The role of disulfide bond replacements in analogues of the Tarantula toxin ProTx-II and their effects on inhibition of the voltage-gated sodium ion channel Nav1.7

Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate

Modulation of innate immune-related genes and glucocorticoid synthesis in gnotobiotic full-sibling European sea bass (<i>Dicentrarchus labrax</i>) larvae challenged with <i>Vibrio anguillarum</i>

Although several efforts have been made to describe the immunoendocrine interaction in fish, there are no studies to date focusing on the characterization of the immune response and glucocorticoid synthesis using the host–pathogen interaction on larval stage as an early developmental stage model of study. Therefore, the aim of this study was to evaluate the glucocorticoid synthesis and the modulation of stress- and innate immune-related genes in European sea bass (Dicentrarchus labrax) larvae challenged with Vibrio anguillarum. For this purpose, we challenged by bath full-sibling gnotobiotic sea bass larvae with 107 CFU mL−1 of V. anguillarum strain HI 610 on day 5 post-hatching (dph). The mortality was monitored up to the end of the experiment [120 hours post-challenge (hpc)]. While no variations were registered in non-challenged larvae maintained under gnotobiotic conditions (93.20% survival at 120 hpc), in the challenged group a constant and sustained mortality was observed from 36 hpc onward, dropping to 18.31% survival at 120 hpc. Glucocorticoid quantification and expression analysis of stress- and innate immunity-related genes were carried out in single larvae. The increase of cortisol, cortisone and 20β-dihydrocortisone was observed at 120 hpc, although did not influence upon the modulation of stress-related genes (glucocorticoid receptor 1 [gr1], gr2, and heat shock protein 70 [hsp70]). On the other hand, the expression of lysozyme, transferrin, and il-10 differentially increased at 120 hpc together with a marked upregulation of the pro-inflammatory cytokines (il-1β and il-8) and hepcidin, suggesting a late activation of defense mechanisms against V. anguillarum. Importantly, this response coincided with the lowest survival observed in challenged groups. Therefore, the increase in markers associated with glucocorticoid synthesis together with the upregulation of genes associated with the anti-inflammatory response suggests that in larvae infected with V. anguillarum a pro-inflammatory response at systemic level takes place, which then leads to the participation of other physiological mechanisms at systemic level to counteract the effect and the consequences of such response. However, this late systemic response could be related to the previous high mortality observed in sea bass larvae challenged with V. anguillarum

Alert classification for the ALeRCE broker system: The real-time stamp classifier

We present a real-time stamp classifier of astronomical events for the Automatic Learning for the Rapid Classification of Events broker, ALeRCE. The classifier is based on a convolutional neural network, trained on alerts ingested from the Zwicky Transient Facility (ZTF). Using only the science, reference, and difference images of the first detection as inputs, along with the metadata of the alert as features, the classifier is able to correctly classify alerts from active galactic nuclei, supernovae (SNe), variable stars, asteroids, and bogus classes, with high accuracy (~94%) in a balanced test set. In order to find and analyze SN candidates selected by our classifier from the ZTF alert stream, we designed and deployed a visualization tool called SN Hunter, where relevant information about each possible SN is displayed for the experts to choose among candidates to report to the Transient Name Server database. From 2019 June 26 to 2021 February 28, we have reported 6846 SN candidates to date (11.8 candidates per day on average), of which 971 have been confirmed spectroscopically. Our ability to report objects using only a single detection means that 70% of the reported SNe occurred within one day after the first detection. ALeRCE has only reported candidates not otherwise detected or selected by other groups, therefore adding new early transients to the bulk of objects available for early follow-up. Our work represents an important milestone toward rapid alert classifications with the next generation of large etendue telescopes, such as the Vera C. Rubin Observatory.The authors acknowledge support from the National Agency of Research and Development’s Millennium Science Initiative through grant IC12009, awarded to the Millennium Institute of Astrophysics (RC, ER, CV, FF, PE, GP, FEB, IR, PSS, GC, SE, Ja, EC, DR, DRM, MC) and from the National Agency for Research and Development (ANID) grants: BASAL Center of Mathematical Modelling AFB-170001 (CV, FF, IR, ECN, CS, ECI) and Centro de Astrofísica y Tecnologías Afines AFB170002 (FEB, PSS, MC); FONDECYT Regular #1171678 (PE), #1200710 (FF), #1190818(FEB), #1200495 (FEB), #1171273 (MC), #1201793(GP); FONDECYT Postdoctorado #3200250 (PSS); FONDECYT Iniciación #11191130 (CV); Magíster Nacional 2019 #22190947 (ER). This work was funded in part by project CORFO 10CEII-9157 Inria Chile (PS). The authors acknowledge financial support from the Spanish Ministry of Science, Innovation, and Universities (MICIU) under the 2019 Ramón y Cajal program RYC2019- 027683 (LG)

Biopolímeros de cáscaras de mango y su importancia en la soberanía alimentaria

Mediante la presente revisión bibliográfica se ha encontrado que los biopolímeros a base de subproductos del mango serían capaces de prolongar la vida útil de los alimentos sin afectar su calidad y propiedades organolépticas. Los compuestos bioactivos de la cáscara de este fruto protegerían a un producto de daños fisicoquímicos y contaminación microbiana. Además, estos empaques podrían disminuir los residuos y contaminantes ambientales. Esta revisión se realizó considerando como indicadores de calidad: la permeabilidad al vapor de agua y cantidad de compuestos fenólicos principalmente. Se encontró que la película de gelatina de pescado con 5% de extracto de cáscara de mango (MPE) tendría una baja permeabilidad al vapor de agua WVP: 1.98 ± 0.15 g mm/kPa s m2 mientras que sus compuestos antioxidantes permitirían el aumento de la vida útil del alimento, por sus propiedades de barrera, contribuyendo así a reducir los desperdicios de la industria alimentaria. Asimismo, los biopolímeros de subproductos de cáscara de mango contribuirían al concepto de soberanía alimentaria pues promueven la conservación de los alimentos de manera sustentable, sostenible y accesible, manteniendo al mismo tiempo la calidad, inocuidad y el valor nutricional del producto. Los biopolímeros son una alternativa a los envases sintéticos

A partial wave analysis of the centrally produced K+K- and K0K0 systems in pp interactions at 450 GeV/c and new information on the spin of the fJ(1710)

A partial wave analysis of the centrally produced K+K- and K0K0 channels has been performed in pp collisions using an incident beam momentum of 450 GeV/c. An unambiguous physical solution has been found in each channel. The striking feature is the observation of peaks in the S-wave corresponding to the f0(1500) and fJ(1710) with J = 0. The D-wave shows evidence for the f2(1270)/a2(1320), the f2(1525) and the f2(2150) but there is no evidence for a statistically significant contribution in the D-wave in the 1.7 GeV mass region.Comment: 15 pages, Latex, 5 Figure

Semaphorin 3F signaling actively retains neutrophils at sites of inflammation

Neutrophilic inflammation is central to disease pathogenesis, for example, in chronic obstructive pulmonary disease, yet the mechanisms that retain neutrophils within tissues remain poorly understood. With emerging evidence that axon guidance factors can regulate myeloid recruitment and that neutrophils can regulate expression of a class 3 semaphorin, SEMA3F, we investigated the role of SEMA3F in inflammatory cell retention within inflamed tissues. We observed that neutrophils upregulate SEMA3F in response to proinflammatory mediators and following neutrophil recruitment to the inflamed lung. In both zebrafish tail injury and murine acute lung injury models of neutrophilic inflammation, overexpression of SEMA3F delayed inflammation resolution with slower neutrophil migratory speeds and retention of neutrophils within the tissues. Conversely, constitutive loss of sema3f accelerated egress of neutrophils from the tail injury site in fish, whereas neutrophil-specific deletion of Sema3f in mice resulted in more rapid neutrophil transit through the airways, and significantly reduced time to resolution of the neutrophilic response. Study of filamentous-actin (F-actin) subsequently showed that SEMA3F-mediated retention is associated with F-actin disassembly. In conclusion, SEMA3F signaling actively regulates neutrophil retention within the injured tissues with consequences for neutrophil clearance and inflammation resolution

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362