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

Acesso a Tratamento Endovascular para Acidente Vascular Cerebral Isquémico em Portugal

Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Discussion: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.info:eu-repo/semantics/publishedVersio

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Accuracy versus precision in boosted top tagging with the ATLAS detector

Abstract The identification of top quark decays where the top quark has a large momentum transverse to the beam axis, known as top tagging, is a crucial component in many measurements of Standard Model processes and searches for beyond the Standard Model physics at the Large Hadron Collider. Machine learning techniques have improved the performance of top tagging algorithms, but the size of the systematic uncertainties for all proposed algorithms has not been systematically studied. This paper presents the performance of several machine learning based top tagging algorithms on a dataset constructed from simulated proton-proton collision events measured with the ATLAS detector at √ s = 13 TeV. The systematic uncertainties associated with these algorithms are estimated through an approximate procedure that is not meant to be used in a physics analysis, but is appropriate for the level of precision required for this study. The most performant algorithms are found to have the largest uncertainties, motivating the development of methods to reduce these uncertainties without compromising performance. To enable such efforts in the wider scientific community, the datasets used in this paper are made publicly available.</jats:p

Adequação do consumo energético e de macronutrientes de crianças menores de seis anos Adecuación del consumo energético y de macronutrientes de niños con menos de seis años en una ciudad en el sur de Brasil Adequacy of energy consumption and macronutrients of children under six years of age

OBJETIVO: Conhecer a adequação do consumo energético e de macronutrientes da alimentação de crianças menores de seis anos de idade da zona urbana de Pelotas, Rio Grande do Sul. MÉTODOS: Recorte de um estudo transversal que compõe a quarta avaliação de uma pesquisa de série temporal realizada na cidade de Pelotas, Rio Grande do Sul, em 2008. A amostra foi constituída por 799 crianças menores de seis anos de idade. Para avaliação da ingestão calórica e da contribuição percentual de macronutrientes no total de calorias da dieta, foram utilizadas as ingestões dietéticas de referência do Instituto de Medicina. As análises incluíram a descrição da amostra e o teste do qui-quadrado para avaliação das associações, considerando-se um nível de significância de 5%. RESULTADOS: A ingestão calórica deficiente foi maior nos meninos (58,0%) e meninas (63,0%) com idade igual ou menor do que seis meses. Foi observada ingestão calórica excessiva nas idades entre 7 e 12 meses e um e dois anos: 61,3 e 73,5% nos meninos e 56,0 e 74,1% nas meninas, respectivamente. A maioria das crianças com três anos de idade ou mais (meninos com 44,9% e meninas com 47,4%) apresentou ingestão calórica adequada para a idade. A ingestão energética de macronutrientes apresentou-se adequada para carboidratos e proteínas e apontou que 54,5% das crianças tinham ingestão deficiente de lipídeos na faixa etária de um a três anos. CONCLUSÕES: Foi evidenciada a necessidade do estímulo de hábitos alimentares saudáveis que equilibrem a ingestão energética e distribuam o consumo de macronutrientes nesse grupo etário.<br>OBJETIVO: Conocer la adecuación del consumo energético y de macronutrientes de la alimentación de niños menores de seis años de edad del área urbana de Pelotas, Rio Grande do Sul. MÉTODOS: Recorte de un estudio transversal que compone la cuarta evaluación de una investigación de serie atemporal realizada en la ciudad de Pelotas, Rio Grande do Sul, en 2008. La muestra se constituyó por 799 niños con menos de seis años de edad. Para evaluar la ingestión calórica y el aporte porcentual de macronutrientes en el total de calorías de la dieta, se utilizaron las Ingestiones Dietéticas de Referencia del Instituto de Medicina. Los análisis incluyeron la descripción de la muestra y prueba de chi cuadrado para evaluación de las asociaciones, considerándose un nivel de significancia de 5%. RESULTADOS: La ingestión calórica deficiente fue más grande en los muchachos (58,0%) y muchachas (63,0%) con edad igual o inferior a seis meses. Se observó ingestión calórica excesiva en las edades entre 7 y 12 meses y uno y dos años: 61,3 y 73,5% en los muchachos y 56,0 y 74,1% en las muchachas, respectivamente. La mayoría de los niños con tres años de edad o más (44,9% muchachos y 47,4% muchachas) presentó ingestión calórica adecuada para la edad. La ingestión energética de macronutrientes se presentó adecuada para carbohidratos y proteínas y señaló que 54,5% de los niños tenían ingestión deficiente de lípidos en la franja de edad de uno a tres años. CONCLUSIÓNS: Se evidenció la necesidad del estímulo de hábitos alimentares sanos que equilibren la ingestión energética y distribuyan el consumo de macronutrientes en ese grupo de edad.<br>OBJECTIVE: To recognize the adequacy of dietary energy consumption and macronutrients of children under the age of six in the urban zone of Pelotas, in Southern Brazil. METHODS: A cross-sectional study that comprises the fourth evaluation of a temporal series study conducted in the city of Pelotas, Rio Grande do Sul, Brazil, in 2008. The sample consisted of 799 children under six years of age. In order to evaluate caloric intake rates and macronutrient percentage of contribution to the overall food diet calories, the dietary reference intakes (DRI) of the Institute of Medicine were used. These analyses included descriptions of the sample and chi-square test in order to assess associations at a 5% significance level. RESULTS: The deficient caloric intake was prevalent among male (58.0%) and female (63.0%) children aged six months or less. An excessive caloric intake was noted in children aged 7 to 12 months and one to two years: 61.3 and 73.5% for boys, and 56.0 and 74.1% for girls, respectively. Among the children aged three years or more, 44.9% of boys and of 47.4% of girls presented proper caloric intake rates for their age group. The energy intake deriving from macronutrients was adequate regarding carbohydrates and proteins; and 54.5% of the studied children aged between one and three years presented deficient intake of lipids. CONCLUSIONS: The need of healthy dieting practices stimulation was clear in order to balance the energetic intake rates and the distribution of macronutrients consumption within this target age group