Últimos itens adicionados do Acervo: Harvard University

A Universidade de Harvard (em inglês: Harvard University) é uma universidade privada membro da Ivy League, localizada em Cambridge, Massachusetts, Estados Unidos, e cuja história, influência e riqueza tornam-a uma das mais prestigiadas universidades do mundo.

Página 22 dos resultados de 27340 itens digitais encontrados em 0.006 segundos

‣ PIE *gne¯- 'recognize, know'

Jasanoff, Jay H.
Fonte: C. Winter Publicador: C. Winter
Tipo: Monograph or Book
Português
Linguistics

‣ Old Irish Tair 'Come!'

Jasanoff, Jay H.
Fonte: Wiley-Blackwell Publicador: Wiley-Blackwell
Tipo: Artigo de Revista Científica
Português
Linguistics

‣ Proteasome Activator Enhances Survival of Huntington's Disease Neuronal Model Cells

Kim, Woori; Cattaneo, Elena; Seo, Hyemyung; Sonntag, Kai-Christian; Isacson, Ole Stefan
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
In patients with Huntington's disease (HD), the proteolytic activity of the ubiquitin proteasome system (UPS) is reduced in the brain and other tissues. The pathological hallmark of HD is the intraneuronal nuclear protein aggregates of mutant huntingtin. We determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved in either the ubiquitinated or the non-ubiquitinated proteolysis were overexpressed in HD patients' skin fibroblasts or mutant huntingtin-expressing striatal neurons. Following compromise of the UPS, overexpression of the proteasome activator subunit PA28γ, but not subunit S5a, recovered proteasome function in the HD cells. PA28γ also improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors, such as the excitotoxin quinolinic acid and the reversible proteasome inhibitor MG132. These results demonstrate the specific functional enhancements of the UPS that can provide neuroprotection in HD cells.

‣ Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation

Folli, Franco; Guzzi, Valeria; Perego, Lucia; Coletta, Dawn K.; Finzi, Giovanna; Placidi, Claudia; La Rosa, Stefano; Capella, Carlo; Socci, Carlo; Lauro, Davide; Tripathy, Devjit; Jenkinson, Christopher; Paroni, Rita; Orsenigo, Elena; Cighetti, Giuliana;
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Background: In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold. Methods and Findings: We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients...

‣ Patterns of Abdominal Fat Distribution

Massaro, Joseph M.; Lieb, Kathrin; Vasan, Ramachandran S.; Pou, Karla Michelle; Hoffmann, Udo; O'Donnell, Christopher Joseph; Fox, Caroline
Fonte: American Diabetes Association Publicador: American Diabetes Association
Tipo: Artigo de Revista Científica
Português
OBJECTIVE—The prevalence of abdominal obesity exceeds that of general obesity. We sought to determine the prevalence of abdominal subcutaneous and visceral obesity and to characterize the different patterns of fat distribution in a community-based sample. RESEARCH DESIGN AND METHODS—Participants from the Framingham Heart Study (n = 3,348, 48% women, mean age 52 years) underwent multidetector computed tomography; subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were assessed. Sex-specific high SAT and VAT definitions were based on 90th percentile cut points from a healthy referent sample. Metabolic risk factors were examined in subgroups with elevated SAT and VAT. RESULTS—The prevalence of high SAT was 30% (women) and 31% (men) and that for high VAT was 44% (women) and 42% (men). Overall, 27.8% of the sample was discordant for high SAT and high VAT: 19.9% had SAT less than but VAT equal to or greater than the 90th percentile, and 7.9% had SAT greater than but VAT less than the 90th percentile. The prevalence of metabolic syndrome was higher among women and men with SAT less than the 90th percentile and high VAT than in those with high SAT but VAT less than the 90th percentile, despite lower BMI and waist circumference. Findings were similar for hypertension...

‣ Attitudes of Healthcare Workers in U.S. Hospitals Regarding Smallpox Vaccination

Rêgo, Virginia H; O'Brien, Megan A; Shay, David K; Yih, Katherine Katherine; Lieu, Tracy Ann; Yokoe, Deborah Stephanie; Platt, Richard
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Background: The United States is implementing plans to immunize 500,000 hospital-based healthcare workers against smallpox. Vaccination is voluntary, and it is unknown what factors drive vaccine acceptance. This study's aims were to estimate the proportion of workers willing to accept vaccination and to identify factors likely to influence their decisions. Methods: The survey was conducted among physicians, nurses, and others working primarily in emergency departments or intensive care units at 21 acute-care hospitals in 10 states during the two weeks before the U.S. national immunization program for healthcare workers was announced in December 2002. Of the questionnaires distributed, 1,165 were returned, for a response rate of 81%. The data were analyzed by logistic regression and were adjusted for clustering within hospital and for different number of responses per hospital, using generalized linear mixed models and SAS's NLMIXED procedure. Results: Sixty-one percent of respondents said they would definitely or probably be vaccinated, while 39% were undecided or inclined against it. Fifty-three percent rated the risk of a bioterrorist attack using smallpox in the United States in the next two years as either intermediate or high. Forty-seven percent did not feel well-informed about the risks and benefits of vaccination. Principal concerns were adverse reactions and the risk of transmitting vaccinia. In multivariate analysis...

‣ Catastrophic NAD+ Depletion in Activated T Lymphocytes Through Nampt Inhibition Reduces Demyelination and Disability in EAE

Bruzzone, Santina; Fruscione, Floriana; Morando, Sara; Ferrando, Tiziana; Poggi, Alessandro; Garuti, Anna; D'Urso, Agustina; Selmo, Martina; Benvenuto, Federica; Cea, Michele; Zoppoli, Gabriele; Moran, Eva; Soncini, Debora; Ballestrero, Alberto; Sordat, B
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally...

‣ Genetic Correlates of Longevity and Selected Age-related Phenotypes: A Genome-wide Association Study in the Framingham Study

Lunetta, Kathryn L; D'Agostino, Ralph B; Benjamin, Emelia J; Govindaraju, Raju; Kelly-Hayes, Margaret; Massaro, Joseph M; Pencina, Michael J; Seshadri, Sudha; Murabito, Joanne M; Karasik, David; Guo, Chao-yu; Kiel, Douglas P.
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Background: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. Methods: We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate ≥80%, minor allele frequency ≥10%, Hardy-Weinberg test p ≥ 0.001). Results: In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10^-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes...

‣ Morphologic and Immunophenotypic Evidence of In-Situ Kaposi's Sarcoma

Dezube, Bruce J; Pantanowitz, Liron; Konstantinopoulos, Panagiotis
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Background: The spectrum of Kaposi's sarcoma (KS) has been expanded to include pre-KS lesions. Case Presentation: We report, for the first time, a case providing direct histological evidence of the development of early (in-situ) KS from mediastinal lymphatic vessels in the setting of chronic lymphedema in an HIV-positive patient. Spindle-shaped and endothelial cells in these early KS-appearing lesions were immunoreactive for HHV8, D2-40 and CD34. Conclusion: Our findings suggest that HHV8-infected spindle-shaped cells associated with lymphangiogenesis that evolve into KS lesions, acquire from the outset an aberrant mixed vascular and lymphatic endothelial cell phenotype.

‣ Cytological profiling: providing more haystacks for chemists' needles

Lorang, Janet; King, Randall Wharton
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Conventional high-throughput ‘chemical genetic’ screening seeks to identify small-molecule inhibitors of a specific protein or pathway. A recent study describes how unbiased screening of cellular morphology, followed by affinity purification to identify targets of compounds with interesting effects, can lead to the identification of novel inhibitors.

‣ Aging Syndrome Genes and Premature Coronary Artery Disease

Low, Adrian F; Kathiresan, Sekar; O'Donnell, Christopher Joseph; Everett, Brendan Murphy; Chae, Claudia Un-Yong; Shaw, Stanley Yang; Ellinor, Patrick Thomas; MacRae, Calum A
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Background: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. Methods: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan® probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. Results: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele...

‣ Neuroinflammation Mediated by IL-1β Increases Susceptibility of Dopamine Neurons to Degeneration in an Animal Model of Parkinson's Disease

Koprich, James B; Reske-Nielsen, Casper; Mithal, Prabhakar; Isacson, Ole Stefan
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Background: The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease. Methods: We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology. Results: We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1β), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-α and interferon-γ and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration. Conclusion: These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease.

‣ Therapeutic Angiogenesis for Cardiovascular Disease

Ng, Yin-Shan; D'Amore, Patricia Ann
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
The identification of angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor, has fueled interest in using such factors to induce therapeutic angiogenesis. The results of numerous animal studies and clinical trials have offered promise for new treatment strategies for various ischemic diseases. Increased understanding of the cellular and molecular biology of vessel growth has, however, prompted investigators and clinicians alike to reconsider the complexity of therapeutic angiogenesis. The realization that formation of a stable vessel is a complex, multistep process may provide useful insights into the design of the next generation of angiogenesis therapy.

‣ Parents’ Disclosure of Their HIV Infection to Their Children in the Context of the Family

Cowgill, Burton O.; Corona, Rosalie; Ryan, Gery W.; Murphy, Debra A.; Nguyen, Theresa; Kennedy, David P.; Bogart, Laura M; Schuster, Mark A.
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
Português
We interviewed 33 HIV-infected parents from the HIV Cost and Services Utilization Study (HCSUS), 27 of their minor children, 19 adult children, and 15 caregivers about the process of children learning that their parents were HIV positive. We summarize the retrospective descriptions of parents’ disclosure of their HIV status to their children, from the perspective of multiple family members. We analyzed transcripts of these interviews with systematic qualitative methods. Both parents and children reported unplanned disclosure experiences with positive and negative outcomes. Parents sometimes reported that disclosure was not as negative as they feared. However, within-household analysis showed disagreement between parents and children from the same household regarding disclosure outcomes. These findings suggest that disclosure should be addressed within a family context to facilitate communication and children’s coping. Parents should consider negative and positive outcomes, unplanned disclosure and children’s capacity to adapt after disclosure when deciding whether to disclose.

‣ Non-Human Primate Model of Kaposi's Sarcoma-Associated Herpesvirus Infection

Chang, Heesoon; Lee, Jong-Soo; Lee, Hye-Ra; Vieira, Jeffrey; Wachtman, Lynn M; Pearson, Christine B; Lee, Steven H; Mansfield, Keith G.; Jung, Jae Ung
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.

‣ Selective Disruption of the Cerebral Neocortex in Alzheimer's Disease

Desikan, Rahul S.; Schmansky, Nicholas J.; Cabral, Howard J.; Hess, Christopher P.; Weiner, Michael W.; Kemper, Thomas L.; Dale, Anders M.; Sabuncu, Mert R; the Alzheimer’s Disease Neuroimaging Initiative; Reuter, Martin; Biffi, Alessandro; Anderson, Ch
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Background: Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown. Methodology/Principal Findings: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aß levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults...

‣ MicroRNAs and Their Target Gene Networks in Breast Cancer

O'Day, Elizabeth; Lal, Ashish
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
MicroRNAs (miRNAs) are a major class of small endogenous RNA molecules that post-transcriptionally inhibit gene expression. Many miRNAs have been implicated in several human cancers, including breast cancer. Here we describe the association between altered miRNA signatures and breast cancer tumorigenesis and metastasis. The loss of several tumor suppressor miRNAs (miR-206, miR-17-5p, miR-125a, miR-125b, miR-200, let-7, miR-34 and miR-31) and the overexpression of certain oncogenic miRNAs (miR-21, miR-155, miR-10b, miR-373 and miR-520c) have been observed in many breast cancers. The gene networks orchestrated by these miRNAs are still largely unknown, although key targets have been identified that may contribute to the disease phenotype. Here we report how the observed perturbations in miRNA expression profiles may lead to disruption of key pathways involved in breast cancer.

‣ PrEP implementation: moving from trials to policy and practice

Cáceres, Carlos F; O'Reilly, Kevin R; Mayer, Kenneth H; Baggaley, Rachel
Fonte: International AIDS Society Publicador: International AIDS Society
Tipo: Outros
Português
Introduction: It is increasingly clear that the HIV response will not be sustainable if the number of infections is not significantly reduced. Discussion For two decades, research has been ongoing to identify new behavioural and biomedical strategies to prevent HIV infection. In the past few years, the efficacy of several new strategies has been demonstrated, including oral pre-exposure prophylaxis (PrEP; i.e. daily use of tenofovir/emtricitabine). Because several social, political and logistic barriers remain, however, optimal PrEP implementation will require a better dissemination of new evidence in a number of areas and additional implementation research from various disciplinary perspectives (i.e. social science, policy and ethics; health systems; and economics, including cost-effectiveness studies). Discussion of new evidence on those topics, as well as case studies of potential PrEP implementation in diverse environments, can improve the understanding of the role that PrEP may play in addressing the global HIV/AIDS epidemic. In light of these needs, the Network for Multidisciplinary Studies in ARV-based HIV Prevention (NEMUS) and the World Health Organization (WHO) were honoured to co-organize a special issue of JIAS aimed at contributing to a scholarly discussion of current conditions surrounding PrEP implementation...

‣ John Winthrop's "City of Women"

Ulrich, Laurel Thatcher
Fonte: Massachusetts Historical Society Publicador: Massachusetts Historical Society
Tipo: Artigo de Revista Científica
Português
History

‣ "Never Born": Angelina Weld Grimké's Rachel as Ironic Response to Topsy

Bernstein, Robin M
Fonte: CASTA, CUNY Graduate School Publicador: CASTA, CUNY Graduate School
Tipo: Artigo de Revista Científica
Português
Other Research Unit; African and African American Studies