Exploring early combination strategy in Latin American patients with newly diagnosed type 2 diabetes : a sub-analysis of the VERIFY study

Background Patients with type 2 diabetes mellitus (T2DM) from Latin American countries face challenges in access to healthcare, leading to under-diagnosis, under-achievement of glycemic target, and long-term complications. Early diagnosis and treatment initiation are of paramount importance in this population due to the high prevalence of risk factors such as obesity and metabolic syndrome. The VERIFY study in patients with newly diagnosed T2DM (across 34 countries), assessed the normoglycemic durability (5 years), with early combination (EC) therapy approach versus the traditional stepwise approach of initiating treatment with metformin monotherapy (MET). Here we present the results from the VERIFY study for participants from eight countries in Latin America. Methods Newly diagnosed adult patients with T2DM, HbA1c 6.5-7.5% and body-mass index (BMI) of 22-40 kg/m(2) were enrolled. The primary endpoint was time to initial treatment failure (TF; HbA1c >= 7.0% at two consecutive scheduled visits 13 weeks apart). Time to second TF was evaluated when patients in both groups were receiving and failing on the vildagliptin combination. Safety and tolerability were also assessed for both treatment approaches during the study. Results A total of 537 eligible patients (female, 58.8%) were randomly assigned to receive either EC (n = 266) or MET (n = 271). EC significantly reduced the relative risk of time to initial TF by 47% versus MET [HR (95% CI) 0.53 (0.4, 0.7) p < 0.0001]. Overall, 46.4% versus 66.3% of patients achieved the primary endpoint in the EC and MET groups, with a median [interquartile range (IQR)] time to TF of 59.8 (27.5, not evaluable) and 33.4 (12.2, 60.1) months, respectively. The risk for time to second TF was 31% lower with EC (p < 0.0092). A higher proportion of patients receiving EC maintained durable HbA1c < 7.0%, < 6.5%, and < 6.0%. Both treatment approaches were well tolerated, and only 3.2% of participants discontinued the study due to adverse events. All hypoglycemic events (EC: n = 7 and MET: n = 3) were single, mild episodes and did not lead to study discontinuation. Conclusion Similar to the global population, long-term clinical benefits were achieved more frequently and without tolerability issues with EC versus standard-of-care MET in this Latin American sub-population. This study is registered with ClinicalTrials.gov, NCT01528254.Peer reviewe

EFECTO DE LA REFRIGERACIÓN SOBRE LA MOTILIDAD, INTEGRIDAD DE MEMBRANA ACROSOMAL Y REACCIÓN ACROSOMAL EN ESPERMATOZOIDES CANINOS

Métodos de preservación de espermatozoides mediante la refrigeración o el congelamiento han sido desarrollados para espermatozoides caninos; sin embargo, la tasa de fecundación artificial es baja, posiblemente por daños celulares aún no determinados. El objetivo de este estudio fue evaluar el efecto de la refrigeración sobre la motilidad, actividad mitocondrial, integridad de membrana acrosomal y reacción acrosomal en espermatozoides caninos incubados en tres medios distintos (Ferp Talp, CCMm, Sp Talp), utilizando nuevas metodologías (Mito Tracker, Lyso Tracker, SBTI). Los resultados indicaron una disminución significativa (p&lt;0.05) en la motilidad, viabilidad e integridad del acrosoma en espermatozoides refrigerados en comparación con los frescos; así como una dinámica de reacción diferente en espermatozoides refrigerados respecto a los frescos. Por otra parte, los medios Sp Talp y CCMm dieron mejores resultados en mantenimiento de la motilidad, actividad mitocondrial e integridad de membrana acrosomal.Preservation methods of spermatozoa using refrigeration have been developed for canine sperm; however, the rate of fertilization is still low, possibly due to cell damage for unknown reasons. The objective of this study was to evaluate the effect of refrigeration upon motility, mitochondrial activity, acrosomal membrane integrity, and acrosomal reaction in dog sperm incubated in three culture media (Ferp Talp, CCMm, Sp Talp) using new methodologies (Mito Tracker, Lyso Tracker, SBTI). The results indicated that exist a significant decrease (p&lt;0.05) in motility, mitochondrial activity, and acrosomal membrane integrity in refrigerated sperm in comparison with fresh sperm. Also, the dynamic of acrosomal reaction was different in refrigerated sperm in comparison with fresh sperm. The Sp Talp and CCMm media showed the best results in holding the mitochondrial activity and acrosomal membrane integrity

Reimagining pheromone signalling in the model nematode Caenorhabditis elegans

Caenorhabditis elegans is an important, widely used developmental and genetic model. A pheromone has long been known to cause juvenile developmental arrest in C. elegans, a phenomenon that is common among nematodes more widely. Many novel effects of this pheromone are now being discovered—most recently, that exogenous supply of this pheromone controls adult worms reproduction. Here, we suggest that to properly understand and interpret these phenomena, C. elegans natural ecology must be considered, about which rather little is known. With this perspective, we suggest that C. elegans pheromone signalling evolves very locally, such that there are different dialects of pheromone signalling among ecological communities and among kin groups, and we also argue that pheromone signals may also evolve to be manipulative and dishonest. New approaches must be undertaken to study these phenomena in C. elegans. While model systems have been tremendously important tools in modern biological research, taking account of their natural history is necessary, and key, to properly understand and interpret laboratory-based discoveries.understand and interpret laboratory-based discoveries

Arabidopsis leucine-rich repeat receptor–like kinase NILR1 is required for induction of innate immunity to parasitic nematodes

Plant-parasitic nematodes are destructive pests causing losses of billions of dollars annually. An effective plant defence against pathogens relies on the recognition of pathogen-associated molecular patterns (PAMPs) by surface-localised receptors leading to the activation of PAMP-triggered immunity (PTI). Extensive studies have been conducted to characterise the role of PTI in various models of plant-pathogen interactions. However, far less is known about the role of PTI in roots in general and in plant-nematode interactions in particular. Here we show that nematode-derived proteinaceous elicitor/s is/are capable of inducing PTI in Arabidopsis in a manner dependent on the common immune co-receptor BAK1. Consistent with the role played by BAK1, we identified a leucine-rich repeat receptor-like kinase, termed NILR1 that is specifically regulated upon infection by nematodes. We show that NILR1 is essential for PTI responses initiated by nematodes and nilr1 loss-of-function mutants are hypersusceptible to a broad category of nematodes. To our knowledge, NILR1 is the first example of an immune receptor that is involved in induction of basal immunity (PTI) in plants or in animals in response to nematodes. Manipulation of NILR1 will provide new options for nematode control in crop plants in future

Tomato TFT1 Is Required for PAMP-Triggered Immunity and Mutations that Prevent T3S Effector XopN from Binding to TFT1 Attenuate Xanthomonas Virulence

XopN is a type III effector protein from Xanthomonas campestris pathovar vesicatoria that suppresses PAMP-triggered immunity (PTI) in tomato. Previous work reported that XopN interacts with the tomato 14-3-3 isoform TFT1; however, TFT1's role in PTI and/or XopN virulence was not determined. Here we show that TFT1 functions in PTI and is a XopN virulence target. Virus-induced gene silencing of TFT1 mRNA in tomato leaves resulted in increased growth of Xcv ΔxopN and Xcv ΔhrpF demonstrating that TFT1 is required to inhibit Xcv multiplication. TFT1 expression was required for Xcv-induced accumulation of PTI5, GRAS4, WRKY28, and LRR22 mRNAs, four PTI marker genes in tomato. Deletion analysis revealed that the XopN C-terminal domain (amino acids 344–733) is sufficient to bind TFT1. Removal of amino acids 605–733 disrupts XopN binding to TFT1 in plant extracts and inhibits XopN-dependent virulence in tomato, demonstrating that these residues are necessary for the XopN/TFT1 interaction. Phos-tag gel analysis and mass spectrometry showed that XopN is phosphorylated in plant extracts at serine 688 in a putative 14-3-3 recognition motif. Mutation of S688 reduced XopN's phosphorylation state but was not sufficient to inhibit binding to TFT1 or reduce XopN virulence. Mutation of S688 and two leucines (L64,L65) in XopN, however, eliminated XopN binding to TFT1 in plant extracts and XopN virulence. L64 and L65 are required for XopN to bind TARK1, a tomato atypical receptor kinase required for PTI. This suggested that TFT1 binding to XopN's C-terminal domain might be stabilized via TARK1/XopN interaction. Pull-down and BiFC analyses show that XopN promotes TARK1/TFT1 complex formation in vitro and in planta by functioning as a molecular scaffold. This is the first report showing that a type III effector targets a host 14-3-3 involved in PTI to promote bacterial pathogenesis

Rotation and pulsation in Ap stars: first light results from TESS sectors 1 and 2

We present the first results from the Transiting Exoplanet Survey Satellite (TESS) on the ro- tational and pulsational variability of magnetic chemically peculiar A-type stars. We analyse TESS 2-min cadence data from sectors 1 and 2 on a sample of 83 stars. Five new rapidly oscillating Ap (roAp) stars are announced. One of these pulsates with periods around 4.7 min, making it the shortest period roAp star known to date. Four out of the five new roAp stars are multiperiodic. Three of these, and the singly-periodic one show the presence of rotational mode splitting. Individual frequencies are provided in all cases. In addition, seven previously known roAp stars are analysed. Additional modes of oscillation are found in some stars, while in others we are able to distinguish the true pulsations from possible aliases present in the ground-based data. We find that the pulsation amplitude in the TESS filter is typically a factor 6 smaller than that in the B filter which is usually used for ground-based observations. For four roAp stars we set constraints on the inclination angle and magnetic obliquity, through the application of the oblique pulsator model. We also confirm the absence of roAp-type pulsa- tions down to amplitude limits of 6 and 13 µmag, respectively, in two of the best characterised non-oscillating Ap (noAp) stars. We announce 27 new rotational variables along with their ro- tation periods, and provide different rotation periods for seven other stars. Finally, we discuss how these results challenge state-of-the-art pulsation models for roAp stars

TESS Cycle 1 observations of roAp stars with 2-min cadence data

We present the results of a systematic search for new rapidly oscillating Ap (roAp) stars using the 2-min cadence data collected by the Transiting Exoplanet Survey Satellite (TESS) during its Cycle 1 observations. We identify 12 new roAp stars. Amongst these stars we discover the roAp star with the longest pulsation period, another with the shortest rotation period, and six with multiperiodic variability. In addition to these new roAp stars, we present an analysis of 44 known roAp stars observed by TESS during Cycle 1, providing the first high-precision and homogeneous sample of a significant fraction of the known roAp stars. The TESS observations have shown that almost 60 per cent (33) of our sample of stars are multiperiodic, providing excellent cases to test models of roAp pulsations, and from which the most rewarding asteroseismic results can be gleaned. We report four cases of the occurrence of rotationally split frequency multiplets that imply different mode geometries for the same degree modes in the same star. This provides a conundrum in applying the oblique pulsator model to the roAp stars. Finally, we report the discovery of non-linear mode interactions in $\alpha$ Cir (TIC 402546736, HD 128898) around the harmonic of the principal mode -- this is only the second case of such a phenomenon...

3 HISTONE H4 ACETYLATION AT LYSINE 12 AND Cdc2a EXPRESSION ARE DECREASED IN AGED MOUSE GERMINAL VESICLE-STAGE OOCYTES

Ageing is a phenomenon related to mammalian female infertility. One cause of ageing-induced infertility is the abnormal meiotic maturation from germinal vesicle stage oocytes (GVs). GVs are immature oocytes, which stay arrested in the ovaries during the life span. The abnormal oocyte maturation in aged animals is partially originated from molecular changes, not well defined, such as chromatin modifications and differential gene expression. Here, we analyze chromatin modifications such as histone acetylation and the corresponding gene expression changes induced by ageing in mouse GVs. We measured by immunofluorescence histone H4 acetylation at lysine residues 5 (H4-K5), 8 (H4-K8), and 12 (H4-K12) in GVs collected from young (1 month old) and aged (12–18 months old) CDC1 female mice. Immunofluorescence was analyzed with a microscope (Leica TCS SP2 AOBS) and its image analysis software. Whereas H4-K5 and H4-K8 show similar acetylation levels in both young and old mice, significant lower acetylation of H4-K12 is detected in GVs from old mice. Since H4-K12 acetylation has been related to Cdc2a expression during oocyte maturation (Akiyama et al. 2004 Mol. Reprod. Dev. 69, 222–227; Minuzzo et al. 2005 Mol. Pharmacol. 68, 1496–1503), we investigated whether Cdc2a mRNA levels change in aged mice. Cdc2a expression was measured by RT-PCR and quantified with a densitometer (BioRad GS800). We observed a decrease of Cdc2a expression in GVs of old mice. This result is further confirmed by an immunofluorescence analysis where lower levels of Cdc2a protein in old mouse GVs was observed. In conclusion, we find that the levels of H4-K12 acetylation and Cdc2a mRNA are lower in old compared to young mouse GVs. Our observations suggest that ageing affects histone modifications such as H4-K12, which might induce chromatin remodelling and gene expression changes like that of Cdc2a.Peer reviewe

Intra-amoebic localization of Arcobacter butzleri as an endocytobiont of Acanthamoeba castellanii

Acanthamoeba castellanii is a free-living amoeba found mainly in humid environments and Arcobacter butzleri is an emerging zoonotic pathogen, both can establish in vitro endosymbiotic relationships in the absence of bacterial replication. We analyzed the localization of A. butzleri within A. castellanii establishing their association with endoplasmic reticulum vesicles and mitochondria. Through confocal microscopy, we observed that during the early stages of endosymbiosis, there is not colocalization between amoebic vacuoles containing A. butzleri and mitochondria or ER vesicles of A. castellanii. Considering that energy production of this bacterium occurs via metabolism of amino acids or the tricarboxylic acid cycle, these results contribute to explain the absence of bacterial replication, since A. butzleri would not have access to the nutrients found in endoplasmic reticulum vesicles and mitochondria. In addition, we observe that A. butzleri induces significantly the actin polymerization of A. castellanii during the early stages of endosymbiosis