Biology subjects

Espinosa, J.

Publications and source records attributed to Espinosa, J..

7 recordsLinked to original sources

bioRxiv2025

Deciphering the role of autophagy under Cd toxicity in Arabidopsis thaliana

Cadmium (Cd) is a toxic pollutant in soil and water affecting plants, animals, and humans. Autophagy, a cellular recycling process, is crucial for different biotic and abiotic plant stress responses. This study explores the autophagy role in Arabidopsis under Cd stress, using wild-type, autophagy-deficient mutants (atg5, and atg7) and overexpressing lines (35S:ATG5, 35S:ATG7). Cd exposure induced autophagy, as evidenced by ATG8a and ATG8a-PE accumulation, GFP-ATG8a fluorescence, and upregulation of ATG genes and proteins. Responses differed between Col-0 and Ws backgrounds, with Ws showing higher Cd tolerance. atg5 mutants were more sensitive to Cd, indicating the autophagy protective role, whereas ATG5/ATG7 overexpression did not significantly enhance Cd tolerance. Although oxidative stress may activate autophagy, ATG5/ATG7 overexpression did not significantly change the oxidative stress response. Notably, atg5 mutants displayed marked disruptions in metal/ion homeostasis under control and Cd conditions, reinforcing autophagys role inion homeostasis. In contrast, atg7 showed no significant differences from its WT (Ws), suggesting genotype-specific effects. Transcriptional analysis of metal transporters and ion flux analyses indicates that autophagy can regulate metal/ion accumulation through transcriptional control and post-translational modifications (e.g., ROS) with a differential response being observed between Ws and Col-0 plants.

plant biology↗

bioRxiv2025

Enterococcus faecium sagA mutants have cell envelope defects influencing antibiotic resistance and bacteriophage susceptibility

Enterococcus faecium is a Gram-positive bacterium that is resident to the intestines of animals including humans. E. faecium is also an opportunistic pathogen that causes multidrug resistant (MDR) infections. Bacteriophages (phages) have been proposed as therapeutics for the treatment of MDR infections, however, an obstacle for phage therapy is the emergence of phage resistance. Despite this, the development of phage resistance can impact bacterial fitness, thus, understanding the molecular basis of fitness costs associated with phage resistance can likely be leveraged as an antimicrobial strategy. We discovered that phage resistant E. faecium harbor mutations in the cell wall hydrolase gene sagA. SagA cleaves crosslinked peptidoglycan (PG) involved in PG remodeling. We show that mutations in sagA compromise E. faecium PG hydrolysis rendering them sensitive to {beta}-lactam antibiotics. sagA mutants have cell envelope integrity defects, increased cellular permeability, and aberrant distribution of penicillin binding proteins. This corresponds to a growth defect where cells have abnormal division septa, membrane blebbing, and the formation of mini cells. The dysregulation of the cell envelope in sagA mutants alters the binding of phages to the E. faecium cell surface. Our data support a model where phage infection of E. faecium requires phages to localize to sites of peptidoglycan remodeling at the cell poles and division septa. Our findings show that by altering the function of a single PG hydrolase, E. faecium loses intrinsic {beta}-lactam resistance. This indicates that phage therapy could help revive certain antibiotics when used in combination.

microbiology↗

bioRxiv2024

Metabolic vulnerabilities in Down syndrome B-cell acute lymphoblastic leukemia can be targeted using Venetoclax

Children with Down syndrome (DS) and B-cell acute lymphoblastic leukemia (B-ALL) are at increased risk for treatment-related mortality and relapse, highlighting the need for new therapies. Leukemia cell lines (CLs) have been fundamental to understanding therapeutic responses to pharmacological agents. We generated three DS B-ALL CLs characterized with diverse genomic alterations, including IGH::CRLF2 rearrangement (BCR::ABL1 like), mutations in FLT3 and TP53, and a novel ERG::CEBPD rearrangement. DS CLs had diminished proliferation, metabolism, and mitochondrial function when compared to non-DS (NDS) CLs and interestingly, these findings were similar to NDS Philadelphia chromosome-like (Ph-like) B-ALL CLs. Based on similar mitochondrial defects and prior preclinical data using Venetoclax for Ph-like B-ALL, we hypothesized that Venetoclax would be effective in DS. Intriguingly, Venetoclax was more effective in DS when compared to both NDS and Ph-like CLs. Efficacy was observed in DS patient derived xenografts (PDXs) and diagnostic/relapsed patient samples treated with Venetoclax, which synergized with Trametinib and Vincristine. Mass spectrometry-based multiomics analyses in DS and NDS B-ALL patient samples revealed an enriched metabolite profile in DS, particularly in the hubs of glucose metabolism and polyunsaturated phosphatidylcholines and phosphatidylinositols. Transcriptome analyses in DS B-ALL patients (n=249) supported enhanced glucose and fatty acid metabolism. Glucose regulated B-ALL viability through de novo serine biosynthesis. Targeting serine synergized with Venetoclax in DS B-ALL CLs. In summary, we have generated novel tools for studying DS B-ALL and identify altered metabolism in DS that responds to Venetoclax.

cancer biology↗

bioRxiv2021

Machine learning techniques to derive bioclimatic classifications for Colombia

Bioclimatic classifications seek to divide a study region into geographic areas with similar bioclimatic characteristics. In this study we proposed two bioclimatic classifications for Colombia using machine learning techniques. We firstly characterized the precipitation space of Colombia using principal component analysis. Based on Lang classification, we then projected all background sites in the precipitation space with their corresponding categories. We sequentially fit logistic regression models to reclassify all background sites in the precipitation space with six redefined Lang categories. New categories were the used to define a new modified Lang and Caldas-Lang classifications.

ecology↗

bioRxiv2021

A supervised learning algorithm to evaluate occurrence records in virtual species

Digital and open access of occurrence data have encouraged the development of tools to improve biodiversity conservation and management. In this study, we proposed a methodology to evaluate point-occurrence records based on expert knowledge. We firstly generated virtual data to test our methodology without confounding factors by simulating geographical distributions, virtual sampling, and expert checking of occurrence records. We used a set of non-linear bioclimatic variables and principal component analysis (PCA) to define a duality function between niche and biotope spaces. Subsequently, a supervised-learning model was fit to classify records between true and doubtful presence based on the virtual expert checking. We then tested our methodology using three virtual species and 10-fold cross validation. Also, we evaluated the prediction performance of the supervise model compared with the virtual observer using a virtual external database of occurrence data.

ecology↗

bioRxiv2020

Enterococcus peptidoglycan remodeling promotes immune checkpoint inhibitor therapy

The antitumor efficacy of cancer immunotherapy has been correlated with specific species within the gut microbiota. However, molecular mechanisms by which these microbes affect host response to immunotherapy remain elusive. Here we show that specific members of the bacterial genus Enterococcus can promote anti-PD-L1 immunotherapy in mouse tumor models. The active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote antitumor activity of clinically approved checkpoint targets, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also promoted checkpoint inhibitor antitumor activity. Our data suggest that microbiota species with unique peptidoglycan remodeling activity may enhance immunotherapy and could be leveraged for next-generation adjuvants. One Sentence SummaryA conserved family of secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus promote antitumor activity of immune checkpoint inhibitors.

cancer biology↗

bioRxiv2020

JAK1 inhibition blocks lethal sterile immune responses:implications for COVID-19 therapy

Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic. One Sentence SummaryInhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.

immunology↗