Substrate-selective repair and restart of replication forks by DNA translocases

Stalled replication forks are sources of genetic instability. Multiple fork-remodeling enzymes are recruited to stalled forks, but how they work to promote fork restart is poorly understood. By combining ensemble biochemical assays and single-molecule studies with magnetic tweezers, we show that SMARCAL1 branch migration and DNA-annealing activities are directed by the single-stranded DNA-binding protein RPA to selectively regress stalled replication forks caused by blockage to the leading-strand polymerase and to restore normal replication forks with a lagging-strand gap. We unveil the molecular mechanisms by which RPA enforces SMARCAL1 substrate preference. E. coli RecG acts similarly to SMARCAL1 in the presence of E. coli SSB, whereas the highly related human protein ZRANB3 has different substrate preferences. Our findings identify the important substrates of SMARCAL1 in fork repair, suggest that RecG and SMARCAL1 are functional orthologs, and provide a comprehensive model of fork repair by these DNA translocases.

Análisis comparativo del "inventario de actitudes y creencias" (ABI) y la "escala de actitudes disfuncionales" (DAS)

De acuerdo con los planteamientos de la Terapia Cognitiva (TC) de Aaron Beck y la terapia Racional Emotivo Conductual (TREC) de Albert Ellis, el mantenimiento de creencias rígidas y actitudes disfuncionales constituyen factores de vulnerabilidad a los trastornos psicológicos. En base a estos planteamientos, la adecuada evaluación de las creencias y actitudes disfuncionales es fundamental, no sólo para saber cuáles están en el origen y mantenimiento de la perturbación emocional que puede aquejar a una persona, sino también para su cambio y prevención, e incluso para la promoción de actitudes más funcionales o saludables.El presente estudio se centra específicamente en el análisis de las similitudes y diferencias existentes entre los instrumentos de evaluación de las creencias y actitudes disfuncionales elaborados desde tales enfoques teóricos. Concretamente, entre el Inventario de Actitudes y Creencias (ABI) y la Escala de Actitudes Disfuncionales (DAS) desarrollados desde la perspectiva de la TREC y la TC, respectivamente. Para ello se han administrado sendos cuestionarios a una muestra de 156 estudiantes universitarios con un rango de edad comprendido entre los 19 y 57 años (media: 22.03; desviación típica: 5.09), y sus puntuaciones se han sometido a diversos análisis de correlación (de Spearman y canónica) y de regresión para verificar el grado de variancia compartida, así como a un análisis factorial de componentes principales (ACP) para comprobar la estructura de la agrupación de las escalas respectivas...

Sensitivity of Spring Phenology to Warming Across Temporal and Spatial Climate Gradients in Two Independent Databases

Disparate ecological datasets are often organized into databases post hoc and then analyzed and interpreted in ways that may diverge from the purposes of the original data collections. Few studies, however, have attempted to quantify how biases inherent in these data (for example, species richness, replication, climate) affect their suitability for addressing broad scientific questions, especially in under-represented systems (for example, deserts, tropical forests) and wild communities. Here, we quantitatively compare the sensitivity of species first flowering and leafing dates to spring warmth in two phenological databases from the Northern Hemisphere. One-PEP725-has high replication within and across sites, but has low species diversity and spans a limited climate gradient. The other-NECTAR-includes many more species and a wider range of climates, but has fewer sites and low replication of species across sites. PEP725, despite low species diversity and relatively low seasonality, accurately captures the magnitude and seasonality of warming responses at climatically similar NECTAR sites, with most species showing earlier phenological events in response to warming. In NECTAR, the prevalence of temperature responders significantly declines with increasing mean annual temperature, a pattern that cannot be detected across the limited climate gradient spanned by the PEP725 flowering and leafing data. Our results showcase broad areas of agreement between the two databases, despite significant differences in species richness and geographic coverage, while also noting areas where including data across broader climate gradients may provide added value. Such comparisons help to identify gaps in our observations and knowledge base that can be addressed by ongoing monitoring and research efforts. Resolving these issues will be critical for improving predictions in understudied and under-sampled systems outside of the temperature seasonal mid-latitudes.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Forecasting the Earth"s radiation belts and modeling solar energetic particle events: Recent results from SPACECAST

High-energy charged particles in the van Allen radiation belts and in solar energetic particle events can damage satellites on orbit leading to malfunctions and loss of satellite service. Here we describe some recent results from the SPACECAST project on modelling and forecasting the radiation belts, and modelling solar energetic particle events. We describe the SPACECAST forecasting system that uses physical models that include wave-particle interactions to forecast the electron radiation belts up to 3 h ahead. We show that the forecasts were able to reproduce the >2 MeV electron flux at GOES 13 during the moderate storm of 7-8 October 2012, and the period following a fast solar wind stream on 25-26 October 2012 to within a factor of 5 or so. At lower energies of 10- a few 100 keV we show that the electron flux at geostationary orbit depends sensitively on the high-energy tail of the source distribution near 10 RE on the nightside of the Earth, and that the source is best represented by a kappa distribution. We present a new model of whistler mode chorus determined from multiple satellite measurements which shows that the effects of wave-particle interactions beyond geostationary orbit are likely to be very significant. We also present radial diffusion coefficients calculated from satellite data at geostationary orbit which vary with Kp by over four orders of magnitude. We describe a new automated method to determine the position at the shock that is magnetically connected to the Earth for modelling solar energetic particle events and which takes into account entropy, and predict the form of the mean free path in the foreshock, and particle injection efficiency at the shock from analytical theory which can be tested in simulations.

Ciudad y ferrocarril en la España del siglo XXI. La integración de alta velocidad ferroviaria en el medio urbano

La reciente implantación y extensión de la red de alta velocidad ferroviaria en España está permitiendo relanzar un debate que en muchas ciudades no había sido resuelto de forma satisfactoria: la integración del ferrocarril en el medio urbano. En muchos casos, la llegada del nuevo tren se ha convertido en un instrumento urbanístico de primer orden, ya que conlleva una transformación de gran calado. En este artículo se realiza una lectura transversal, a través de las experiencias de diferentes ciudades españolas, para desarrollar una clasificación de las formas de integración de la alta velocidad ferroviaria y su impacto en la estructura urbana.

Das Koenigreich Schweden und Norwegen - [Yleisnäkymä - Overview]

Kartta on ilmestynyt todennäköisesti vuonna 1749 atlaksessa: Atlas selectus von allen Königreichen und Ländern der Welt / J. G. Schreiber.

Nkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation.

Guidepost cells present at and surrounding the midline provide guidance cues that orient the growing axons through commissures. Here we show that the transcription factor Nkx2.1 known to control the specification of GABAergic interneurons also regulates the differentiation of astroglia and polydendrocytes within the mouse anterior commissure (AC). Nkx2.1-positive glia were found to originate from three germinal regions of the ventral telencephalon. Nkx2.1-derived glia were observed in and around the AC region by E14.5. Thereafter, a selective cell ablation strategy showed a synergistic role of Nkx2.1-derived cells, both GABAergic interneurons and astroglia, towards the proper formation of the AC. Finally, our results reveal that the Nkx2.1-regulated cells mediate AC axon guidance through the expression of the repellent cue, Slit2. These results bring forth interesting insights about the spatial and temporal origin of midline telencephalic glia, and highlight the importance of neurons and astroglia towards the formation of midline commissures.

Avainhenkilöiden sitouttaminen organisaatioon

Tutkielman tavoitteena oli tarkastella ja tuoda esiin sitouttamisen merkitys organisaatioille, selvittää yritysjohtojen avuksi avainhenkilöiden sitoutumista ja löytää parempia keinoja organisaatioon sitouttamiseen. Lähtökohtana oli tarkastella sitouttamista henkilöstövoimavarojen johtamisen ja sitoutumisen kautta. Viitekehykseksi valittiin Allenin ja Meyerin (1990) sitoutumismalli. Sitouttaminen vaikuttaa organisaation taloudelliseen, laadulliseen, tuotannolliseen ja kilpailulliseen menestykseen. Empiirinen tutkimus suoritettiin puolistrukturoiduilla haastatteluilla ja kyselylomakkeella. Aineisto käsiteltiin teemoittelun kautta. Empiirisen tutkimuksen mukaan tärkeimmät sitoutumista nostavat tekijät liittyvät esimiestoimintaan ja johtamiseen, työn piirteisiin ja työoloihin sekä vaikutusmahdollisuuteen. Tärkeimmät sitoutumista nostavat tekijät vaikuttivat tunnepitoisen sitoutumisen muodostumiseen. Erityisesti esiin nousivat työtehtävässä viihtymisestä muodostunut ”5 vuoden- sääntö”, organisaatioiden järjestämien vapaa-ajan tapahtumien vähäinen tärkeys sekä halu pitää perhe- ja työelämä erillään. Järjestettyjen vapaa-ajan tapahtumien merkityksen vähyys liittyy haluun viettää aikaa perheen kanssa. Organisaatioiden tulisi ottaa selvää oman henkilöstönsä sitoutumiseen vaikuttavat tekijät, jolloin organisaation käyttämät sitouttamiskeinot toimisivat parhaiten ja vastaisivat henkilöstön tarpeita.

Lower incisor dentoalveolar compensation and symphysis dimensions among Class I and III malocclusion patients with different facial vertical skeletal patterns

Objective: To compare lower incisor dentoalveolar compensation and mandible symphysis morphology among Class I and Class III malocclusion patients with different facial vertical skeletal patterns. Materials and Methods: Lower incisor extrusion and inclination, as well as buccal (LA) and lingual (LP) cortex depth, and mandibular symphysis height (LH) were measured in 107 lateral cephalometric x-rays of adult patients without prior orthodontic treatment. In addition, malocclusion type (Class I or III) and facial vertical skeletal pattern were considered. Through a principal component analysis (PCA) related variables were reduced. Simple regression equation and multivariate analyses of variance were also used. Results: Incisor mandibular plane angle (P < .001) and extrusion (P  =  .03) values showed significant differences between the sagittal malocclusion groups. Variations in the mandibular plane have a negative correlation with LA (Class I P  =  .03 and Class III P  =  .01) and a positive correlation with LH (Class I P  =  .01 and Class III P  =  .02) in both groups. Within the Class III group, there was a negative correlation between the mandibular plane and LP (P  =  .02). PCA showed that the tendency toward a long face causes the symphysis to elongate and narrow. In Class III, alveolar narrowing is also found in normal faces. Conclusions: Vertical facial pattern is a significant factor in mandibular symphysis alveolar morphology and lower incisor positioning, both for Class I and Class III patients. Short-faced Class III patients have a widened alveolar bone. However, for long-faced and normal-faced Class III, natural compensation elongates the symphysis and influences lower incisor position.

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

Fischbesatz: Komplex und emotional

In fast allen Schweizer Gewässern werden von Fischern und Natur- schützern Besatzmassnahmen mit verschiedenen Fischarten durchge- führt. Es gibt allerdings viele offene Fragen, die die Forschung nur zu- sammen mit der Praxis beantworten kann.

Screening of mental health and substance users in frequent users of a general Swiss emergency department.

BACKGROUND: The objectives of this study were to determine the proportions of psychiatric and substance use disorders suffered by emergency departments' (EDs') frequent users compared to the mainstream ED population, to evaluate how effectively these disorders were diagnosed in both groups of patients by ED physicians, and to determine if these disorders were predictive of a frequent use of ED services. METHODS: This study is a cross-sectional study with concurrent and retrospective data collection. Between November 2009 and June 2010, patients' mental health and substance use disorders were identified prospectively in face-to-face research interviews using a screening questionnaire (i.e. researcher screening). These data were compared to the data obtained from a retrospective medical chart review performed in August 2011, searching for mental health and substance use disorders diagnosed by ED physicians and recorded in the patients' ED medical files (i.e. ED physician diagnosis). The sample consisted of 399 eligible adult patients (≥18 years old) admitted to the urban, general ED of a University Hospital. Among them, 389 patients completed the researcher screening. Two hundred and twenty frequent users defined by >4 ED visits in the previous twelve months were included and compared to 169 patients with ≤4 ED visits in the same period (control group). RESULTS: Researcher screening showed that ED frequent users were more likely than members of the control group to have an anxiety, depressive disorder, post-traumatic stress disorder (PTSD), or suffer from alcohol, illicit drug abuse/addiction. Reviewing the ED physician diagnosis, we found that the proportions of mental health and substance use disorders diagnosed by ED physicians were low both among ED frequent users and in the control group. Using multiple logistic regression analyses to predict frequent ED use, we found that ED patients who screened positive for psychiatric disorders only and those who screened positive for both psychiatric and substance use disorders were more likely to be ED frequent users compared to ED patients with no disorder. CONCLUSIONS: This study found high proportions of screened mental health and/or substance use disorders in ED frequent users, but it showed low rates of detection of such disorders in day-to-day ED activities which can be a cause for concern. Active screening for these disorders in this population, followed by an intervention and/or a referral for treatment by a case-management team may constitute a relevant intervention for integration into a general ED setting.

Associations between perceived discrimination and health status among frequent Emergency Department users

Objective: Frequent Emergency Department (ED) users are vulnerable individuals and discrimination is usually associated with increased vulnerability. The aim of this study was to investigate frequent ED users' perceptions of discrimination and to test whether they were associated with increased vulnerability. Methods: In total, 250 adult frequent ED users were interviewed in Lausanne University Hospital. From a previously published questionnaire, we assessed 15 dichotomous sources of perceived discrimination. Vulnerability was assessed using health status: objective health status (evaluation by a healthcare practitioner including somatic, mental health, behavioral, and social issues - dichotomous variables) and subjective health status [self-evaluation including health-related quality of life (WHOQOL) and quality of life (EUROQOL) - mean-scores]. We computed the prevalence rates of perceived discrimination and tested associations between perceived discrimination and health status (Fischer's exact tests, Mann-Whitney U-tests)