bluuebunny/crossref_metadata_2025_split huggingface dataset:
West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands
Authors: Jung Keun-Ok , Khan Asif M. , Tan Benjamin Yong Liang , Hu Yongli , Simon Gregory G. , Nascimento Eduardo J. M. , Lemonnier Francois , Brusic Vladimir , Miotto Olivo , Tan Tin Wee , Marques Ernesto T. A. , Dhalia Rafael , Salmon Jerome , August J. Thomas 
Published: May 2012

ABSTRACTPhylogenetic relatedness and cocirculation of several major human pathogen flaviviruses are recognized as a possible cause of deleterious immune responses to mixed infection or immunization and call for a greater understanding of the inter-Flavivirusprotein homologies. This study focused on the identification of human leukocyte antigen (HLA)-restrictedWest Nile virus(WNV) T-cell ligands and characterization of their distribution in reported sequence data of WNV and other flaviviruses. H-2-deficient mice transgenic for either A2, A24, B7, DR2, DR3, or DR4 HLA alleles were immunized with overlapping peptides of the WNV proteome, and peptide-specific T-cell activation was measured by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays. Approximately 30% (137) of the WNV proteome peptides were identified as HLA-restricted T-cell ligands. The majority of these ligands were conserved in ∼≥88% of analyzed WNV sequences. Notably, only 51 were WNV specific, and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amino acids with sequences of 64 other flaviviruses, including several major human pathogens. Many of the shared ligands had an incidence of >50% in the analyzed sequences of one or more of six major flaviviruses. The multitude of WNV sequences shared with other flaviviruses as interspecies variants highlights the possible hazard of defective T-cell activation by altered peptide ligands in the event of dual exposure to WNV and other flaviviruses, by either infection or immunization. The data suggest the possible preferred use of sequences that are pathogen specific with minimum interspecies sequence homology for the design ofFlavivirusvaccines.
Mosquito Bite Delivery of Dengue Virus Enhances Immunogenicity and Pathogenesis in Humanized Mice
Authors: Cox Jonathan , Mota Javier , Sukupolvi-Petty Soila , Diamond Michael S. , Rico-Hesse Rebeca 
Published: May 2012

ABSTRACT

Dengue viruses (DENV) are transmitted to humans by the bite of
Aedes aegypti
or
Aedes albopictus
mosquitoes, with millions of infections annually in over 100 countries. The diseases they produce, which occur exclusively in humans, are dengue fever (DF) and dengue hemorrhagic fever (DHF). We previously developed a humanized mouse model of DF in which mice transplanted with human hematopoietic stem cells produced signs of DENV disease after injection with low-passage, wild-type isolates. Using these mice, but now allowing infected
A. aegypti
to transmit dengue virus during feeding, we observed signs of more severe disease (higher and more sustained viremia, erythema, and thrombocytopenia). Infected mice mounted innate (gamma interferon [IFN-γ] and soluble interleukin 2 receptor alpha [sIL-2Rα]) and adaptive (anti-DENV antibodies) immune responses that failed to clear viremia until day 56, while a mosquito bite alone induced strong immunomodulators (tumor necrosis factor alpha [TNF-α], IL-4, and IL-10) and thrombocytopenia. This is the first animal model that allows an evaluation of human immunity to DENV infection after mosquito inoculation.
Specific CD8
+
T Cell Responses Correlate with Control of Simian Immunodeficiency Virus Replication in Mauritian Cynomolgus Macaques
Authors: Budde Melisa L. , Greene Justin M. , Chin Emily N. , Ericsen Adam J. , Scarlotta Matthew , Cain Brian T. , Pham Ngoc H. , Becker Ericka A. , Harris Max , Weinfurter Jason T. , O'Connor Shelby L. , Piatak Michael , Lifson Jeffrey D. , Gostick Emma , Price David A. , Friedrich Thomas C. , O'Connor David H. 
Published: May 2012

ABSTRACT

Specific major histocompatibility complex (MHC) class I alleles are associated with an increased frequency of spontaneous control of human and simian immunodeficiency viruses (HIV and SIV). The mechanism of control is thought to involve MHC class I-restricted CD8
+
T cells, but it is not clear whether particular CD8
+
T cell responses or a broad repertoire of epitope-specific CD8
+
T cell populations (termed T cell breadth) are principally responsible for mediating immunologic control. To test the hypothesis that heterozygous macaques control SIV replication as a function of superior T cell breadth, we infected MHC-homozygous and MHC-heterozygous cynomolgus macaques with the pathogenic virus SIVmac239. As measured by a gamma interferon enzyme-linked immunosorbent spot assay (IFN-γ ELISPOT) using blood, T cell breadth did not differ significantly between homozygotes and heterozygotes. Surprisingly, macaques that controlled SIV replication, regardless of their MHC zygosity, shared durable T cell responses against similar regions of Nef. While the limited genetic variability in these animals prevents us from making generalizations about the importance of Nef-specific T cell responses in controlling HIV, these results suggest that the T cell-mediated control of virus replication that we observed is more likely the consequence of targeting specificity rather than T cell breadth.
The Dominant-Negative Inhibition of Double-Stranded RNA-Dependent Protein Kinase PKR Increases the Efficacy of Rift Valley Fever Virus MP-12 Vaccine
Authors: Lihoradova Olga , Kalveram Birte , Indran Sabarish V. , Lokugamage Nandadeva , Juelich Terry L. , Hill Terence E. , Tseng Chien-Te K. , Gong Bin , Fukushi Shuetsu , Morikawa Shigeru , Freiberg Alexander N. , Ikegami Tetsuro 
Published: May 2012

ABSTRACTRift Valley fever virus (RVFV), belonging to the genusPhlebovirus, familyBunyaviridae, is endemic to sub-Saharan Africa and causes a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. MP-12 is the only RVFV strain excluded from the select-agent rule and handled at a biosafety level 2 (BSL2) laboratory. MP-12 encodes a functional major virulence factor, the NSs protein, which contributes to its residual virulence in pregnant ewes. We found that 100% of mice subcutaneously vaccinated with recombinant MP-12 (rMP12)-murine PKRN167 (mPKRN167), which encodes a dominant-negative form of mouse double-stranded RNA (dsRNA)-dependent protein kinase (PKR) in place of NSs, were protected from wild-type (wt) RVFV challenge, while 72% of mice vaccinated with MP-12 were protected after challenge. rMP12-mPKRN167 induced alpha interferon (IFN-α) in sera, accumulated RVFV antigens in dendritic cells at the local draining lymph nodes, and developed high levels of neutralizing antibodies, while parental MP-12 induced neither IFN-α nor viral-antigen accumulation at the draining lymph node yet induced a high level of neutralizing antibodies. The present study suggests that the expression of a dominant-negative PKR increases the immunogenicity and efficacy of live-attenuated RVFV vaccine, which will lead to rational design of safe and highly immunogenic RVFV vaccines for livestock and humans.
Refined Identification of Neutralization-Resistant HIV-1 CRF02_AG Viruses
Authors: Jacob Rajesh Abraham , Abrahams Fatima , Tongo Marcel , Schomaker Michael , Roux Paul , Mpoudi Ngole Eitel , Burgers Wendy A. , Dorfman Jeffrey R. 
Published: May 2012

ABSTRACT
We studied neutralization of CRF02_AG HIV-1-infected plasma samples. In contrast to previous reports, these samples neutralized CRF02_AG viruses better than other viruses. This included six of eight CRF02_AG viruses previously designated resistant (tier 2/3 or 3). Only viruses 253-11 and 278-50 remained highly resistant, but they were sensitive to membrane-proximal external region (MPER)-specific monoclonal antibodies, suggesting neutralization targets for even these viruses. We propose using high-neutralizing-within-subtype samples for evaluation of neutralization resistance of viruses.
SYM ANOMALOUS DIMENSION FROM OPEN STRING ENGINEERED CURVATURE
Authors: PARK I. Y. 
Published: May 2012

In the full type IIB open superstring setup, we show that there exists a vertex operator, denoted by VL, whose renormalization reproduces the same anomalous dimension matrix that was obtained by Minahan and Zarembo (MZ) [J. High Energy Phys. 0303, 013 (2003)]. The vertex operator is a gauge singlet, and has the same SO(6) index structure as the operator used by MZ. To obtain the SYM anomalous dimensions, one of the key ingredients is the non-abelianization of the nonlinear sigma model action in a D-brane background. Park [Phys. Lett. B 660, 583 (2008)] conjectured that quantum effects of open strings on a stack of D-branes should generate the curvature. Even though the conjecture had passed a few consistency checks, the role of the higher order curvature terms has remain mostly unobserved until now. By choosing a special form of the non-abelianized counter vertex, VG, we show that the SYM result is reproduced. We comment on fermionic completion of VL and on how the special form of the non-Abelian vertex VG may arise.
Circulating Levels of TNF Receptor II Are Prognostic for Patients with Peripheral T-cell Non–Hodgkin Lymphoma
Authors: Heemann Christina , Kreuz Markus , Stoller Irene , Schoof Nils , von Bonin Frederike , Ziepert Marita , Löffler Markus , Jung Wolfram , Pfreundschuh Michael , Trümper Lorenz , Kube Dieter 
Published: May 2012

Abstract
Purpose: Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs.
Experimental Design: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay.
Results: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with P = 0.056]. A protective role of IL-10–1087A, −824T, and −597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.
Conclusions: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. Clin Cancer Res; 18(13); 3637–47. ©2012 AACR.
Glycolytic Inhibition Alters Anaplastic Thyroid Carcinoma Tumor Metabolism and Improves Response to Conventional Chemotherapy and Radiation
Authors: Sandulache Vlad C. , Skinner Heath D. , Wang Yuan , Chen Yunyun , Dodge Cristina T. , Ow Thomas J. , Bankson James A. , Myers Jeffrey N. , Lai Stephen Y. 
Published: May 2012

AbstractAnaplastic thyroid carcinoma (ATC) accounts for more than 50% of thyroid cancer mortality and is generally refractory to conventional treatment. On the basis of recent studies, we hypothesized that ATC metabolism can be targeted to improve response to chemoradiotherapy. Eight established and authenticated ATC cell lines were sequenced at 140 sites contained within 26 commonly mutated genes to identify novel potential therapeutic targets. Cellular proliferation, energy, and reducing potential stores were measured under conditions of specific nutrient deprivation. Tumor metabolism was evaluated using hyperpolarized 13C MRI in a murine orthotopic xenograft model of ATC. Sensitivity to chemotherapeutic agents and radiation (XRT) was assayed using cytotoxicity assays. We identified mutations in BRAF, NRAS, and KIT but failed to identify generalized novel targets for therapeutic intervention. ATC cell lines exhibited a mesenchymal phenotype and generalized dependence on glucose for energy, reducing potential and survival. Glycolytic inhibition using 2-deoxyglucose (2-DG) sensitized ATC cells to conventional chemotherapy and external beam radiation. In vivo, 2-DG induced a transient, but significant reduction in ATC metabolic activity. Generalized dependence of ATC cells on glucose catabolism makes them susceptible to the sensitizing effects of 2-DG for radiation therapy and chemotherapy. Under in vivo conditions, 2-DG can inhibit ATC metabolism. However, the modest magnitude and transient nature of this effect suggest the need for antimetabolic agents with more favorable pharmacodynamics to achieve therapeutic effects. Mol Cancer Ther; 11(6); 1373–80. ©2012 AACR.
Cdc42 and the Guanine Nucleotide Exchange Factors Ect2 and Trio Mediate Fn14-Induced Migration and Invasion of Glioblastoma Cells
Authors: Fortin Shannon P. , Ennis Matthew J. , Schumacher Cassie A. , Zylstra-Diegel Cassandra R. , Williams Bart O. , Ross Julianna T.D. , Winkles Jeffrey A. , Loftus Joseph C. , Symons Marc H. , Tran Nhan L. 
Published: May 2012

Abstract
Malignant glioblastomas are characterized by their ability to infiltrate into normal brain. We previously reported that binding of the multifunctional cytokine TNF-like weak inducer of apoptosis (TWEAK) to its receptor fibroblast growth factor–inducible 14 (Fn14) induces glioblastoma cell invasion via Rac1 activation. Here, we show that Cdc42 plays an essential role in Fn14-mediated activation of Rac1. TWEAK-treated glioma cells display an increased activation of Cdc42, and depletion of Cdc42 using siRNA abolishes TWEAK-induced Rac1 activation and abrogates glioma cell migration and invasion. In contrast, Rac1 depletion does not affect Cdc42 activation by Fn14, showing that Cdc42 mediates TWEAK-stimulated Rac1 activation. Furthermore, we identified two guanine nucleotide exchange factors (GEF), Ect2 and Trio, involved in TWEAK-induced activation of Cdc42 and Rac1, respectively. Depletion of Ect2 abrogates both TWEAK-induced Cdc42 and Rac1 activation, as well as subsequent TWEAK-Fn14–directed glioma cell migration and invasion. In contrast, Trio depletion inhibits TWEAK-induced Rac1 activation but not TWEAK-induced Cdc42 activation. Finally, inappropriate expression of Fn14 or Ect2 in mouse astrocytes in vivo using an RCAS vector system for glial-specific gene transfer in G-tva transgenic mice induces astrocyte migration within the brain, corroborating the in vitro importance of the TWEAK-Fn14 signaling cascade in glioblastoma invasion. Our results suggest that the TWEAK-Fn14 signaling axis stimulates glioma cell migration and invasion through two GEF-GTPase signaling units, Ect2-Cdc42 and Trio-Rac1. Components of the Fn14-Rho GEF-Rho GTPase signaling pathway present innovative drug targets for glioma therapy. Mol Cancer Res; 10(7); 958–68. ©2012 AACR.
The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data
Authors: Cerami Ethan , Gao Jianjiong , Dogrusoz Ugur , Gross Benjamin E. , Sumer Selcuk Onur , Aksoy Bülent Arman , Jacobsen Anders , Byrne Caitlin J. , Heuer Michael L. , Larsson Erik , Antipin Yevgeniy , Reva Boris , Goldberg Arthur P. , Sander Chris , Schultz Nikolaus 
Published: May 2012

Abstract
The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications. Cancer Discov; 2(5); 401–4. ©2012 AACR.
Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study
Authors: Thanassoulis George , Lyass Asya , Benjamin Emelia J. , Larson Martin G. , Vita Joseph A. , Levy Daniel , Hamburg Naomi M. , Widlansky Michael E. , O'Donnell Christopher J. , Mitchell Gary F. , Vasan Ramachandran S. 
Published: May 2012

Background—
Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension, and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community.

Methods and Results—

Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry, and brachial artery flow-mediated dilation testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol–to–high-density cholesterol ratio (
P
≤0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (
P
=0.02), central pulse pressure (
P
<0.0001), mean arterial pressure (
P
=0.04), and baseline brachial flow (
P
=0.002) were positively associated with exercise systolic BP, whereas flow-mediated dilation was negatively associated (
P
<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (
P
<0.0001), whereas mean arterial pressure was positively related (
P
<0.0001).

Conclusions—
Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.
Dietary Nitrate Ameliorates Pulmonary Hypertension
Authors: Baliga Reshma S. , Milsom Alexandra B. , Ghosh Suborno M. , Trinder Sarah L. , MacAllister Raymond J. , Ahluwalia Amrita , Hobbs Adrian J. 
Published: May 2012

Background—

Pulmonary hypertension (PH) is a multifactorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH, and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO
3
−
) and nitrite (NO
2
−
) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity.

Methods and Results—
Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular remodeling in wild-type mice exposed to 3 weeks of hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma and lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase or treated with the xanthine oxidoreductase inhibitor allopurinol.

Conclusions—
These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile depends on endothelial NO synthase and xanthine oxidoreductase -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (ie, dietary nitrate/nitrite supplementation) represents a viable, orally active therapy for PH.
Possible Dynamical Mechanisms for Southern Hemisphere Climate Change due to the Ozone Hole
Authors: Orr Andrew , Bracegirdle Thomas J. , Hosking J. Scott , Jung Thomas , Haigh Joanna D. , Phillips Tony , Feng Wuhu 
Published: May 2012

Abstract
The authors report a hypothesis for the dynamical mechanisms responsible for the strengthening of the Southern Hemisphere circumpolar winds from the lower stratosphere to the surface due to the ozone hole. A general circulation model forced by stratospheric ozone depletion representative of the ozone hole period successfully reproduced these observed changes. Investigation of the dynamical characteristics of the model therefore provides some insight into the actual mechanisms. From this the authors suggest the following: 1) An initial (radiative) strengthening of the lower-stratospheric winds as a result of ozone depletion conditions the polar vortex so that fewer planetary waves propagate up from the troposphere, resulting in weaker planetary wave driving. 2) This causes further strengthening of the vortex, which results in an additional reduction in upward-propagating planetary waves and initiates a positive feedback mechanism in which the weaker wave driving and the associated strengthened winds are drawn downward to the tropopause. 3) In the troposphere the midlatitude jet shifts poleward in association with increases in the synoptic wave fluxes of heat and momentum, which are the result of a positive feedback mechanism consisting of two components: 4) increases in low-level baroclinicity, and the subsequent generation of baroclinic activity (associated with a poleward heat flux), are collocated with the jet latitudinal position, and 5) strengthening anticyclonic shear increases the refraction of wave activity equatorward (associated with a poleward momentum flux). Finally, 6) confinement of planetary waves in the high-latitude troposphere is an important step to couple the stratospheric changes to the tropospheric response.