bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection
Authors: Seu Lillian , Sabbaj Steffanie , Duverger Alexandra , Wagner Frederic , Anderson Joshua C. , Davies Elizabeth , Wolschendorf Frank , Willey Christopher D. , Saag Michael S. , Goepfert Paul , Kutsch Olaf 
Published: April 2015

ABSTRACTThe extreme stability of the latent HIV-1 reservoir in the CD4+memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status.IMPORTANCEThe extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4+memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.
Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors
Authors: Wollmann Guido , Drokhlyansky Eugene , Davis John N. , Cepko Connie , van den Pol Anthony N. 
Published: April 2015

ABSTRACT

High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on
in vitro
infections of normal and tumor cells, we selected two viruses to test
in vivo
. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain.

IMPORTANCE
Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma.
Patterns and correlates of physical activity behaviour over 10 years in older adults: prospective analyses from the English Longitudinal Study of Ageing
Authors: Smith Lee , Gardner Benjamin , Fisher Abigail , Hamer Mark 
Published: April 2015

ObjectiveFew studies have examined how levels of activity intensity fluctuate throughout later life in older adults and no study has identified correlates of sustained activity levels in this age group. The aim of the present analysis was to investigate stability of activity over a 10-year period and identify potential correlates of sustained activity levels in older adults.DesignAnalyses of data from the English Longitudinal Study of Ageing. Participant-reported physical activity data were collected in 2002 (baseline), 2004, 2006, 2008, 2010 and 2012. Participant age, sex, smoking, depressive symptoms, work status, wealth, and long-standing illness were recorded at baseline. Multiple logistic regression was used to examine associations between baseline exposure variables and persistent physical activity (reporting moderate and/or vigorous physical activity at least once a week at all 6 assessments over the 10-year time period).ResultsA total of 5022 participants (mean age 61 years; 2114 male) were included in the analyses. There was reasonable stability in the physical activity measure over the 6 time points (Cronbach's α 0.85). There was an overall trend for increasing levels of inactivity and a reduction in vigorous activity. Age, female sex, having ever smoked, long-standing illness, arthritis, obesity, and depressive symptoms were associated with a lower likelihood of being persistently active (defined as reporting moderate and/or vigorous physical activity at least once a week over all 6 assessment points). Those with greater wealth were 4 times more likely to be persistently active.ConclusionsIn the present analyses time spent in vigorous-intensity activity declined in later life. A range of sociodemographic and biomedical factors were associated with being persistently active in older adults.
Genetics of RA susceptibility, what comes next?
Authors: Ding James , Eyre Stephen , Worthington Jane 
Published: April 2015

SummaryGenome-wide association studies (GWASs) have been used to great effect to identify genetic susceptibility loci for complex disease. A series of GWAS and meta-analyses have informed the discovery of over 100 loci for rheumatoid arthritis (RA). In common with findings in other autoimmune diseases the lead signals for the majority of these loci do not map to known gene sequences. In order to realise the benefit of investment in GWAS studies it is vital we determine how disease associated alleles function to influence disease processes. This is leading to rapid development in our knowledge as to the function of non-coding regions of the genome. Here we consider possible functional mechanisms for intergenic RA-associated variants which lie within lncRNA sequences.
NMMHC IIA inhibition impedes tissue factor expression and venous thrombosis via Akt/GSK3β-NF-κB signalling pathways in the endothelium
Authors: Zhai Kefeng , Tang Youmei , Zhang Yuanyuan , Li Fang , Wang Yan , Cao Zhengyu , Yu Boyang , Yu Jun , Kou Junping 
Published: April 2015

SummaryNon-muscle myosin heavy chain IIA (NMMHC IIA) has been shown to be involved in thrombus formation and inflammatory microparticle release in endothelial cells. However, the role of NMMHC IIA in regulating the expression of tissue factor (TF) and deep venous thrombosis remains to be elucidated. In the present study, endothelial cells were stimulated with tumour necrosis factor-α (TNF-α) to induce TF expression. Pretreatment with the NMMHC II inhibitor blebbistatin suppressed the mRNA and protein expressions as well as the procoagulant activity of TF in a dose-dependent manner. Blebbistatin enhanced Akt and GSK3β phosphorylation and inhibited NF-κB p65 nuclear translocation and IκBα degradation. These observations were similar to the effect of CHIR99021, a GSK3β inhibitor. TF downregulation by blebbistatin was antagonised by the PI3K inhibitor, wortmannin. Furthermore, siRNA knockdown of NMMHC IIA but not IIB or IIC, inhibited TF expression, activated Akt/GSK3β and suppressed NF-κB signalling pathways, whereas the overexpression of NMMHC IIA increased TF expression. The binding of NMMHC IIA and TNF receptor 2 mediated signal internalisation in TNF-α-stimulated endothelial cells. Importantly, blebbistatin decreased endothelium NMMHC IIA and TF expression, deactivated GSK3β by inducing its phosphorylation, suppressed p65 nuclear translocation, and inhibited thrombus formation in a mouse deep venous thrombosis model. Our findings provide solid evidence that inhibition of NMMHC II most likely NMMHC IIA impedes TF expression and venous thrombosis via Akt/GSK3β-NF-κB signalling pathways in the endothelium both in vitro and in vivo. NMMHC IIA might be a potential novel target for the treatment of thrombotic disorders.
A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders
Authors: Mumford Andrew D. , Frelinger III Andrew L. , Gachet Christian , Gresele Paolo , Noris Patrizia , Harrison Paul , Mezzano Diego 
Published: April 2015

SummaryMeasurement of platelet granule release to detect inherited platelet secretion disorders (IPSDs) is essential for the evaluation of patients with abnormal bleeding and is necessary to distinguish which granule sub-types are affected and whether there is abnormal granule bio-synthesis or secretion. The radioactive serotonin incorporation and release assay, described before 1970, is still considered the “gold standard” test to assess platelet δ-granule release, although is unsuitable for clinical diagnostic laboratories. Luciferin-based assays, such as lumiaggregometry, are the most widely performed alternatives, although these methods do not distinguish defects in δ-granule biosyn-thesis from defects in secretion. Platelet α-granule release is commonly evaluated using flow cytometry by measuring surface exposure of P-selectin after platelet activation. However, this assay has poor sensitivity for some α-granule disorders. Only few studies have been published with more recently developed assays and no critical reviews on these methods are available. In this review, we describe the rationale for developing robust and accurate laboratory tests of platelet granule release and describe the characteristics of the currently available tests. We identify an unmet need for further systematic evaluation of new assays and for standardisation of methodologies for clinical diagnostic laboratories.
Análise da tradução/adaptação de textos dramáticos sob a perspectiva da Linguística de Corpus
Authors: Perroti-Garcia Ana Julia 
Published: April 2015

As ferramentas computadorizadas podem ajudar na análise de textos em geral. O objetivo do presente estudo foi testar se tais ferramentas também poderiam ser úteis ao analisar textos dramáticos. As ferramentas computacionais incluídas no presente estudo são: um gerador de listas de palavras, um alinhador e um concordanciador paralelo. Para a análise, utilizamos a peça Ruckus in the Garden, escrita por David Farr, dramaturgo britânico e sua tradução ao português. A partir da pesquisa aqui realizada, pudemos concluir que as ferramentas computacionais ajudam na sistematização e no tratamento dos dados a serem analisados, tornando mais ágil e consistente a manipulação dos textos a serem pesquisados.
Aspectos semântico-lexicais dos tabus linguísticos em atlas linguísticos estaduais
Authors: Almeida Laura De 
Published: April 2015

O presente trabalho tem por objetivo abordar os tabus linguísticos presentes nos atlas Atlas Prévio dos Falares Baianos (APFB), Atlas Linguístico de Sergipe I (ALSE I), Atlas Linguístico da Paraíba (Alpa). Selecionamos os temas referentes ao item II- Homem do Questionário Semântico-Lexical (QSL) do Alib, mais especificamente aos ciclos da vida, ou seja, variantes linguísticas que ocorreram em resposta à seguinte questão: “as mulheres perdem sangue todos os meses. Como se chama isso? (menstruação). Inicialmente, apresentaremos o tabu em questão conforme a visão de Freud quando ele discute entre tabus temporários e permanentes. Estudaremos como esse tabu Linguístico é visto por teóricos como GUÉRIOS (1979) quando este ressalta o significado que o sangue tem em todos os povos. Além disso, traçaremos um paralelo entre “pureza e perigo” que é abordado pela antropóloga Mary Douglas. Sob a luz dos teóricos mencionados, buscaremos traçar um percurso que permita estabelecer um confronto de todos os mapas apresentados e as conclusões que podemos tirar de caráter geral. Dessa forma, visamos propor uma tipologia dos tabus existentes nos atlas linguísticos mencionados. Elaboramos uma classificação com base em GUÉRIOS(1979), seguida de uma análise das lexias e suas variantes. Com este estudo pretendemos traçar um mapeamento da ocorrência deste fenômeno Linguístico nos atlas linguísticos mencionados, mostrando a cultura e a visão de mundo próprias dessas localidades. Busca também contribuir para um estudo mais aprofundado do material apresentado nos atlas linguísticos.
The Correa Coup
Authors: Becker Marc 
Published: April 2015

On September 30, 2010, discontented police officers and military troops plunged Ecuador into a political crisis as they took President Rafael Correa hostage, seized airports, and stormed the National Assembly building. In response, Correa declared a state of emergency and denounced what he termed a coup attempt. To outside observers, what appeared to be in process was yet another potentially extraconstitutional transfer of power in Ecuador’s tumultuous political history, with some pointing to the presence of the heavy imperial hand of the United States. Some grassroots activists, however, cast the political disruptions as little more than a labor dispute that Correa manipulated to entrench his increasingly authoritarian control over the country. At play in these competing narratives were debates over what political and economic direction Ecuador should take and whose interests those developments would benefit. Furthermore, the September 30 protests raise questions of how various domestic and international actors opportunistically exploit political developments to advance their own competing interests. Analyzing these events leads to a deeper understanding and appreciation for the compromises local social movements make, as well as the difficulties inherent in building transnational solidarity networks. El 30 de septiembre de 2010, tropas militares y oficiales de la policía descontentos sumieron al Ecuador en una crisis política al tomar como rehén al Presidente Rafael Correa, ocupar aereopuertos y asaltar el edificio de la Asamblea Nacional. En respuesta, Correa declaró un estado de emergencia y denunció lo que él consideró un intento de golpe de estado. Para los observadores externos, lo que parecía que estaba ocurriendo era un nuevo intento de cambio de poder potencialmente extra constitucional en la tumultuosa historia política del Ecuador, y algunos llegaron a señalar la presencia de la pesada mano imperial de los Estados Unidos. Algunos activistas populares, sin embargo, vieron las perturbaciones políticas como poco más que una disputa laboral que Correa manipuló para afianzar su control cada vez más autoritario sobre el país. En juego en estas narrativas antagónicas estaba el debate sobre qué dirección política y económica el Ecuador debería tomar y a quiénes beneficiarán esos desarrollos. Además, las protestas del 30 de septiembre suscitan interrogantes sobre cómo varios actores domésticos e internacionales explotaron de manera oportunista estos desarrollos políticos para adelantar sus propios intereses antagónicos. El análisis de estos acontecimientos nos lleva a un mejor entendimiento y apreciación sobre las conceciones que los movimientos sociales locales tienen que hacer, y también sobre las dificultades inherentes en la creación de redes de solidaridad transnacionales.
A Severe Case of Recalcitrant Pompholyx
Authors: Gill Jeewanjit , Pratt Melanie 
Published: April 2015

Background: Pompholyx is an inflammatory vesiculobullous skin disease of the hands and feet belonging to the spectrum of eczema. Objective: To report a severe case of pompholyx, its clinical presentation, and its management. Methods: A medical chart review was conducted on a patient with this condition. Results: The patient was patch tested according to the North American Contact Dermatitis Group (NACDG) Standard Screening Series, and results were negative. In the past, she was treated with corticosteroid creams as well as narrow band ultraviolet B (UVB), and Psoralen ultraviolet A (PUVA) therapies, and none were beneficial. When the frequency of the episodes increased, methotrexate was introduced but failed to control the condition. Next, mycophenolate mofetil was started and gradually increased to 3.5 g daily along with a separate trial of radiotherapy with marked success. Conclusion: Pompholyx can be challenging to manage, and treatment can involve an assortment of therapies over a prolonged period of time.
School social cohesion, student-school connectedness, and bullying in Colombian adolescents
Authors: Springer Andrew E. , Cuevas Jaramillo Maria Clara , Ortiz Gómez Yamileth , Case Katie , Wilkinson Anna 
Published: April 2015

Background: Student-school connectedness is inversely associated with multiple health risk behaviors, yet research is limited on the relative contributions of a student’s connectedness with school and an overall context of school social cohesion to peer victimization/bullying. Purpose: We examined associations of perceived school cohesion and student-school connectedness with physical victimization, verbal victimization, and social exclusion in the past six months in adolescents in grades 6–11 ( N = 774) attending 11 public and private urban schools in Colombia. Methods: Cross-sectional data were collected via a self-administered questionnaire and analyzed using mixed-effects linear regression models. Results: Higher perceived school cohesion was inversely related with exposure to three bullying types examined ( p < 0.05); student-school connectedness was negatively related to verbal victimization among girls only ( p < 0.01). In full models, school cohesion maintained inverse associations with three bullying types after controlling for student-school connectedness ( p ≤ 0.05). Conclusion: Enhancing school cohesion may hold benefits for bullying prevention beyond a student’s individual school connectedness.
Mammalian target of rapamycin complex 2 (mTORC2) regulates LPS-induced expression of IL-12 and IL-23 in human dendritic cells
Authors: Wei Wen-Chi , Liu Chih-Pin , Yang Wen-Chin , Shyur Lie-Fen , Sheu Jyh-Horng , Chen Swey-Shen , Yang Ning-Sun 
Published: April 2015

Abstract
IL-12 p40, a common subunit for both IL-12 p70 and IL-23, plays a critical role in the development of Th1 and Th17 cells and autoimmune diseases. Regulation of IL-12 p40 expression is thus considered to be a strategy for developing therapies for Th1- and Th17-mediated autoimmune diseases. The mTOR protein is a subunit mTORC1 and mTORC2. Although mTORC1 has been shown to mediate IL-12 p40 expression in DCs and relevant signaling, the role of mTORC2 in IL-12 p40 expression remains largely unclear. In the present study, we demonstrate that blocking mTORC2 activity using the phytochemical cytopiloyne can specifically inhibit LPS-induced expression of IL-12 p70, IL-23, and IL-12 p40 in human DCs. This regulation by mTORC2 involving Akt activation and the persistent phase of NF-κB activation is further confirmed by siRNA knockdown of Rictor and Sin1 gene expression and the use of alternative inhibition approaches. In terms of IL-12 p40 expression, our findings reveal a new role for the mTORC2 pathway that is antagonistic to that of mTORC1. Our study provides new insight into mTOR regulation of IL-12 p40-mediated Th1 (IFN-γ) and Th17 (IL-17) responses and suggests that the phytochemical cytopiloyne might have useful applications in therapies for Th1 and Th17 cell-mediated inflammatory diseases.
Expression and role of a2 vacuolar-ATPase (a2V) in trafficking of human neutrophil granules and exocytosis
Authors: Gilman-Sachs Alice , Tikoo Anjali , Akman-Anderson Leyla , Jaiswal Mukesh , Ntrivalas Evangelos , Beaman Kenneth 
Published: April 2015

Abstract
Neutrophils kill microorganisms by inducing exocytosis of granules with antibacterial properties. Four isoforms of the “a” subunit of V-ATPase—a1V, a2V, a3V, and a4V—have been identified. a2V is expressed in white blood cells, that is, on the surface of monocytes or activated lymphocytes. Neutrophil associated-a2V was found on membranes of primary (azurophilic) granules and less often on secondary (specific) granules, tertiary (gelatinase granules), and secretory vesicles. However, it was not found on the surface of resting neutrophils. Following stimulation of neutrophils, primary granules containing a2V as well as CD63 translocated to the surface of the cell because of exocytosis. a2V was also found on the cell surface when the neutrophils were incubated in ammonium chloride buffer (pH 7.4) a weak base. The intracellular pH (cytosol) became alkaline within 5 min after stimulation, and the pH increased from 7.2 to 7.8; this pH change correlated with intragranular acidification of the neutrophil granules. Upon translocation and exocytosis, a2V on the membrane of primary granules remained on the cell surface, but myeloperoxidase was secreted. V-ATPase may have a role in the fusion of the granule membrane with the cell surface membrane before exocytosis. These findings suggest that the granule-associated a2V isoform has a role in maintaining a pH gradient within the cell between the cytosol and granules in neutrophils and also in fusion between the surface and the granules before exocytosis. Because a2V is not found on the surface of resting neutrophils, surface a2V may be useful as a biomarker for activated neutrophils.