloid leukemia. However, the exact mechanism and the extent to which TET2 mutations affect DNA methylation remain in question. Here, we report on DNA methylomes in TET2 wild-type (TET2-WT) and mutant (TET2-MT) cases of chronic myelomonocytic leukemia (CMML). We analyzed 85,134 CpG sites [28,114 sites in CpG islands (CGI) and 57,020 in non-CpG islands (NCGI)]. TET2 mutations do not explain genome-wide differences in DNA methylation in CMML, and we found few and inconsistent differences at CGIs between TET2-WT and TET2-MT cases. In contrast, we identified 409 (0.71%) TET2-specific differentially methylated CpGs (tet2-DMCs) in NCGIs, 86% of which were hypermethylated in TET2-MT cases, suggesting a strikingly different biology of the effects of TET2 mutations at CGIs and NCGIs. DNA methylation of tet2-DMCs at promoters and nonpromoters repressed gene expression. Tet2-DMCs showed significant enrichment at hematopoietic-specific enhancers marked by H3K4me1 and at binding sites for the transcription factor p300. Tet2-DMCs showed significantly lower 5-hydroxymethylcytosine in TET2-MT cases. We conclude that leukemia-associated TET2 mutations affect DNA methylation at NCGI regions containing hematopoietic-specific enhancers and transcription factor–binding sites. Cancer Res; 75(14); 2833–43. ©2015 AACR.
A Systematic Comparison of 18F-C-SNAT to Established Radiotracer Imaging Agents for the Detection of Tumor Response to Treatment
Authors: Witney Timothy H. , Hoehne Aileen , Reeves Robert E. , Ilovich Ohad , Namavari Mohammad , Shen Bin , Chin Frederick T. , Rao Jianghong , Gambhir Sanjiv S. 
Published: May 2015

Abstract
Purpose: An early readout of tumor response to therapy through measurement of drug or radiation-induced cell death may provide important prognostic indications and improved patient management. It has been shown that the uptake of 18F-C-SNAT can be used to detect early response to therapy in tumors by positron emission tomography (PET) via a mechanism of caspase-3–triggered nanoaggregation.
Experimental Design: Here, we compared the preclinical utility of 18F-C-SNAT for the detection of drug-induced cell death to clinically evaluated radiotracers, 18F-FDG, 99mTc-Annexin V, and 18F-ML-10 in tumor cells in culture, and in tumor-bearing mice in vivo.
Results: In drug-treated lymphoma cells, 18F-FDG, 99mTc-Annexin V, and 18F-C-SNAT cell-associated radioactivity correlated well to levels of cell death (R2 &gt; 0.8; P &lt; 0.001), with no correlation measured for 18F-ML-10 (R2 = 0.05; P &gt; 0.05). A similar pattern of response was observed in two human NSCLC cell lines following carboplatin treatment. EL-4 tumor uptake of 99mTc-Annexin V and 18F-C-SNAT were increased 1.4- and 2.1-fold, respectively, in drug-treated versus naïve control animals (P &lt; 0.05), although 99mTc-Annexin V binding did not correlate to ex vivo TUNEL staining of tissue sections. A differential response was not observed with either 18F-FDG or 18F-ML-10.
Conclusions: We have demonstrated here that 18F-C-SNAT can sensitively detect drug-induced cell death in murine lymphoma and human NSCLC. Despite favorable image contrast obtained with 18F-C-SNAT, the development of next-generation derivatives, using the same novel and promising uptake mechanism, but displaying improved biodistribution profiles, are warranted for maximum clinical utility. Clin Cancer Res; 21(17); 3896–905. ©2015 AACR.
The Causes of Foehn Warming in the Lee of Mountains
Authors: Elvidge Andrew D. , Renfrew Ian A. 
Published: May 2015

Abstract
The foehn effect is well known as the warming, drying, and cloud clearance experienced on the lee side of mountain ranges during “flow over” conditions. Foehn flows were first described more than a century ago when two mechanisms for this warming effect were postulated: an isentropic drawdown mechanism, where potentially warmer air from aloft is brought down adiabatically, and a latent heating and precipitation mechanism, where air cools less on ascent—owing to condensation and latent heat release—than on its dry descent on the lee side. Here, for the first time, the direct quantitative contribution of these and other foehn warming mechanisms is shown. The results suggest a new paradigm is required after it is demonstrated that a third mechanism, mechanical mixing of the foehn flow by turbulence, is significant. In fact, depending on the flow dynamics, any of the three warming mechanisms can dominate. A novel Lagrangian heat budget model, back trajectories, high-resolution numerical model output, and aircraft observations are all employed. The study focuses on a unique natural laboratory—one that allows unambiguous quantification of the leeside warming—namely, the Antarctic Peninsula and Larsen C Ice Shelf. The demonstration that three foehn warming mechanisms are important has ramifications for weather forecasting in mountainous areas and associated hazards such as ice shelf melt and wildfires.
Global Seasonal Precipitation Anomalies Robustly Associated with El Niño and La Niña Events—An OLR Perspective*,+
Authors: Chiodi Andrew M. , Harrison D. E. 
Published: May 2015

Abstract
El Niño–Southern Oscillation (ENSO) events are associated with particular seasonal weather anomalies in many regions around the planet. When the statistical links are sufficiently strong, ENSO state information can provide useful seasonal forecasts with varying lead times. However, using conventional sea surface temperature or sea level pressure indices to characterize ENSO state leads to many instances of limited forecast skill (e.g., years identified as El Niño or La Niña with weather anomalies unlike the average), even in regions where there is considerable ENSO-associated anomaly, on average. Using outgoing longwave radiation (OLR) conditions to characterize ENSO state identifies a subset of the conventional ENSO years, called OLR El Niño and OLR La Niña years herein. Treating the OLR-identified subset of years differently can both usefully strengthen the level of statistical significance in the average (composite) and also greatly reduce the year-to-year deviations in the composite precipitation anomalies. On average, over most of the planet, the non-OLR El Niño and non-OLR La Niña years have much more limited statistical utility for precipitation. The OLR El Niño and OLR La Niña indices typically identify years in time to be of use to boreal wintertime and later seasonal forecasting efforts, meaning that paying attention to tropical Pacific OLR conditions may offer more than just a diagnostic tool. Understanding better how large-scale environmental conditions during ENSO events determine OLR behavior (and deep atmospheric convection) will lead to improved seasonal precipitation forecasts for many areas.
Seasonal Variability of Salinity and Salt Transport in the Northern Indian Ocean
Authors: D’Addezio Joseph M. , Subrahmanyam Bulusu , Nyadjro Ebenezer S. , Murty V. S. N. 
Published: May 2015

AbstractAnalyses using a suite of observational datasets (Aquarius and Argo) and model simulations are carried out to examine the seasonal variability of salinity in the northern Indian Ocean (NIO). The model simulations include Estimating the Circulation and Climate of the Ocean, Phase II (ECCO2), the European Centre for Medium-Range Weather Forecasts–Ocean Reanalysis System 4 (ECMWF–ORAS4), Simple Ocean Data Assimilation (SODA) reanalysis, and the Hybrid Coordinate Ocean Model (HYCOM). The analyses of salinity at the surface and at depths up to 200 m, surface salt transport in the top 5-m layer, and depth-integrated salt transports revealed different salinity processes in the NIO that are dominantly related to the semiannual monsoons. Aquarius proves a useful tool for observing this dynamic region and reveals some aspects of sea surface salinity (SSS) variability that Argo cannot resolve. The study revealed large disagreement between surface salt transports derived from observed- and analysis-derived salinity fields. Although differences in SSS between the observations and the model solutions are small, model simulations provide much greater spatial variability of surface salt transports due to finer detailed current structure. Meridional depth-integrated salt transports along 6°N revealed dominant advective processes from the surface toward near-bottom depths. In the Arabian Sea (Bay of Bengal), the net monthly mean maximum northward (southward) salt transport of ~50 × 106 kg s −1 occurs in July, and annual-mean salt transports across this section are about −2.5 × 106 kg s −1 (3 × 106 kg s −1).
Diagnosing the Conditional Probability of Tornado Damage Rating Using Environmental and Radar Attributes
Authors: Smith Bryan T. , Thompson Richard L. , Dean Andrew R. , Marsh Patrick T. 
Published: May 2015

Abstract
Radar-identified convective modes, peak low-level rotational velocities, and near-storm environmental data were assigned to a sample of tornadoes reported in the contiguous United States during 2009–13. The tornado segment data were filtered by the maximum enhanced Fujita (EF)-scale tornado event per hour using a 40-km horizontal grid. Convective mode was assigned to each tornado event by examining full volumetric Weather Surveillance Radar-1988 Doppler data at the beginning time of each event, and 0.5° peak rotational velocity (Vrot) data were identified manually during the life span of each tornado event. Environmental information accompanied each grid-hour event, consisting primarily of supercell-related convective parameters from the hourly objective mesoscale analyses calculated and archived at the Storm Prediction Center. Results from examining environmental and radar attributes, featuring the significant tornado parameter (STP) and 0.5° peak Vrot data, suggest an increasing conditional probability for greater EF-scale damage as both STP and 0.5° peak Vrot increase, especially with supercells. Possible applications of these findings include using the conditional probability of tornado intensity as a real-time situational awareness tool.