Neonatal tolerance to Mls-1a determinants: deletion or anergy of Vβ6 + T lymphocytes depending upon MHC compatibility of neonatally injected cells

Recent investigations in mice revealed that natural immunologlcal tolerance to endogenous minor lymphocyte-stimulating locus 1a (MIs-1a antigen correlates primarily with deletion of Mls-1aspeciflc Vβ6+ T lymphocytes In the thymus. Similar mechanisms account for acquired tolerance in some Instancessince the neonatal injection of Mls-1 a-expressing MHC compatible cells in neonatal mice within the first 24 hof life causes clonal deletion of Vβ6+ T cells. Here we demonstrate that Vβ6+ T cells are not deleted In mice neonatally treated with Mls-1a spleen cells expressing allogenelc H-2 molecules. However, when such non-deleted Vβ6+ T cells were tested In vitro, no interleukin 2 (IL-2) secretion or proliferation was observed after Mls-1a stimulation. This non-responsive state could be overcome by addition of exogenous IL-2, consistent with the fact that Vβ6+ cells enlarged and expressed IL-2 receptors upon Mls-1a stimulation. Furthermore, the same neonatally treated mice showed In vitro functional unresponsiveness of cytotoxic T cells but not of IL-2-secreting cells specific for the tolerated allogeneic MHC antigens. Taken together, our data Indicate that neonatal tolerance to Mls-1a can be accomplished by either clonal deletion or clonal anergy, and that it does not necessarily correlate with tolerance to MHC determinant

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

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Consumption habits and preferences by type of drink coffee (Coffea arabica L.) between young people from Machado / MG

Objetivou-se, neste trabalho, identificar quais são os hábitos de consumo e a preferência entre diferentes tipos de bebidas de café (estritamente mole, mole, dura, riada e rio), entre jovens estudantes na cidade de Machado/MG. A pesquisa foi conclusiva descritiva, de natureza quantitativa, para analisar os hábitos da população entrevistada através de aplicação de questionários. Para identificar qual a preferência, entre os cinco tipos de bebida fornecidas, cada uma foi codificada e servida, e o entrevistado escolhia a que mais preferia, assinalando no questionário. O método das entrevistas foi pessoal. O tipo de amostragem foi não probabilística por quota e os questionários individuais foram tabulados e analisados pelo software SPSS. Concluiu-se que a maioria dos jovens tomam café, mas os sucos e refrigerantes são consumidos com maior frequência. As bebidas de café escolhidas entre os jovens foram aquelas que possuíam melhores atributos sensoriais, mole e estritamente mole.The objective of this work was to identify the patterns of consumption and preference between different types of coffee (strictly soft, soft, hard, Riada and rio) among students in the city of Machado / MG. The research was conclusive descriptive, of a quantitative nature, to analyze the habits of the people interviewed through questionnaires. To identify a preference among the five types of drink provided, each one was coded and served, and the respondent chose the most preferred and noted it in the questionnaire. The method was carried out through individual interviews. The type of sampling was a randomized control trial and the individual questionnaires were tabulated and analyzed by SPSS software. It was concluded that most young people drink coffee, but juices and soft drinks are consumed more frequently. The coffee selected among young people was those that had the best sensory attributes, soft and strictly soft

Skilful interannual climate prediction from two large initialised model ensembles

Climate prediction skill on the interannual timescale, which sits between that of seasonal and decadal, is investigated using large ensembles from the Met Office and CESM initialised coupled prediction systems. A key goal is to determine what can be skillfully predicted about the coming year when combining these two ensembles together. Annual surface temperature predictions show good skill at both global and regional scales, but skill diminishes when the trend associated with global warming is removed. Skill for the extended boreal summer (months 7-11) and winter (months 12-16) seasons are examined, focusing on circulation and rainfall predictions. Skill in predicting rainfall in tropical monsoon regions is found to be significant for the majority of regions examined. Skill increases for all regions when active ENSO seasons are forecast. There is some regional skill for predicting extratropical circulation, but predictive signals appear to be spuriously weak

Use of polyethylene naphthalate as a self-vetoing structural material

The discovery of scintillation in the blue regime from polyethylene naphthalate (PEN), a commonly used high-performance industrial polyester plastic, has sparked considerable interest from the physics community as a new type of plastic scintillator material. This observation in addition to its good mechanical and radiopurity properties makes PEN an attractive candidate as an active structure scintillator for low-background physics experiments. This paper reports on investigations of its potential in terms of production tests of custom made tiles and various scintillation light output measurements. These investigations substantiate the high potential of usage of PEN in low-background experiments

Developmentally regulated extinction of Ly-49 receptor expression permits maturation and selection of NK1.1+ T cells.

Clonally distributed inhibitory receptors negatively regulate natural killer (NK) cell function via specific interactions with allelic forms of major histocompatibility complex (MHC) class I molecules. In the mouse, the Ly-49 family of inhibitory receptors is found not only on NK cells but also on a minor (NK1.1+) T cell subset. Using Ly-49 transgenic mice, we show here that the development of NK1.1+ T cells, in contrast to NK or conventional T cells, is impaired when their Ly-49 receptors engage self-MHC class I molecules. Impaired NK1.1+ T cell development in transgenic mice is associated with a failure to select the appropriate CD1-reactive T cell receptor repertoire. In normal mice, NK1.1+ T cell maturation is accompanied by extinction of Ly-49 receptor expression. Collectively, our data imply that developmentally regulated extinction of inhibitory MHC-specific receptors is required for normal NK1.1+ T cell maturation and selection

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD