Biology subjects

Acosta, H.

Publications and source records attributed to Acosta, H..

5 recordsLinked to original sources

bioRxiv2023

Metabolic changes that allow Plasmodium falciparum artemisinin-resistant parasites to tolerate the oxidative stress

1.1.1 BackgroundArtemisinin-based treatments (ACTs) are the first therapy currently used to treat malaria produced by Plasmodium falciparum. However, in recent years increasing evidence shows that some strains of P. falciparum are less susceptible to ACT in the Southeast Asian region. 1.2 Materials & MethodsA data reanalysis of several omics approaches currently available about parasites of P. falciparum that have some degree of resistance to ACT was carried out. The data used was from transcriptomics and metabolomics studies. One mitochondrial carrier of the parasite possibly involved in the mechanisms of tolerance to oxidative stress was modelled and subjected to molecular dockings with citrate and oxoglutarate. 1.3 ResultsAn increase in glutathione production was detected, changing the direction of the flux of metabolites in the tricarboxylic acid cycle, and boosting glucose consumed. The models of the mitochondrial carrier, called PfCOCP, show that it may be important in transporting citrate and oxoglutarate from the mitochondrial matrix to cytosol. If so, it may allow the parasite to tolerate the oxidative stress produced by artemisinin. 1.4 ConclusionsThis in-silico analysis shows that P. falciparum may tolerate the artemisinins oxidative stress through metabolic changes not reported before, showing the need for further research on the many metabolic aspects linked to this phenotype.

bioinformatics↗

bioRxiv2022

The Nanog epigenetic remodeling complex was essential to vertebrate mesoderm evolution

Pluripotency defines the unlimited potential of cells in the primitive ectoderm of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programing of pluripotency evolved has been obscured by the study of early development in models from lower vertebrates in which pluripotency is not conserved. Here we investigated how the axolotl ortholog of the mammalian core pluripotency factor NANOG, programs pluripotency during axolotl development to model the tetrapod ancestor from which terrestrial vertebrates evolved. We show that in axolotl primitive ectoderm (animal caps; AC) NANOG synergizes with NODAL activity and the epigenetic modifying enzyme DPY30 to direct the deposition of H3K4me3 in chromatin prior to the waves of transcription required for lineage commitment and developmental progression. We show that the interaction of NANOG and NODAL with DPY30 is required to direct development downstream of pluripotency and this is conserved in axolotls and human. These data demonstrate that the interaction of NANOG and NODAL signaling represents the basal state of vertebrate pluripotency.

developmental biology↗

bioRxiv2022

Intranasal Nanoemulsion Adjuvanted S-2P Vaccine Demonstrates Protection in Hamsters and Induces Systemic, Cell-Mediated and Mucosal Immunity in Mice

With the rapid progress made in the development of vaccines to fight the SARS-CoV-2 pandemic, almost >90% of vaccine candidates under development and a 100% of the licensed vaccines are delivered intramuscularly (IM). While these vaccines are highly efficacious against COVID-19 disease, their efficacy against SARS-CoV-2 infection of upper respiratory tract and transmission is at best temporary. Development of safe and efficacious vaccines that are able to induce robust mucosal and systemic immune responses are needed to control new variants. In this study, we have used our nanoemulsion adjuvant (NE01) to intranasally (IN) deliver stabilized spike protein (S-2P) to induce immunogenicity in mouse and hamster models. Data presented demonstrate the induction of robust immunity in mice resulting in 100% seroconversion and protection against SARS-CoV-2 in a hamster challenge model. There was a significant induction of mucosal immune responses as demonstrated by IgA- and IgG-producing memory B cells in the lungs of animals that received intranasal immunizations compared to an alum adjuvanted intramuscular vaccine. The efficacy of the S-2P/NE01 vaccine was also demonstrated in an intranasal hamster challenge model with SARS-CoV-2 and conferred significant protection against weight loss, lung pathology, and viral clearance from both upper and lower respiratory tract. Our findings demonstrate that intranasal NE01-adjuvanted vaccine promotes protective immunity against SARS-CoV-2 infection and disease through activation of three arms of immune system: humoral, cellular, and mucosal, suggesting that an intranasal SARS-CoV-2 vaccine may play a role in addressing a unique public health problem and unmet medical need.

immunology↗

bioRxiv2021

Prediction and validation of the three-dimensional structure of glucokinase-1 from Phytophthora infestans

According to its primary structure, the [PITG_06016] gene encodes for one of the 7 glucokinases present in Phytophthora infestans (PiGlcK-1), the causal agent of late blight disease. Currently, there are no structural studies of any of its enzymes, being the determination of the three-dimensional (3D) structure of PiGlcK-1 a necessary contribution in the deduction of its functions, its interaction with ligands, and possible regulatory mechanisms. In this work we present the first structural model obtained by in silico tools for PiGlcK-1. For the prediction of this model, different algorithms were used to find the best annealing, refinement, and qualitative evaluation of them. A structural comparison of the predicted model with other structures of crystallized kinase enzymes allowed us to identify the regions of interaction with their classical substrates (glucose and ATP), as well as to identify the amino acid residues involved in the binding of other substrates such as fructose and ADP. In addition, we propose a possible recognition region of PPi, an activator of kinase activity that includes the GXGE motif, conserved in enzymes of the ribokinase (RK) family, which distinguishes this PiGlcK-1 from a classical glucokinase. Accordingly, these findings suggest PPi-binding motif as potential targets for the development of inhibitors of PiGlcK-1 activity.

biochemistry↗

bioRxiv2020

Linkage Analysis in Caribbean Hispanic Families with Puerto Rican Ancestry Idenitfies an Alzheimer Disease Locus on chromosome 9.

BackgroundThe ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease. In this study, we performed whole genome sequencing in multiplex Caribbean Hispanic Puerto Rican families to identify rare causal variants influencing Alzheimer disease through linkage and segregation-based approaches. MethodsAs part of the Puerto Rican Alzheimer Disease Initiative, whole genome sequencing data were generated for 100 individuals (61 affected) from 23 Puerto Rican families. To identify the genetic loci likely to carry risk variants, we performed a parametric multipoint affected individuals-only linkage analysis using MERLIN software. Following the linkage analysis, we identified the consensus region (heterogeneity logarithm of the odds score (HLOD) > 5.1), annotated variants using Ensembl Variant Effect Predictor, and combined annotation dependent depletion score (CADD). Finally, we prioritized variants according to allele frequency (< 0.01), function (CADD > 10), and complete segregation among affected individuals. ResultsA locus at 9p21 produced a linkage HLOD score of 5.1 in the parametric affecteds-only multipoint affected individuals-only model supported by 9 families. Through the prioritization step, we selected 36 variants (22 genic variants). Candidate genes in the regions include C9orf72, UNC13B, and ELAVL2. ConclusionsLinkage analysis of Caribbean Hispanics Puerto Rican families confirmed previously reported linkage to 9p21 in non-Hispanic White and Israeli-Arap families. Our results suggest several candidates in the region as conferring AD risk. Identified putative damaging rare variants in multiplex families indicates the critical role of rare variation in Alzheimer disease etiology.

genetics↗