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.

Directional dominance on stature and cognition in diverse human populations

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Covalent tethering of the dimer interface annuls aggregation in thymidylate synthase

Thymidylate synthase (TS), a dimeric enzyme, forms large soluble aggregates at concentrations of urea (3.3-5 M), well below that required for complete denaturation, as established by fluorescence and size-exclusion chromatography. In contrast to the wild-type enzyme, an engineered mutant of TS (T155C/E188C/C244T), TSMox, in which two subunits are crosslinked by disulfide bridges between residues 155-188' and 188-155', does not show this behavior. Aggregation behavior is restored upon disulfide bond reduction in the mutant protein, indicating the involvement of interface segments in forming soluble associated species. Intermolecular disulfide crosslinking has been used as a probe to investigate the formation of larger non-native aggregates. The studies argue for the formation of large multimeric species via a sticky patch of polypeptide from the dimer interface region that becomes exposed on partial unfolding. Covalent reinforcement of relatively fragile protein-protein interfaces may be a useful strategy in minimizing aggregation of non-native structures in multimeric proteins.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Crystallographic characterization of the conformation of the 1-aminocyclohexane-1-carboxylic acid residue in simple derivatives and peptides

The crystal structures of 1-aminocyclohexane-1-carboxylic acid (H-Acc6-OH) and six derivatives (including dipeptides) have been determined. The derivatives are Boc-Acc6-OH, Boc-(Acc6)2-OH, Boc-L-Met-Acc6-OMe, ClCH2CO-Acc6-OH, p-BrC6H4CO-Acc6-OH oxazolone, and the symmetrical anhydride from Z-Acc6-OH, [(Z-Acc6)2O]. The cyclohexane rings in all the structures adopt an almost perfect chair conformation. The amino group occupies the axial position in six structures; the free amino acid is the only example where the carbonyl group occupies an axial position. The values determined for the torsion angles about the N–Cα(φ) and Cα–CO (ψ) bonds correspond to folded, potentially helical conformations for the Acc6 residue.

b-Turn conformations in crystal structures of model peptides containing a,a-di-n-propylglycine (Dpg) and a,a-di-n-butyl-glycine (Dbg).

The crystal state conformations of three peptides containing the a,a-dialkylated residues, a,adi n-propylglycine (Dpg) and a,@-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Ala-OMe ( I ) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II @-turn conformations with Ala ( I ) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: 4 = 66.23 J/ = 19.3'; III: 4 = 66S0, J. = 21 .la)deviate appreciablyfrom ideal values for the i + 2 residue in a type II @-turn. In both peptides the observed(N. 0) distances between the Boc CO andAla(3) NHgroups are far too long (I:3.44 k; III: 3.63 k) for an intramolecular 4 + 1 hydrogen bond. Boc-Ala-Dpg-Ala-NHMe (II)crystallizes with two independent molecules in the asymmetric unit. Both molecules IIA and IIB adopt consecutive @-turn (type III-III in IIA and type III-I in IIB) or incipient 3,,,-helical structures, stabilized by two intramolecular 4 --t I hydrogen bonds. In all four molecules the bond angle N-C"-C' ( T ) at the Dxg residues are 2 1109 The observation of conformational angles in the helical region of 4,J/ space at these residues is consistent with theoretical predictions

Effect of amino acid substitutions at the subunit interface on the stabiity and aggregation properties of a dimeric protein: role of Arg 178 and Arg 218 at the dimer interface of thymidylate synthase

The significance of two interface arginine residues on the structural integrity of an obligatory dimeric enzyme thymidylate synthase (TS) from Lactobacillus casei was investigated by thermal and chemical denaturation. While the R178F mutant showed apparent stability to thermal denaturation by its decreased tendency to aggregate, the Tm of the R218K mutant was lowered by 5 degrees C. Equilibrium denaturation studies in guanidinium chloride (GdmCl) and urea indicate that in both the mutants, replacement of Arg residues results in more labile quaternary and tertiary interactions. Circular dichroism studies in aqueous buffer suggest that the protein interior in R218K may be less well-packed as compared to the wild type protein. The results emphasize that quaternary interactions may influence the stability of the tertiary fold of TS. The amino acid replacements also lead to notable alteration in the ability of the unfolding intermediate of TS to aggregate. The aggregated state of partially unfolded intermediate in the R178F mutant is stable over a narrower range of denaturant concentrations. In contrast, there is an exaggerated tendency on the part of R218K to aggregate in intermediate concentrations of the denaturant. The 3 A crystal structure of the R178F mutant reveals no major structural change as a consequence of amino acid substitution. The results may be rationalized in terms of mutational effects on both the folded and unfolded state of the protein. Site specific amino acid substitutions are useful in identifying specific regions of TS involved in association of non-native protein structures.

Modelling multiple disulphide loop containing polypeptides by random conformation generation. The test cases of α-conotoxin GI and edothelin I

A general procedure for arriving at 3-D models of disulphiderich olypeptide systems based on the covalent cross-link constraints has been developed. The procedure, which has been coded as a computer program, RANMOD, assigns a large number of random, permitted backbone conformations to the polypeptide and identifies stereochemically acceptable structures as plausible models based on strainless disulphide bridge modelling. Disulphide bond modelling is performed using the procedure MODIP developed earlier, in connection with the choice of suitable sites where disulphide bonds could be engineered in proteins (Sowdhamini,R., Srinivasan,N., Shoichet,B., Santi,D.V., Ramakrishnan,C. and Balaram,P. (1989) Protein Engng, 3, 95-103). The method RANMOD has been tested on small disulphide loops and the structures compared against preferred backbone conformations derived from an analysis of putative disulphide subdatabase and model calculations. RANMOD has been applied to disulphiderich peptides and found to give rise to several stereochemically acceptable structures. The results obtained on the modelling of two test cases, a-conotoxin GI and endothelin I, are presented. Available NMR data suggest that such small systems exhibit conformational heterogeneity in solution. Hence, this approach for obtaining several distinct models is particularly attractive for the study of conformational excursions.

Influence of ethanol/water mixture on the undrained shear strength of pure clays

The mechanical properties of clays are highly dependent not only on the stress/strain ratio to which the material is subjected but also on the chemistry of the pore fluids which in turn affects the intergranular or the effective stresses. Atterberg limits and vane shear tests were performed with different pore fluids in order to observe how the fine-grained material mechanically responded. The diffuse double layer theory has been used to interpret the data of vane shear tests in order to explain the variation of geotechnical responses with the different clays. Van der Waals forces and double layer forces were obtained and capillary forces calculated. The results show that while for kaolinite and illite the chemistry of the pore fluids has no influence on the water content and hence on the mechanical behaviour of the material, Na-smectite shows a strong correlation between the dielectric constant of the pore fluids and an increase in undrained shear strength. The data obtained extends an understanding of the influence of the dielectric constant (epsilon) of the pore fluids on the geotechnical properties of fine-grained materials.

Hemoparásitos en bovinos de engorde en las fincas Cañas Gordas y Las Alturas, comarca San Agustín, Acoyapa, Chontales, en los meses de agosto - octubre 2012

Con el objetivo de determinar la prevalencia de hemoparásitos en bovinos de engorde y su efecto sobre la productividad de los animales; se identificó la presencia de ectoparásitos vectores y se analizaron los factores agroecológicos que permiten la presencia de estas parasitosis en Las fincas Cañas Gordas y Las Alturas ubicadas en la comarca San Agustín, municipio de Acoyapa, departamento de Chontales; Cañas Gordas con las coordenadas geográficas latitud norte 11° 52´ 60” y longitud oeste 85°24´0”, con una elevación de 36 msnm y Las Alturas con las coordenadas geográficas latitud norte 11° 58´ 03.41”, longitud oeste 85°21´47.47” y con una elevación de 136 msnm, comprendidas en una zona subtropical de montaña, ambas fincas con una humedad relativa del 76%, precipitación promedio anual de 1 134,1 mm y una temperatura anual promedio 27. 2 °C. Para realizar el estudio se tomó un lote de 150 animales por cada finca en un rango de peso de 280 a 320 kg muestreando el 10% de la población total, tomando 15 animales por finca, para un total de 30 exámenes, efectuando 4 muestreos con intervalos de 21 días entre los meses de agosto, septiembre y octubre. La toma de muestra se realizó mediante venopunción de la yugular, trasladándose estas al laboratorio de Parasitología (FACA – UNA) se procedió a realizar 2 frotis sanguíneos por cada muestra utilizando el método de tinción coloración Giemsa, para la posterior observación de los hemoparásitos. Obteniendo tres especies de hemoparásitos Babesia, Anaplasma y Tripanosoma, Se determinó que en la finca Cañas Gordas la prevalencia de Babesia es de 53%, en Las Alturas es del 73%; en ambas fincas la prevalencia de Anaplasma es de 93%; de Tripanosoma es del 27% únicamente en Cañas Gordas, este último debido a la presencia del lago Cocibolca en las inmediaciones de la finca que permite un ambiente húmedo favorable para una mayor presencia del hospedero intermediario (Tábanus). Las pérdidas económicas anuales ocasionadas por la presencia de hemoparásitos en Las Alturas fué de C$ 139,243.50 en un lote de 150 animales; en Cañas Gordas fué de C$ 234,837.00. Para realizar un control eficaz de los hemoparásitos se debe contar con un plan de control de ectoparásitos, efectuar exámenes complementarios periódicamente para determinar la especie de hemoparásitos y así aplicar un tratamiento específico, además de mantener un plan de vigilancia permanente.

La práctica política en la Roma antigua, especificidad y debates

En esta intervención, desarrollaré algunas consideraciones sobre la política en el mundo romano antiguo y el reciente debate acerca de ella. Me refiero a la política como práctica; entendiendo por esto lo que sea funcional a los mecanismos de la vida pública, a la formación del consenso, al ejercicio del poder, al cursus honorum en sus varios niveles, a los procesos decisorios y a la determinación de los rumbos del gobierno.

Letras, 2007, nº 55-56 (número completo)

Contenido: La naissance du roman moderne / Pierre Brunel – Tras las huellas de María Teresa Maiorana y Rubén Darío / Martha V. de Burbridge – Ver en la oscuridad. Poéticas de la ceguera según Rimbaud y Borges / Magdalena Cámpora – Giovanni Papini, un escritor olvidado / Daniel Capano – Recreación del laberinto kafkiano en “El Proceso”, de Orson Welles / Adriana Cid – Amistades paralelas: Miguel Cané-Martín García Mérou/Jorge Luis Borges-Adolfo Bioy Casares / Jorge Cruz – Crítica literaria y literatura comparada. Entre selectores y comediantes / Biagio D’Angelo – Lucía Miranda: un mito de origen protonacional en varias lenguas: castellano, latín, francés e inglés / María Rosa Lojo – Don Juan diabólico y periodización literaria / José Manuel Losada – Reseñas bibliográficas

La dimensione salvifica e pastorale del diritto canonico

Introducción: Il diritto canonico – autentica ed originale realtà della Chiesa, che affonda le sue radici nel medesimo mistero della chiesa come comunità divino-umana1 –, è uno strumento che aiuta l’uomo nel raggiungimento dello scopo finale, che è la salvezza. Poiché questo diritto è esercitato nella Chiesa, il suo scopo è quello di costruire una comunità, e dunque dovrebbe tendere a realizzare una vita comunitaria ecclesiale. Papa Paolo VI, tra gli altri, ha voluto vedere, nella realizzazione della comunità, lo scopo del diritto canonico, nonché il criterio normativo di tutta la legislazione ecclesiastica. Anche Pio XII e Giovanni Paolo II hanno indicato tale direzione riguardo al compito di realizzare lo scopo della Chiesa attraverso il diritto canonico

Evaluación de variables dasométricas de rebrotes en Eucalyptus camaldulensis DEHNH, en la finca El Plantel, Nindirí, Masaya

El estudio de evaluación de la capacidad de rebrote de Eucaliptus camaldulensis Dehnh, tuvo como objetivo evaluar el comportamiento de los rebrotes en plantaciones a través de la aplicación de tratamiento silviculturales de poda en áreas que han sido aprovechadas. La metodología consistió en establecer un recorrido de campo en la plantación de eucalipto en la unidad experimental finca El Plantel, con el propósito de seleccionar áreas para el establecimiento de parcelas en áreas que habían sido aprovechadas anteriormente. Una vez seleccionadas las parcelas se procedió a la selección de los rebrotes, de los cuales se dejaron los más vigorosos y que tuviesen un fuste recto, se seleccionaron los tres mejores ejes de los tocones. La toma de datos en el campo se realizó evaluando las siguientes variables: altura del tocón mayor de 20 cm, altura del tocón menor de 20 cm, diámetro del tocón de 15 cm, y diámetro del tocón entre 15 a 20 cm. Los tratamientos silviculturales tuvieron influencia en el incremento del crecimiento en diámetro y altura en los rebrotes, la limpieza de la maleza, eliminación de lianas y raleo de rebrotes, favoreciéndolos al no existir competencia para los rebrotes seleccionados. De acuerdo al análisis estadístico t-Studen la variable tocón menor de 20 cm de altura, es la mejor variable para la realización de futuro manejo de rebrotes. La sobrevivencia en las parcelas establecidas independientemente de las cuatro variables que se aplicaron, es buena según la clasificación utilizada en el experimento. Se recomienda seguir aplicando tratamientos silviculturales para un mejor rendimiento en el crecimiento tanto en diámetro y altura de los rebrotes.