Elliptic Curves over Real Quadratic Fields are Modular

We prove that all elliptic curves defined over real quadratic fields are modular.Comment: 38 pages. Magma scripts available as ancillary files with this arXiv versio

The supercuspidal representations of p-adic classical groups

Let G be a unitary, symplectic or special orthogonal group over a locally compact non-archimedean local field of odd residual characteristic. We construct many new supercuspidal representations of G, and Bushnell-Kutzko types for these representations. Moreover, we prove that every irreducible supercuspidal representation of G arises from our constructions.Comment: 55 pages -- minor changes from 1st version (mostly in sections 2.2, 4.2 and 6.2). To appear in Inventiones mathematicae, 2008 (DOI is not yet active as at 12 Nov 2007

Whole-genome sequencing analysis of semi-supercentenarians

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events

Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario

<p>Abstract</p> <p>Background</p> <p>Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly <it>MLH1 </it>and <it>MSH2</it>, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population.</p> <p>Methods</p> <p>We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information.</p> <p>Results</p> <p>The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among <it>MLH1 </it>mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in <it>MSH2 </it>carriers (about 54%). The relative risk associated with <it>MLH1 </it>was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for <it>MSH2 </it>decreased with age (from 13.1 at age 30 to 5.4 at age 70).</p> <p>Conclusion</p> <p>This study provides a unique population-based study of CRC risks among <it>MSH2</it>/<it>MLH1 </it>mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.</p

How does working on university-industry collaborative projects affect science and engineering doctorates' careers? Evidence from a UK research-based university

This paper examines the impact of industrial involvement in doctoral projects on the particular nature of the training and careers of doctorates. We draw on an original survey of job histories of doctorates in physical sciences and engineering from a research-based university in the UK. Using multivariate probit analysis and linearised (robust) and resampling (jackknife) variance estimation techniques, we found that projects with industrial involvement are associated with higher degree of socialisation with industry. There is some evidence showing that these projects are also more likely to focus on solving firm-specific technical problems or developing firm-specific specifications/prototypes, rather than exploring high-risk concepts or generating knowledge in the subject areas. Crucially, these projects result in fewer journal publications. Not surprisingly, in line with existing literature, we found that engaging in projects with industrial involvement (in contrast to projects without industrial involvement) confers advantages on careers in the private sector. Nevertheless, there is also a hint that engaging in projects with industrial involvement may have a negative effect on careers in academia or public research organisations. While acknowledging that the modelling results are based on a small sample from a research-based university and that therefore the results need to be treated with caution, we address implications for doctorates, universities and policymakers

Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients

International audienceBackground: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. Results: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient's unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. Conclusion: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs

Using Affiliation Networks to Study the Determinants of Multilateral Research Cooperation Some empirical evidence from EU Framework Programs in biotechnology

This paper studies multilateral cooperation networks among organizations and work on a two-mode representation to study the decision to participate in a consortium. Our objective is to explain the underlying processes that give rise to multilateral collaboration networks. Particularly, we are interested in how heterogeneity in organizations' attributes plays a part and in the geographical dimension of this formation process. We use the data on project proposals submitted to the 7th Framework Program (FP) in the area of Life sciences, Biotechnology and Biochemistry for Sustainable Non-Food. We employ exponential random graph models (p* models) (Frank and Strauss, 1986 ; Wasserman and Pattison, 1996) with node attributes (Agneessens et al., 2004), and we make use of extensions for affiliation networks (Wang et al., 2009). These models do not only enable handling variability in consortium sizes but also relax the assumption on tie/triad independence. We obtained some preliminary results indicating institutional types as a source of heterogeneity affecting participation decisions. Also, these initial results point out that organizations take their potential partners' participations in other projects into account in giving their decision ; organizations located in the core European countries tend to participate in the same project ; the tendency to preserve the composition of a consortium across projects and the tendency of organizations with the same institutional type to co-participate are not significant

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis

Generation of a Novel Regulatory NK Cell Subset from Peripheral Blood CD34+ Progenitors Promoted by Membrane-Bound IL-15

BACKGROUND: NK cells have been long time considered as cytotoxic lymphocytes competent in killing virus-infected cells and tumors. However, NK cells may also play essential immuno-regulatory functions. In this context, the real existence of a defined NK subset with negative regulatory properties has been hypothesized but never clearly demonstrated. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we show the in vitro generation from human peripheral blood haematopoietic progenitors (PB-HP), of a novel subset of non-cytolytic NK cells displaying a mature phenotype and remarkable immuno-regulatory functions (NK-ireg). The main functional hallmark of these NK-ireg cells is represented by the surface expression/release of HLA-G, a major immunosuppressive molecule. In addition, NK-ireg cells secrete two powerful immuno-regulatory factors: IL-10 and IL-21. Through these factors, NK-ireg cells act as effectors of the down-regulation of the immune response: reconverting mature myeloid DC (mDC) into immature/tolerogenic DC, blocking cytolytic functions on conventional NK cells and inducing HLA-G membrane expression on PB-derived monocytes. The generation of "NK-ireg" cells is obtained, by default, in culture conditions favouring cell-to-cell contacts, and it is strictly dependent on reciprocal trans-presentation of membrane-bound IL-15 forms constitutively and selectively expressed by human CD34(+) PB-HP. Finally, a small subset of NKp46(+) HLA-G(+) IL-10(+) is detected within freshly isolated decidual NK cells, suggesting that these cells could represent an in vivo counterpart of the NK-ireg cells. CONCLUSIONS/SIGNIFICANCE: In conclusion, NK-ireg cells represent a novel truly differentiated non-cytolytic NK subset with a self-sustainable phenotype (CD56(+) CD16(+) NKp30(+) NKp44(+) NKp46(+) CD94(+) CD69(+) CCR7(+)) generated from specific pSTAT6(+) GATA3(+) precursors. NK-ireg cells could be employed to develop new immuno-suppressive strategies in autoimmune diseases, transplant rejection or graft versus host diseases. In addition, NK-ireg cells can be easily derived from peripheral blood of the patients and could constitute an autologous biotherapic tool to be used combined or in alternative to other immuno-regulatory cells

Ethanol-Mediated Regulation of Cytochrome P450 2A6 Expression in Monocytes: Role of Oxidative Stress-Mediated PKC/MEK/Nrf2 Pathway

Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer. Recently, we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species (ROS) in U937 monocytes. However, the mechanism by which CYP2A6 is induced by ethanol is unknown. In this study, we have examined the role of the PKC/Nrf2 pathway (protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus) in ethanol-mediated CYP2A6 induction. Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein (∼150%) and increased ROS formation, and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor (diallyl sulfide) or an antioxidant (vitamin C). The results suggest the role of oxidative stress in the regulation of CYP2A6 expression. Subsequently, we investigated the role of Nrf2 pathway in oxidative stress-mediated regulation of CYP2A6 expression in U937 monocytes. Our results showed that butylated hydroxyanisole, a stabilizer of nuclear Nrf2, increased CYP2A6 levels >200%. Staurosporine, an inhibitor of PKC, completely abolished ethanol-induced CYP2A6 expression. Furthermore, our results showed that a specific inhibitor of mitogen-activated protein kinase kinase (MEK) (U0126) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation. Overall, these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway, resulting in the induction of CYP2A6 in monocytes. An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism. Thus, this study has clinical relevance because of the high incidence of alcohol use among smokers, especially in HIV-infected individuals