Venezuelan Institute for Scientific Research

The fitness of multidrug-resistant tuberculosis (MDR-TB) is thought to be an important determinant of a strain's ability to be transmitted and cause outbreaks. Studies in the laboratory have demonstrated that MDR-TB strains have reduced fitness but the relative transmissibility of MDR-TB versus drug-susceptible (DS) TB strains in human populations remains unresolved. We used data on genomic clustering from our previous molecular epidemiological study in Songjiang (2011-2020) and Wusheng (2009-2020), China, to compare the relative transmissibility of MDR-TB versus DS-TB. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms and the risk for MDR-TB clustering was analyzed by logistic regression. In total, 2212 culture-positive pulmonary TB patients were enrolled in Songjiang and 1289 in Wusheng. The clustering rates of MDR-TB and DS-TB strains were 19.4% (20/103) and 26.3% (509/1936), respectively in Songjiang, and 43.9% (29/66) and 26.0% (293/1128) in Wusheng. The risk of MDR-TB clustering was 2.34 (95% CI 1.38-3.94) times higher than DS-TB clustering in Wusheng and 0.64 (95% CI 0.38-1.06) times lower in Songjiang. Neither lineage 2, compensatory mutations nor rpoB S450L were significantly associated with MDR-TB transmission, and katG S315T increased MDR-TB transmission only in Wusheng (OR 5.28, 95% CI 1.42-19.21). MDR-TB was not more transmissible than DS-TB in either Songjiang or Wusheng. It appears that the different transmissibility of MDR-TB in Songjiang and Wusheng is likely due to differences in the quality of the local TB control programs. These results suggest that the most effective way to control MDR-TB is by improving local TB control programs.

On the Tibetan Plateau, most tuberculosis is caused by indigenous Mycobacterium tuberculosis strains with a monophyletic structure and high-level drug resistance. This study investigated the emergence, evolution, and transmission dynamics of multidrug-resistant tuberculosis (MDR-TB) in Tibet. The whole-genome sequences of 576 clinical strains from Tibet were analyzed with the TB-profiler tool to identify drug-resistance mutations. The evolution of the drug resistance was then inferred based on maximum-likelihood phylogeny and dated trees that traced the serial acquisition of mutations conferring resistance to different drugs. Among the 576 clinical M. tuberculosis strains, 346 (60.1%) carried at least 1 resistance-conferring mutation and 231 (40.1%) were MDR-TB. Using a pairwise distance of 50 single nucleotide polymorphisms (SNPs), most strains (89.9%, 518/576) were phylogenetically separated into 50 long-term transmission clusters. Eleven large drug-resistant clusters contained 76.1% (176/231) of the local multidrug-resistant strains. A total of 85.2% of the isoniazid-resistant strains were highly transmitted with an average of 6.6 cases per cluster, of which most shared the mutation KatG Ser315Thr. A lower proportion (71.6%) of multidrug-resistant strains were transmitted, with an average cluster size of 2.9 cases. The isoniazid-resistant clusters appear to have undergone substantial bacterial population growth in the 1970s to 1990s and then subsequently accumulated multiple rifampicin-resistance mutations and caused the current local MDR-TB burden. These findings highlight the importance of detecting and curing isoniazid-resistant strains to prevent the emergence of endemic MDR-TB. IMPORTANCE Emerging isoniazid resistance in the 1970s allowed M. tuberculosis strains to spread and form into large multidrug-resistant tuberculosis clusters in the isolated plateau of Tibet, China. The epidemic was driven by the high risk of transmission as well as the potential of acquiring further drug resistance from isoniazid-resistant strains. Eleven large drug-resistant clusters consisted of the majority of local multidrug-resistant cases. Among the clusters, isoniazid resistance overwhelmingly evolved before all the other resistance types. A large bacterial population growth of isoniazid-resistant clusters occurred between 1970s and 1990s, which subsequently accumulated rifampicin-resistance-conferring mutations in parallel and accounted for the local multidrug-resistant tuberculosis burden. The results of our study indicate that it may be possible to restrict MDR-TB evolution and dissemination by prioritizing screening for isoniazid (INH)-resistant TB strains before they become MDR-TB and by adopting measures that can limit their transmission.

“Druggable genome” is a novel concept that emphasizes the importance of using the information of genome-wide genetic studies for drug discovery and development. Successful precedents of “druggable genome” have recently emerged for some disorders by combining genomic and gene expression profiles with medical and pharmacological knowledge. One of the key premises for the success is the good access to disease-relevant tissues from “living” patients in which we may observe molecular expression changes in association with symptomatic alteration. Thus, given brain biopsies are ethically and practically difficult, the application of the “druggable genome” approach is challenging for neuropsychiatric disorders. Here, to fill this gap, we propose the use of olfactory neuronal cells (ONCs) biopsied and established via nasal biopsy from living subjects. By using candidate genes that were proposed in a study in which genetic information, postmortem brain expression profiles, and pharmacological knowledge were considered for cognition in the general population, we addressed the utility of ONCs in the “druggable genome” approach by using the clinical and cell resources of an established psychosis cohort in our group. Through this pilot effort, we underscored the chloride voltage-gated channel 2 (CLCN2) gene as a possible druggable candidate for early-stage psychosis. The CLCN2 gene expression was associated with verbal memory, but not with other dimensions in cognition, nor psychiatric manifestations (positive and negative symptoms). The association between this candidate molecule and verbal memory was also confirmed at the protein level. By using ONCs from living subjects, we now provide more specific information regarding molecular expression and clinical phenotypes. The use of ONCs also provides the opportunity of validating the relationship not only at the RNA level but also protein level, leading to the potential of functional assays in the future. Taken together, we now provide evidence that supports the utility of ONCs as a tool for the “druggable genome” approach in translational psychiatry.

Synergistic studies of microorganisms in the last decade have been mostly directed towards their biofertilizing effects on growth and crop yield. Our research examines the role of a microbial consortium (MC) on physiological responses of Allium cepa hybrid F1 2000 under water and nutritional deficit in a semi-arid environment. An onion crop was established with normal irrigation (NIr) (100% ETc) and water deficit (WD) (67% ETc) and different fertilization treatments (MC with 0%, 50% and 100% NPK). Gas exchange (Stomatal conductance (Gs), transpiration (E) and CO 2 assimilation rates (A)) and leaf water status were evaluated throughout its growth cycle. The MC + 50% NPK treatment with NIr maintained similar A rates to the production control. A. cepa decreased Gs by approximately 50% in the WD treatment. The highest water use efficiency (WUE) and an increase in the modulus of elasticity in response to water stress were obtained for the 100% NPK treatment under non-inoculated WD. The onion hybrid F1 2000 was tolerant to water stress and under non-limiting nutrient conditions, irrigation may be reduced. The MC facilitated the availability of nutrients under NIr allowing a 50% reduction in the application of high doses of fertilization without affecting yield, resulting in a suitable agroecological strategy for this crop. Keywords CO2 assimilation · Leaf conductance · Onion · Nutrient stress · PGPR · Water stress

The resources and platforms available on the internet for collect-ing and sharing information and performing genomic sequence analysis have made it possible to follow closely the evolution the evolution of SARS-CoV-2. However, the current monkeypox outbreak in the world brings us back to the need to use these resources to appraise the extent of this outbreak. The ob-jective of this work was an analysis of the information presented so far in the genomic database GISAID EpiPox™, using various tools available on the web. The results indicate that the monkeypox outbreak is referred as MPXV clade II B.1 lineage and sub-lineages, isolated from male patients mainly from the Euro-pean and American continents. In the current scenario, the access to genomic sequences, epidemiological information, and tools available to the scientific community is of great importance for global public health in order to follow the evolution of pathogens.

Potential effects of climate change on plant reproductive phenology include asynchronies with pollinators, and reductions in plant fitness, leading to extinction and loss of ecosystem function. In particular plant phenology is sensitive to extreme weather events, which are occurring with increasing severity and frequency in recent decades and are linked to anthropogenic climate change and shifts in atmospheric circulation. For 15 plant species in a Venezuelan cloud forest, we documented dramatic changes in monthly flower and fruit community composition over a 35-year time series, from 1983 to 2017, and these changes were linked directly to higher temperatures, lower precipitation, and decreased soil water availability. The patterns documented here do not mirror trends in temperate zones, but corroborate results from the Asian tropics. More intense droughts are predicted to occur in the region, which will cause dramatic changes in flower and fruit availability. This article is protected by copyright. All rights reserved.

Understanding complexity in fluid mechanics is a major problem that has attracted the attention of physicists and mathematicians during the last decades. Using the concept of renormalization in dynamics, we show the existence of a locally dense set G\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathscr {G}}$$\end{document} of stationary solutions to the Euler equations in R3\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathbb {R}}^3$$\end{document} such that each vector field X∈G\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$X\in {\mathscr {G}}$$\end{document} is universal in the sense that any area preserving diffeomorphism of the disk can be approximated (with arbitrary precision) by the Poincaré map of X at some transverse section. We remark that this universality is approximate but occurs at all scales. In particular, our results establish that a steady Euler flow may exhibit any conservative finite codimensional dynamical phenomenon; this includes the existence of horseshoes accumulated by elliptic islands, increasing union of horseshoes of Hausdorff dimension 3 or homoclinic tangencies of arbitrarily high multiplicity. The steady solutions we construct are Beltrami fields with sharp decay at infinity. To prove these results we introduce new perturbation methods in the context of Beltrami fields that allow us to import deep techniques from bifurcation theory: the Gonchenko-Shilnikov-Turaev universality theory and the Newhouse and Duarte theorems on the geometry of wild hyperbolic sets. These perturbation methods rely on two tools from linear PDEs: global approximation and Cauchy–Kovalevskaya theorems. These results imply a strong version of V.I. Arnold’s vision on the complexity of Beltrami fields in Euclidean space.

BACKGROUND: As international commitments to prevent extinction and improve the status of threatened species go unmet, a crisis of species loss unprecedented in human history intensifies. The field of conservation biology has, however, begun to demonstrate that species can be recovered, and extinctions in the wild prevented and even reversed. These successes suggest that the post-2020 global biodiversity draft targets of arresting the increase in extinction rates and reducing the proportion of threatened species are within our capacity. A nexus of responsibility, vulnerability, and opportunity lies in those species that-having been entirely extirpated in the wild-exist solely in zoos, aquariums, botanical gardens, or seed banks-i.e., those that qualify for the International Union for Conservation of Nature (IUCN) Red List of Threatened

Duchenne muscular dystrophy (DMD) is an inherited muscular disorder caused by mutations in the dystrophin gene. DMD patients have hypoxemic events due to sleep-disordered breathing. We reported an anomalous regulation of resting intracellular Ca2+ ([Ca2+]i) in vascular smooth muscle cells (VSMCs) from a mouse (mdx) model of DMD. We investigated the effect of hypoxia on [Ca2+]i in isolated and quiescent VSMCs from C57BL/10SnJ (WT) and C57BL/10ScSn-Dmd (mdx) male mice. [Ca2+]i was measured using Ca2+-selective microelectrodes under normoxic conditions (95% air, 5% CO2) and after hypoxia (glucose-free solution aerated with 95% N2-5% CO2 for 30 min). [Ca2+]i in mdx VSMCs was significantly elevated compared to WT under normoxia. Hypoxia-induced [Ca2+]i overload, which was significantly greater in mdx than in WT VSMCs. A low Ca2+ solution caused a reduction in [Ca2+]i and prevented [Ca2+]i overload secondary to hypoxia. Nifedipine (10 µM), a Ca2+ channel blocker, did not modify resting [Ca2+]i in VSMCs but partially prevented the hypoxia-induced elevation of [Ca2+]i in both genotypes. SAR7334 (1 µM), an antagonist of TRPC3 and TRPC6, reduced the basal and [Ca2+]i overload caused by hypoxia. Cell viability, assessed by tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, was significantly reduced in mdx compared to WT VSMCs. Pretreatment with SAR7341 increases cell viability in normoxic mdx (p < 0.001) and during hypoxia in WT and mdx VSMCs. These results provide evidence that the lack of dystrophin makes VSMCs more susceptible to hypoxia-induced [Ca2+]i overload, which appears to be mediated by increased Ca2+ entry through L-type Ca2+ and TRPC channels.

In a time of rapid global change, the question of what determines patterns in species abundance distribution remains a priority for understanding the complex dynamics of ecosystems. The constrained maximization of information entropy provides a framework for the understanding of such complex systems dynamics by a quantitative analysis of important constraints via predictions using least biased probability distributions. We apply it to over two thousand hectares of Amazonian tree inventories across seven forest types and thirteen functional traits, representing major global axes of plant strategies. Results show that constraints formed by regional relative abundances of genera explain eight times more of local relative abundances than constraints based on directional selection for specific functional traits, although the latter does show clear signals of environmental dependency. These results provide a quantitative insight by inference from large-scale data using cross-disciplinary methods, furthering our understanding of ecological dynamics.

Purpose Plant domestication altered leaf litter quality. Since litter traits relate to soil functions and organisms (i.e., litter decomposition and soil decomposer communities), in this study we explore if domestication-induced changes in litter quality have affected their decomposability, and bacterial, fungal, and nematode communities in the soil. Methods We collected leaf litter from herbaceous crops and their wild progenitors, and measured litter chemical and physical traits. Then, we performed a litter decomposition assay on a common soil. After three months of litter incubation, we measured mass loss, nematode richness and community composition in ten crops. We also measured soil bacterial and fungal richness and community composition in six crops. Results Domesticated litters had less carbon (C) and leaf dry matter content (LDMC), which accelerated decomposition in comparison to wild litters. Fungal richness was higher in microcosms incubated with domesticated litters, while the effects of domestication on bacterial richness differed among crops. Domestication did not affect nematode richness. The effects of domestication on bacterial and fungal community compositions differed among crops. Soils with domesticated litters tended to have nematode communities with a higher abundance of bacterial feeding nematodes, in comparison to soils fed with wild litters. Conclusion Domestication altered decomposition at different levels. Leaf litter decomposability increased with domestication, which might alter resource inputs into the soil. Feeding soils with domesticated litters had idiosyncratic effects on soil microbes, but consistent effects on soil nematodes. Overall, domestication altered the linkages between crop residues and soil communities differently for bacteria, fungi, and nematodes.

ClpXP complex is an ATP-dependent mitochondrial matrix protease that binds, unfolds, translocates, and subsequently degrades specific protein substrates. Its mechanisms of operation are still being debated, and several have been proposed, including the sequential translocation of two residues (SC/2R), six residues (SC/6R), and even long-pass probabilistic models. Therefore, it has been suggested to employ biophysical-computational approaches that can determine the kinetics and thermodynamics of the translocation. In this sense, and based on the apparent inconsistency between structural and functional studies, we propose to apply biophysical approaches based on elastic network models (ENM) to study the intrinsic dynamics of the theoretically most probable hydrolysis mechanism. The proposed models ENM suggest that the ClpP region is decisive for the stabilization of the ClpXP complex, contributing to the flexibility of the residues adjacent to the pore, favoring the increase in pore size and, therefore, with the energy of interaction of its residues with a larger portion of the substrate. It is predicted that the complex may undergo a stable configurational change once assembled and that the deformability of the system once assembled is oriented, to increase the rigidity of the domains of each region (ClpP and ClpX) and to gain flexibility of the pore. Our predictions could suggest under the conditions of this study the mechanism of the interaction of the system, of which the substrate passes through the unfolding of the pore in parallel with a folding of the bottleneck. The variations in the distance calculated by molecular dynamics could allow the passage of a substrate with a size equivalent to ∼3 residues. The theoretical behavior of the pore and the stability and energy of binding to the substrate based on ENM models suggest that in this system, there are thermodynamic, structural, and configurational conditions that allow a possible translocation mechanism that is not strictly sequential.

Background The Horned Screamer (Anhima cornuta) is an herbivorous bird that inhabits wetlands of the South American tropical region. We hypothesize that due to its herbivorous niche, its digestive tract compartments may have bacteria specialized in fermenting complex plant carbohydrates. To test this hypothesis, we compared the bacterial communities along the gastrointestinal tract (GIT) of a Horned Screamer captured in Venezuela. Methods Samples were taken from tissues and content of the proventriculus and the small intestine (considered for this study as upper GIT), and the large intestine and cecum (lower GIT). The bacterial community was characterized by sequencing the V4 region of the 16S rRNA gene. Bioinformatic analysis was performed using QIIME, QIITA and Microbiome Analyst. The association between microbial taxonomy and function was analyzed using their Greengenes OTU IDs and a custom KEGG BRITE hierarchical tree and visualized with BURRITO. Results The Screamer’s gastrointestinal microbiota was composed by seven phyla being Firmicutes and Bacteroidetes the most predominant. The dominant taxa in the upper GIT were Helicobacter, Vibrio, Enterobacter, Acinetobacter and Staphylococcus. The dominant taxa in the lower GIT were Oribacterium, Blautia, Roseburia, Ruminococcus, Desulfovibrio, Intestinimonas, Marvinbryantia and Parabacteroides. Complete degradation of cellulose to the end-products acetate, propanoate, butanoate and acetoacetate was found in the upper and lower GIT without significant differences. Conclusion Our study confirmed changes in bacterial community composition throughout the GIT of the Horned Screamer primarily associated with the production of metabolic end-products of carbohydrate digestion essential for the fermentation of the herbivorous diet.

The earliest Bronze Age Mediterranean primate representations on frescoes are found at the Aegean sites of Knossos (Crete) and Akrotiri (Thera). By contrast, monkeys have so far been missing from Mycenaean frescoes in mainland Greece. A fresco fragment of a cultic scene from Tiryns changes this; it depicts a bipedal partial lower body, with a hanging tail. This image, previously interpreted as a human wearing an animal hide, had already been suggested to represent a monkey. A re-examination of this miniature fresco identified various features that seem to confirm the representation of a monkey, most probably of a baboon-like primate. Assuming that the fresco from Tiryns is part of a cult scene, similar to those from Akrotiri, this adds a further image to a small corpus of Aegean depictions connecting monkeys with important female figures or deities. Furthermore, the Tiryns fresco fragment indicates that primates were not entirely absent from local Mycenaean iconography.

Oxidative stress is the result of an imbalance between the formation of reactive oxygen species (ROS) and the levels of enzymatic and non-enzymatic antioxidants. The assessment of biological redox status is performed by the use of oxidative stress biomarkers. An oxidative stress biomarker is defined as any physical structure or process or chemical compound that can be assessed in a living being (in vivo) or in solid or fluid parts thereof (in vitro), the determination of which is a reproducible and reliable indicator of oxidative stress. The use of oxidative stress biomarkers allows early identification of the risk of developing diseases associated with this process and also opens up possibilities for new treatments. At the end of the last century, interest in oxidative stress biomarkers began to grow, due to evidence of the association between the generation of free radicals and various pathologies. Up to now, a significant number of studies have been carried out to identify and apply different oxidative stress biomarkers in clinical practice. Among the most important oxidative stress biomarkers, it can be mentioned the products of oxidative modifications of lipids, proteins, nucleic acids, and uric acid as well as the measurement of the total antioxidant capacity of fluids in the human body. In this review, we aim to present recent advances and current knowledge on the main biomarkers of oxidative stress, including the discovery of new biomarkers, with emphasis on the various reproductive complications associated with variations in oxidative stress levels.

Pregnancies are a critical window period for environmental influences over the mother and the offspring. There is a growing body of evidence associating indoor and outdoor air pollution exposure to adverse pregnancy outcomes such as preterm birth and hypertensive disorders of pregnancy. Particulate matter (PM) could trigger oxi-inflammation and could also reach the placenta leading to placental damage with fetal consequences. The combination of strategies such as risk assessment, advise about risks of environmental exposures to pregnant women, together with nutritional strategies and digital solutions to monitor air quality can be effective in mitigating the effects of air pollution during pregnancy.

Background: Several clinical studies have shown that cellular therapy based on mesenchymal stromal cells (MSCs) transplantation may accelerate wound healing. One major challenge is the delivery system used for MSCs transplantation. In this work, we evaluated the capacity of a scaffold based on polyethylene terephthalate (PET) to maintain the viability and biological functions of MSCs, in vitro. We examined the capacity of MSCs loaded on PET (MSCs/PET) to induce wound healing in an experimental model of full-thickness wound. Methods: Human MSCs were seeded and cultured on PET membranes at 37 °C for 48 h. Adhesion, viability, proliferation, migration, multipotential differentiation and chemokine production were evaluated in cultures of MSCs/PET. The possible therapeutic effect of MSCs/PET on the re-epithelialization of full thickness wounds was examined at day 3 post-wounding in C57BL/6 mice. Histological and immunohistochemical (IH) studies were performed to evaluate wound re-epithelialization and the presence of epithelial progenitor cells (EPC). As controls, wounds without treatment or treated with PET were established. Results: We observed MSCs adhered to PET membranes and maintained their viability, proliferation and migration. They preserved their multipotential capacity of differentiation and ability of chemokine production. MSCs/PET implants promoted an accelerated wound re-epithelialization, after three days post-wounding. It was associated with the presence of EPC Lgr6+ and K6+. Discussion: Our results show that MSCs/PET implants induce a rapid re-epithelialization of deep- and full-thickness wounds. MSCs/PET implants constitute a potential clinical therapy for treating cutaneous wounds.