Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development.

Notch proteins influence cell-fate decisions in many developing systems. Several gain-of-function studies have suggested a critical role for Notch 1 signaling in CD4-CD8 lineage commitment, maturation and survival in the thymus. However, we show here that tissue-specific inactivation of the gene encoding Notch 1 in immature (CD25+CD44-)T cell precursors does not affect subsequent thymocyte development. Neither steady-state numbers nor the rate of production of CD4+ and CD8+ mature thymocytes is perturbed in the absence of Notch 1. In addition, Notch 1-deficient thymocytes are normally sensitive to spontaneous or glucocorticoid-induced apoptosis. In contrast to earlier reports, these data formally exclude an essential role for Notch 1 in CD4-CD8 lineage commitment, maturation or survival.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Official Positions for FRAX® clinical regarding international differences from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Osteoporosis is a serious worldwide epidemic. Increased risk of fractures is the hallmark of the disease and is associated with increased morbidity, mortality and economic burden. FRAX® is a web-based tool developed by the Sheffield WHO Collaborating Center team, that integrates clinical risk factors, femoral neck BMD, country specific mortality and fracture data and calculates the 10 year fracture probability in order to help health care professionals identify patients who need treatment. However, only 31 countries have a FRAX® calculator at the time paper was accepted for publication. In the absence of a FRAX® model for a particular country, it has been suggested to use a surrogate country for which the epidemiology of osteoporosis most closely approximates the index country. More specific recommendations for clinicians in these countries are not available. In North America, concerns have also been raised regarding the assumptions used to construct the US ethnic specific FRAX® calculators with respect to the correction factors applied to derive fracture probabilities in Blacks, Asians and Hispanics in comparison to Whites. In addition, questions were raised about calculating fracture risk in other ethnic groups e.g., Native Americans and First Canadians. In order to provide additional guidance to clinicians, a FRAX® International Task Force was formed to address specific questions raised by physicians in countries without FRAX® calculators and seeking to integrate FRAX® into their clinical practice. The main questions that the task force tried to answer were the following: The Task Force members conducted appropriate literature reviews and developed preliminary statements that were discussed and graded by a panel of experts at the ISCD-IOF joint conference. The statements approved by the panel of experts are discussed in the current paper.

Scaling of semivariograms and the kriging estimation of field-measured properties

Two methods were evaluated for scaling a set of semivariograms into a unified function for kriging estimation of field-measured properties. Scaling is performed using sample variances and sills of individual semivariograms as scale factors. Theoretical developments show that kriging weights are independent of the scaling factor which appears simply as a constant multiplying both sides of the kriging equations. The scaling techniques were applied to four sets of semivariograms representing spatial scales of 30 x 30 m to 600 x 900 km. Experimental semivariograms in each set successfully coalesced into a single curve by variances and sills of individual semivariograms. To evaluate the scaling techniques, kriged estimates derived from scaled semivariogram models were compared with those derived from unscaled models. Differences in kriged estimates of the order of 5% were found for the cases in which the scaling technique was not successful in coalescing the individual semivariograms, which also means that the spatial variability of these properties is different. The proposed scaling techniques enhance interpretation of semivariograms when a variety of measurements are made at the same location. They also reduce computational times for kriging estimations because kriging weights only need to be calculated for one variable. Weights remain unchanged for all other variables in the data set whose semivariograms are scaled.

Dessorção, extração e fracionamento de manganês em latossolos

A pesquisa sobre a avaliação da disponibilidade de manganês tem apresentado resultados discordantes, em grande parte em decorrência dos teores considerados disponíveis pelos diversos extratores. O conhecimento das formas químicas em que se encontra o elemento e suas relações com os teores disponíveis são importantes para a previsão do seu comportamento no sistema solo-planta. Nesse sentido, este trabalho teve como objetivo estudar a influência da calagem e de doses de manganês sobre a dessorção, extração e fracionamento desse elemento em amostras de seis Latossolos. Essas amostras, submetidas ou não à calagem, receberam o manganês nas doses de 0, 16 e 32 mg dm-3 e permaneceram incubadas por 30 dias. Terminada a incubação, o Mn foi determinado utilizando-se os extratores Mehlich-1, Mehlich-3, DTPA e EDTA. As amostras foram submetidas a um fracionamento que separou o Mn na fração trocável (Tr), matéria orgânica (MO), óxido de manganês (OxMn), óxido de ferro amorfo (OxFeA), óxido de ferro cristalino (OxFeC) e residual (R), além dos teores totais. A dessorção foi avaliada mediante extrações sucessivas com resina de troca catiônica. Concluiu-se que o elemento foi retido, principalmente, na fração trocável e matéria orgânica. De modo geral, a calagem provocou redução nos teores trocáveis e aumento nas frações óxidos de ferro amorfo e de manganês. Na ausência da calagem, a ordem de dessorção apresentada foi Tr >> MO > OxFeA, com o Mehlich-3 sendo o melhor extrator para o Mn lábil. A calagem provocou acentuado decréscimo nos teores de Mn dessorvidos. O Mehlich-1 mostrou-se inadequado para a determinação dos teores disponíveis de Mn em solos corrigidos, condição na qual o DTPA foi o extrator mais indicado.

Fracionamento, dessorção e extração química de zinco em latossolos

O conhecimento das formas químicas do Zn no solo, bem como de suas relações com os teores disponíveis para as plantas, é importante para a previsão do comportamento desse micronutriente. Este trabalho teve como objetivo estudar a influência da calagem e de doses de Zn sobre a dessorção, extração e fracionamento desse elemento em amostras de seis Latossolos. As amostras, com e sem calagem, receberam 0, 20 e 40 mg dm-3 de Zn e foram incubadas por 30 dias. Após a incubação, foram determinados os teores de Zn pelos extratores Mehlich-1, Mehlich-3, DTPA e EDTA. Os teores de Zn foram determinados nas frações: trocável, matéria orgânica, óxido de manganês, óxido de ferro amorfo e óxido de ferro cristalino, residual, além dos teores totais. A dessorção foi avaliada mediante extrações sucessivas com resina de troca catiônica. Com a aplicação de Zn, esse elemento foi retido, principalmente, nas frações trocável e matéria orgânica. A calagem provocou drástica redução nos teores de Zn trocável e aumento nas frações: matéria orgânica, óxidos de ferro amorfo e cristalino e óxidos de manganês. Nos solos sem calagem, todos os extratores correlacionaram-se significativamente com a fração Zn trocável, enquanto, nos solos com calagem, essa correlação foi significativa com o Zn na fração orgânica. Nos solos sem calagem, o teor de Zn dessorvido das frações decresceu na seguinte ordem: trocável = matéria orgânica > óxido de manganês > óxido de ferro amorfo >> óxido de ferro cristalino, com os extratores EDTA, Mehlich-1 e Mehlich-3, apresentando as melhores correlações com o total dessorvido. A calagem provocou ausência de dessorção para o Zn

Correlação entre características de latossolos e parâmetros de equações de adsorção de cobre e zinco

A adsorção de Cu e Zn é um dos principais fenômenos responsáveis pela disponibilidade desses elementos para as plantas. Portanto, estudos sobre a adsorção desses elementos em solos podem ser ferramentas úteis para compreensão da relação entre características dos solos e retenção desses micronutrientes. Nesse sentido, o presente trabalho objetivou caracterizar a adsorção de Cu e Zn em amostras de seis Latossolos de Minas Gerais e as influências de características dos solos sobre os parâmetros de adsorção obtidos pelas equações de Langmuir e de Freundlich. Para tanto, foram utilizadas soluções de cloreto de cobre e cloreto de zinco nas concentrações 0, 10, 20, 40, 60, 80, 100, 120 e 140 mg L-1, ajustadas a pH 5,5. As equações de Langmuir e Freundlich foram eficientes na determinação dos parâmetros de adsorção de Zn e Cu, sendo os teores de argila e de matéria orgânica, respectivamente, as características mais bem relacionadas com a capacidade de adsorção desses elementos pelos solos. Os solos estudados apresentaram maior energia de ligação dos sítios de troca e maior capacidade de adsorção máxima para Cu relativamente ao Zn. O P remanescente não se correlacionou com os parâmetros de adsorção de Zn, em virtude, provavelmente, da influência da matéria orgânica em sua determinação. Este fato pode limitar sua eficiência na previsão da adsorção deste elemento em solos com alto teor de C orgânico.

Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: the Swiss HIV Cohort Study.

OBJECTIVES: HIV infection and exposure to certain antiretroviral drugs is associated with dyslipidemia and increased risk for coronary events. Whether this risk is mediated by highly atherogenic lipoproteins is unclear. We investigated the association of highly atherogenic small dense low-density lipoproteins (LDLs) and apolipoprotein B and coronary events in HIV-infected individuals receiving antiretroviral therapy. METHODS: We conducted a case-control study nested into the Swiss HIV Cohort Study to investigate the association of small dense LDL and apolipoprotein B and coronary events in 98 antiretroviral drug-treated patients with a first coronary event (19 fatal and 79 nonfatal coronary events with 53 definite and 15 possible myocardial infarctions, 11 angioplasties or bypasses) and 393 treated controls matched for age, gender, and smoking status. Lipids were measured by ultracentrifugation. RESULTS: In models including cholesterol, triglycerides, high-density lipoprotein cholesterol, blood pressure, central obesity, diabetes, and family history, there was an independent association between small dense LDL and coronary events [odds ratio (OR) for 1 mg/dL increase: 1.06, 95% confidence interval (CI): 1.00 to 1.11] and apolipoprotein B (OR for 10 mg/dL increase: 1.16, 95% CI: 1.02 to 1.32). When adding HIV and antiretroviral therapy-related variables, ORs were 1.04 (95% CI: 0.99 to 1.10) for small dense LDL and 1.13 (95% CI: 0.99 to 1.30) for apolipoprotein B. In both models, blood pressure and HIV viral load was independently associated with the odds for coronary events. CONCLUSIONS: HIV-infected patients receiving antiretroviral therapy with elevate small dense LDL and apolipoprotein B are at increased risk for coronary events as are patients without sustained HIV suppression.

Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes.

Progressive destruction of the insulin-producing beta cells in nonobese diabetic mice is observed after infiltration of the pancreas with lymphocytes [Makino, S., Kunimoto, K., Muraoka, Y., Mizushima, Y., Katagiri, K. & Tochino, Y. (1980) Exp. Anim. (Tokyo) 29, 1-13]. We show that the genes for tumor necrosis factor alpha and granzyme A, a serine protease associated with cytoplasmic granules of cytotoxic cells, are expressed during the development of spontaneous diabetes mellitus in the nonobese diabetic mouse. Granzyme A-positive cells are found both in and surrounding the islets, implying induction prior to islet infiltration. Tumor necrosis factor alpha expression is exclusively observed in the intra-islet infiltrate, predominantly in lymphocytes adjacent to insulin-producing beta cells, the targets of the autoimmune destruction, implying that tumor necrosis factor alpha expression is induced locally--i.e., in the islet. A considerable portion of cells expressing tumor necrosis factor alpha appear to be CD4+ T cells. This T-cell subset was previously shown to be necessary for development of the disease. Thus, these findings may be important for understanding the pathogenesis of autoimmune diabetes mellitus and potentially also for that of other T-cell-mediated autoimmune diseases.

Pharmacogenomics of HIV Therapy: Summary of a Workshop Sponsored by the National Institute of Allergy and Infectious Diseases

Approximately 1 million people in the United States and over 30 million worldwide are living with human immunodeficiency virus type 1 (HIV-1). While mortality from untreated infection approaches 100%, survival improves markedly with use of contemporary antiretroviral therapies (ART). In the United States, 25 drugs are approved for treating HIV-1, and increasing numbers are available in resource-limited countries. Safe and effective ART is a cornerstone in the global struggle against the acquired immunodeficiency syndrome. Variable responses to ART are due at least in part to human genetic variants that affect drug metabolism, drug disposition, and off-site drug targets. Defining effects of human genetic variants on HIV treatment toxicity, efficacy, and pharmacokinetics has far-reaching implications. In 2010, the National Institute of Allergy and Infectious Diseases sponsored a workshop entitled, Pharmacogenomics A Path Towards Personalized HIV Care. This article summarizes workshop objectives, presentations, discussions, and recommendations derived from this meeting.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Precision determination of r(0)Lambda((MS)over-bar) from the QCD static energy

We use the recently obtained theoretical expression for the complete QCD static energy at next-to-next-to-next-to leading-logarithmic accuracy to determine r(0)Lambda((MS) over bar) by comparison with available lattice data, where r(0) is the lattice scale and Lambda((MS) over bar) is the QCD scale. We obtain r(0)Lambda((MS) over bar) = 0.622(-0.015)(+0.019) for the zero-flavor case. The procedure we describe can be directly used to obtain r(0)Lambda((MS) over bar) in the unquenched case, when unquenched lattice data for the static energy at short distances becomes available. Using the value of the strong coupling alpha(s) as an input, the unquenched result would provide a determination of the lattice scale r(0).

Ligand-dependent inhibition of CD1d-restricted NKT cell development in mice transgenic for the activating receptor Ly49D.

In addition to their CD1d-restricted T cell receptor (TCR), natural killer T (NKT) cells express various receptors normally associated with NK cells thought to act, in part, as modulators of TCR signaling. Immunoreceptor-tyrosine activation (ITAM) and inhibition (ITIM) motifs associated with NK receptors may augment or attenuate perceived TCR signals respectively, potentially influencing NKT cell development and function. ITIM-containing Ly49 family receptors expressed by NKT cells are proposed to play a role in their development and function. We have produced mice transgenic for the ITAM-associated Ly49D and ITIM-containing Ly49A receptors and their common ligand H2-Dd to determine the importance of these signaling interplays in NKT cell development. Ly49D/H2-Dd transgenic mice had selectively and severely reduced numbers of thymic and peripheral NKT cells, whereas both ligand and Ly49D transgenics had normal numbers of NKT cells. CD1d tetramer staining revealed a blockade of NKT cell development at an early precursor stage. Coexpression of a Ly49A transgene partially rescued NKT cell development in Ly49D/H2-Dd transgenics, presumably due to attenuation of ITAM signaling. Thus, Ly49D-induced ITAM signaling is incompatible with the early development of cells expressing semi-invariant CD1d-restricted TCRs and appropriately harmonized ITIM-ITAM signaling is likely to play an important role in the developmental program of NKT cells.