bluuebunny/crossref_metadata_2025_split huggingface dataset:
Foxp3+ Regulatory T Cells Impede the Priming of Protective CD8+ T Cells
Authors: Ertelt James M. , Rowe Jared H. , Mysz Margaret A. , Singh Charanjeet , Roychowdhury Monika , Aguilera Marijo N. , Way Sing Sing 
Published: August 2011

Abstract
T cell activation is controlled by incompletely defined opposing stimulation and suppression signals that together sustain the balance between optimal host defense against infection and peripheral tolerance. In this article, we explore the impacts of Foxp3+ regulatory T cell (Treg) suppression in priming Ag-specific T cell activation under conditions of noninfection and infection. We find the transient ablation of Foxp3+ Tregs unleashes the robust expansion and activation of peptide-stimulated CD8+ T cells that provide protection against Listeria monocytogenes infection in an Ag-specific fashion. By contrast, Treg ablation had nonsignificant impacts on the CD8+ T cell response primed by infection with recombinant L. monocytogenes. Similarly, nonrecombinant L. monocytogenes administered with peptide stimulated the expansion and activation of CD8+ T cells that paralleled the response primed by Treg ablation. Interestingly, these adjuvant properties of L. monocytogenes did not require CD8+ T cell stimulation by IL-12 produced in response to infection, but instead were associated with sharp reductions in Foxp3+ Treg suppressive potency. Therefore, Foxp3+ Tregs impose critical barriers that, when overcome naturally during infection or artificially with ablation, allow the priming of protective Ag-specific CD8+ T cells.
Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death
Authors: Suárez-Fueyo Abel , Barber Domingo F. , Martínez-Ara Jorge , Zea-Mendoza Antonio C. , Carrera Ana C. 
Published: August 2011

Abstract
Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class IA PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (∼70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3Kδ in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3Kδ activity, suggesting that PI3Kδ contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3Kδ as a target of clinical interest for SLE.
Cutting Edge: Structural Basis for the Recognition of β-Linked Glycolipid Antigens by Invariant NKT Cells
Authors: Yu Esther Dawen , Girardi Enrico , Wang Jing , Zajonc Dirk M. 
Published: August 2011

Abstract
Invariant NKT (iNKT) cells expressing a semi-invariant Vα14 TCR recognize self and foreign lipid Ags when presented by the nonclassical MHCI homolog CD1d. Whereas the majority of known iNKT cell Ags are characterized by the presence of a single α-linked sugar, mammalian self Ags are β-linked glycosphingolipids, posing the interesting question of how the semi-invariant TCR can bind to such structurally distinct ligands. In this study, we show that the mouse iNKT TCR recognizes the complex β-linked Ag isoglobotrihexosylceramide (iGb3; Galα1-3-Galβ1-4-Glcβ1-1Cer) by forcing the proximal β-linked sugar of the trisaccharide head group to adopt the typical binding orientation of α-linked glycolipids. The squashed iGb3 orientation is stabilized by several interactions between the trisaccharide and CD1d residues. Finally, the formation of novel contacts between the proximal and second sugar of iGb3 and CDR2α residues of the TCR suggests an expanded recognition logic that can possibly distinguish foreign Ags from self Ags.
Activity of Ca2+‐Activated Cl− Channels Contributes to Regulating Receptor‐ and Store‐Operated Ca2+ Entry in Human Pulmonary Artery Smooth Muscle Cells
Authors: Yamamura Aya , Yamamura Hisao , Zeifman Amy , Yuan Jason X.‐J. 
Published: August 2011

Intracellular Ca2+ plays a fundamental role in regulating cell functions in pulmonary arterial smooth muscle cells (PASMCs). A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. [Ca2+]cyt is increased mainly by Ca2+ release from intracellular stores and Ca2+ influx through plasmalemmal Ca2+‐permeable channels. Given the high concentration of intracellular Cl− in PASMCs, Ca2+‐activated Cl− (ClCa) channels play an important role in regulating membrane potential and cell excitability of PASMCs. In this study, we examined whether activity of ClCa channels was involved in regulating [Ca2+]cyt in human PASMCs via regulating receptor‐ (ROCE) and store‐ (SOCE) operated Ca2+ entry. The data demonstrated that an angiotensin II (100 nM)‐mediated increase in [Ca2+]cyt via ROCE was markedly attenuated by the ClCa channel inhibitors, niflumic acid (100 µM), flufenamic acid (100 µM), and 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid (100 µM). The inhibition of ClCa channels by niflumic acid and flufenamic acid significantly reduced both transient and plateau phases of SOCE that was induced by passive depletion of Ca2+ from the sarcoplasmic reticulum by 10 µM cyclopiazonic acid. In addition, ROCE and SOCE were abolished by SKF‐96365 (50 µM) and 2‐aminoethyl diphenylborinate (100 µM), and were slightly decreased in the presence of diltiazem (10 µM). The electrophysiological and immunocytochemical data indicate that ClCa currents were present and TMEM16A was functionally expressed in human PASMCs. The results from this study suggest that the function of ClCa channels, potentially formed by TMEM16A proteins, contributes to regulating [Ca2+]cyt by affecting ROCE and SOCE in human PASMCs.
Vasoreactivity to Inhaled Nitric Oxide with Oxygen Predicts Long‐Term Survival in Pulmonary Arterial Hypertension
Authors: Malhotra Rajeev , Hess Dean , Lewis Gregory D. , Bloch Kenneth D. , Waxman Aaron B. , Semigran Marc J. 
Published: August 2011

Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established. Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O2 for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long‐term survival (median follow‐up 2.4 years). Five‐year survival was 56%. Baseline PVR (mean±SD 850±580 dyne‐sec/cm5) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO and O2 was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O2 had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23–0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O2 had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22–0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O2 were independent predictors of survival. Reduction in PVR or mPAP during short‐term administration of inhaled NO and O2 predicts survival in PAH patients.
An Adjoint State Method for Numerical Approximation of Continuous Traffic Congestion Equilibria
Authors: Luo Songting , Leung Shingyu , Qian Jianliang 
Published: August 2011

AbstractThe equilibrium metric for minimizing a continuous congested traffic model is the solution of a variational problem involving geodesic distances. The continuous equilibrium metric and its associated variational problem are closely related to the classical discrete Wardrop’s equilibrium. We propose an adjoint state method to numerically approximate continuous traffic congestion equilibria through the continuous formulation. The method formally derives an adjoint state equation to compute the gradient descent direction so as to minimize a nonlinear functional involving the equilibrium metric and the resulting geodesic distances. The geodesic distance needed for the state equation is computed by solving a factored eikonal equation, and the adjoint state equation is solved by a fast sweeping method. Numerical examples demonstrate that the proposed adjoint state method produces desired equilibrium metrics and outperforms the subgradient marching method for computing such equilibrium metrics.
A High Order Spectral Volume Formulation for Solving Equations Containing Higher Spatial Derivative Terms: Formulation and Analysis for Third Derivative Spatial Terms Using the LDG Discretization Procedure
Authors: Kannan Ravi 
Published: August 2011

AbstractIn this paper, we develop a formulation for solving equations containing higher spatial derivative terms in a spectral volume (SV) context; more specifically the emphasis is on handling equations containing third derivative terms. This formulation is based on the LDG (Local Discontinuous Galerkin) flux discretization method, originally employed for viscous equations containing second derivatives. A linear Fourier analysis was performed to study the dispersion and the dissipation properties of the new formulation. The Fourier analysis was utilized for two purposes: firstly to eliminate all the unstable SV partitions, secondly to obtain the optimal SV partition. Numerical experiments are performed to illustrate the capability of this formulation. Since this formulation is extremely local, it can be easily parallelized and a h-p adaptation is relatively straightforward to implement. In general, the numerical results are very promising and indicate that the approach has a great potential for higher dimension Korteweg-de Vries (KdV) type problems.
Resonance Clustering in Wave Turbulent Regimes: Integrable Dynamics
Authors: Bustamante Miguel D. , Kartashova Elena 
Published: August 2011

AbstractTwo fundamental facts of the modern wave turbulence theory are 1) existence of power energy spectra ink-space, and 2) existence of “gaps” in this spectra corresponding to the resonance clustering. Accordingly, three wave turbulent regimes are singled out:kinetic, described by wave kinetic equations and power energy spectra;discrete, characterized by resonance clustering; andmesoscopic, where both types of wave field time evolution coexist. In this review paper we present the results on integrable dynamics of resonance clusters appearing in discrete and mesoscopic wave turbulent regimes. Using a novel method based on the notion of dynamical invariant we show that some of the frequently met clusters are integrable in quadratures for arbitrary initial conditions and some others-only for particular initial conditions. We also identify chaotic behaviour in some cases. Physical implications of the results obtained are discussed.
The Approximate Solutions of FPK Equations in High Dimensions for Some Nonlinear Stochastic Dynamic Systems
Authors: Er Guo-Kang , Iu Vai Pan 
Published: August 2011

AbstractThe probabilistic solutions of the nonlinear stochastic dynamic (NSD) systems with polynomial type of nonlinearity are investigated with the subspace-EPC method. The space of the state variables of large-scale nonlinear stochastic dynamic system excited by white noises is separated into two subspaces. Both sides of the Fokker-Planck-Kolmogorov (FPK) equation corresponding to the NSD system is then integrated over one of the subspaces. The FPK equation for the joint probability density function of the state variables in another subspace is formulated. Therefore, the FPK equation in low dimensions is obtained from the original FPK equation in high dimensions and it makes the problem of obtaining the probabilistic solutions of large-scale NSD systems solvable with the exponential polynomial closure method. Examples about the NSD systems with polynomial type of nonlinearity are given to show the effectiveness of the subspace-EPC method in these cases.
Community-Implemented Trauma Therapy for Former Child Soldiers in Northern Uganda
Authors: Ertl Verena , Pfeiffer Anett , Schauer Elisabeth , Elbert Thomas , Neuner Frank 
Published: August 2011

ContextThe psychological rehabilitation of former child soldiers and their successful reintegration into postconflict society present challenges. Despite high rates of impairment, there have been no randomized controlled trials examining the feasibility and efficacy of mental health interventions for former child soldiers.ObjectiveTo assess the efficacy of a community-based intervention targeting symptoms of posttraumatic stress disorder (PTSD) in formerly abducted individuals.Design, Setting, and ParticipantsRandomized controlled trial recruiting 85 former child soldiers with PTSD from a population-based survey of 1113 Northern Ugandans aged 12 to 25 years, conducted between November 2007 and October 2009 in camps for internally displaced persons. Participants were randomized to 1 of 3 groups: narrative exposure therapy (n = 29), an academic catch-up program with elements of supportive counseling (n = 28), or a waiting list (n = 28). Symptoms of PTSD and trauma-related feelings of guilt were measured using the Clinician-Administered PTSD Scale. The respective sections of the Mini International Neuropsychiatric Interview were used to assess depression and suicide risk, and a locally adapted scale was used to measure perceived stigmatization. Symptoms of PTSD, depression, and related impairment were assessed before treatment and at 3 months, 6 months, and 12 months postintervention.InterventionTreatments were carried out in 8 sessions by trained local lay therapists, directly in the communities.Main Outcome MeasuresChange in PTSD severity, assessed over a 1-year period after treatment. Secondary outcome measures were depression symptoms, severity of suicidal ideation, feelings of guilt, and perceived stigmatization.ResultsPTSD symptom severity (range, 0-148) was significantly more improved in the narrative exposure therapy group than in the academic catch-up (mean change difference, −14.06 [95% confidence interval, −27.19 to −0.92]) and waiting-list (mean change difference, −13.04 [95% confidence interval, −26.79 to 0.72]) groups. Contrast analyses of the time × treatment interaction of the mixed-effects model on PTSD symptom change over time revealed a superiority of narrative exposure therapy compared with academic catch-up (F1,234.1 = 5.21, P = .02) and wait-listing (F1,228.3 = 5.28, P = .02). Narrative exposure therapy produced a larger within-treatment effect size (Cohen d = 1.80) than academic catch-up (d = 0.83) and wait-listing (d = 0.81).ConclusionAmong former Ugandan child soldiers, short-term trauma-focused treatment compared either with an academic catch-up program including supportive counseling or with wait-listing resulted in greater reduction of PTSD symptoms.Trial Registrationclinicaltrials.gov Identifier: NCT00552006
Adjunctive Risperidone Treatment for Antidepressant-Resistant Symptoms of Chronic Military Service–Related PTSD
Authors: Krystal John H. , Rosenheck Robert A. , Cramer Joyce A. , Vessicchio Jennifer C. , Jones Karen M. , Vertrees Julia E. , Horney Rebecca A. , Huang Grant D. , Stock Christopher ,   for the Veterans Affairs Cooperative Study No. 504 Group
Published: August 2011

ContextSerotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).ObjectiveTo determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD.Design, Setting, and ParticipantsA 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure.InterventionRisperidone (up to 4 mg once daily) or placebo.Main Outcome MeasuresThe Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V).ResultsChange in CAPS scores from baseline to 24 weeks in the risperidone group was −16.3 (95% CI, −19.7 to −12.9) and in the placebo group, −12.5 (95% CI, −15.7 to −9.4); the mean difference was 3.74 (95% CI, −0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, −0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, −0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, −0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, −0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, −1.13, 95% CI, −2.58 to 0.32; P = .13; SF-36V mental component mean difference, −0.26; 95% CI, −2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively.ConclusionAmong patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms.Trial Registrationclinicaltrials.gov Identifier: NCT00099983
Association between TCF4 and schizophrenia does not exert its effect by common nonsynonymous variation or by influencing cis‐acting regulation of mRNA expression in adult human brain
Authors: Williams Hywel J. , Moskvina Valentina , Smith Rhodri L. , Dwyer Sarah , Russo Giancarlo , Owen Michael J. , O'Donovan Michael C. 
Published: August 2011

AbstractLarge collaborative Genome‐wide Association studies of schizophrenia have identified genes and genomic regions that are associated with the disorder at highly stringent levels of statistical significance. Among these, transcription factor 4 (TCF4) is one of the best supported although the associated SNP (rs9960767) is located within intron 3 and has no obvious function. Seeking the mechanism at TCF responsible for the association, we examined TCF4 for coding variants, and for cis regulated variation in TCF4 gene expression correlated with the associated SNP using an assay to detect differential allelic expression. Using data from the 1000 genomes project, we were unable to identify any nonsynonymous coding variants at the locus. Allele specific expression analysis using human post mortem brain samples revealed no evidence for cis‐regulated mRNA expression related to genotype at the schizophrenia associated SNP. We conclude that association between schizophrenia and TCF4 is not mediated by a relatively common non‐synonymous variant, or by a variant that alters mRNA expression as measured in adult human brain. It remains possible that the risk allele at this locus exerts effects on expression exclusively in a developmental context, in cell types or brain regions not adequately represented in our analysis, or through post‐transcriptional effects, for example in the abundance of the protein or its sub‐cellular distribution. © 2011 Wiley‐Liss, Inc.
Genome scan of age‐at‐onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity
Authors: Choi Yoonha , Marchani Elizabeth E. , Bird Thomas D. , Steinbart Ellen J. , Blacker Deborah , Wijsman Ellen M. 
Published: August 2011

AbstractAlzheimer's disease (AD) is a common neurodegenerative disorder of late life with a complex genetic basis. Although several genes are known to play a role in rare early onset AD, only theAPOEgene is known to have a high contribution to risk of the common late‐onset form of the disease (LOAD, onset >60 years).APOEgenotypes vary in their AD risk as well as age‐at‐onset distributions, and it is likely that other loci will similarly affect AD age‐at‐onset. Here we present the first analysis of age‐at‐onset in the NIMH LOAD sample that allows for both a multilocus trait model and genetic heterogeneity among the contributing sites, while at the same time accommodating age censoring, effects of known genetic covariates, and full pedigree and marker information. The results provide evidence for genomic regions not previously implicated in this data set, including regions on chromosomes 7q, 15, and 19p. They also affirm evidence for loci on chromosomes 1q, 6p, 9q, 11, and, of course, theAPOElocus on 19q, all of which have been reported previously in the same sample. The analyses failed to find evidence for linkage to chromosome 10 with inclusion of unaffected subjects and extended pedigrees. Several regions implicated in these analyses in the NIMH sample have been previously reported in genome scans of other AD samples. These results, therefore, provide independent confirmation of AD loci in family‐based samples on chromosomes 1q, 7q, 19p, and suggest that further efforts towards identifying the underlying causal loci are warranted. © 2011 Wiley‐Liss, Inc.
Distinct De Novo deletions in a brother–sister pair with RTT: A case report
Authors: Mittal Kirti , Gupta Neerja , Kabra Madhulika , Juyal Ramesh , Thelma B.K. 
Published: August 2011

AbstractRett syndrome (RTT), a neurodevelopmental disorder caused by mutations in the X‐linked gene encoding methyl‐CpG‐binding protein2 (MeCP2), is a leading cause of mental retardation in females. Majority of cases are sporadic (99%) but some familial cases have also been observed. We describe a familial study with a brother–sister pair with symptoms of RTT and exhibiting distinct deletions in the MECP2. The non‐shared de novo deletion in the two sibs provides important insights into the disease etiology, especially for male sibs showing varied phenotypes as compared to the classical ones seen in the females. © 2011 Wiley‐Liss, Inc.