Biology subjects

Cervantes, M.

Publications and source records attributed to Cervantes, M..

10 recordsLinked to original sources

bioRxiv2026

The liver compensates for zonal loss of glucose 6-phosphatase to prevent glycogen storage disease

The liver is organized into spatial zones with distinct metabolic roles, but how this architecture contributes to disease remains unclear. Glucose production is concentrated in periportal hepatocytes and depends on G6PC1; loss of this enzyme causes glycogen storage disease type Ia (GSD1a). We tested whether G6PC1 loss in specific zones, including its primary periportal location, is sufficient to cause disease. Unexpectedly, loss of G6pc1 in any single zone caused local glycogen accumulation but did not produce the systemic metabolic abnormalities or liver tumors seen after whole-liver deletion. Instead, disease developed only after near-complete loss of G6pc1 across the entire liver. These findings show that organ-wide compensation preserves metabolic homeostasis and suppresses tumorigenesis despite localized disruption. TeaserSpatial G6pc1 loss causes local glycogen storage without systemic metabolic disease.

physiology↗

bioRxiv2026

UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism

The ubiquitin-fold modifier 1 (UFM1) post-translational modification (PTM), or UFMylation, regulates protein homeostasis and is essential for human development. Yet the roles of the de-UFMylase, UFM1-specific peptidase 2 (UFSP2), which removes UFM1 from UFMylated proteins, remain poorly characterized. Here, we demonstrate that UFMylation and UFSP2 regulate mitochondrial metabolism. Quantitative proteomics in UFSP2-deficient cells revealed the accumulation of many proteins previously unknown to be impacted by UFMylation. These included components of the mitochondrial ribosome, electron transport chain (ETC), and pyruvate dehydrogenase (PDH) complex. Functional analyses demonstrated that excessive UFMylation in UFSP2-deficient cells increases mitochondrial respiration, glucose oxidation in the tricarboxylic acid (TCA) cycle, and PDH enzymatic activity. We identified dihydrolipoamide S-acetyltransferase (DLAT), the E2 component of PDH, as a direct UFMylation substrate, with lysine 118 (K118) as the primary conjugation site. Mutating K118 to arginine (K118R) abolished DLAT UFMylation and reduced pyruvate oxidation, identifying this modification as an activator of PDH. These findings reveal a UFMylation-based regulatory mechanism that controls mitochondrial function by inducing utilization of pyruvate as a TCA cycle fuel.

biochemistry↗

bioRxiv2026

Function within Disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation

In numerous neurodegenerative diseases known collectively as tauopathies, the microtubule-associated protein tau forms fibrillar aggregates that are hallmarks of disease pathology. Tauopathies represent a substantial fraction of diseases associated with protein misfolding. Cellular chaperones known as small heat shock proteins (sHSPs) play a critical role in maintaining protein homeostasis by delaying the onset of protein aggregation. Two sHSPs, HSPB1 (Hsp27) and HSPB5 (B-crystallin), are constitutively expressed in brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms dictated by their disordered N-terminal regions (NTRs). HSPB1 inhibits tau aggregation under normal cellular conditions, whereas HSPB5 displays activity towards tau when activated by stress conditions such as pH acidosis. Using chimeric HSPB1/HSPB5 constructs in which small NTR subregions are swapped, we identify functional regions within the NTRs that modulate chaperone function for tau. The functional regions contain known sites of phosphorylation, suggesting that they are also control points that respond to cellular stress conditions. Our findings support an emerging model in which specific functional motifs within disordered regions of sHSPs govern activity and client engagement under normal and stress conditions. Broader AudienceIn many neurodegenerative diseases, the microtubule-associated protein tau forms fibrillar aggregates in the brain. Small heat shock proteins (sHSP) help prevent such aggregation, but their mechanisms of action remain enigmatic. We show HSPB1 and HSBP5, two sHSPs that are abundant and co-localize with tau, delay the onset of tau aggregation through distinct mechanisms. Each relies on specific small regions within their disordered N- terminal domains whose accessibility can be regulated by stress conditions and post- translational modifications.

biochemistry↗

bioRxiv2025

Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 CD8 Memory T cells

Aging impacts immune function, but the mechanisms driving age-related changes in immune cell subsets remain unclear. To explore age-dependent changes in immune cell populations, we analyzed human peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20-82 years using a 36-color spectral flow cytometry panel focused on T cells. We identified a unique population of memory CD8 T cells, which lack CXCR3 and produce a Th2-like cytokine response, accumulate with age. We discovered an age-dependent bias in naive CD8 T cells toward Th2 cytokine production, accompanied by transcriptional and epigenetic changes supporting this phenotype. Moreover, health outcome association analysis linked the accumulation of these unique CXCR3- central memory CD8 T cells to asthma, chronic liver conditions, and type 2 diabetes. Together, our results support the model that an age-dependent drift in epigenetic regulation towards a Th2-like phenotype drives a pathogenic Th2-like immune population.

immunology↗

bioRxiv2022

The ACE-2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion.

The SARS-CoV-2 coronavirus infects human cells via the ACE-2 receptor. Circumstantial evidence suggests that ACE-2 may not just serve as an attachment factor but also help activate the SARS-CoV-2 spike protein for membrane fusion. Here, we test that hypothesis directly, using DNA-lipid tethering as a synthetic attachment factor in the place of ACE-2. We find that SARS-CoV-2 pseudovirus and viruslike particles are both capable of membrane fusion if attached in the absence of ACE-2 and activated with an appropriate protease. However, addition of soluble ACE-2 speeds the fusion reaction. This is observed for both the Wuhan strain and the B.1.1.529 Omicron variant. Kinetic analysis suggests that there are at least two rate-limiting steps for SARS-CoV-2 membrane fusion, one of which is ACE-2 dependent and one of which is not. These data establish that, in the presence of an alternative attachment factor, ACE-2 is not biochemically required for SARS-CoV-2 membrane fusion. Since ACE-2 serves as the high-affinity attachment factor on human cells, the possibility to replace it with other factors has implications for the evolvability of SARS-CoV-2 and the fitness landscape for future related coronaviruses.

microbiology↗

bioRxiv2022

Mechanistic dissection of antibody inhibition of influenza entry yields unexpected heterogeneity

Neutralizing antibodies against influenza have generally been classified according to their recognition sites, with antibodies against the head domain of hemagglutinin thought to inhibit attachment and antibodies against the stalk region thought to inhibit fusion. Here, we report the development of a microfluidic assay to measure neutralization of viral entry that can clearly differentiate between effects on attachment and fusion. Testing multiple broadly-neutralizing antibodies against the hemagglutinin stalk domain, we obtain a surprising result: some broadly-neutralizing antibodies inhibit fusion only, while others inhibit both fusion and viral attachment. Antibodies binding the globular head domain primarily inhibit attachment but can also reduce the fusogenic capability of viral particles that nonetheless bind receptor. These findings shed light on the unexpectedly heterogeneous mechanisms of antibody neutralization even within similar recognition sites. The assay we have developed also provides a tool to optimize vaccine design by permitting assessment of the elicited antibody response with greater mechanistic resolution.

biophysics↗

bioRxiv2022

Transcriptome analysis of the binucleate ciliate Tetrahymena thermophila with asynchronous nuclear cell cycles

As a prototypic ciliated protozoan, Tetrahymena thermophila harbors two functionally and physically distinct nuclei within a shared cytoplasm. During vegetative growth, the cell cycles of the diploid germline micronucleus and polyploid somatic macronucleus are offset. Micronuclear S phase initiates just before cell division and is completed in daughter cells prior to the onset of macronuclear S phase. Whereas mitotic micronuclear division occurs mid-cell cycle, amitotic macronuclear division immediately precedes cytokinesis. Here we report the first RNA-seq analysis across the cell cycle of a binucleated organism. RNA was isolated at 30 min intervals across 1.5 vegetative cell cycles, starting with a macronuclear G1 population synchronized by centrifugal elutriation. Using MetaCycle, 3244 of the predicted 26,000+ T. thermophila genes were shown to be cell cycle regulated. Proteins that are required in micro- and macronuclei exhibit a single mRNA peak that correlates with their macronuclear function, while the expression of nucleus-limited protein-coding genes, including nucleoporins and importins, peak prior to their respective nucleus-specific role. Cyclin D and cyclin A/B genes showed distinct expression patterns that predict nucleus-specific functions. Clustering of periodically expressed genes revealed seven gene expression patterns. Four clusters have known PANTHER GO biological processes that are overrepresented for G1/S and G2/M phase functions. We propose that these clusters encode known and novel factors that coordinate micro- and macronuclear-specific events such as mitosis, amitosis, DNA replication and cell division.

bioinformatics↗

bioRxiv2022

The central clock suffices to drive the majority of circulatory metabolic rhythms

Life on Earth anticipates recurring 24-h environmental cycles via genetically-encoded molecular clocks active in all mammalian organs. Communication between these clocks is believed to control circadian homeostasis. Metabolism can be considered a form of inter- tissue communication language that results in temporal coordination of systemic metabolism between tissues. Here we characterize the extent to which clocks in different organs employ this means of communication, an area which remains largely unexplored. For this, we analysed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Notably, having functional hepatic and muscle clocks can only drive a minority (13%) of the oscillating metabolites in circulation. Conversely, limiting Bmal1 expression to Syt10- expressing neurons (which are enriched in the suprachiasmatic nucleus [SCN], the master pacemaker that regulates circadian rhythms) restores rhythms to 57% of circulatory metabolites and 28% of liver transcripts, and rescues glucose intolerance. Importantly, these parameters were also restored in clock-less mice upon rhythmic feeding, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

physiology↗

bioRxiv2021

Online learning for orientation estimation during translation in an insect ring attractor network

Insect neural systems are a promising source of inspiration for new algorithms for navigation, especially on low size, weight, and power platforms. There have been unprecedented recent neuroscience breakthroughs with Drosophila in behavioral and neural imaging experiments as well as the mapping of detailed connectivity of neural structures. General mechanisms for learning orientation in the central complex (CX) of Drosophila have been investigated previously; however, it is unclear how these underlying mechanisms extend to cases where there is translation through an environment (beyond only rotation), which is critical for navigation in robotic systems. Here, we develop a CX neural connectivity-constrained model that performs sensor fusion, as well as unsupervised learning of visual features for path integration; we demonstrate the viability of this circuit for use in robotic systems in simulated and physical environments. Furthermore, we propose a theoretical understanding of how distributed online unsupervised network weight modification can be leveraged for learning in a trajectory through an environment by minimizing of orientation estimation error. Overall, our results here may enable a new class of CX-derived low power robotic navigation algorithms and lead to testable predictions to inform future neuroscience experiments. SummaryAn insect neural connectivity-constrained model performs sensor fusion and online learning for orientation estimation.

neuroscience↗

bioRxiv2019

Prevalence of chronic chikungunya and associated risks factors in the French West Indies (La Martinique). A prospective cohort study

BackgroundThe chikungunya virus (CHIKV) is a re-emerging alphavirus that can cause chronic rheumatic musculoskeletal disorders, named chronic chikungunya (CHIKC+), which may be long-term incapacitating. A chikungunya outbreak occurred in 2013 in La Martinique. We constituted the first prospective cohort study of CHIKV-infected subjects in the Caribbean to assess the prevalence of CHIKC+ at 12 months and to search for factors present at the acute stage significantly associated with chronicity.\n\nMethodology/Principal findingsA total of 193 patients who tested positive for RT-PCR CHIKV, were submitted to clinical investigations in the acute phase (<21 days), and 3, 6, and 12 months after their inclusion. A total of 167 participants could be classified as either suffering or not from CHIKC+. They were analyzed using logistic regression models. At 12 months, the overall prevalence of CHIKC+ was 52.1% (95%CI: 44.5-59.7). In univariate analysis, age (OR: 1.04; 95% CI: 1.02-1.07; p=0.0003), being male (OR: 0.51; 95%CI: 0.27-0.98; p=0.04), headache (OR: 1.90; 95%CI: 1.02-3.56; p=0.04), vertigo (OR: 2.06; 95%CI: 1.05-4.03; p=0.04), vomiting (OR: 2.51; 95%CI: 1.07-5.87; p = 0.03), urea (OR: 1.33; 95%CI: 1.05-1.70; p=0.02) were associated with CHIKC+. In final multivariate logistic regression models for 167 participants, predictors of CHIKC+ were age (OR 1.06; 95%CI: 1.03-1.08; p<0.0001), male sex (OR: 0.40; 95%CI: 0.19-0.84; p=0.015), vertigo (OR: 2.46; 95%CI: 1.16-5.20; p=0.019), hypotension (OR 4.72; 95% -CI: 1.19-18.79; p=0.028), recoloration time >3 seconds (OR: 3.79; 95%-CI: 1.01-14.25).\n\nConclusionsThis cohort study in La Martinique confirms that CHIKC+ is a frequent complication of acute chikungunya disease. Analysis emphasized the importance of age and female sex for CHIKC occurrence, and pointed out the potential aggravating role of dehydration at the acute phase. Early and adequate hydration could reduce the risk chronic chikungunya disorders.\n\nAuthor SummaryChikungunya is a mosquito-borne virus found in tropical countries that has been re-emerging in the last decade. It has caused major epidemics in recent years, such as in Reunion Island and in Southeast Asia. Nearly 2.5 billion people around the world are at risk of contracting the virus. During the acute phase of the illness, patients experience a flu-like syndrome with fever, headache, myalgia, rash, and severe arthralgia. These symptoms can persist for several months in some patients, and can lead to significant functional disability. During the 2013 epidemic in Martinique, we followed nearly 200 patients who had contracted chikungunya. More than half of the patients had a chronic form of the disease--mainly women over 50 years of age. Our statistical analyses indicate that poor hydration during the acute phase may be a risk factor for developing chronic rheumatism. Therefore, in the context of a chikungunya epidemic, it seems important to encourage patients to drink plenty of fluids as soon as the first symptoms appear.

microbiology↗