The rockefeller university

Only about 10% of individuals infected with Mycobacterium tuberculosis develop tuberculosis, yet there are over eight million new cases and two million deaths each year Complex interactions between environmental factors (microbial and non microbial) and human factors (genetic and non genetic) determine the clinical outcome of M. tuberculosis infection, accounting for the lack of symptoms in most individuals and the development of disseminated disease in childhood or pulmonary disease in adulthood in a minority of cases. Epidemiological evidence points to a major role of human genetic factors in the development of tuberculosis. Numerous association studies of various candidate genes have been conducted, with variable results. The most consistent findings concern certain HLA class II alleles and variants of the natural resistance-associated macrophage protein I (NRAMPI) gene. The first major locus identified by genome-wide linkage screening was recently mapped to chromosome region 8q12-q13 in a Moroccan population, and precise identification of this major gene is ongoing One fascinating finding in recent years is a Mendelian predisposition to tuberculosis. Tuberculosis was found to be the only phenotypic manifestation in several children with genetic defects of the IL-12/23-IFN gamma circuit, and particularly those with complete IL-12R beta 1 deficiency The human genetics of tuberculosis shows a continuum from Mendelian to complex predisposition with intermediate effects of major genes. A more thorough understanding of the molecular genetic basis of tuberculosis will have fundamental immunological and medical implications, particularly for the development of new vaccines and treatments.

The mu-opioid receptor is the site of action of many endogenous opioids as well as opiates. We hypothesize that differences in DNA methylation of specific CpG dinucleotides between former severe heroin addicts in methadone maintenance treatment and control subjects will depend, in part, upon ethnicity. DNA methylation analysis of the mu-opioid receptor gene (OPRM1) promoter region was performed on African-Americans (118 cases, 80 controls) and Hispanics (142 cases, 61 controls) and these were compared with a similar Caucasian cohort from our earlier study. In controls, a higher methylation level was found in the African-Americans compared with the Hispanics or Caucasians. Significant experiment-wise differences in methylation levels were found at the -25 and +12 CpG sites in the controls among the three ethnicities. The overall methylation level of the CpG sites were significantly higher in the former heroin addicts when compared with the controls (point-wise P = 0.0457). However, in the African-Americans, the degree of methylation was significantly decreased experiment-wise in the former heroin addicts at the +12 CpG site (P = 0.0032, Bonferroni corrected general estimating equations). In Hispanics, the degree of methylation was increased in the former heroin addicts at the -25 (P < 0.001, experiment-wise), -14 (P = 0.001, experiment-wise), and +27 (P < 0.001, experiment-wise) CpG sites. These changes in methylation of the OPRM1 promoter region may lead to altered expression of the mu-opioid receptor gene in the lymphocytes of former heroin addicts who are stabilized in methadone maintenance treatment.

Background: Chronic but not acute treatment with antidepressants increases hippocampal neurogenesis. Because chronic treatment with antidepressants also upregulates p11, we hypothesized that p11 might regulate effects of antidepressants on aspects of neurogenesis. Methods: Fluoxetine was administered chronically to wild-type (WT) and p11 knockout (KO) mice. In the neurogenic subgranular zone of hippocampus, the effects of fluoxetine on cell survival were examined with bromodeoxyuridine immunohistochemistry, whereas in the same brains cell proliferation was measured with Ki-67 immunohistochemistry, neurogenesis was measured with doublecortin immunohistochemistry, and apoptosis was measured with activated caspase-3. The behavioral action of fluoxetine was assessed in the novelty suppressed feeding test, which is considered neurogenesis-dependent. The localization of p11 in the dentate gyrus was studied with immunohistochemistry. Results: Vehicle-treated p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis relative to WT mice. In response to fluoxetine, p11 KO mice have reduced cell proliferation, neurogenesis, cell survival, and cell apoptosis in the subgranular zone of hippocampus when compared with WT littermates. P11 was not expressed in neurogenic cells but in different subtypes of neighboring gamma-aminobutyric acid (GABA)ergic interneurons, which also express serotonin 1B and serotonin 4 receptors. The behavioral effects of fluoxetine in the novelty suppressed feeding test were abolished in p11 KO mice. Conclusions: P11 is abundantly expressed in hippocampal GABAergic interneurons. The p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis and an attenuated response to fluoxetine in measures of neurogenesis and in a neurogenesis-dependent behavioral test.

Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTRs). The immune system plays a major role in the fight against SCC, however, little is known about the local inflammatory response in SCC at all. We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmuno-suppressed OTRs. RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis. SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4, CD8, TBET, GATA-3, FOXP3, RORC, IFN-g, IL-4, TGF-beta, IL-10, and IL-17A mRNA expression. Immunohistochemistry was carried out in SCC for CD3, CD4, CD8, and FOXP3 expression. Considerable inflammation was seen in both patient groups. SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature. CD4(+) mRNA was diminished in immunosuppression. Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients. T-BET and IFN-g mRNA expression were decreased in the OTR group. Although Th17-weighted inflammation was unchanged, IL-17A mRNA level was markedly decreased with immunosuppression. Regulatory T cells, characterized by FOX-P3 and TGF-beta mRNA level, were decreased in OTRs. Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients.

This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x.

Structural data of integrin alpha IIb beta 3 have been interpreted as supporting a model in which: 1) the receptor exists primarily in a "bent," low affinity conformation on unactivated platelets and 2) activation induces an extended, high affinity conformation prior to, or following, ligand binding. Previous studies found that "clasping" the alpha IIb head domain to the beta 3 tail decreased fibrinogen binding. To study the role of alpha IIb extension about the genu, we introduced a disulfide "clamp" between the alpha IIb thigh and calf-1 domains. Clamped alpha IIb beta 3 had markedly reduced ability to bind the large soluble ligands fibrinogen and PAC-1 when activated with monoclonal antibody (mAb) PT25-2 but not when activated by Mn(2+) or by coexpressing the clamped alpha IIb with a beta 3 subunit containing the activating mutation N339S. The clamp had little effect on the binding of the snake venom kistrin (M(r) 7,500) or alpha IIb beta 3-mediated adhesion to immobilized fibrinogen, but it did diminish the enhanced binding of mAbAP5 in the presence of kistrin. Collectively, our studies support a role for alpha IIb extension about the genu in the binding of ligands of 340,000 and 900,000 M(r) with mAb-induced activation but indicate that it is not an absolute requirement. Our data are consistent with alpha IIb extension resulting in increased access to the ligand-binding site and/or facilitating the conformational change(s) in beta 3 that affect the intrinsic affinity of the binding pocket for ligand.

We report the construction and analysis of 4,836 heterozygous diploid deletion mutants covering 98.4% of the fission yeast genome providing a tool for studying eukaryotic biology. Comprehensive gene dispensability comparisons with budding yeast-the only other eukaryote for which a comprehensive knockout library exists-revealed that 83% of single-copy orthologs in the two yeasts had conserved dispensability. Gene dispensability differed for certain pathways between the two yeasts, including mitochondrial translation and cell cycle checkpoint control. We show that fission yeast has more essential genes than budding yeast and that essential genes are more likely than nonessential genes to be present in a single copy, to be broadly conserved and to contain introns. Growth fitness analyses determined sets of haploinsufficient and haploproficient genes for fission yeast, and comparisons with budding yeast identified specific ribosomal proteins and RNA polymerase subunits, which may act more generally to regulate eukaryotic cell growth.

We report a measurement of the ratio of the t (t) over bar to Z/gamma* production cross sections in root s = 1.96 TeV p (p) over bar collisions using data corresponding to an integrated luminosity of up to 4.6 fb(-1), collected by the CDF II detector. The t (t) over bar cross section ratio is measured using two complementary methods, a b-jet tagging measurement and a topological approach. By multiplying the ratios by the well-known theoretical Z/gamma* -> ll cross section predicted by the standard model, the extracted t (t) over bar cross sections are effectively insensitive to the uncertainty on luminosity. A best linear unbiased estimate is used to combine both measurements with the result sigma(t (t) over bar) = 7.70 +/- 0.52 pb, for a top-quark mass of 172.5 GeV/c(2).