Biology subjects

Rivas, M.

Publications and source records attributed to Rivas, M..

15 recordsLinked to original sources

bioRxiv2025

Differential effects of postpartum sleep restriction on maternal and offspring immunity in the rat

Backgroundsleep disturbances can trigger a wide range of physiological consequences, affecting hormonal regulation, metabolism, cognitive function, and immune responses. Human mothers worldwide frequently experience sleep restriction and fragmentation, a pattern also observed in other mammalian mothers, such as rats. These alterations may add to sleep disturbances unrelated to motherhood. Considering this, we wondered about the impact of sleep restriction in postpartum mother rats on their immunological status. Furthermore, given that early-life experiences can shape the immune system and that even subtle parental changes can influence offspring development, we hypothesized that maternal sleep loss might also exert detrimental effects on the pups. In this study, we investigated the effects of acute and chronic maternal sleep restriction during the postpartum period on immune parameters in both mother rats and their offspring by analyzing antibody titers and systemic inflammation. Methodsmother rats were surgically implanted with electrodes for polysomnographic recordings and for sleep deprivation (deep electrodes targeting the mesopontine wake-promoting area). From postpartum day 5 to day 9, lactating dams were randomly assigned to one of three groups: chronic sleep restriction (CSR; 6 h of sleep deprivation per day for five consecutive days), acute sleep restriction (ASR; 6 h of sleep deprivation only on postpartum day 9), or control (undisturbed). On postpartum day 9, mothers were milked, and blood samples from both mothers and pups were subsequently collected. ELISA assays quantified IL-17A, IL-6, IgG, and IgG2a in maternal serum; IgG and IgG2a in milk; and IgG in pup serum. Hematological parameters, including leukocyte profiles, were also assessed in peripheral blood of dams and pups. Resultsmaternal immune parameters analyzed remained unaffected by sleep restriction. IgG levels were lower in male pups from mothers subjected to ASR (5560 {+/-} 734 {micro}g/mL) compared with the control group (8666 {+/-} 463 {micro}g/mL; p = 0.025), whereas female pups showed no significant changes. Additionally, both female (4.10 {+/-} 0.58) and male (3.81 {+/-} 0.42) pups from dams subjected to CSR exhibited higher absolute lymphocytes counts relative to the control group (females: 2.28 {+/-} 0.25, p = 0.004; males: 2.44 {+/-} 0.25; p = 0.029). ConclusionsChronic and acute maternal sleep restriction had distinct impacts on offspring immunity, altering serum antibody and leukocyte profiles, while leaving maternal parameters unaffected. These results indicate that maternal sleep loss can influence the offspring even in the absence of detectable maternal immune alterations, with male pups being especially susceptible.

immunology↗

bioRxiv2025

Discovery of circulating cell-free DNA 5hmC biomarkers for peritoneal metastasis in colorectal and appendiceal cancer

IntroductionPeritoneal metastases (PM) are associated with poor prognosis in patients with colorectal cancer (CRC) or appendiceal adenocarcinoma (AA), yet detection of PM is unreliable using current circulating DNA technology. Leveraging novel 5hmC-seal technology to detect ultra-low amounts of DNA in plasma, we demonstrate the feasibility of 5-hydroxymethylcytosine (5hmC) signatures derived from circulating cell-free DNA (cfDNA) as biomarkers for PM. MethodsUsing a highly sensitive and robust 5hmC sequencing approach on genomic DNA isolated from peripheral blood samples, we developed predictive models to identify biomarkers for peritoneal metastases. ResultsWe obtained genome-wide 5hmC profiles from 71 CRC/AA patients with PM, 41 without PM, and 73 non-cancer controls. Predictive models trained on genomic region 5hmC levels in patients with cancer could distinguish PM status with high sensitivity and moderate specificity (AUC 0.827, sensitivity 92.4%, specificity 46.1%). Pathway enrichment analysis identified epigenetically dysregulated cancer, cell migration, adhesion, and immune-related pathways in PM. ConclusionNovel 5hmC-Seal technology based 5hmC signatures can detect patients with peritoneal metastases from CRC and AA, albeit with reduced specificity. This study lays a foundation for future clinical assay development for PM. Statement of significanceWe demonstrate high-sensitivity detection of peritoneal metastasis in colorectal and appendiceal adenocarcinomas using 5hmC-Seal of plasma cfDNA. Earlier detection of this condition could expand curative treatments in [~]20,000 affected U.S. patients.

cancer biology↗

bioRxiv2025

Dual hypocretin receptor antagonism enhances sleep and nursing behavior in lactating rats.

Hypocretins (also known as orexins) are neuropeptides that regulate the sleep-wake cycle and modulate various behaviors, including maternal behavior. They act through two receptor subtypes: hypocretin receptor 1 (HcrtR1) and hypocretin receptor 2 (HcrtR2). Although Dual Orexin Receptor Antagonists (DORAs) are clinically used as hypnotics, most preclinical studies with these drugs have been conducted in males, with limited research in females, leaving the postpartum period largely unexplored. Here, we examined the impact of the DORA Suvorexant on sleep and maternal behavior in lactating rats. Lactating and virgin female rats were implanted with electrodes for polysomnographic recording. Using a counterbalanced design, Suvorexant was orally administered at doses of 0, 10 (SUV10), and 30 mg/kg (SUV30) to virgin rats in diestrus and to lactating rats between postpartum days 4 and 8. Sleep recordings and maternal behaviors were assessed during the light phase for six hours following the administration of the drug. Suvorexant reduced wakefulness and increased slow wave sleep, intermediate state, and REM sleep in both groups, with a stronger effect in virgin females. In lactating rats, Suvorexant increased nursing time and milk ejections, while reducing active maternal behavior such as pup-licking. These findings demonstrate that dual hypocretin receptor antagonism produces hypnotic effects and selectively modulates maternal behavior, promoting nursing while reducing active maternal behavior.

neuroscience↗

bioRxiv2023

Dorsal and median raphe neuronal firing dynamics characterized by non-linear metrics

The dorsal (DRN) and median (MRN) raphe are the main serotonergic nuclei, being implicated in sleep and mood regulation. The DRN is mainly serotonergic, where neurons have regular spiking activity, slow firing rate (FR), and long action potential duration (APD). The MRN is divided in a median serotonergic region and a paramedian region, containing principally GABAergic neurons, resulting in more diverse neurochemical and electrophysiological features. In the present study, we aimed to enrich the characterization of the raphe nuclei neurons by using non-linear metrics. This was done by analyzing the neuronal basal firing profile in both nuclei of urethane-anesthetized rats using Ordinal Patterns (OP) Entropy, Bins Entropy, and Permutation Lempel-Ziv Complexity (PLZC). In a first step, we found that typical linear metrics - such as FR, coefficient of variation (CV), and APD - fail to distinguish between MRN and DRN neurons, while OP entropy is significantly different between these nuclei. We also found that the FR has a strong linear relationship with CV, Bins Entropy, and PLZC. Similarly, CV has a strong correlation with FR and Bins Entropy, whereas PLZC shows a strong linear fit with Bins Entropy. However, OP Entropy has either a weak or no linear relationship with the rest of the metrics tested, suggesting that OP Entropy is a good metric to differentiate neuronal firing profiles. In a second step, we studied how these metrics are affected by the oscillatory properties of the firing patterns. We found that all metrics are sensitive to rhythmicity - with the exception of OP Entropy. Again, this highlights OP Entropy as a powerful and useful quantity for the characterization of neuronal discharge patterns.

neuroscience↗

bioRxiv2023

A lipopeptidomimetic of transcriptional activation domains selectively disrupts Med25 PPIs

Short amphipathic peptides are capable of binding to transcriptional coactivators, often targeting the same binding surfaces as native transcriptional activation domains. However, they do so with modest affinity and generally poor selectivity, limiting their utility as synthetic modulators. Here we show that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic (34913-8) increases the affinity for the coactivator Med25 >10-fold (Ki >>100 M to 10 M). Importantly, the selectivity of 34913-8 for Med25 compared to other coactivators is excellent. 34913-8 engages Med25 through interaction with the H2 face of its Activator Interaction Domain and in doing so stabilizes full-length protein in the cellular proteome. Further, genes regulated by Med25-activator PPIs are inhibited in a cell model of triple-negative breast cancer. Thus, 34913-8 is a useful tool for studying Med25 and the Mediator complex biology and the results indicate that lipopeptidomimetics may be a robust source of inhibitors for activator-coactivator complexes.

biochemistry↗

bioRxiv2023

Error-corrected Duplex Sequencing enables direct detection and quantification of mutations in human TK6 cells with remarkable inter-laboratory consistency

Error-corrected Duplex Sequencing (DuplexSeq) enables direct quantification of low-frequency mutations and offers tremendous potential for chemical mutagenicity assessment. We investigated the utility of DuplexSeq to quantify induced mutation frequency (MF) and spectrum in human lymphoblastoid TK6 cells exposed to a prototypical DNA alkylating agent, N-ethyl-N-nitrosourea (ENU). Furthermore, we explored appropriate experimental parameters for this application, and assessed inter-laboratory reproducibility. In two independent experiments in two laboratories, TK6 cells were exposed to ENU (25-200 {micro}M) and DNA was sequenced 48, 72, and 96 h post-exposure. A DuplexSeq mutagenicity panel targeting twenty 2.4-kb regions distributed across the genome was used to sample diverse, genome-representative sequence contexts. A robust increase in MF that was unaffected by time was observed in both laboratories. Concentration-response in the MF from the two laboratories was strongly positively correlated (R2=0.95). C:G>T:A, T:A>C:G, T:A>A:T, and T:A>G:C mutations increased in consistent, concentration-dependent manners in both laboratories, with high proportions of C:G>T:A at all time points. The target sites responded similarly between the two laboratories and revealed a higher average MF in intergenic regions. These results, demonstrating remarkable reproducibility across time and laboratory for both MF and spectrum, support the high value of DuplexSeq for characterizing chemical mutagenicity in both research and regulatory evaluation.

genomics↗

bioRxiv2022

Electrophysiological characterization of medial preoptic neurons in lactating rats and its modulation by hypocretin-1

The medial preoptic area (mPOA) undergoes through neuroanatomical changes across the postpartum period, during which its neurons play a critical role in the regulation of maternal behavior. In addition, this area is also crucial for sleep-wake regulation. We have previously shown that hypocretins (HCRT) within the mPOA facilitate active maternal behaviors in postpartum rats, while the blockade of endogenous HCRT in this area promotes nursing and sleep. To explore the mechanisms behind these HCRT actions, we aimed to evaluate the effects of juxta-cellular HCRT-1 administration on mPOA neurons in urethane-anesthetized postpartum and virgin female rats. We recorded mPOA single units and the electroencephalogram (EEG) and applied HCRT-1 juxta-cellular by pressure pulses. Our main results show that the electrophysiological characteristics of the mPOA neurons and their relationship with the EEG of postpartum rats did not differ from virgin rats. Additionally, neurons that respond to HCRT-1 had a slower firing rate than those that did not. In addition, administration of HCRT increased the activity in one group of neurons while decreasing it in another, both in postpartum and virgin rats. The mechanisms by which HCRT modulate functions controlled by the mPOA involve different cell populations.

neuroscience↗

bioRxiv2021

Role of hypocretin in the medial preoptic area in the regulation of sleep, maternal behavior and body temperature of lactating rats.

The hypocretins (HCRT), also known as orexin, includes two neuroexcitatory peptides, HCRT-1 and HCRT-2 (orexin A y B, respectively), synthesized by neurons located in the postero-lateral hypothalamus, whose projections and receptors are widely distributed throughout the brain, including the medial preoptic area (mPOA). HCRT have been associated with a wide range of physiological functions including sleep-wake cycle, maternal behavior and body temperature, all regulated by the mPOA. Previously we showed that HCRT in the mPOA facilitates certain active maternal behaviors, while the blockade of HCRT-R1 increased the time spent in nursing. As mother rats mainly sleep while they nurse, we hypothesize that HCRT in the mPOA of lactating rats reduce sleep and nursing, while the intra-mPOA administration of the dual orexin receptor antagonist (DORA) would generate the opposite effect. Therefore, the aim of this study was to determine the role of HCRT within the mPOA, in the regulation and integration of the sleep-wake cycle, maternal behavior and body temperature of lactating rats. To evaluate this idea, we assessed the sleep-wake states, maternal behavior and body temperature of lactating rats following microinjections of HCRT-1 (100 and 200 M) and DORA (5mM) into the mPOA. As expected, our data shows that HCRT-1 in mPOA promoted wakefulness and a slightly increase in body temperature, whereas DORA increased both NREM and REM sleep along with nursing and milk ejection. Taken together, our results strongly suggest that the reduction of the endogenous HCRT within the mPOA of lactating rats is important to promote sleep, nursing and milk ejection.

neuroscience↗

bioRxiv2021

Local administration of bicuculline into the ventrolateral and medial preoptic nuclei modifies sleep and maternal behavior in lactating rats.

The preoptic area (POA) is a brain structure classically involved in a wide variety of animal behavior including sleep and maternal care. In the current study, we evaluate the specific effect of disinhibition of two specific regions of the POA, the medial POA nucleus (mPOA) and the ventrolateral POA area (VLPO) on sleep and maternal behavior in lactating rats. For this purpose, mother rats on postpartum day 1 (PPD1) were implanted for polysomnographic recordings and with bilateral cannulae either in the mPOA or in the VLPO. The rats were tested for sleep and maternal behavior on PPD4-8 after the infusion of the GABA-A antagonist, bicuculline (0, 10 or 30 ng/0.2 {micro}l/side). Infusion of bicuculline into the mPOA augmented retrieving and nest building behaviors and reduced both nursing and milk ejections but had almost no effect on sleep. When bicuculine was microinjected into the VLPO, the rats significantly increase the number of retrievings and mouthings and reduced the nursing time without changes in milk ejections, which was associated with an increase in wakefulness and a reduction in light sleep. Our results show that disinhibition of the mPOA, a key area in the control of maternal behavior, increased active maternal behaviors and reduced nursing without affecting wakefulness or sleep time. In contrast, the enhancement of some active maternal behaviors when the drug was infused into the VLPO, a sleep-promoting area, with a concomitant increase in wakefulness suggests that mother rats devote this additional waking time in the active maternal care of the pups. We hypothesize that maternal behavior changes after bicuculine microinjection into the VLPO is caused by a reduction in the sleep drive, rather than a direct effect on maternal behavior.

neuroscience↗

bioRxiv2021

Surveillance of Shiga toxin-producing Escherichia coli associated bloody diarrhea in Argentina

In Argentina, the hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS) infection is endemic, and reliable data about prevalence and risk factors are available since 2000. However, information about STEC-associated bloody diarrhea (BD) cases is limited. A prospective study was carried out in seven tertiary-hospitals and 18 Referral Units from different regions, aiming to determine (i) STEC-positive BD cases frequency in 714 children aged 1 to 9 years old; and (ii) rate of progression to HUS. The number and regional distribution of STEC-HUS cases assisted in the same hospitals and period was also assessed. A total of 29 (4.1%) STEC-positive BD cases were confirmed by Shiga Toxin Quik Chek (STQC) and/or mPCR. The highest frequencies were found in the Southern region (Neuquen, 8.7%; Bahia Blanca, 7.9%), in children between 12 and 23 month of age (8.8%), during summertime. Four (13.8%) cases progressed to HUS, three to five days after BD onset. Twenty-seven STEC-HUS children mainly under 5 years old (77.8%) were enrolled, 51.9% were female; 44% were Stx-positive by STQC and all by mPCR. The most common serotypes were O157:H7 and O145:H28 and prevalent genotypes were stx2a-only or associated, both among BD and HUS cases. Considering the endemic behavior of HUS and its impact on public health, it is important to have updated information about the epidemiology of the diarrheal disease for early recognition of infected patients and initiation of supportive treatment. Finally, it also gives the opportunity to respond to outbreak situations effectively and in timely manner.

microbiology↗

bioRxiv2019

Constraint-based analysis for causal discovery in population-based biobanks

Availability of large genetic databases has led to the development of powerful causal inference methods that use genetic variables as instruments to estimate causal effects. Such methods typically make many assumptions about the underlying causal graphical model, are limited in the patterns they search for in the data, and there is no guide for systematic analysis of a large database. Here, we present cGAUGE, a new pipeline for causal Graphical Analysis Using GEnetics that utilizes large changes in the significance of local conditional independencies between the genetic instruments and the phenotypes. We detect cases where causal inference can be performed with minimal risk of horizontal pleiotropy. Moreover, we search for new graphical patterns to reveal novel information about the underlying causal diagram that is not covered by extant methods, including new direct links, colliders, and evidence for confounding. We present theoretical justification, simulations, and apply our pipeline to 70 complex phenotypes from 337,198 subjects from the UK Biobank. Our results cover 102 detected causal relationships, of which some are new and many are expected. For example, we detect a direct causal link from high cholesterol to angina and a feedback loop between angina and myocardial infarction. We also corroborate a recent observational link between asthma and Crohns disease. Finally, we detect important features of the causal network structure including several causal hubs such as intelligence and waist circumference.

genetics↗

bioRxiv2019

Phenome-wide burden of copy number variation in UK Biobank

Copy number variations (CNV) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high-mortality, we describe genetic burden from syndromic and previously uncharacterized CNV loci across nearly 2,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, as well as novel associations at 9p23, in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy number variation, as well as a series of known and novel dosage-mediated genic associations across the medical phenome.

genomics↗

bioRxiv2018

Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight novel adipocyte biology

To characterize latent components of genetic associations, we applied truncated singular value decomposition (DeGAs) to matrices of summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured in 337,199 White British individuals in the UK Biobank study. We systematically identified key components of genetic associations and the contributions of variants, genes, and phenotypes to each component. As an illustration of the utility of the approach to inform downstream experiments, we report putative loss of function variants, rs114285050 (GPR151) and rs150090666 (PDE3B), that substantially contribute to obesity-related traits, and experimentally demonstrate the role of these genes in adipocyte biology. Our approach to dissect components of genetic associations across human phenotypes will accelerate biomedical hypothesis generation by providing insights on previously unexplored latent structures.

genetics↗

bioRxiv2018

Global Biobank Engine: enabling genotype-phenotype browsing for biobank summary statistics

Large biobanks linking phenotype to genotype have led to an explosion of genetic association studies across a wide range of phenotypes. Sharing the knowledge generated by these resources with the scientific community remains a challenge due to patient privacy and the vast amount of data. Here we present Global Biobank Engine (GBE), a web-based tool that enables the exploration of the relationship between genotype and phenotype in large biobank cohorts, such as the UK Biobank. GBE supports browsing for results from genome-wide association studies, phenome-wide association studies, gene-based tests, and genetic correlation between phenotypes. We envision GBE as a platform that facilitates the dissemination of summary statistics from biobanks to the scientific and clinical communities. GBE currently hosts data from the UK Biobank and can be found freely available at biobankengine.stanford.edu.

bioinformatics↗

bioRxiv2017

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

There is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.\n\nMain abbreviations

genetics↗