Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

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

Particulate Fillers in Thermoplastics

The characteristics of particulate filled thermoplastics are determined by four factors: component properties, composition, structure and interfacial interactions. The most important filler characteristics are particle size, size distribution, specific surface area and particle shape, while the main matrix property is stiffness. Segregation, aggregation and the orientation of anisotropic particles determine structure. Interfacial interactions lead to the formation of a stiff interphase considerably influencing properties. Interactions are changed by surface modification, which must be always system specific and selected according to its goal. Under the effect of external load inhomogeneous stress distribution develops around heterogeneities, which initiate local micromechanical deformation processes determining the macroscopic properties of the composites

Un procedimiento para la determinación de la capacidad de intercambio catiónico de raíces

Se propone un método para la determinación de la Capacidad de Intercambio Catiónico de Raíces. La muestra, limpia de sustancias extrañas por adecuado lavaje, es tratada con oxálico 0.5N., dos veces sucesivas, durante un total de una hora. Las raíces hidrogenadas son lavadas hasta eliminación de oxálico y luego secadas entre papeles de filtro; cinco gramos de raíces así tratadas se ponen en contacto con 100 ml. de solución de Ca (OH)2 aproximadamente 0.05N. Al cabo de media hora se extraen porciones alícuotas de la solución de Ca (OH)2 en equilibrio con las raíces y de un testigo sin raíces y se titula directamente la concentración de calcio con solución valorada de versenato de sodio (sal disódica del ácido etileno diaminotetracético) en presencia de murexido como indicador. La diferencia de concentración de calcio entre la solución testigo y las de los sistemas Ca (OH)2 – raíces, se refiere a Calcio adsorbido y se expresa en m.e. /100 gr. De raíces secas a estufa. El procedimiento no afecta la vitalidad de las raíces y demuestra ser sencillo, satisfactoriamente reproducible y adaptado a determinaciones en serie.A Procedure for the Determination of the Cation Exchange Capacity of Plant Roots A rapid and simple method for the determination of the exchange capacity of excised plants roots is proposed. The sample, free of foreign substances through a thorough washing, is treated with oxalic acid 0.5N for two successive times during a whole hour. The hydrogenised roots are washed till the elimination of oxalic and then dried between sheets of filter papers. Five grams approximately, of these roots are put into contact in a 200 ml. beaker with 100 ml. of a Ca (OH)2 solution about 0.05N; at the same time another portion of 100 ml. of the Ca (OH)2 solution is poured into another beaker but without roots. Half an hour later, aliquots of both solutions are removed and their calcium concentration are determined by titration with ethylenediaminetetraacetate (Versenate) in the presence of ammonium purpurate indicator. The difference between the calcium concentration of the blank solution and the one of the “calcium hydroxide-roots" system is refered to adsorbed calcium and expressed as Cation Exchange Capacity in milliequivalents per 100 grams of oven dried roots. The procedure proposed does not affect the roots vitality and it proves to be simple, reproductible and adapted to serial determination.Fil: Nijensohn, León. Universidad Nacional de Cuyo. Facultad de Ciencias AgrariasFil: Olmos, Felix. Universidad Nacional de Cuyo. Facultad de Ciencias Agraria

Aspidosperma huberianum (apocynaceae), a new species from the brazilian Amazon

We describe Aspidosperma huberianum, a new species from the Brazilian Amazon. The new taxon is morphologically similar to A. darienense, but can be distinguished readily by characters of the leaf (including venation), flower (including calyx lobe number and indument of the corolla and ovary), pollen, fruit, and seed. We provide a taxonomic description, pollen characterization, illustration, photographs, and a distribution map for the new taxon, as well as information on its conservation status, habitat, and phenology442363370CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES141291/2018-4; 302839/2016-0Sem informaçã

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN.

Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). To assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN. The authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers. Apalutamide 240 mg/d. The association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods. By 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18-0.33] or 0.13 [0.08-0.21]), MFS (0.41 [0.29-0.57] or 0.3 [0.19-0.47]), and OS (0.45 [0.35-0.59] or 0.26 [0.18-0.38]; p Apalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring. In this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

International audienceThe emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure−activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer.

There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial. In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020. Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT. Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis. Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P  The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide

Red Bull® energy drink increases consumption of higher concentrations of alcohol

Mixing alcohol with caffeinated energy drinks is a common practice, especially among young people. In humans, the research on this issue has mainly focused on the use of the mass-marketed energy drinks themselves, whereas in animal models, it has focused on the individual effects of their active ingredients (i.e. caffeine). Here, we have characterized how Red Bull®, one of the most consumed caffeinated energy drink worldwide, modulates operant alcohol self-administration in Wistar rats. We found that animals readily and steadily responded for Red Bull (mean: 90 responses, 30 minutes and fixed-ratio 1), which was accompanied by locomotor stimulating effects (26 percent increase). The higher the concentration of alcohol (3–20 percent), the higher the consumption of alcohol (g/kg) and associated blood alcohol levels (91.76 percent) in the mixed Red Bull–alcohol group (60 percent increase). Blood caffeine levels in the Red Bull group were 4.69 μg/ml and 1.31 μg/ml in the Red Bull–alcohol group after the 30-minute session. Because Red Bull also contains 11 percent sucrose, we examined the time course of blood glucose as well as insulin and corticosterone. The correlation between intake of Red Bull and blood glucose levels was higher at 90 minutes than 5 minutes after its consumption, and there was no relationship with blood insulin or blood corticosterone levels. Red Bull did not alter extinction and reacquisition of responding for alcohol nor did it affect relapse-like drinking. Overall, our results suggest that Red Bull might be a vulnerability factor to develop alcoholism given that it intensifies the consumption of higher concentrations of alcohol.European Foundationfor Alcohol ResearchFondo de Investigación SanitariaDepto. de Biología CelularSección Deptal. de Biología Celular (Medicina)Fac. de MedicinaTRUEpu