Background Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. Methods Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. Results We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95% CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. Conclusions There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19. / Revisión por pares

Knowledge of how intermolecular interactions of amyloidogenic proteins cause protein aggregation and how those interactions are affected by sequence and solution conditions is essential to our understanding of the onset of many degenerative diseases. Of particular interest is the aggregation of the amyloid-β (Aβ) peptide, linked to Alzheimer's disease, and the aggregation of the Sup35 yeast prion peptide, which resembles the mammalian prion protein (PrP) linked to spongiform encephalothopies. To facilitate the study of these important peptides, experimentalists have identified small peptide congeners of the full-length proteins that exhibit amyloidogenic behavior, including the KLVFFAE sequence of the Aβ protein, and the GNNQQNY sequence of Sup35. Reverse micelles provide an important environment for the study of protein folding and aggregation. In a reverse micelle, it is possible to observe the effects that confinement and water activity, believed to play a critical role in an in vivo cellular environment, have on protein folding, misfolding, and aggregation. We employed molecular dynamics simulations of reverse micelles as well as peptides encapsulated in reverse micelles in order to characterize the reverse micelle environment and identify fundamental principles that inform how sequence and solution environment influence protein aggregation. The peptides studied include the alanine-rich peptide AKA2 as well as the amyloidogenic KLVFFAE and GNNQQNY peptide fragments. The results of these studies suggest that substantial fluctuations in reverse micelle shape away from an idealized spherical geometry enables significant interaction between peptides and the surfactant interface. Analysis these results, including evaluation of water dynamics and calculated IR spectra of the amide I vibration of the peptides, indicate that our model of the reverse micelle is a robust one which captures essential features of this complex system. Moreover, our studies provide critical insight into the complex role played by a heterogeneous cellular environment in the earliest stages of protein aggregation and amyloid formation.

No description available.

Aim: To evaluate the association between elevated serum transaminase levels and insulin resistance (IR) in a population of healthy individuals. Methods: We define IR with a cut-off point of homeostatic model assessment (HOMA-IR) ≥ 3.8. For aspartate aminotransferase (AST), we consider elevated values >30 U/L in women and values >36 U/L in men. For alanine aminotransferase (ALT), we consider elevated values >30 U/L in women and values >40 U/L in men. We performed a crude and adjusted generalized linear model from Poisson family with robust variance, in order to evaluate the association between elevated serum transaminase levels and IR. The associations were presented as prevalence ratio (PR) with their respective 95% confidence intervals (95% CI). Results: We included 261 participants in the study. The median age was 39 years (31–45) and 23.7% of the participants were men. The prevalence of elevated serum transaminase for AST and ALT were, 13.8% and 26.1%, respectively. The prevalence of IR was 34.1%. In the crude analysis we found statistical significance between elevated AST and ALT with IR (PR = 3.18; 95% CI: 2.33–4.34 and PR = 2.44; 95% CI: 1.88–3.30; respectively). However, in the multivariate analysis, the association only remained statistically significance with ALT, but lost its significance with AST, PR = 1.90; CI 95%: 1.31–2.77 and a PR = 1.23; CI 95%: 0.93–1.61; respectively. Conclusion: Elevated serum levels of ALT were associated with insulin resistance. ALT could be used in clinical practice as an additional tool to assess IR in apparently healthy people. / Dirección de Gestión de la Investigación, Universidad de Antofagasta / Revisión por pares

No description available.

The purpose of this study was to compare the efficacy of two dose levels of L-Alanyl-LGlutamine in a commercially available sports drink to the sports drink only on time to exhaustion, neuromuscular fatigue and physiological measures during prolonged endurance exercise. Twelve endurance-trained males (23.5±3.7 yrs; 175.5±5.4 cm; 70.7±7.6 kg) performed four trials, each consisting of 1 hr treadmill runs at 75% of VO2peak followed by a run to exhaustion at 90% of VO2peak. The trials differed in type of hydration. One trial consisted of no hydration (NHY), another required ingestion of only a sports drink (ET), and two trials required ingestion of a low dose (LD) (300 mg∙500 ml-1) and high dose (HD) of L-Alanyl-L-Glutamine (1 g∙500 ml-1) mixed in the sports drink. During the fluid ingestion trials 250 ml were consumed every 15 min. Plasma glutamine, glucose, electrolytes, and osmolality were measured prior to the run (PRE), and at 30, 45, and 60 min. VO2, RQ, and HR were measured every 15 min and surface electromyography (EMG) of the vastus lateralis and rectus femoris were measured every 10 min during the 1 hr run. Time to exhaustion was significantly longer during the LD and HD trials compared with NHY. Plasma glutamine concentrations were significantly elevated at 45 min in LD and HD trials, and remained elevated at 60 min during HD. Sodium concentrations increased with the beginning of exercise and remained stable for the duration of the 1 hr run. At 60 min plasma sodium was significantly lower in all trials compared with NHY. The results from this study indicated that ingestion of the alanine-glutamine dipeptide at either the low or high dose significantly improved time to exhaustion during high intensity exercise compared to a no hydration trial. These differences were not noted between ET and NHY.

In malting barley, rapid germination is desirable and linked to end use quality. Modern malting varieties have been bred for low seed dormancy leading to issues with pre-harvest sprouting in wetter growing regions. To maintain malting capacity while minimizing germination on the maternal plant requires in-depth understanding of the genetic regulation of dormancy in malting barley. Currently, the major effect QTLs SD1 and SD2 have been shown to influence dormancy across multiple populations of barley, though the physiological mechanisms involved remain unclear. To search for novel genetic regions that influence primary dormancy, three mapping populations were assessed including two Canadian biparental populations (Synch and Legci) as well as a diversity panel sourced from multiple locations worldwide (ICARDA AM-14). The SD2 locus had a major effect in the Synch population while the SD1 locus had a major effect in the Legci population and neither SD1 nor SD2 were linked to dormancy in the diversity panel. Instead, 14 additional marker trait associations were identified in AM-14 suggesting that investigating a broader range of genetic regulation of dormancy outside of North American varieties may provide solutions to regulate this trait. Additional testing on SD1 revealed that variation at this locus did not affect ABA sensitivity during germination or GA or ABA-regulated gene expression during grain fill. Indeed, lines containing the non-dormant SD1 allele germinate at a similar rate as the dormant SD1 seeds when the glumella was removed from the embryo. This indicated that the effect of the alanine aminotransferase gene underlying the SD1 allele is dependent on physical restriction on the embryo or the hypoxic effects produced by the glumella. Imposing a hypoxic (5% oxygen) environment on exposed embryos revealed an association between non-dormancy at SD1 and reduced sensitivity to the suppressive effects of hypoxia on germination. This suggests that alanine aminotransferase regulates dormancy release during barley germination at least in part through regulation of the seed’s response to hypoxia.

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No description available.

Ce mémoire présente trois approches différentes vers la synthèse du 3–(trans–2–nitrocyclopropyl)alanine, un intermédiaire synthétique de la hormaomycine. Cette molécule naturelle démontre d’intéressantes activités biologiques et pharmacologiques. Il est intéressant de souligner que ce dérivé donne facilement accès au 3–(trans–2–aminocyclopropyl)alanine, unité centrale de la bélactosine A. Ce composé naturel possédant lui aussi d’intéressantes propriétés biologiques, plusieurs études relationnelles structures-activités menant à des dérivés plus actifs de cette molécule ont été entreprises, démontrant l’intérêt toujours présent de synthétiser de façon efficace et optimale ces dérivés cyclopropaniques. Une méthodologie développée au sein de notre groupe de recherche et basée sur une réaction de cyclopropanation intramoléculaire diastéréosélective sera mise à profit afin d’élaborer une nouvelle voie de synthèse aussi élégante qu’efficace à la construction du 3–(trans–2–nitrocyclopropyl) alanine. En utilisant un carbène de rhodium généré soit par la dégradation d’un dérivé diazoïque, soit par la formation d’un réactif de type ylure d’iodonium, une réaction de cyclopropanation diastéréosélective permettra la formation de deux autres centres contigus et ce, sans même utiliser d’auxiliaire ou de catalyseur énantioenrichis. Ensuite, un réarrangement intramoléculaire précédant deux réactions synchronisées d’ouverture de cycle et de décarboxylation permettront l’obtention du composé d’intérêt avec un rendement global convenable et en relativement peu d’étapes. De cette manière, la synthèse formelle de la bélactosine A et de l’hormaomycine a été effectuée. Cette synthèse se démarque des autres par l’utilisation d’une seule transformation catalytique énantiosélective. / This master’s thesis presents three different approaches toward the synthesis of 3–(trans–2–nitrocyclopropyl)alanine, a key constituent of the natural product hormaomycin. This unusual compound demonstrates interesting biological and pharmaceutical activity. It is noteworthy that this unique amino acid can be readily converted to the corresponding 3–(trans–2–aminocyclopropyl)alanine, the central core of belactosin A, a natural compound exhibiting interesting biological properties. Efficient syntheses of these aminocyclopropane derivatives are of current interest since several structure-activity relationships in syntheses of belactosin A and hormaomycin analogues are currently under study in an effort to discover enhanced biological activity. A methodology developed in our research group based on a diastereoselective intramolecular cyclopropanation reaction will be used to elaborate a unique and elegant pathway to the synthesis of the 3–(trans–2–nitrocyclopropyl)alanine. By using a rhodium carbene generated either by the degradation of a diazoic derivative or by the formation of the corresponding iodonium ylide, a diastereoselective cyclopropanation reaction can be applied in the concerted elaboration of two chiral centers needed in the desired aminocyclopropanes, avoiding in this way the utilisation of chiral reagents. Following this key sequence, an intramolecular rearrangement followed by synchronous ring–opening/decarboxylation reactions will permit a convenient formation of the desired product in an acceptable overall yield and in few ensuing steps. In this manner, the formal synthesis of the hormaomycin and the belactosin A can be achieved. This synthesis is unique since it involves only one asymmetric step in the whole synthetic process.