BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery.

Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS models to place BLOC-2 within a cargo transport pathway from recycling endosomal domains to maturing melanosomes. In BLOC-2-deficient melanocytes, the melanosomal protein TYRP1 was largely depleted from pigment granules and underwent accelerated recycling from endosomes to the plasma membrane and to the Golgi. By live-cell imaging, recycling endosomal tubules of wild-type melanocytes made frequent and prolonged contacts with maturing melanosomes; in contrast, tubules from BLOC-2-deficient cells were shorter in length and made fewer, more transient contacts with melanosomes. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Large Scale Structure of the Universe

Galaxies are not uniformly distributed in space. On large scales the Universe displays coherent structure, with galaxies residing in groups and clusters on scales of ~1-3 Mpc/h, which lie at the intersections of long filaments of galaxies that are >10 Mpc/h in length. Vast regions of relatively empty space, known as voids, contain very few galaxies and span the volume in between these structures. This observed large scale structure depends both on cosmological parameters and on the formation and evolution of galaxies. Using the two-point correlation function, one can trace the dependence of large scale structure on galaxy properties such as luminosity, color, stellar mass, and track its evolution with redshift. Comparison of the observed galaxy clustering signatures with dark matter simulations allows one to model and understand the clustering of galaxies and their formation and evolution within their parent dark matter halos. Clustering measurements can determine the parent dark matter halo mass of a given galaxy population, connect observed galaxy populations at different epochs, and constrain cosmological parameters and galaxy evolution models. This chapter describes the methods used to measure the two-point correlation function in both redshift and real space, presents the current results of how the clustering amplitude depends on various galaxy properties, and discusses quantitative measurements of the structures of voids and filaments. The interpretation of these results with current theoretical models is also presented.Comment: Invited contribution to be published in Vol. 8 of book "Planets, Stars, and Stellar Systems", Springer, series editor T. D. Oswalt, volume editor W. C. Keel, v2 includes additional references, updated to match published versio

A new matrix-free algorithm for the large-scale trust-region subproblem

We present a new method for the large-scale trust-region subproblem. The method is matrix-free in the sense that only matrix-vector products are required. We recast the trust-region subproblem as a parameterized eigenvalue problem and compute an optimal value for the parameter. We then nd the solution of the trust-region subproblem from the eigenvectors associated with two of the smallest eigenvalues of the parameterized eigenvalue problem corresponding to the optimal parameter. The new algorithm uses a different interpolating scheme than existing methods and introduces a uni ed iteration that naturally includes the so-called hard case. We show that the new iteration is well defined and convergent at a superlinear rate. We present computational results to illustrate convergence properties and robustness of the method.11361164

Resistencia de unión de cerámica feldespática a esmalte bovino empleando diferentes cementos resinosos

OBJETIVO: Comparar la resistencia de unión de cerámica feldespática al esmalte bovino entre las diferentes marcas de cementos resinosos autoadhesivos y un cemento resinoso dual universal.MATERIALES Y MÉTODOS: Se utilizaron ocho incisivos inferiores sanos de bovino divididos en cuatro grupos. Al grupo del cemento resinoso dual se le realizó un tratamiento previo de ácido ortofosfórico al 37% y adhesivo Single Bond Universal y a los 3 grupos de cementos resinosos autoadhesivos se les realizó un tratamiento previo sólo con ácido ortofosfórico al 37% sobre el esmalte dentario. Grupo I: ICem (Heraus Kulzer), Grupo II: Panavia Cement Automix (Kuraray), Grupo III: Relyx Ultimate (3M-ESPE), GC: Maxcem Elite (Kerr). Los especímenes obtenidos (n=30 por grupo) se obtuvieron con una máquina tipo Isomet y se almacenaron en agua destilada por 24 horas a 37° C. La prueba de microtensión se realizó haciendo uso del Microtensile Tester (Bisco). Para el análisis estadístico se utilizaron las pruebas de Anova y Tukey (p=0.05).RESULTADOS: Los valores promedio de resistencia en los grupos experimentales fueron GI: ICem, 17.4 ± 4.94; GII: Panavia Automix, 17.5± 5.65; GIII: Relyx Ultimate, 17.2 ± 5.06 y en el Grupo Control: Maxcem fue 17.8 ± 4.48. No hubo diferencias estadísticamente significativas (p=0.974 - Prueba de Anova). Cuando se compararon los valores entre grupos, tampoco hubo diferencias (p>0.05).CONCLUSIONES: La resistencia de unión de los cementos resinosos autoadhesivos y el cemento resinoso dual universal es similar

Discourses of conflict and collaboration and institutional context in the implementation of forest conservation policies in Soria, Spain

This article examines the emergence of conflict and collaboration in the implementation of forest conservation policies in Soria, Spain. We draw insights from discursive institutionalism and use a comparative case study approach to analyse and compare a situation of social conflict over the Natural Park declaration in the Sierra de Urbión, and a civil society led collaborative process to develop management plans for the “Sierra de Cabrejas” in Soria. The implementation of the EU Habitats Directive generated different outcomes in these two cases, which unfolded in the context of the same nature conservation legislation and national and provincial administrative structures but differed in terms of types of forests involved, property rights arrangements and forest use histories. We critically examine the influence of the institutional context and dominant discourses on the emergence of outcomes: conflict emerged where local institutions and discourses were threatened by the EU directive, while collaboration was possible where local institutions and counter-discourses were weak. We find that the institutional context plays an important part in determining local discourses in the implementation of forest conservation policies. Yet local counter-discourses have limited influence in the implementation and policy processes in the face of contestation by the discourses of regional civil servants conservation activists

Alcohol, binge drinking and associated mental health problems in young urban Chileans

OBJECTIVE: To explore the link between alcohol use, binge drinking and mental health problems in a representative sample of adolescent and young adult Chileans. METHODS: Age and sex-adjusted Odds Ratios (OR) for four mental wellbeing measures were estimated with separate conditional logistic regression models for adolescents aged 15-20 years, and young adults aged 21-25 years, using population-based estimates of alcohol use prevalence rates from the Chilean National Health Survey 2010. RESULTS: Sixty five per cent of adolescents and 85% of young adults reported drinking alcohol in the last year and of those 83% per cent of adolescents and 86% of young adults reported binge drinking in the previous month. Adolescents who reported binging alcohol were also more likely, compared to young adults, to report being always or almost always depressed (OR 12.97 [95% CI, 1.86-19.54]) or to feel very anxious in the last month (OR 9.37 [1.77-19.54]). Adolescent females were more likely to report poor life satisfaction in the previous year than adolescent males (OR 8.50 [1.61-15.78]), feel always or almost always depressed (OR 3.41 [1.25-9.58]). Being female was also associated with a self-reported diagnosis of depression for both age groups (adolescents, OR 4.74 [1.49-15.08] and young adults, OR 4.08 [1.65-10.05]). CONCLUSION: Young people in Chile self-report a high prevalence of alcohol use, binge drinking and associated mental health problems. The harms associated with alcohol consumption need to be highlighted through evidence-based prevention programs. Health and education systems need to be strengthened to screen and support young people. Focussing on policy initiatives to limit beverage companies targeting alcohol to young people will also be needed

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Comparison of machine learning and semi-quantification algorithms for (I123)FP-CIT classification: the beginning of the end for semi-quantification?

Background Semi-quantification methods are well established in the clinic for assisted reporting of (I123) Ioflupane images. Arguably, these are limited diagnostic tools. Recent research has demonstrated the potential for improved classification performance offered by machine learning algorithms. A direct comparison between methods is required to establish whether a move towards widespread clinical adoption of machine learning algorithms is justified. This study compared three machine learning algorithms with that of a range of semi-quantification methods, using the Parkinson’s Progression Markers Initiative (PPMI) research database and a locally derived clinical database for validation. Machine learning algorithms were based on support vector machine classifiers with three different sets of features: Voxel intensities Principal components of image voxel intensities Striatal binding radios from the putamen and caudate. Semi-quantification methods were based on striatal binding ratios (SBRs) from both putamina, with and without consideration of the caudates. Normal limits for the SBRs were defined through four different methods: Minimum of age-matched controls Mean minus 1/1.5/2 standard deviations from age-matched controls Linear regression of normal patient data against age (minus 1/1.5/2 standard errors) Selection of the optimum operating point on the receiver operator characteristic curve from normal and abnormal training data Each machine learning and semi-quantification technique was evaluated with stratified, nested 10-fold cross-validation, repeated 10 times. Results The mean accuracy of the semi-quantitative methods for classification of local data into Parkinsonian and non-Parkinsonian groups varied from 0.78 to 0.87, contrasting with 0.89 to 0.95 for classifying PPMI data into healthy controls and Parkinson’s disease groups. The machine learning algorithms gave mean accuracies between 0.88 to 0.92 and 0.95 to 0.97 for local and PPMI data respectively. Conclusions Classification performance was lower for the local database than the research database for both semi-quantitative and machine learning algorithms. However, for both databases, the machine learning methods generated equal or higher mean accuracies (with lower variance) than any of the semi-quantification approaches. The gain in performance from using machine learning algorithms as compared to semi-quantification was relatively small and may be insufficient, when considered in isolation, to offer significant advantages in the clinical context