Biology subjects

Castro, L.

Publications and source records attributed to Castro, L..

15 recordsLinked to original sources

bioRxiv2026

PRDX1 regulates T cell effector function in the ovarian tumor microenvironment

T cell-based immunotherapies have remained ineffective against high-grade serous ovarian carcinoma (HGSOC). The metabolic environment of HGSOC suppresses the activity of cellular therapies, however, the metabolites that enhance or suppress T cell antitumor activity are not fully understood. Here, a pooled CRISPR-Cas9 knockout screen in primary human T cells cultured with patient-derived ascites was used to identify metabolic enzymes that inhibit effector cytokine production and cytolytic function. The screen identified PRDX1 as a negative regulator of T cell effector function. Targeted deletion of PRDX1 increased the frequency of IFN-{gamma}-producing T cells, enhanced glucose uptake, increased mitochondrial mass, and improved T cell viability under suppressive ascites conditions. Mechanistically, PRDX1 deficiency increased intracellular reactive oxygen species (ROS) and impaired autophagic flux. The effects of PRDX1 deletion enhanced aspects of T cell function, while its effects on chimeric antigen receptor (CAR)-T cell cytotoxicity were donor dependent. Collectively, this study identifies PRDX1 as a regulator of T cell activation, metabolism, and effector function in the inhibitory physiological suppressive environment of HGSOC ascites.

immunology↗

bioRxiv2024

Structure of the E3 ligase CRL2-ZYG11B with substrates reveals the molecular basis for N-degron recognition and ubiquitination

ZYG11B is a substrate specificity factor for Cullin-RING ubiquitin ligase (CRL2) involved in many biological processes, including Gly/N-degron pathways. Yet how the binding of ZYG11B with CRL2 is coupled to substrate recognition and ubiquitination is unknown. We present the Cryo-EM structures of the CRL2-ZYG11B holoenzyme alone and in complex with a Gly/N-peptide from the inflammasome-forming pathogen sensor NLRP1. The structures indicate ZYG11B folds into a Leucine-Rich Repeat followed by two armadillo repeat domains that promote assembly with CRL2 and recognition of NLRP1 Gly/N-degron. ZYG11B promotes activation of the NLRP1 inflammasome through recognition and subsequent ubiquitination of the NLRP1 Gly/N-degron revealed by viral protease cleavage. Our structural and functional data indicate that blocking ZYG11B recognition of the NLRP1 Gly/N-degron inhibits NLRP1 inflammasome activation by a viral protease. Overall, we show how the CRL2-ZYG11B E3 ligase complex recognizes Gly/N-degron substrates, including those that are involved in viral protease-mediated activation of the NLRP1 inflammasome.

molecular biology↗

bioRxiv2023

Linking the evolution of two prefrontal brain regions to social and foraging challenges in primates

The diversity of cognitive skills across primates remains both a fascinating and a controversial issue. Recent comparative studies provided conflicting results regarding the contribution of social vs ecological constraints to the evolution of cognition. Here, we used an interdisciplinary approach combining comparative cognitive neurosciences and behavioral ecology. Using brain imaging data from 16 primate species, we measured the size of two prefrontal brain regions, the frontal pole (FP) and the dorso-lateral prefrontal cortex (DLPFC), respectively involved in metacognition and working memory, and examined their relation to a combination of socio-ecological variables. The size of these prefrontal regions, as well as the whole brain, was best explained by three variables: body mass, daily traveled distance (an index of ecological constraints) and population density (an index of social constraints). The strong influence of ecological constraints on FP and DLPFC volumes suggests that both metacognition and working memory are critical for foraging in primates. Interestingly, FP volume was much more sensitive to social constraints than DLPFC volume, in line with laboratory studies showing an implication of FP in complex social interactions. Thus, our data highlights the relative weight of social vs ecological constraints on the evolution of specific prefrontal brain regions and their associated cognitive operations in primates. FundingThis work was supported by recurrent funding from CNRS to SB, SP and CG. It was also supported by the ANR-17-CE27-0005 (HOMTECH).

neuroscience↗

bioRxiv2022

SARS-CoV-2 variant transition dynamics are associated with vaccination rates, number of co-circulating variants, and natural immunity

BackgroundThroughout the COVID-19 pandemic, the SARS-CoV-2 virus has continued to evolve, with new variants outcompeting existing variants and often leading to different dynamics of disease spread. MethodsIn this paper, we performed a retrospective analysis using longitudinal sequencing data to characterize differences in the speed, calendar timing, and magnitude of 13 SARS-CoV-2 variant waves/transitions for 215 countries and sub-country regions, between October 2020 and October 2022. We then clustered geographic locations in terms of their variant behavior across all Omicron variants, allowing us to identify groups of locations exhibiting similar variant transitions. Finally, we explored relationships between heterogeneity in these variant waves and time-varying factors, including vaccination status of the population, governmental policy, and the number of variants in simultaneous competition. FindingsThis work demonstrates associations between the behavior of an emerging variant and the number of co-circulating variants as well as the demographic context of the population. We also observed an association between high vaccination rates and variant transition dynamics prior to the Mu and Delta variant transitions. InterpretationThese results suggest the behavior of an emergent variant may be sensitive to the immunologic and demographic context of its location. Additionally, this work represents the most comprehensive characterization of variant transitions globally to date. FundingLaboratory Directed Research and Development (LDRD), Los Alamos National Laboratory Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 variants with a selective advantage are continuing to emerge, resulting in variant transitions that can give rise to new waves in global COVID-19 cases and changing dynamics of disease spread. While variant transitions have been well studied individually, more work is needed to better understand how variant transitions have occurred in the past and how properties of these transitions may relate to vaccination rates, natural immunity, and population demographics. Added value of this studyOur retrospective study integrates metadata based on 12.8 million SARS-CoV-2 sequences available through the Global Initiative on Sharing All Influenza Data (GISAID) with clinical and demographic data to characterize heterogeneity in variant waves/transitions across the globe throughout the COVID-19 pandemic. We demonstrate that properties of the variant transitions (e.g., speed, timing, and magnitude of the transition) are associated with vaccination rates, prior COVID-19 cases, and the number of co-circulating variants in competition. Implications of all the available evidenceOur results indicate that there is substantial heterogeneity in how an emerging variant may compete with other viral variants across locations, and suggest that each locations contemporaneous immunologic landscape may play a role in these interactions.

bioinformatics↗

bioRxiv2022

Transcriptional response of the xerotolerant Arthrobacter sp. Helios strain to PEG-induced drought stress

A new bacterial strain highly tolerant to desiccation and to UV radiation has been isolated from the microbiome of solar panels. This strain showed a high xerotolerance in the exponential and the stationary phase of growth and it has been classified as Arthrobacter sp. Helios according to its 16S rDNA, positioning this new strain in the Arthrobacter citreus group. The complete genome of Arthrobacter sp. Helios consists in a single circular chromosome of 3,895,998 bp, with a 66% GC content and no plasmids. A total of 3,586 genes were predicted, of which 2,275 protein-encoding genes were functionally assigned. The genome analysis suggests that it is motile, ecologically versatile, capable of growing in a variety of carbon sources and well poised to respond to environmental stresses. Using PEG6000 to mimic arid stress conditions, we have studied the transcriptional response of this strain to matric stress when cells are cultured on media containing 10% (PEG10) and 35% PEG (PEG35). The transcriptomic analysis revealed that cells can be easily adapted to moderate matric stress (PEG10) by modifying the expression of a small number of genes to maintain a high growth rate, while a higher matric stress (PEG35) altered the expression of many more genes. Remarkably, these metabolic changes do not confer the cells a higher tolerance to desiccation, suggesting that mechanisms to support matric stress and desiccation tolerance are different. The peculiar observation that Arthrobacter sp. Helios seems to be permanently prepared to handle the desiccation stress makes it an exciting chassis for biotechnological applications.

microbiology↗

bioRxiv2021

Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Transformation

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in elderly individuals. In this work, we analyzed the transcriptome of human HSCs purified from young and elderly healthy donors, as well as MDS patients, identifying transcriptional alterations following eight different patterns of expression. While aging-associated lesions seemed to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detected the upregulation of the transcription factor DDIT3. Overexpression of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis. Such effect was associated with downregulation of transcription factors required for normal erythropoiesis, and with a failure in the activation of their transcriptional programs. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia was able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing MDS patients. STATEMENT OF SIGNIFICANCEThis study defines how human aging and MDS development are characterized by transcriptional alterations in HSCs that follow different patterns, some of which may contribute to myeloid transformation. Among them, we demonstrate how MDS-specific upregulation of DDIT3 in HSCs induces dyserythropoiesis, while its knockdown in HSPCs from MDS patients restores proper erythroid differentiation.

cancer biology↗

bioRxiv2021

Temporal and sex-dependent gene expression patterns in a renal ischemia-reperfusion injury and recovery pig model

Men are more prone to acute kidney injury (AKI) and chronic kidney disease (CKD), progressing to end-stage renal disease (ESRD) than women. Severity and capacity to regenerate after AKI are important determinants of CKD progression, and of patient morbidity and mortality in the hospital setting. To determine sex differences during injury and recovery we have generated a female and male renal ischemia/reperfusion injury (IRI) pig model, which represents a major cause of AKI. Although no differences were found in blood urea nitrogen (BUN) and serum creatinine (SCr) levels between both sexes, females exhibited higher mononuclear infiltrates at basal and recovery, while males showed more tubular damage at injury. Global transcriptomic analyses of kidney biopsies from our IRI pig model revealed a sexual dimorphism in the temporal regulation of genes and pathways relevant for kidney injury and repair, which was also detected in human samples. Enrichment analysis of gene sets revealed five temporal and four sexual patterns governing renal IRI and recovery. Overall, this study constitutes an extensive characterization of the time and sex differences occurring during renal IRI and recovery at gene expression level and offers a template of translational value for further study of sexual dimorphism in kidney diseases. AUTHOR SUMMARYKidneys correct functioning is essential for optimal body homeostasis, being their basic functions blood filtration and excretion of wastes and toxins. Inherited or acquired conditions can cause renal dysfunction requiring renal replacement therapy, which will affect patients life quality and survival. A major cause of kidney failure is the renal ischemia/reperfusion injury (IRI), which occurs in many clinical situations like kidney transplantation or aortic aneurysm surgery. Interestingly, men are more susceptible to IRI than women, being women more protected against kidney injury. However, the genetics regulating these sex differences in injury and renal repair remained unknown. Here, we provide a novel porcine model to study renal injury and recovery in both males and females. Using this model, we have identified the gene sets involved in renal injury and recovery processes. Moreover, global genetic analyses allowed us to discover the temporal and sex-dependent patterns that regulate those gene sets and, finally, kidney damage and repair. A relevant finding of our study is that males develop a feminized genetic profile during recovery, which may represent a survival mechanism to diminish the androgenic pro-damage effects on kidney cells. To sum up, our results provide novel sex-dependent targets to prevent renal injury and promote kidney recovery.

genomics↗

bioRxiv2020

Sequential development of embryoblast memory entities in human cancer tissues, architectural metamorphosis from spiral cleavage to micro - macroscopic structures

Hidden collective organization of cancer cells can partially or completely return to embryoid genotype-phenotype with the plasticity to transform their morphology on cell embryoblast-like memory entities by expression of dormant genes that arise from embryogenesis. After hundreds of driver mutations, cancer cells gain new abilities or attributes and recapitulate early stages of embryogenesis. Our findings document how malignant tissues reactivated ancestral storage memory and elaborate inside tumor glands spiral- pyramidal-fractal chiral crystals (Tc) as geometric attractors proteins and biomimicry the primitive cellular blastocyst embryoblast fluid-filled cavity. The resultant evolutionary embryoblast-like entity has higher survivability and spatial cephalic-caudal growth organization with pluripotentiality that carry the correct DNA instructions to repair, and regenerate. The isolation and manipulation of these order structures can guide and control the regenerative pathway mechanism in human tumors as follows: modify and reprogram the phenotype of the tumor where these entities are generated, establish a reverse primordial microscopic mold to use the swirlonic collective behavior of cellular building blocks to regenerate injured tissues, convert cancer cells to a normal phenotype through regeneration using the organizational level and scale properties of reverse genetic guidance, global control of mitotic activity and morphogenetic movements avoiding their spread and metastasis, determining a better life prognosis for patients who incubate these entities in their tumors compared to those who do not express them. An emergent self-repair order structure, biological template to develop targeted therapeutic alternatives not only in cancer but also in treatment of autoimmune, viral diseases, and in regenerative medicine and rejuvenation.

pathology↗

bioRxiv2020

Optimizing the molecular diagnosis of Covid-19 by combining RT-PCR and a pseudo-convolutional machine learning approach to characterize virus DNA sequences

The proliferation of the SARS-Cov-2 virus to the whole world caused more than 250,000 deaths worldwide and over 4 million confirmed cases. The severity of Covid-19, the exponential rate at which the virus proliferates, and the rapid exhaustion of the public health resources are critical factors. The RT-PCR with virus DNA identification is still the benchmark Covid-19 diagnosis method. In this work we propose a new technique for representing DNA sequences: they are divided into smaller sequences with overlap in a pseudo-convolutional approach, and represented by co-occurrence matrices. This technique analyzes the DNA sequences obtained by the RT-PCR method, eliminating sequence alignment. Through the proposed method, it is possible to identify virus sequences from a large database: 347,363 virus DNA sequences from 24 virus families and SARS-Cov-2. Experiments with all 24 virus families and SARS-Cov-2 (multi-class scenario) resulted 0.822222 {+/-} 0.05613 for sensitivity and 0.99974 {+/-} 0.00001 for specificity using Random Forests with 100 trees and 30% overlap. When we compared SARS-Cov-2 with similar-symptoms virus families, we got 0.97059 {+/-} 0.03387 for sensitivity, and 0.99187 {+/-} 0.00046 for specificity with MLP classifier and 30% overlap. In the real test scenario, in which SARS-Cov-2 is compared to Coronaviridae and healthy human DNA sequences, we got 0.98824 {+/-} 001198 for sensitivity and 0.99860 {+/-} 0.00020 for specificity with MLP and 50% overlap. Therefore, the molecular diagnosis of Covid-19 can be optimized by combining RT-PCR and our pseudo-convolutional method to identify SARS-Cov-2 DNA sequences faster with higher specificity and sensitivity.

bioinformatics↗

bioRxiv2019

Caspase-8 Modulates Angiogenesis By Regulating A Cell Death Independent Pathway In Endothelial Cells

During developmental angiogenesis blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates both cell death via apoptosis and necroptosis. Here we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal angiogenesis. EC specific Casp-8 knockout pups (Casp-8ECko) have reduced retinal angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting and migration independent of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 mitogen-activated protein kinase (MAPK) downstream of receptorinteracting serine/threonine-protein kinase 3 (RIPK3) and destabilization of VE-cadherin at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR), resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs is beneficial, as pathological neovascularization was reduced in Casp-8ECko pups. Taken together, we identify that Casp-8 signals in a cell-death independent manner in ECs during postnatal and pathological blood vessel formation.

developmental biology↗

bioRxiv2019

Single-cell RNA-seq analysis reveals the crucial role of Collagen Triplex Helix Repeat Containing 1 (CTHRC1) cardiac fibroblasts for ventricular remodeling after myocardial infarction

Cardiac fibroblasts have a central role during the ventricular remodeling process associated with different types of cardiac injury. Recent studies have shown that fibroblasts do not respond homogeneously to heart damage, suggesting that the adult myocardium may contain specialized fibroblast subgroups with specific functions. Due to the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population dynamics in response to cardiac damage is still missing. Using single-cell RNA-seq, we identified and characterized a fibroblast subpopulation that emerges in response to myocardial infarction (MI) in a murine model. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of the hormone CTHRC1 and of the immunomodulatory co-receptor CD200 and localize to the injured myocardium. Combining epigenomic profiling with functional assays, we show Sox9 and the non-canonical TGF-{beta} signaling as important regulators mediating their response to cardiac damage. We show that the absence of CTHRC1, in this activated fibroblast subpopulation, results in pronounced lethality due to ventricular rupture in a mouse model of myocardial infarction. Finally, we find evidence for the existence of similar mechanisms in a pig pre-clinical model of MI and establish a correlation between CTHRC1 levels and cardiac function after MI.

cell biology↗

bioRxiv2019

Early Prediction of Antigenic Transitions for Influenza A H3N2

Influenza A/H3N2 is a rapidly evolving virus which experiences major antigenic transitions every two to eight years. Anticipating the timing and outcome of transitions is critical to developing effective seasonal influenza vaccines. Using simulations from a published phylodynamic model of influenza transmission, we identified indicators of future evolutionary success for an emerging antigenic cluster. The eventual fate of a new cluster depends on its initial epidemiological growth rate--which is a function of mutational load and population susceptibility to the cluster--along with the variance in growth rate across co-circulating viruses. Logistic regression can predict whether a cluster at 5% relative frequency will eventually succeed with [~]80% sensitivity, providing up to eight months advance warning. As a cluster expands, the predictions improve while the lead-time for vaccine development and other interventions decreases. By focusing surveillance efforts on estimating population-wide susceptibility to emerging viruses, we can better anticipate major antigenic transitions.

epidemiology↗

bioRxiv2019

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of a paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (AKAR3) to record PKA signals and by analyzing the distribution of D1R-and D2R/A2aR-SPNs in the TS, we characterized three evolutionary highly conserved subterritories: a D2R/A2aR-lacking area, a D1R/D2-SPNs-enriched and an D1R/D2R-intermingled area. The analysis of ERK phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate or learned avoidance responses, fasting, satiety or palatable signals. In contrast, D1R-SPNs of the intermingled and D2R/A2AR-lacking areas are strongly activated by both direct stimulation of D1R and psychostimulant drugs (d-amphetamine, cocaine, MDMA or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals.

neuroscience↗

bioRxiv2018

Neighbor signals perceived by phytochrome B increase thermotolerance in Arabidopsis

Due to the preeminence of reductionist approaches, our understanding of plant responses to combined stresses is limited. We speculated that light-quality signals of neighboring vegetation might increase susceptibility to heat shocks because shade reduces tissue temperature and hence the likeness of heat shocks. In contrast, plants of Arabidopsis thaliana grown under low red / far-red ratios typical of shade were less damaged by heat stress than plants grown under simulated sunlight. Shade reduces the activity of phytochrome B (phyB) and the phyB mutant showed high tolerance to heat stress even under simulated sunlight. The enhanced heat tolerance under low red / far-red ratios failed in a multiple mutant of PHYTOCHROME INTERACTING FACTORs. The phyB mutant showed reduced expression of several fatty acid desaturase (FAD) genes, proportion of fully unsaturated fatty acids and electrolyte leakage of membranes exposed to a heat shock. Activation of phyB by red light also reduced thermotolerance of dark-grown (etiolated) seedlings but not via changes in FAD gene expression and membrane stability. We propose that the reduced photosynthetic capacity linked to thermotolerant membranes would be less costly under shade, where the light input itself limits photosynthesis.

plant biology↗

bioRxiv2017

Facilitation between plants shapes pollination networks

SignificanceAlthough it is known that plant-plant and plant-pollinator interactions can strongly influence biodiversity and its effects on ecosystem functioning, the details of how competition and facili-tation among plants scale up to mutualistic interactions with pollinators and thus affect pollina-tion networks are poorly understood. We introduce a simple experimental system in which we control local plant interactions, measure pollinator responses and characterize plant-pollinator networks. We find that facilitation among plants produces synergistic and antagonistic effects on the pollinator community affecting the architecture and robustness of plant-pollinator net-works. Our results provide evidence for bottom-up non-additive effects of plant interactions on pollination networks and have implications for the way we study and manage ecosystems.

ecology↗