Biology subjects

Perez, N.

Publications and source records attributed to Perez, N..

13 recordsLinked to original sources

bioRxiv2026

Co-Expressed MicroRNAs Identify Potential Mechanisms Underlying Risk for Multimorbid Depression and Type 2 Diabetes in Midlife Women

BackgroundWomen are disproportionately affected by multimorbid depression and type 2 diabetes (T2D), with prevalence peaking during midlife (40-64 years), a biologically dynamic timeframe due to changes associated with reproductive aging. Yet, phenotypic and mechanistic factors contributing to midlife womens disproportionate risk for co-occurrence remain poorly defined. We previously identified co-expressed microRNAs (miRs) in midlife women with prediabetes that increased odds of assignment to a high psychometabolic risk phenotype. Here, we extend these findings by characterizing putative mRNA targets of these co-expressed miRs and pathways overrepresented among mRNAs, providing insights into potential mechanisms underlying psychometabolic risk in midlife women. MethodsThis study included baseline data from midlife women (ages 40-64 years) with prediabetes who participated in the Diabetes Prevention Program (DPP) (n = 603). In silico analyses were performed using miRTarBase to identify mRNAs regulated by 3 or more of the miRs that most prominently loaded a principal component previously identified to increase odds of assignment to a high psychometabolic risk phenotype defined in this sample. Pathway enrichment analysis was conducted to assess for overrepresentation of KEGG pathways among predicted mRNA targets. To enhance interpretability, pathways were thematically clustered based on their evidenced role in human physiology. ResultsWe identified a total of 13 mRNAs targeted by co-expressed miRs associated with increased odds of assignment to a high psychometabolic risk phenotype in midlife women with prediabetes. Pathway enrichment analysis revealed a total of 71 KEGG pathways with overrepresentation of identified mRNA targets. Four overarching biological themes emerged, reflecting involvement of metabolic, inflammatory, endocrine, and stress/biological weathering-related processes. ConclusionsExperimentally validated mRNA targets related biological pathways were identified, providing multisystem insights into potential mechanisms underlying risk for multimorbid depression and T2D in midlife women. Findings offer mechanistic targets for experimental validation and future precision health research focused on this high-risk population. Overall, this work positions the utility of miRs as context-sensitive biomarkers in the characterization of risk for complex, multimorbid conditions in women during biologically dynamic timeframes.

genomics↗

bioRxiv2026

Dismantling Chromosomal Stasis Across the Eukaryotic Tree of Life

Chromosome number shapes genome organization, recombination, and speciation, yet how fast it evolves across the tree of life has never been measured. We analyzed 63,682 karyotypes across 55 eukaryotic clades and found that dysploidy rates vary by 844-fold, from approximately 0.0008 to 0.7 events per million years. This variation does not follow kingdom boundaries or deep phylogeny; intraclade variance exceeds interclade differences by more than an order of magnitude. Even birds, the textbook example of chromosomal stasis, exceed the global median rate once microchromosome dynamics are resolved. Contrasting the stasis of Odonata with the volatility of Orchidaceae reveals that life history and population structure, rather than deep phylogenetic constraints, govern the tempo of karyotypic change.

evolutionary biology↗

bioRxiv2026

Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation

Variants in TMEM106B and GRN, which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN-mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

cell biology↗

bioRxiv2025

Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation

Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analysed mitochondrial morphology and dynamics, by live-cell confocal microscopy, and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits. MFN2 mutations impaired mitochondrial fusion and displayed distinct effects on fission and cellular metabolism. L248H-expressing cells showed hyper-elongated mitochondria, impaired fission, and increased OCR, while, M376V cells exhibited fragmentation, enhanced fission, and elevated ECAR. These effects correlated with differential Drp1 phosphorylation. Our findings demonstrate that MFN2 mutants differentially influences fission and metabolism, highlighting the need to consider these effects in therapies aimed at modulating mitochondrial dynamics.

cell biology↗

bioRxiv2023

Investigation of astrocytes' morphological changes in response to laser-induced shockwave

Traumatic Brain Injury (TBI) arises from an external force affecting the brain, leading to a range of outcomes from mild to severe. Despite continuous scientific advancements, it continues to pose a persistent threat and remains a significant cause of physical impairment and mortality. Various models, including blast-induced TBI (bTBI), have been proposed to simulate TBI. Laser-induced shockwaves (LIS) us emerging as an effective method. LIS generates shockwaves via pulsed laser-induced plasma formation, offering a controlled means to study TBI at the cellular level. Astrocytes, pivotal in maintaining brain function post-injury, undergo dynamic morphological changes, contributing to the understanding of injury responses and neurodegenerative diseases. This study introduces a system combining Laser-Induced Shockwaves (LIS) and Quantitative Phase Microscopy (QPM) to quantify morphological changes in astrocytes during and after LIS exposure. QPM, a label-free method, facilitates 3D imaging and captures real-time cellular dynamics. The integration of LIS and QPM enables the assessment of astrocyte responses to shear stress caused by LIS, revealing immediate and sustained morphological transformations. Analysis post-LIS exposure indicates significant alterations in circularity, volume, surface area, and other features. Statistical tests affirm of observed trends, providing insights into astrocyte responses to mechanical forces. The findings contribute to understanding how mechanical stimuli impact astrocyte morphology, holding promise for targeted therapeutic strategies in traumatic brain injuries and related neurological disorders. The integrated LIS and QPM approach serves as a powerful tool for 3D imaging and quantitative measurement of astrocyte morphological changes, offering deeper insights into cellular dynamics and potential therapeutic interventions.

bioengineering↗

bioRxiv2022

Stac1 Regulates Sensory Stimulus Induced Escape Locomotion

The stac family of genes are expressed by several cell types including neurons and muscles in a wide variety of animals. In vertebrates, stac3 encodes an adaptor protein specifically expressed by skeletal muscle that regulates L-type calcium channels (CaChs) and excitation-contraction coupling. The function of Stac proteins expressed by neurons in the vertebrate CNS, however, is unclear. To better understand neuronal Stac proteins, we identified the stac1 gene in zebrafish. stac1 is expressed selectively in the embryonic CNS including in Kolmer-Agduhr (KA) neurons, the cerebral fluid-contacting neurons (CSF-cNs) in the spinal cord. Previously CSF-cNs in the spinal cord were implicated in locomotion by zebrafish larvae. Thus, expression of stac1 by CSF-cNs and the regulation of CaChs by Stac3 suggest the hypothesis that Stac1 may be important for normal locomotion by zebrafish embryos. We tested to see if optogenetic activation of CSF-cNs was sufficient to induced swimming in embryos as it is in larvae. Indeed, optogenetic activation of CSF-cNs in embryos induced swimming in embryos. Next, we generated stac1-/- null embryos and found that both mechanosensory and noxious stimulus-induced swimming were decreased. We further found that zebrafish embryos respond more vigorously to tactile stimulation in the light compared to the dark. Interestingly, light enhancement of touch-induced swimming was eliminated in stac1 mutants. Thus, Stac1 regulates escape locomotion in zebrafish embryos perhaps by regulating the activity of CSF-cNs. SIGNIFICANCE STATEMENTThe stac genes are a small family of genes found in neurons and muscle in both vertebrates and invertebrates. Stac3 is a muscle protein that controls excitation-contraction coupling via regulation of L-type calcium channels and in humans a STAC3 mutation is responsible for a congenital myopathy. The function of neural Stac proteins, however, is unknown in vertebrates. The findings of this report show that neural stac1 is expressed by cerebral fluid-contacting neurons (CSF-cNs) in the spinal cord of zebrafish embryos and that it is necessary for normal sensory stimulus induced escape swimming. To our knowledge this is the first demonstration of a function for stac genes in neurons in the vertebrate nervous system.

neuroscience↗

bioRxiv2022

Automatic identification of intestinal parasites in reptiles using microscopic stool images and convolutional neural networks

Captive environments trigger the propagation and multiplication of parasites among different reptile species, thus weakening their immune response and causing infections and diseases. Technological advances of convolutional neural networks have opened a new field for detecting and classifying diseases which have shown great potential to overcome the shortcomings of manual detection performed by experts. Therefore, we propose an approach to identify six captive reptiles parasitic agents (Ophionyssus natricis, Blastocystis sp, Oxiurdo egg, Rhytidoides similis, Strongyloides, Taenia) from a microscope stool images dataset. Towards this end, we first use an image segmentation stage to detect the parasite within the image, which combines the Contrast Limited Adaptive Histogram Equalization (CLAHE) technique, the OTSU binarization method, and morphological operations. Then, we carry out a classification stage through Mobilenet CNN under a transfer learning scheme. This method was validated on a stool image dataset containing 3616 images data samples and 26 videos from the six parasites mentioned above. The results obtained indicate that our transfer learning-based approach can learn a helpful representation from the dataset. We obtained an average accuracy of 98.66% across the six parasitic agent classes, which statistically outperformed, at a 95% confidence level, a custom CNN trained from scratch.

zoology↗

bioRxiv2021

Activation of T cell checkpoint pathways during beta-cell antigen presentation by engineered dendritic cells promotes protection of non-obese diabetic mice from type 1 diabetes

Defective immune regulation has been recognized in type 1 diabetes (T1D). Immune regulatory T cell check-point receptors, which are generally upregulated on activated T cells, have been the molecules of attention as therapeutic targets for enhancing immune response in tumor therapy. We reported that dendritic cells (DCs) that are engineered to express selective ligands for checkpoint receptors can induce effective T cell tolerance in antigen-immunization models. Here, we show that pancreatic {beta} -cell antigen (BcAg) presentation by engineered tolerogenic-DCs (tDCs) that express CTLA4 selective ligand (B7.1wa) or a combination of CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively; multiligand-DCs) causes an increase in regulatory cytokine and T cell (Treg) responses and suppression of the effector T cell function as compared to engineered control-DCs. Non-obese diabetic (NOD) mice treated with BcAg-pulsed CTLA4-ligand-DCs and multiligand-DCs at pre-diabetic and early-hyperglycmic stages showed significantly lower degree of insulitis, higher frequencies of insulin-positive islets, profound delay in, and reversal of, hyperglycemia for a significant duration. Immune cells from the tDC treated mice not only produced lower amounts of IFN{gamma} and higher amounts of IL10 and TGF{beta}1 upon BcAg challenge, but also failed to induce hyperglycemia upon adoptive transfer. While both CTLA4-ligand-DCs and multiligand-DCs were effective in inducing tolerance, multiligand-DC treatment produced an overall higher suppressive effect on effector T cell function and disease outcome. These studies show that enhanced engagement of T cell checkpoint receptors during BcAg presentation can modulate T cell function and suppress autoimmunity and progression of the disease in T1D.

immunology↗

bioRxiv2020

celldeath: a tool for simple detection of cell death in transmitted light microscopy images by visual deep learning analysis

Cell death experiments are routinely done in many labs around the world, these experiments are the backbone of many assays for drug development. Cell death detection is usually performed in many ways, and requires time and reagents. However, cell death is preceded by slight morphological changes in cell shape and texture. In this paper, we trained a neural network to classify cells undergoing cell death. We found that the network was able to highly predict cell death after one hour of exposure to camptothecin. Moreover, this prediction largely outperforms human ability. Finally, we provide a simple python tool that can broadly be used to detect cell death.

cell biology↗

bioRxiv2020

Luciferase Immunoprecipitation Systems immunoassay is a sensitive, rapid method to detect allergen component-specific IgE

Current assays to detect allergen-specific IgE have constraints related to obtaining pure, conformationally active allergen, variability in allergen extracts, sample volume required, and turnaround time. The luciferase immunoprecipitation systems (LIPS) immunoassay is a fast, sensitive assay created using recombinant antigens that requires a low specimen volume. These assays can also be easily modified to detect multiple antigens and antibody isotypes. Here, we demonstrate the use of LIPS assays as an innovative method to quantitatively measure allergen component-specific IgE in small sample volumes. Sera from healthy volunteers, helminth-infected adults, and peanut-allergic children were screened for IgE to cat using ImmunoCAP. These samples were also measured for IgE against Fel d 1 using LIPS. LIPS signal correlated to cat IgE levels with rS = 0.6204, p < 0.001. The LIPS signal: noise ratio differed significantly between cat IgE-samples and cat IgE+ samples with values > 0.5 kU/L, with the ability to differentiate cat IgE - individuals from cat IgE+ individuals with 85% sensitivity and 76% specificity. Given their rapidity, efficiency, sensitivity, and quantitation over a broad dynamic range, LIPS immunoassays can be a robust and flexible tool with potential uses in allergy research, diagnostics, and treatment.

immunology↗

bioRxiv2019

Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

Inhibitory/repressor-receptors are upregulated significantly on activated T cells, and have been the molecules of attention as targets for inducing immune tolerance. Induction of effective antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these inhibitory receptors. Here, we show, for the first time that dendritic cells (DCs) can be efficiently engineered to express multiple T cell inhibitory ligands, and enhanced engagement of T cell inhibitory receptors, upon antigen presentation, by these DCs can induce effective CD4+ T cell tolerance and suppress autoimmunity. Compared to control DCs, antigen presentation by DCs that ectopically express CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively) individually (mono-ligand DCs) or in combination (multi-ligand DCs) causes an inhibition of CD4+ T cell proliferation and pro-inflammatory cytokine response, as well as increase in Foxp3+ Treg frequency and immune regulatory cytokine production. Administration of self-antigen (mouse thyroglobulin; mTg) loaded multi-ligand DCs caused hyporesponsiveness to mTg challenge, suppression of autoantibody production, and amelioration of experimental autoimmune thyroiditis. Overall, this study shows that engineered DC-directed enhanced concurrent activation of multiple T cell coinhibitory pathways is an effective way to induce self-antigen specific T cell tolerance to suppress ongoing autoimmunity.

immunology↗

bioRxiv2019

Analysis of the expression of PIWI-interacting RNAs during cardiac differentiation of human pluripotent stem cells

PIWI-interacting RNAs (piRNAs) are a class of non-coding RNAs initially thought to be restricted almost exclusively to germ line cells. In recent years, accumulating evidence has demonstrated that piRNAs are actually expressed in somatic cells like pluripotent, neural, cardiac and even cancer cells. However, controversy still remains around the existence and function of somatic piRNAs. Using small RNA-seq samples from H9 pluripotent stem cells differentiated to mesoderm progenitors and cardiomyocytes we identified the expression of 447 piRNAs, of which 241 were detected in pluripotency, 218 in mesoderm and 171 in cardiac cells. The majority of them originated from the sense strand of protein coding and lncRNAs genes in all stages of differentiation, though no evidences for secondary piRNAs (ping-pong loop) were found. Genes hosting piRNAs in cardiac samples were related to critical biological processes in the heart, like contraction and cardiac muscle development. Our results indicate that somatic piRNAs might have a role in fine-tuning the expression of genes involved in the differentiation of pluripotent cells to cardiomyocytes.

molecular biology↗

bioRxiv2018

Complex dietary-polysaccharide modulates gut immune function and microbiota, and promotes protection from autoimmune diabetes

Since the dietary supplement and prebiotic value of {beta}-glucan-rich products have been widely recognized and the dietary approaches for modulating autoimmunity have been increasingly explored, we assessed the impact of oral administration of high-pure yeast {beta}-glucan (YBG) on gut immune function, microbiota and type 1 diabetes (T1D) using mouse models. Oral administration of this non-digestible complex polysaccharide caused a Dectin-1-dependent immune response involving increased expression of IL10, retinaldehyde dehydrogenase (Raldh) and pro-inflammatory cytokines in the gut mucosa. YBG-exposed intestinal DCs induced/expanded primarily Foxp3+, IL10+ and IL17+ T cells, ex vivo. Importantly, prolonged oral administration of low-dose YBG at pre-diabetic stage suppressed insulitis and significantly delayed the T1D incidence in non-obese diabetic (NOD) mice. Further, prolonged treatment with YBG showed increased Foxp3+ T cell frequencies, and a significant change in the gut microbiota, particularly an increase in the abundance of Bacteroidetes and a decrease in the Firmicute members. Oral administration of YBG, together with Raldh-substrate and {beta}-cell antigen, resulted in a better protection of NOD mice from T1D. These observations suggest that YBG not only has a prebiotic property, but also has an oral tolerogenic-adjuvant-like effect, and these features could be exploited for modulating autoimmunity in T1D.

immunology↗