Repression of SOX6 transcriptional activity by SUMO modification

AbstractSOX6 plays key functions in several developmental processes, including neurogenesis and skeleton formation. In this report, we show that SOX6 is modified in vitro and in vivo by small ubiquitin-related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. Furthermore, co-expression of SOX6 with SUMO2 results in the appearance of SOX6 in a punctate nuclear pattern that colocalized with promyelocytic leukemia protein, which was partially abolished by mutations in SOX6 sumoylation sites

Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels

Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA

Ciclo de charlas científicas: una instancia de discusión, orientación, y acercamiento.

Numerosos estudios hacen referencia a las transformaciones sociales y culturales actuales que suponen un llamado a la institución escolar a renovar la propuesta educativa, en este sentido, Dussel y Caruso (2001) expresan acertadamente que enfrentarse con los restos del naufragio como se ha denominado a la pérdida de la esperanza ciega en la escolaridad, requiere un cambio en la sociedad y un cambio en la escuela para no quedar girando en el vacío. Ello requiere un nuevo posicionamiento de la escuela respecto a su finalidad, frente a condicionantes adversos y al concepto de expulsado social, (que desde este programa se pretende evitar), que refiere a un sujeto que desaparece de los escenarios públicos y está marcado por la falta de trabajo, la violencia, estrategias de supervivencia en el marco de la ilegalidad, disolución de vínculos familiares, drogadicción y la falta de un proyecto de vida. Por ello el objetivo fue ofrecer desde el Programa de Extensión, a alumnos del penúltimo año del secundario, información y un espacio de reflexión y debate respecto a la problemática de su inserción tanto en la vida universitaria como en el mundo del trabajo. La primera actividad programada: Ciclo de Charlas Científicas incluyó alumnos del 5to año del Centro Educativo Nº9, de la Ciudad de Villa Mercedes (SL) con orientación científica, docentes secundarios de esa orientación, profesores universitarios del Área de Agronomía y del Área de Educación y alumnos del 3er ano de agronomía. El objetivo fue informar a los alumnos del secundario de las distintas opciones de estudio que tienen una vez finalizado el nivel secundario y despejar las dudas en relación al ingreso universitario. Los docentes e investigadores expusieron seminarios con diferentes temáticas dentro de las Ciencias Biológicas y los alumnos de agronomía contaron sus experiencias como tales, sus dificultades al ingresar y las herramientas valiosas que ofrece la universidad, becas, horarios, centro de estudiantes, etc. Se generó un ambiente de discusión y de consultas sobre la instancia de ingreso a la universidad, la curricula de carreras científicas, el modo de los exámenes universitarios y detalles sobre el ingreso. El puente que queremos construir recién está comenzado a formarse

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Situación de salud de reclusos de un centro de cumplimiento penitenciario, Chile

Introducción: La población penitenciaria ha ido en aumento, y con ello las necesidades en salud, siendo catalogada como una población vulnerable. Por otro lado, las personas privadas de libertad mantienen los derechos inherentes al ser humano, entre ellos el derecho a la salud, el cual en algunas oportunidades se encuentra relegado. Objetivo: Caracterizar la situación de salud de reclusos de un centro de cumplimiento penitenciario, y su grado de satisfacción con la atención en salud brindada. Material y métodos: Estudio descriptivo de corte transversal, llevado a cabo en el centro de cumplimiento penitenciario El Manzano, Concepción, durante octubre 2011-febrero 2012 mediante la aplicación del Examen de medicina preventiva y un cuestionario de antecedentes sociodemográficos y de salud, incluyendo reclusos de sexo masculino y femenino mayores de 18 años en régimen cerrado. Resultados: Un 85% de la población estudiada eran hombres, la edad promedio fue 34 años, el 91,2% recibe visitas, el promedio de reclusión fue 38 meses. El 45% posee al menos una enfermedad diagnosticada, primando los desórdenes mentales, patologías del sistema respiratorio y circulatorio. Un 56% de los reclusos ha solicitado atención en salud con poca frecuencia, encontrándose 33% muy satisfecho y 32% satisfecho en lo relativo a los servicios sanitarios del penal. Discusión: El estado de salud de la población penal se encuentra más deteriorado que el de la población general, con necesidades mayores y distintas, sin embargo existe una percepción de un buen estado de salud y una tendencia al alto grado de satisfacción de los servicios sanitarios

Dolor cervical como presentación de neumomediastino espontáneo en urgencia pediátrica. Caso clínico

Spontaneous Pneumomediastinum is a rare clinical situation in pediatric emergency services, sometimes it presents with guiding symptoms, but in other occasions in a very nonspecific way. Definitely, needs to be highly suspected, emphasizing in the anamnesis the antecedent of intense physical exercise before the development of the triggering symptoms that determinates the consult, generally having a good evolution that gets solved in 3-4 days. There is a pediatric clinical case presented, that permits us to discuss the more relevant aspects of the clinical presentation, diagnosis methods and the updated management, in pediatric emergency services

Global‐Krigger: A Global Kriging Interpolation Toolbox With Paleoclimatology Examples

Abstract Many applications in Earth sciences require spatial prediction, that is, obtaining a continuous scalar field from a set of discrete scalar data points on the Earth's surface. Such applications include model‐data comparisons and derivation of continuous scalar fields as input for Earth system models. The advantage of kriging as an interpolation method is that it provides predictions with confidence intervals for data sets of irregularly distributed points in space. However, the theory of kriging for non‐Euclidean domains such as oblate spheroids (e.g., the Earth's surface) is poorly developed, and existing kriging algorithms for global interpolation oftentimes cannot guarantee the validity of their predictions. Here, we present Global‐Krigger, a new kriging interpolation algorithm adapted for local to global applications that (a) incorporates a numerical check to guarantee that the necessary conditions for the kriging system of linear equations are met, and (b) derives a combined uncertainty field due both to spatial variations in data density and measurement error. The robustness of the method is demonstrated by cross‐validating predictions against reanalysis fields of traditional climatological scalar variables. We also show an example application in paleoclimatology for Holocene mineral dust deposition fluxes. The toolbox includes a user‐friendly graphical user interface that guides users through a range of choices during data pre‐interpolation analysis, kriging, and post‐processing

Hypoxanthine enters human vascular endothelial cells (ECV 304) via the nitrobenzylthioinosine-insensitive equilibrative nucleoside transporter.

The transport properties of the nucleobase hypoxanthine were examined in the human umbilical vein endothelial cell line ECV 304. Initial rates of hypoxanthine influx were independent of extracellular cations: replacement of Na+ with Li+, Rb+, N-methyl-D-glucamine or choline had no significant effect on hypoxanthine uptake by ECV 304 cells. Kinetic analysis demonstrated the presence of a single saturable system for the transport of hypoxanthine in ECV 304 cells with an apparent K(m) of 320 +/- 10 microM and a Vmax of 5.6 +/- 0.9 pmol/10(6) cells per s. Hypoxanthine uptake was inhibited by the nucleosides adenosine, uridine and thymidine (apparent Ki 41 +/- 6, 240 +/- 27 and 59 +/- 8 microM respectively) and the nucleoside transport inhibitors nitrobenzylthioinosine (NBMPR), dilazep and dipyridamole (apparent Ki 2.5 +/- 0.3, 11 +/- 3 and 0.16 +/- 0.006 microM respectively), whereas the nucleobases adenine, guanine and thymine had little effect (50% inhibition at > 1 mM). ECV 304 cells were also shown to transport adenosine via both the NBMPR-sensitive and -insensitive nucleoside carriers. Hypoxanthine specifically inhibited adenosine transport via the NBMPR-insensitive system in a competitive manner (apparent Ki 290 +/- 14 microM). These results indicate that hypoxanthine entry into ECV 304 endothelial cells is mediated by the NBMPR-insensitive nucleoside carrier present in these cells