Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Active site labeling of cysteine cathepsins by a straightforward diazomethylketone probe derived from the N-terminus of human cystatin C

We designed a straightforward biotinylated probe using the N-terminal substrate-like region of the inhibitory site of human cystatin C as a scaffold, linked to the thiol-specific reagent diazomethylketone group as a covalent warhead (i.e. Biot-(PEG)2-Ahx-LeuValGly-DMK). The irreversible activity-based probe bound readily to cysteine cathepsins B, L, S and K. Moreover affinity labeling is sensitive since active cathepsins were detected in the nM range using an ExtrAvidin®-peroxidase conjugate for disclosure. Biot-(PEG)2-Ahx-LeuValGly-DMK allowed a slightly more pronounced labeling for cathepsin S with a compelling second-order rate constant for association (kass = 2,320,000 M−1 s−1). Labeling of the active site is dose-dependent as observed using 6-cyclohexylamine-4-piperazinyl-1,3,5-triazine-2-carbonitrile, as competitive inhibitor of cathepsins. Finally we showed that Biot-(PEG)2-Ahx-LeuValGly-DMK may be a simple and convenient tool to label secreted and intracellular active cathepsins using a myelomonocytic cell line (THP-1 cells) as model.

Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma

Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10-2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A-T haplotype from rs963248-rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only one control (P = 0.015). This SNP is located in the 3'-UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.

Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke

Neurons are continuously generated from stem cells in discrete regions in the adult mammalian brain. We found that ependymal cells lining the lateral ventricles were quiescent and did not contribute to adult neurogenesis under normal conditions in mice but instead gave rise to neuroblasts and astrocytes in response to stroke. Ependymal cell quiescence was actively maintained by canonical Notch signaling. Inhibition of this pathway in uninjured animals allowed ependymal cells to enter the cell cycle and produce olfactory bulb neurons, whereas forced Notch signaling was sufficient to block the ependymal cell response to stroke. Ependymal cells were depleted by stroke and failed to self-renew sufficiently to maintain their own population. Thus, although ependymal cells act as primary cells in the neural lineage to produce neurons and glial cells after stroke, they do not fulfill defining criteria for stem cells under these conditions and instead serve as a reservoir that is recruited by injury.

Methylene Blue-Loaded Dissolving Microneedles: Potential Use in Photodynamic Antimicrobial Chemotherapy of Infected Wounds

Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed "photodynamic antimicrobial chemotherapy" (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez(®) AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1-2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for S. aureus and >99% for E. coli and C. albicans with the combination of PACT and methylene blue concentrations between 0.1 and 2.5 mg/mL. A reduction in the colony count was also observed when incorporating the photosensitiser without irradiation, this reduction was more notable in S. aureus and E. coli strains than in C. albicans.

Atmospheric cold plasma process for vegetable leaf decontamination: A feasibility study on radicchio (red chicory, Cichorium intybus L.)

Cold plasma is an emerging non-thermal processing technology that could be used for large scale leaf decontamination as an alternative to chlorine washing. In this study the effect of an atmospheric cold plasma apparatus (air DBD, 15 kV) on the safety, antioxidant activity and quality of radicchio (red chicory, Cichorium intybus L.) was investigated after 15 and 30 min of treatment (in afterglow at 70 mm from the discharge, at 22 °C and 60% of RH) and during storage. Escherichia coli O157:H7 inoculated on radicchio leaves was significantly reduced after 15 min cold plasma treatment (-1.35 log MPN/cm²). However, a 30 min plasma treatment was necessary to achieve a significant reduction of Listeria monocytogenes counts (-2.2 log CFU/cm²). Immediately after cold plasma treatment, no significant effects emerged in terms of antioxidant activity assessed by the ABTS and ORAC assay and external appearance of the radicchio leaves. Significant changes between treated and untreated radicchio leaves are quality defects based on the cold plasma treatment. Atmospheric cold plasma appears to be a promising processing technology for the decontamination of leafy vegetables although some criticalities, that emerged during storage, need to be considered in future studies.

Pet population management and public health:A web service based tool for the improvement of dog traceability

The risks associated with zoonotic infections transmitted by companion animals are a serious public health concern: the control of zoonoses incidence in domestic dogs, both owned and stray, is hence important to protect human health. Integrated dog population management (DPM) programs, based on the availability of information systems providing reliable data on the structure and composition of the existing dog population in a given area, are fundamental for making realistic plans for any disease surveillance and action system. Traceability systems, based on the compulsory electronic identification of dogs and their registration in a computerised database, are one of the most effective ways to ensure the usefulness of DPM programs. Even if this approach provides many advantages, several areas of improvement have emerged in countries where it has been applied. In Italy, every region hosts its own dog register but these are not compatible with one another. This paper shows the advantages of a web-based-application to improve data management of dog regional registers. The approach used for building this system was inspired by farm animal traceability schemes and it relies on a network of services that allows multi-channel access by different devices and data exchange via the web with other existing applications, without changing the pre-existing platforms. Today the system manages a database for over 300,000 dogs registered in three different Italian regions. By integrating multiple Web Services, this approach could be the solution to gather data at national and international levels at reasonable cost and creating a traceability system on a large scale and across borders that can be used for disease surveillance and development of population management plans. © 2012 Elsevier B.V.

The OpenPMU Project: Challenges and perspectives:Challenges and Perspectives

The OpenPMU project is a platform for the development of Synchrophasor measurement technology, Phasor Measurement Units (PMU), in an open source manner. The project has now been operating for a number of years and has seen increased adoption at Universities and interest from electrical utilities. The OpenPMU device has recently been tested against the IEEE C37.118 standard and shown to operate within the specification. This paper discusses the OpenPMU project from the perspective of the past two years of experience and evaluates successes and opportunities for improvements in both the OpenPMU device and the philosophy of the design.

Design para o futuro: o indivíduo entre o artifício e a natureza

O presente trabalho tem como objectivo contribuir para o aprofundamento de estudos vocacionados para a evolução do mundo material enquanto factor determinante para o futuro do Planeta, do Homem e dos seus artifícios. Sendo o tema central da investigação o Design Industrial enquanto mediador incontornável dessa relação, os conceitos de Design Biónico, de Design Natural, de Biodesign e de Design Simbiótico, assim como as metodologias a si inerentes, assumem-se como protagonistas do estudo desenvolvido. A tese é composta por um primeiro capítulo introdutório onde se define o seu objecto de estudo e se apresentam as linhas condutoras da investigação. O segundo capítulo é dedicado ao enquadramento teórico dos temas a abordar, nomeadamente o conceito de “artifício” considerando os seus tradicionais e novos significados e aplicações e a História do Design Industrial numa perspectiva que considera a evolução da indústria e da disciplina nesse contexto. No terceiro capítulo desenvolve-se a análise das propostas conceptuais e metodológicas dos designers Victor Papanek, Luigi Colani e Paulo Parra, por recurso específico, respectivamente, aos pressupostos inscritos em Design Biónico, Design Natural, Biodesign e Design Simbiótico, perseguindo-se como objectivo a sua sistematização em conteúdos passíveis de contribuírem para novas investigações/aplicações, nomeadamente no âmbito daquilo que a autora designa como Inovação Tecnológica na Concepção e EcoBio-Inovação.

O Léxico do crioulo guineense e as suas relações com o português: ensino bilingue português-crioulo guineense

Tese apresentada para cumprimento dos requisitos necessários á obtenção do grau de Doutor em Linguística, especialidade de Lexicologia, Lexicografia e Terminologia

[Lettre autographe signée d'Henri Montan Berton aux Académiciens, Paris, 17 mars 1838]

Communication à l'Académie : "proposition tendant à améliorer le sort des élèves musiciens à leur retour de Rome dans la capitale". - Signé : Berton, Halévy, Paer, Meyerbeer, Carafa, Cherubini

御覽西方要紀Yu lan xi fang yao ji.Mémoire sur l'Occident présenté à l'Empereur.

Cat. imp., liv. 78, f. 22.Daté de 1669, avec un rapport (1668) des PP. Luigi Buglio, Gabriel de Magalhães et Ferdinand Verbiest.

獅子說Shi zi shuo.Du lion.

Avec une figure. Par le P. Luigi Buglio (1606-1682), à propos d'un lion offert à la cour de Chine (1678). Préface de l'auteur.