Biology subjects

Gonzalez, H.

Publications and source records attributed to Gonzalez, H..

9 recordsLinked to original sources

bioRxiv2026

RasGRP1 promotes efficient intestinal tuft cell differentiation

Intestinal stem and progenitor cells balance proliferation and lineage commitment to maintain epithelial homeostasis and adapt to environmental challenges. Tuft cells are a rare chemosensory lineage that rapidly expands in response to the cytokine IL-13 during helminth infection, yet how epithelial progenitor states influence this response remains incompletely understood. Using genetic mouse models, intestinal organoids, and single-cell approaches, we identify the Ras guanine nucleotide exchange factor RasGRP1 as an epithelial-intrinsic promoter of efficient tuft cell differentiation. Rasgrp1 is expressed in rare crypt epithelial cells distinct from Lgr5-positive stem cells. Once cells entered the tuft cell differentiation trajectory, Rasgrp1 deficiency has little impact on tuft cell maturation, including expression of the Pou2f3 tuft cell transcription factor. Instead, RasGRP1 acts at the progenitor stage, where it restrains EGFR-driven proliferation and supports a transcriptionally heterogeneous transit-amplifying state, including a subset of cells expressing Pou2f3, that is largely lost upon Rasgrp1 deficiency. Consistent with this model, EGFR inhibition restores tuft cell numbers in Rasgrp1-deficient organoids and cooperates with IL-13 to enhance tuft cell differentiation. Rasgrp1-deficient mice exhibit delayed tuft cell hyperplasia and inefficient helminth clearance. Conversely, constitutive epithelial RasGRP1 overexpression, uncoupled from its endogenous regulation, drives spontaneous tuft cell hyperplasia and accelerates parasite clearance, but alters the balance of intestinal epithelial lineages. Together, our findings identify RasGRP1 as a cell-intrinsic regulator that restrains progenitor proliferation and promotes responsiveness to IL-13, thereby coupling growth factor signaling, cell cycle control, and immune-driven epithelial lineage specification.

cell biology↗

bioRxiv2025

Development of a Plant Growth Promoting Bacterial EcoBiome Derived from Desert Soil Isolates

The application of plant growth-promoting (PGP) bacteria is increasingly studied for its potential to improve plant tolerance to biotic and abiotic stress. Developing synthetic microbial consortia represents a promising strategy, as it can enhance colonization success and functional synergy within the rhizosphere. In this study, we designed a stable EcoBiome derived from a synthetic community (SynCom) of 17 bacterial isolates obtained from three desert environments. We evaluated their PGP traits, including siderophore production, indoleacetic acid (IAA) synthesis, phosphate solubilization, and nitrogen fixation. Using Oxford Nanopore Technologies (ONT) sequencing of 16S rRNA genes, we tracked changes in relative abundance across successive subcultures under four temperature conditions. From this analysis, Erwinia rhapontici 1SR, Pseudomonas yamanorum RZ5, and Plantibacter sp. RU18 were identified as the dominant isolates and subsequently selected to construct the EcoBiome. Functional characterization showed that these isolates exhibited complementary PGP traits, biofilm formation capacity, and tolerance to water stress, both individually and in combinations. These findings highlight the potential of desert- derived bacterial consortia as microbial resources for developing biostimulants to enhance plant resilience under environmental stress conditions. ImportanceSeveral studies have focused on obtaining bacterial isolates with plant growth promoting traits, however, their success as microbial inoculants with plant stimulant activity is diminished (or null) because they do not have the ability to compete efficiently with the natural soil microbiome. Thus, in this study we designed a synthetic community of 17 bacteria from desert environments and individually characterized their plant growth-promoting attributes, and in parallel we subjected this synthetic community to co-culture, subsequently evaluating its temporal prevalence (24 and 48 hours of culture) and at four different temperatures. With this, we developed and presented a stable EcoBiome of three isolates (one from each desert), stable over time, with attributes that promote plant growth and proliferation in hostile conditions, such as drought, with the purpose of being used as microbial inoculants as a whole, capable of competing, proliferating and forming part of the rhizosphere microbiome.

microbiology↗

bioRxiv2025

Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." We document neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and are enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation protein by neoplastic cells confers a proliferative advantage that facilitates early tumor growth and therefore conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in additional breast cancer cohorts to determine its potential for patient stratification. Future research should evaluate correlates with distal metastases, progression-free survival, overall survival, and therapeutic response/resistance. Statement of SignificanceNeoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

cancer biology↗

bioRxiv2024

Long-term efficacy of adoptive cell therapy is determined by host CD8+ T cells and undermined by lymphodepleting preconditioning

Adoptive T cell therapy (ACT) has demonstrated remarkable efficacy in treating hematological cancers. However, its efficacy against solid tumors remains limited and the emergence of cancer cells that lose expression of targeted antigens often promotes resistance to ACT. Importantly, the mechanisms underlying effective and durable ACT-mediated tumor control are incompletely understood. Here, we show that adoptive transfer of TCR-transgenic CD8+ T cells eliminates established murine melanoma tumors, with concomitant accumulation of tumor-infiltrating CD8+ T cells exhibiting both progenitor-exhausted and terminally-differentiated phenotypes. Interestingly, host CD8+ T cells contributed to ACT-mediated elimination of primary tumors and rejected ACT-resistant melanoma cells lacking the targeted antigen. Mechanistically, ACT induced TNF-- and cross-presenting dendritic cell-dependent tumor accumulation of endogenous CD8+ T cells and effective tumor elimination. Importantly, although lymphodepleting preconditioning enhanced ACT-mediated tumor elimination, it abrogated host antitumor immunity and protection against ACT-resistant melanoma cells. Enrichment of transcriptional signatures associated with TNF- signaling, cross-presenting dendritic cells and tumor-specific CD8+ T cells in human melanoma tumors correlated with favorable responses to ACT and increased survival. Our findings reveal that long-term efficacy of ACT is determined by the interplay between transferred and endogenous CD8+ T cells and is undermined by lymphodepleting preconditioning, which ultimately favors ACT resistance.

immunology↗

bioRxiv2024

Life on the edge: microbial diversity, resistome, and virulome in soils from the Union Glacier cold desert

The high-latitude regions of Antarctica remain among the most remote, extreme, and least explored areas on Earth. Despite the highly restrictive conditions, microbial life has been found in these environments, although with limited information on their genetic properties and functional capabilities. Moreover, the accelerated melting of the Antarctic permafrost, the increasing exposure of soils, and the growing human transit pose the question of whether these environments could be a source of microbes or genes that could emerge and cause global health problems. In this line, although a high bacterial diversity and autochthonous multidrug-resistant bacteria have been found in soils of the Antarctic Peninsula, we still lack information regarding the resistome of areas closer to the South Pole. Moreover, no previous studies have evaluated the pathogenic potential of microbes inhabiting Antarctic soils. In this work, we combined metagenomic and culture-dependent approaches to investigate the microbial diversity, resistome, virulome, and mobile genetic elements (MGEs) in soils from Union Glacier, a high-latitude cold desert in West Antarctica. Despite the low organic matter content, diverse bacterial lineages were found, predominating Actinomycetota and Pseudomonadota, with limited archaeal and fungal taxa. We recovered more than 80 species-level representative genomes (SRGs) of predominant bacterial taxa and the archaeon Nitrosocosmicus sp. Diverse putative resistance and virulence genes were predicted among the SRGs, metagenomic reads, and contigs. Furthermore, we characterized bacterial isolates resistant to up to 24 clinical antibiotics, mainly Pseudomonas, Arthrobacter, Plantibacter, and Flavobacterium. Moreover, some isolates produced putative virulence factors, including siderophores, pyocyanins, and exoenzymes with hemolytic, lecithinase, protease, and DNAse activity. This evidence uncovers a largely unexplored resistome and virulome hosted by deep Antarcticas soil microbial communities and the presence of bacteria with pathogenic potential, highlighting the relevance of One Health approaches for environmental surveillance in the white continent. HIGHLIGHTS-Union Glacier soils host a microbial community dominated by bacteria, mainly from the phylum Actinomycetota. -Archaea from the Nitrosocosmicus genus (family Nitrosphaeraceae) were ubiquitously detected. -Although extreme and remote, these soils host multidrug-resistant and potentially pathogenic bacteria. Some were cultured and tested in vitro. -Metagenomes and species-level representative genomes revealed diverse putative resistance and virulence genes. -Part of the putative antimicrobial resistance genes and virulence factors could be associated with mobile elements in bacterial genomes.

microbiology↗

bioRxiv2023

Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions.

Normal hematopoiesis requires constant prolific production of different blood cell lineages by multipotent hematopoietic stem cells (HSC). Stem- and progenitor- cells need to balance dormancy with proliferation. How genetic alterations impact frequency, lineage potential, and metabolism of HSC is largely unknown. Here, we compared induced expression of KRASG12D or RasGRP1 to normal hematopoiesis. At low-resolution, both Ras pathway lesions result in skewing towards myeloid lineages. Single-cell resolution CyTOF proteomics unmasked an expansion of HSC- and progenitor- compartments for RasGRP1, contrasted by a depletion for KRASG12D. SCENITH quantitates protein synthesis with single-cell precision and corroborated that immature cells display low metabolic SCENITH rates. Both RasGRP1 and KRASG12D elevated mean SCENITH signals in immature cells. However, RasGRP1-overexpressing stem cells retain a metabolically quiescent cell-fraction, whereas this fraction diminishes for KRASG12D. Our temporal single cell proteomics and metabolomics datasets provide a resource of mechanistic insights into altered hematopoiesis at single cell resolution.

developmental biology↗

bioRxiv2021

SARS-CoV-2 RBD-Tetanus toxoid conjugate vaccine induces a strong neutralizing immunity in preclinical studies

Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to use neutralizing antibodies to block viral sites binding to the hosts cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of the immunization and correlates well with viral neutralization. Here we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid induce a potent immune response in laboratory animals. Some advantages of the immunization with the viral antigen coupled to tetanus toxoid have become evident such as predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. This paper demonstrates that subunit conjugate vaccines can be an alternative for COVID-19, paving the way for other viral conjugate vaccines based on the use of small viral proteins involved in the infection process.

immunology↗

bioRxiv2018

Highly Predictive Transdiagnostic Features Shared across Schizophrenia, Bipolar Disorder, and ADHD Identified Using a Machine Learning Based Approach

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard for diagnosing psychiatric disorders in the United States. However, evidence has suggested that symptoms in psychiatric disorders are not restricted to the boundaries between DSM categories, implying an underlying latent transdiagnostic structure of psychopathology. Here, we applied an importance-guided machine learning technique for model selection to item-level data from self-reported instruments contained within the Consortium for Neuropsychiatric Phenomics dataset. From 578 questionnaire items, we identified a set of features which consisted of 85 items that were shared across diagnoses of schizophrenia (SCZ), bipolar disorder (BD), and attention deficit/hyperactivity disorder (ADHD). A classifier trained on the transdiagnostic features reliably distinguished the patient group as a whole from healthy controls (classification AUC = 0.95) and only 10 items were needed to attain the performance level of AUC being 0.90. A sum score created from the items produced high separability between patients and healthy controls (Cohens d = 2.85), and it outperformed predefined sum scores and sub-scores within the instruments (Cohens d ranging between 0.13 and 1.21). The transdiagnostic features comprised both symptom domains (e.g. dysregulated mood, attention deficit, and anhedonia) and personality traits (e.g. neuroticism, impulsivity, and extraversion). Moreover, by comparing the features that were common across the three patient groups with those that were most predictive of a single patient category, we can describe the unique features for each patient group superimposed on the transdiagnostic feature structure. Overall, our results reveal a latent transdiagnostic symptom/behavioral phenotypic structure shared across SCZ, BD, and ADHD and present a new perspective to understand insights offered by self-report psychiatric instruments.

pathology↗

bioRxiv2018

Machine learning models identify multimodal measurements highly predictive of transdiagnostic symptom severity for mood, anhedonia, and anxiety

Background: Insights from neuroimaging-based biomarker research have not yet translated into clinical practice. This translational gap could be because of a focus of psychiatric biomarker research on diagnostic classification, rather than on prediction of transdiagnostic psychiatric symptom severity. Currently, no transdiagnostic, multimodal predictive models of symptom severity that include neurobiological characteristics have been described. Methods: We built predictive models of three common symptoms in psychiatric disorders (dysregulated mood, anhedonia, and anxiety) from the Consortium for Neuropsychiatric Phenomics dataset (n=272) which contains clinical scale assessments, resting-state functional-MRI (rs-fMRI) and structural-MRI (sMRI) imaging measures from patients with schizophrenia, bipolar disorder, attention deficit and hyperactivity disorder, and healthy control subjects. We used an efficient, data-driven feature selection approach to identify the most predictive features from these high-dimensional data. Results: This approach optimized modeling and explained 65-90% of variance across the three symptom domains, compared to 22% without using the feature selection approach. The top performing multimodal models retained a high level of interpretability which enabled several clinical and scientific insights. First, to our surprise, structural features did not substantially contribute to the predictive strength of these models. Second, the Temperament and Character Inventory scale emerged as a highly important predictor of symptom variation across diagnoses. Third, predictive rs-fMRI connectivity features were widely distributed across many intrinsic resting-state networks (RSN). Conclusions: Combining rs-fMRI with select questions from clinical scales enabled high levels of prediction of symptom severity across diagnostically distinct patient groups and revealed that connectivity measures beyond a few intrinsic RSNs may carry relevant information for symptom severity.

neuroscience↗