Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low‐frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants1,2,3,4,5,6,7,8, as well as rare, population‐specific, coding variants9. Here we identify novel non‐coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole‐genome sequencing (n = 2,882 from UK10K (ref. 10); a population‐based genome sequencing consortium), whole‐exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low‐frequency non‐coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10−14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low‐frequency non‐coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non‐coding variants. These findings provide evidence that low‐frequency non‐coding variants have large effects on BMD and fracture, thereby providing rationale for whole‐genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population

Interacting with molecular models in virtual reality

Molecular visualization software is an upcoming and growing sector than it's tracing its path thanks to the incoming technologies. Not only allows to compute time-consuming CPU and GPU programs and renders in lesser time, but also introduces more complex and complete visualization methods that allo

Effectiveness of social marketing strategies to reduce youth obesity in European school-based interventions : a systematic review and meta-analysis

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Design strategies for positively charged endolysins : Insights into Artilysin development

Altres ajuts: acords transformatius de la UABEndolysins are bacteriophage-encoded enzymes that can specifically degrade the peptidoglycan layer of bacterial cell wall, making them an attractive tool for the development of novel antibacterial agents. The use of genetic engineering techniques for the production and modification of endolysins offers the opportunity to customize their properties and activity against specific bacterial targets, paving the way for the development of personalized therapies for bacterial infections. Gram-negative bacteria possess an outer membrane that can hinder the action of recombinantly produced endolysins. However, certain endolysins are capable of crossing the outer membrane by virtue of segments that share properties resembling those of cationic peptides. These regions increase the affinity of the endolysin towards the bacterial surface and assist in the permeabilization of the membrane. In order to improve the bactericidal effectiveness of endolysins, approaches have been implemented to increase their net charge, including the development of Artilysins containing positively charged amino acids at one end. At present, there are no specific guidelines outlining the steps for implementing these modifications. There is an ongoing debate surrounding the optimal location of positive charge, the need for a linker region, and the specific amino acid composition of peptides for modifying endolysins. The aim of this study is to provide clarity on these topics by analyzing and comparing the most effective modifications found in previous literature

Correspondencias léxicas entre aragonés, catalán y occitano. Algunas relaciones en el mundo vegetal a la luz de las fuentes bibliográficas

Términos propios, préstamos o influencias léxicas de variada índole forman parte del acervo cultural de cada territorio. Esa riqueza patrimonial participa de un fondo lexical común que se ha ido configurando a lo largo de los siglos y en el que se observan evidentes similitudes entre las lenguas, en particular si estas comparten geografía y vínculos históricos. En esta tesis doctoral nos ocupamos precisamente de las afinidades entre las lenguas románicas que se extienden de oeste a este y de norte a sur a lo largo de los Pirineos, cuyos valles aragoneses, catalanes y occitanos presentan un número destacado de paralelismos que han perdurado hasta época reciente y que dan idea del contacto secular de sus respectivos dominios. Claro que, tales paralelismos trascienden las zonas de contacto directo y se distribuyen por cada uno de sus sistemas dialectales, entre los que a lo largo del tiempo se han establecido nuevas zonas de intercambio. De ahí que la ambición de este trabajo no es solo la de señalar las correspondencias entre el léxico pirenaico, sino que abarca un espacio lingüístico que va más allá de su reserva en los valles, siendo el heredero de unos sistemas desarrollados en época medieval.El objetivo principal de esta investigación ha sido el de dar a conocer un buen número de concomitancias léxicas entre aragonés, catalán y occitano dentro del mundo vegetal. La elección de este campo léxico se debe a que en la nomenclatura vulgar de las plantas todavía encuentran refugio formas vernáculas que han sobrevivido a la presión de las lenguas comunes de los Estados. Por no hablar de que muchas denominaciones encierran una manera concreta de relacionarse con el entorno, aportando conocimiento sobre la idiosincrasia cultural de los territorios. Para cumplir con dicho objetivo hemos analizado con detalle la información contenida en una nutrida lista de fuentes bibliográficas (atlas lingüísticos, diccionarios, monografías, repertorios botánicos…), permitiéndonos así situar sobre la geografía bajo estudio los distintos resultados y comprobar los vínculos entre lenguas y dialectos. Esta fase de comparación y contraste ha sido útil también para indagar en la etimología de las diversas tipologías léxicas encontradas, especialmente en los casos en los que su origen no está del todo aclarado. Finalmente, como conclusión podemos afirmar, por un lado, que gracias a nuestra investigación se han constatado lazos léxicos entre los tres dominios más allá de los que se esperaría obtener teniendo en cuenta su inclusión en diferentes diasistemas; por otro, que es posible cuestionar la adscripción de determinada terminología a un dominio concreto, al fin y al cabo cada denominación cuenta con unos límites particulares difíciles de catalogar.<br /

Design and synthesis of FAJANU: A de novo C2 symmetric cyclopeptide family

A novel cyclic peptide has been designed from several potent marine cytotoxic peptides, including IB-01212, luzopeptin, triostin, and thiocoraline. The FAJANU scaffold maintains C2 symmetry, cyclic structure, and the construction of aromatic and aliphatic character at the N- and C-terminal extremes. A first six-member family was previously synthesized and evaluated biologically. Several analogues presented greater activity than IB-01212. Furthermore, on the basis of the most active candidate, we have performed a more exhaustive synthetic and structural analysis: (i) structure - activity relationship provided clues about the key elements in the framework, (ii) NMR assignment confirmed C2 symmetry, and (iii) confocal images revealed its penetration and cellular localization. © 2008 American Chemical Society

A Youth-Led, Social Marketing Intervention Run by Adolescents to Encourage Healthy Lifestyles among Younger School Peers (EYTO-Kids Project) : A Protocol for Pilot Cluster Randomized Controlled Trial (Spain)

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Randomized phase II clinical trial of chemo-immunotherapy in advanced nonsmall cell lung cancer

The purpose of this study was to compare chemotherapy-naive patients with stage IV nonsmall cell lung cancer patients treated with chemotherapy or chemoimmunotherapy. We tested doxetacel plus cisplatinum as chemotherapy protocol. An immunomodulatory adjuvant system was added as chemoimmunotherapy to the previously mentioned protocol. This system contains three well-known and complementary conditioners of protective immune-responses: cyclophosphamide low-dose, granulocyte macrophage-colony stimulant factor and magnesium silicate granuloma. Eighty-eight patients were randomly assigned to receive every 3-weeks one of the treatments under comparison. Patients received four cycles of treatment unless disease progression or unacceptable toxicity was documented. The maximum follow-up was one year. In each arm, tumor response (rate,duration), median survival time, 1-year overall survival, safety, and immunity modifications were assessed. Immunity was evaluated by submitting peripheral blood mononuclear cells to laboratory tests for nonspecific immunity: a) phytohemaglutinin-induced lymphocyte proliferation, b) prevalence of T-Regulatory (CD4+CD25+) cells and for specific immunity: a) lymphocyte proliferation induced by tumor-associated antigens (TAA) contained in a previously described autologous thermostable hemoderivative. The difference (chemotherapy vs. chemoimmunotherapy) in response rate induced by the two treatments (39.0% and 35.0%) was not statistically significant. However, the response duration (22 and 31 weeks), the median survival time (32 and 44 weeks) and 1-year survival (33.3% and 39.1%) were statistically higher with chemoimmunotherapy. No difference in toxicity between both arms was demonstrated. A switch in the laboratory immunity profile, nonspecific and specific, was associated with the chemoimmunotherapy treatment: increase of proliferative lymphocyte response, decrease of tolerogenic T-regulatory cells and eliciting TAA-sensitization