Biology subjects

Ruiz, J.

Publications and source records attributed to Ruiz, J..

16 recordsLinked to original sources

bioRxiv2026

A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

Overnutrition-related liver dysfunction and cancer are increasingly prevalent and highly resistant to immunotherapy. While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear. Here, we show that short-term Western diet (WD) exposure drives near-complete loss of CD8 T cell infiltration and antitumor function in HCC. We identify dietary linoleic acid (LA), the most abundant {omega}-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain {omega}-6 PUFAs drives their accumulation in the tumor interstitial fluid, suppressing infiltrating CD8 T cells via lipid peroxidation. FADS2 inhibition restores CD8 T cell function and sensitizes WD-driven HCC to PD-1-based immunotherapy. Further, the Parkinsons disease-associated deglycase DJ-1 protects LA-handling proteins from methylglyoxal-mediated glycation, sustaining tumoral immunosuppressive PUFA production. Across multiple independent human MASLD-HCC cohorts, LA metabolic activity correlates with CD8 T cell impairment, immune exclusion, and immunotherapy resistance. Overall, these studies identify a dietary lipid axis as a therapeutically actionable vulnerability in WD-associated HCC.

Cancer Biology↗

bioRxiv2025

Contrasting evolutionary forces of specialization and admixture underlie the genomic and phenotypic diversity of Yarrowia lipolytica

Microbial diversity emerges from evolutionary processes that shape genomic and phenotypic traits in response to complex environmental pressures. Deciphering these dynamics is key to understanding microbial ecology and advancing biotechnological applications. Here, we use the yeast Yarrowia lipolytica to study genomic signatures of adaptation across a broad range of environments and to illustrate how population-level data can inform targeted bioprospecting for industrial traits. Whole-genome and phenotypic analyses of 126 isolates from natural and anthropogenic environments reveal a complex population structure in this species, shaped by both niche specialization and admixture events. Structured lineages exhibit ecological filtering, reduced genetic diversity, and distinct gene content, consistent with adaptation to substrates like dairy, hydrocarbons, or industrial substrates. In contrast, admixed populations display greater genetic diversity and broader phenotypic capacity, including enhanced stress tolerance and metabolic flexibility. Genome plasticity, reflected in pangenome and CNV variation, aligns with ecological origin, while trait assays link phenotypic divergence to underlying genetic variation. For instance, better growth performance on acetate, an ecological and industrially relevant trait, is associated with hydrocarbon-adapted strains and likely linked to variation in regulatory regions of acetate metabolism genes. Together, our results reflect how divergent evolutionary trajectories--ranging from ecological specialization to genomic plasticity through admixture-- underpin the species ecological success and provide a framework for harnessing its natural diversity in microbial bioprospecting.

evolutionary biology↗

bioRxiv2025

Duchenne muscular dystrophy is driven by defective membrane repair and annexin-A2 dysregulation in skeletal muscle

BackgroundDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which encodes dystrophin in skeletal muscle cells. Although the role of dystrophin as a structural protein is well known, the cellular processes underlying myofiber degeneration are still not fully understood. Despite advances from studies in murine models, these models do not fully replicate the human pathology. MethodsWe investigated sarcolemmal integrity, membrane repair capacity, and annexin protein expression in DMD patient muscle biopsies and human skeletal muscle cell lines using immunohistochemistry, both shear stress-based and laser irradiation injury assays, western blotting, and live-cell imaging of GFP-tagged annexins. ResultsWe identified defective membrane repair in DMD skeletal muscle cells, independent of increased membrane fragility, by evaluating resealing capacity in control and DMD derived-patient cell lines using both a shear stress assay (N = l2, p < 0.000l) and a laser irradiation assay (N = 3, p < 0.000l). Analyses performed on human DMD muscle biopsies (N = l0) further confirmed this defect, demonstrating massive intracellular IgG uptake (p < 0.000l) together with altered annexin expression profiles. While mechanical stress induces the upregulation of annexin A5 (ANXA5, p < 0.0l) and A6 (ANXA6, p < 0.05) in healthy skeletal muscle cells - suggesting an adaptive response to membrane damage, given the annexin familys central role in membrane repair - we observed dysregulated expression patterns of these proteins in DMD cells. Notably, ANXAl (p < 0.05) and ANXA2 (p < 0.0l) were not only significantly overexpressed but also aberrantly localized to the extracellular space, a putative consequence of defective membrane repair. Since extracellular ANXA2 has been associated with adipocyte accumulation in the muscle tissue of patients with dysferlinopathy, a similar pathological mechanism may be at play in DMD. ConclusionsOur findings propose that ANXA2 contributes to muscle degeneration in DMD and highlight it as a potential therapeutic target to prevent adipogenesis and muscle loss.

cell biology↗

bioRxiv2025

Intracochlear pressure measurements quantify overall noise exposure to the inner ear during mastoidectomy

IntroductionThe acoustic trauma patients are exposed to during otologic surgery is unclear, as previous studies have not captured the effects of vibrational noise on the inner ear. To fill this knowledge gap, we examined inner ear noise directly via intracochlear pressure changes during a mastoidectomy and cochleostomy. MethodsInner ear stimulation was measured using fiber optic pressure sensors inserted into the cochlea of cadaveric heads using a trans-canal approach. A tympanomeatal flap was elevated, cochleostomies were made into scala vestibuli and tympani, and sensors placed and secured to the cochlear promontory, and the flap resecured. Intracochlear pressures were measured with different drill bits, speeds, and during mastoidectomy and cochleostomy. The equivalent sound pressure level in the ear canal (LEq) was calculated using the middle ear transfer function. Microphones were also placed in the surgeons ear, cadaver ear, and approximately three feet away. ResultsResults show sound pressure levels that could exceed 120 dBA (A-weighted dB SPL LEq), with the highest levels observed during cochleostomy. Results showed broad band exposure, with a distinct peak at 1.33 kHz during the 80k RPM drill speed. Importantly, SPLs in the surgeons ear did not always predict patient noise exposure. ConclusionSurgically induced cochlear noise revealed levels high enough to potentially induce acoustic trauma, and sometimes at frequencies that may cause hearing loss not captured by a traditional audiogram (i.e. 1.33 kHz). This data characterizes surgical noise exposures, and will lead to permissible noise exposure guidelines and durations for both patients and surgeons.

bioengineering↗

bioRxiv2025

Single-cell transcriptional profiling reveals a novel RAB13+ endothelial subpopulation and profibrotic mesenchymal cells in the aged human bone marrow

The bone marrow (BM) microenvironment plays a crucial role in regulating hematopoiesis, yet the molecular changes associated with aging in humans remain poorly understood. Using single-cell RNA sequencing, we uncovered transcriptional shifts in BM endothelial cells (EC) and mesenchymal stem cells (MSC) during aging. Aged sinusoidal EC exhibited a prothrombotic phenotype with compromised mitochondrial and vascular function. Additionally, we identified a novel arterial EC subset, emerging in aged individuals, characterized by RAB13 expression and associated with transcriptional regulatory processes. MSC from aged subjects displayed impaired matrix remodeling and epithelial-mesenchymal transition, driven partly by a subpopulation of THY1+ profibrotic cells absent in younger individuals. Finally, immunofluorescent imaging and spatial transcriptomics confirmed the presence of these aging-associated cells in BM samples from aged individuals. In summary, this work provides a comprehensive view of the transcriptional landscape, cellular interactions, and spatial organization of aged EC and MSC, offering novel insights and potential targets that could be exploited for preventing age-associated changes in humans. TeaserAging reshapes the bone marrow with emergence of RAB13+ endothelial cells and profibrotic stromal cells altering tissue function.

molecular biology↗

bioRxiv2024

Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

The bone marrow (BM) is a complex tissue where spatial relationships influence cell behavior, signaling, and function. Consequently, understanding the whole dynamics of cellular interactions requires complementary spatial techniques that preserve and map the architecture of cell populations in situ. We successfully conducted spatial transcriptional profiling using Visium Spatial Gene Expression in formalin-fixed paraffin-embedded (FFPE) BM samples obtained from healthy and Multiple Myeloma (MM) mouse models and patients, addressing the technical challenges of applying spatial technology to long bone samples. A custom data-analysis framework that combines spatial with single-cell transcriptomic profiles identified both the BM cellular composition and the existing cell relations. This allowed us to visualize the spatial distribution of transcriptionally heterogeneous MM plasma cells (MM-PC). We spatially delineated transcriptional programs associated with MM, including NETosis and IL-17-driven inflammatory signaling, which were inversely correlated to malignant PC-enriched regions. Furthermore, a gradient of MM-PC density spatially correlated with a shift from effector-to-exhausted T cell phenotypes. The translational relevance of our findings was confirmed using FFPE BM biopsies from MM patients with varying levels of malignant PC infiltration. In summary, we provide the first spatial transcriptomics analysis applied to a mouse and human mineralized bone tissue and illustrate the BM cellular architecture of MM, revealing deregulated mechanisms underlying MM intercellular communication.

cancer biology↗

bioRxiv2024

Transcriptional Characterization of the Stromal and Endothelial Bone Marrow Microenvironment during Progression from MGUS to Multiple Myeloma

The role of the non-immune bone marrow microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) remains incompletely defined. To address this, we transcriptionally profiled endothelial cells (EC), mesenchymal stem cells (MSC) and MM cells at single-cell resolution from two genetically engineered mouse models (BIc{gamma}1 and MIc{gamma}1) that recapitulate MGUS to MM progression. Our analysis revealed distinct transcriptional trajectories in EC and MSC, uncovering stage-specific BME-PC interactions shaping disease progression. EC acquired a stress phenotype during MGUS transitioning to angiogenesis in MM, while MSC exhibited early impaired differentiation capacity during MGUS that persisted in MM. Notably, an interferon (IFN)-associated MM signature was detected in EC and MSC from the BIc{gamma}1 model but was absent in the more aggressive MIc{gamma}1 model. Treatment with bortezomib, lenalidomide, and dexamethasone remodeled the BME by suppressing MM-IFN signaling, promoting an adaptive response in EC, and restoring osteogenic potential in MSC-- shifting the niche toward a less tumor-permissive state. Importantly, the MM-IFN signature was validated in patients across the MGUS-to-MM spectrum, supporting the translational relevance of our findings. Together, these data define novel dynamic and targetable alterations in the non-immune BME during myeloma progression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/589777v5_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1a0ef62org.highwire.dtl.DTLVardef@c44014org.highwire.dtl.DTLVardef@4b1df6org.highwire.dtl.DTLVardef@19c29a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

OCTOPUS: Disk-based, Multiplatform, Mobile-friendly Metagenomics Classifier

Portable genomic sequencers such as Oxford Nanopores MinION enable real-time applications in clinical and environmental health. However, there is a bottleneck in the downstream analytics when bioinformatics pipelines are unavailable, e.g., when cloud processing is unreachable due to absence of Internet connection, or only low-end computing devices can be carried on site. Here we present a platform-friendly software for portable metagenomic analysis of Nanopore data, the Oligomer-based Classifier of Taxonomic Operational and Pan-genome Units via Singletons (OCTOPUS). OCTOPUS is written in Java, reimplements several features of the popular Kraken2 and KrakenUniq software, with original components for improving metagenomics classification on incomplete/sampled reference databases, making it ideal for running on smartphones or tablets. OCTOPUS obtains sensitivity and precision comparable to Kraken2, while dramatically decreasing (4-to 16-fold) the false positive rate, and yielding high correlation on real-word data. OCTOPUS is available along with customized databases at https://github.com/DataIntellSystLab/OCTOPUS and https://github.com/Ruiz-HCI-Lab/OctopusMobile.

molecular biology↗

bioRxiv2023

Multi-omics framework to reveal the molecular determinants of fermentation performance in wine yeast populations

BackgroundConnecting the composition and function of industrial microbiomes is a major aspiration in microbial biotechnology. Here, we address this question in wine fermentation, a model system where the diversity and functioning of fermenting yeast species is determinant of the flavor and quality of the resulting wines. ResultsFirst, we surveyed yeast communities associated with grape musts collected across wine appellations, revealing the importance of environmental (i.e., biogeography) and anthropic factors (i.e., farming system) in shaping community composition and structure. Then, we assayed the fermenting yeast communities in synthetic grape must under common winemaking conditions. The dominating yeast species defines the fermentation performance and metabolite profile of the resulting wines, and it is determined by the initial fungal community composition rather than the imposed fermentation conditions. Yeast dominance also had a more pronounced impact on wine meta-transcriptome than fermentation conditions. We unveiled yeast-specific transcriptomic profiles, leveraging different molecular functioning strategies in wine fermentation environments. We further studied the orthologs responsible for metabolite production, revealing modules associated with the dominance of specific yeast species. This emphasizes the unique contributions of yeast species to wine flavor, here summarized in an array of orthologs that defines the individual contribution of yeast species to wine ecosystem functioning. ConclusionsOur study bridges the gap between yeast community composition and wine metabolite production, providing insights to harness diverse yeast functionalities with the final aim to producing tailored high-quality wines.

microbiology↗

bioRxiv2023

Pore-forming activity of S. pneumoniae pneumolysin disrupts the paracellular localization of the epithelial adherens junction protein E-cadherin

Streptococcus pneumoniae, a common cause of community-acquired bacterial pneumonia, can cross the respiratory epithelial barrier to cause lethal septicemia and meningitis. S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers robust neutrophil (PMN) infiltration that promotes bacterial transepithelial migration in vitro and disseminated disease in mice. Apical infection of polarized respiratory epithelial monolayers by S. pneumoniae at a multiplicity of infection (MOI) of 20 resulted in recruitment of PMNs, loss of 50% of the monolayer, and PMN-dependent bacterial translocation. Reducing the MOI to 2 decreased PMN recruitment two-fold and preserved the monolayer, but apical-to-basolateral translocation of S. pneumoniae remained relatively efficient. At both MOI of 2 and 20, PLY was required for maximal PMN recruitment and bacterial translocation. Co-infection by wild type S. pneumoniae restored translocation by a PLY-deficient mutant, indicating that PLY can act in trans. Investigating the contribution of S. pneumoniae infection on apical junction complexes in the absence of PMN transmigration, we found that S. pneumoniae infection triggered the cleavage and mislocalization of the adherens junction (AJ) protein E-cadherin. This disruption was PLY-dependent at MOI of 2 and was recapitulated by purified PLY, requiring its pore-forming activity. In contrast, at MOI of 20, E-cadherin disruption was independent of PLY, indicating that S. pneumoniae encodes multiple means to disrupt epithelial integrity. This disruption was insufficient to promote bacterial translocation in the absence of PMNs. Thus, S. pneumoniae triggers cleavage and mislocalization of E-cadherin through PLY-dependent and PLY-independent mechanisms, but maximal bacterial translocation across epithelial monolayers requires PLY-dependent neutrophil transmigration.

microbiology↗

bioRxiv2022

Predictability of the community-function landscape in wine yeast ecosystems

Predictively linking taxonomic composition and quantitative ecosystem functions is a major aspiration in microbial ecology, which must be resolved if we wish to engineer microbial consortia. Here, we have addressed this open question for an ecological function of major biotechnological relevance: alcoholic fermentation in wine yeast communities. By exhaustively phenotyping an extensive collection of naturally occurring wine yeast strains, we find that most enologically-relevant traits exhibit a strong phylogenetic signal, indicating that the most relevant functions in wine yeast communities can be predicted from taxonomy. Further, we demonstrate that the quantitative contributions of individual wine yeast strains to the community function followed simple quantitative rules. These regularities can be integrated to quantitatively predict the function of newly assembled consortia. Besides addressing a fundamental open question in functional ecology, our results and methodologies provide a blueprint for rationally managing microbial processes of biotechnological relevance.

microbiology↗

bioRxiv2022

Extracellular Vesicles derived from Apis mellifera Royal Jelly promote wound healing by modulating inflammation and cellular responses

Apis mellifera Royal Jelly (RJ) is a well-known remedy in traditional medicine around the world and its versatile effects range from antibacterial to anti-inflammatory properties and pro-regenerative properties. Several active compounds have been identified, however, the mechanisms of action still remain widely unknown. As a glandular product, RJ has been shown to contain a substantial number of extracellular vesicles (EVs) and in this study, we aimed to investigate the extent of involvement of RJEVs in wound healing associated effects. Molecular analysis of RJEVs verified the presence of important conserved exosomal markers such as CD63 and syntenin, as well as cargo molecules MRJP1, defensin-1 and jellein-3. RJEV internalization analysis demonstrated the involvement of membrane fusion as well as macropinocytosis or clathrin-dependent endocytosis into mammalian cells. Furthermore, RJEVs have demonstrated to modulate MSCs differentiation and secretome, as well as decrease LPS-induced inflammation in RAW 264.7 macrophages by blocking the MAPK pathway. In vivo studies confirmed anti-bacterial effects of RJEVs, and demonstrated an acceleration of wound healing in a splinted mouse model. Summarizing, this study suggests that RJEVs of potentially exosomal origin play a crucial role in the known effects of RJ by modulating the inflammatory phase and cellular response in wound healing.

bioengineering↗

bioRxiv2022

Genotypic and allelic distribution of the ACE, ACTN3, and IL6 genes in athletes of Artistic Gymnastics and Swimming in the department of Norte de Santander, Colombia

The purpose of the study is to report the allelic and genotypic frequencies of ACTN3, ACE and IL6 genes in Colombian high performance athletes in the sports of artistic gymnastics and swimming, to observe if there is any relationship between athlete status, sport and the polymorphisms found. The study included twenty-one gymnasts and twenty-one swimmers. The ACE and IL6 genes were genotyped by PCR and polyacrylamide electrophoresis, the ACTN3 gene was genotyped by PCR-RFLP. In the ACE gene, a greater number of genotypes with the D allele was observed in both sports, for the ACTN3 gene a predominance of the RX genotype was observed in both gymnastics and swimming, in the IL6 gene the most predominant characteristic is the total absence of the CC genotype. For the ACE gene, the highest allelic frequency is that of the D allele in both sports, the IL6 gene shows a high presence of the G allele, for the ACTN3 gene, in gymnastics the highest frequency of carriers is observed in the R allele and for the sport of swimming the majority is carrying the X allele. Significant differences were observed when comparing the genotypic and allelic frequencies between the population of gymnasts and swimmers only in the ACTN3 gene, the ACE gene and IL6 did not present significant differences between the populations. In conclusion, the genotypes presented by the athletes correspond to the types of efforts of their sport, gymnastics with predominance in strength and power and swimming with an orientation towards both phenotypes, showing a pleiotropic effect of the ACE and ACTN3 genes.

genetics↗

bioRxiv2022

In-silico identification of potential antigenic proteins in Bartonella bacilliformis for the serological diagnosis of Carrions' disease

The current methods for inferring antigenic, pathogenic or virulence factors in bacteria include in-silico or computational tools. Bartonella bacilliformis, the causal agent of Carrio[n]s disease (CD) is a Gram-negative microorganism transmitted by the sand fly Lutzomya verrucarum mainly in Peruvian Inter-Andean valleys. A better understanding of the pathogenicity of B. bacilliformis, the implementation of serological diagnostic methods and the development of candidate vaccines for the control of CD could be facilitated by the identification of outer membrane exposed proteins such as outer-membrane beta-barrels (OMBB) and outer-membrane lipoproteins (OMLPP). In this study we present the in-silico identification of OMBBs and OMLPPs in B. bacilliformis. The present analysis identified 32 OMBBs and 9 OMLPPs, of which 15 and 4 are reported for the first time as potential antigenic, pathogenic and virulence-related proteins, respectively. Future implications of this study are discussed and compared with proteins validated by experimental assays.

microbiology↗

bioRxiv2020

New insights into the paradoxical distribution of IRC7 in Saccharomyces cerevisiae and its associated phenotypic and genomic landscapes

Biotic and abiotic factors of wine fermentations have led to the accumulation of numerous genomic hallmarks of domestication in Saccharomyces cerevisiae wine strains. Here we have studied the paradoxical distribution of a dominant allele of IRC7 in wine yeast strains. This gene encodes a cysteine-S-{beta}-lyase and presents two alleles: a wild full-length allele (IRC7F) and a mutated one (IRC7S), harboring a 38bp-deletion. Interestingly, IRC7S-coding for a less active enzyme-appears in the great majority of wine strains. Studying its global distribution among phylogenetic clades, we observed that IRC7S allele is dominant just in wine strains, having a moderate presence in other domesticated clades (Beer, Bread and Wine-PDM), but being completely absent in wild clades, appearing as a new hallmark of domestication. To explain this paradoxical distribution, we performed an IRC7-rooted phenotypic-wide survey, demonstrating that IRC7S-homozygous (HS) wine strains have both fitness (lower lag phases and higher growth rates) and competitive (killer toxin resistance, pseudohyphal growth) advantages. Hence, we performed a genome-wide survey across domesticated clades, finding a set of mutations that are conserved among wine strains and potentially associated to IRC7S allele, which can help to explain the outstanding phenotype of HS strains and their dominant distribution in wines. Originality-Significance StatementS. cerevisiae is one of the best studied microbes due to its industrial importance and its use as a eukaryotic model organism. S. cerevisiae is also an interesting model for studying the effects of domestication in yeast genomic, phenotype and ecology. The study of how wild S. cerevisiae strains evolved into a greatly adapted domesticated strains and changed its lifestyle drastically is still of great interest. In the case of wine populations, strains have accumulated numerous hallmarks of domestication in their genome, related with their great phenotypic adaptation to this environment. Here, we report a new hallmark of domestication in wine strains; the IRC7 deleted allele (IRC7S) and present the first insights about its unexpected global distribution among phylogenetic clades, understanding the genomic context and the phenotypic implications of this allele in wine strains.

microbiology↗

bioRxiv2020

A mesocosm experiment in ecological physiology: adaptive modulation of energy budget in a hibernating marsupial under chronic caloric restriction

During the last sixty years, mammalian hibernation (i.e., seasonal torpor) has been interpreted as a physiological adaptation for energy economy. However -and crucially for validating this idea - direct field comparisons of energy expenditure in hibernating and active free-ranging animals are scarce. Using replicated mesocosms and a combination of energy budgeting approaches (i.e., doubly labelled water, rates of CO2 production and food intake), we experimentally manipulated energy availability and quantified net energy costs of hibernation in a marsupial. We hypothesized that, when facing chronic caloric restriction (CCR), a hibernator should maximize torpor use for compensating the energetic deficit, compared to ad libitum fed individuals (=controls). However, intensifying torpor duration at low temperatures could increase other burdens (e.g., cost of rewarming, freezing risk). In order to explore this trade-off, we followed the complete hibernation cycle of the relict marsupial Dromiciops gliroides, and estimated its total energy requirements, and compared this with a control condition. Our results revealed: (1) that energy restricted animals, instead of promoting heat conservation strategies during hibernation (e.g., social clustering and thermoregulation), maximized torpor use and saved just enough energy to cover the deficit, and (2) that hibernation represents a net energy saving of 51% compared with animals that remained active. This work provides compelling evidence of a fine-tuning use of hibernation in response to food availability and presents the first direct estimation of energy savings by hibernation encompassing the total hibernation cycle.

ecology↗