Biology subjects

Ortiz, C.

Publications and source records attributed to Ortiz, C..

14 recordsLinked to original sources

bioRxiv2026

Guanine content in the CTCF motif encodes a vulnerability to persistent, alcohol-induced redistribution

Alcohol consumption is a leading contributor to the global disease burden, yet its molecular consequences remain incompletely understood. Ethanols first metabolite, acetaldehyde, modifies guanine to form DNA adducts and DNA-protein crosslinks that block elongating RNA polymerase II. Because acetaldehyde acts specifically on guanine, we hypothesized that chromatin features would be disrupted in a sequence-dependent rather than stochastic manner. Here we confirm that alcohol exposure displaces elongating RNA polymerase II (RNAPIIs2p) from gene bodies, relocating to promoters. In addition to this confirmation, we found that RNAPIIs2p also relocates to discrete guanine-rich intergenic CTCF sites. Loci with high guanine content at the CTCF motifs zinc finger 5 (ZF5) binding position showed the largest increase in both CTCF and cohesin (RAD21), with CTCF occupancy changes persisting even six days after alcohol withdrawal. Surprisingly, using Hi-C, we found that these changes to CTCF and cohesin do not impact the pronounced structural CTCF loops, but are instead primarily associated with altered guanine-rich enhancer-promoter contacts that connect to lasting changes to gene expression. Beyond our cell-line model, the same sequence rule accounts for altered CTCF occupancy in a mouse starvation (metabolic stress) model and in the placentae after paternal alcohol exposure. Together these findings link alcohol exposure to sequence-directed changes to chromatin whose rules are conserved in alcohol-associated disease.

molecular biology↗

bioRxiv2026

Nyx: a flexible framework for sleep scoring across species, lifespan and modalities

Sleep is a key factor in almost every physiological process, yet scoring tools lag behind innovations in basic to clinical research. New automated algorithms are trained on narrow datasets, typically healthy adult mouse or human, and fail to generalise, leaving labs to fall back on slow, laborious, and often poorly reproducible manual scoring. Here we introduce Nyx, an unsupervised framework built on principal component analysis that flexibly clusters epochs into sleep states, akin to how spike-sorting algorithms cluster single-neuron activity. Validated on about 8,000 hours spanning 19 independent datasets, it generalises across species, lifespan, recording modalities, and altered sleep architectures, matching human inter-scorer agreement. Beyond this, Nyx opens new ground for modern sleep research: classifying NREM subtypes in rodents, revealing states that cut across canonical boundaries in non-mammalian species, and enabling real-time, closed-loop manipulation. Distributed as an open-source package with a graphical user interface, Nyx offers an accessible, explainable framework built to scale with the pace of innovation itself.

neuroscience↗

bioRxiv2026

Haplotype-resolved centromeric chromatin organization from a complete diploid human genome

Centromeres ensure proper chromosome segregation during cell division, yet the organization and regulation of centromeric chromatin within satellite DNA arrays remain incompletely understood. Here, we leverage the complete diploid human genome benchmark (T2T-HG002) to provide a detailed study of centromeric sequence and chromatin architecture on individual haplotypes. Using adaptive-sampling-enriched, ultra-long-read DiMeLo-seq, we achieve single-molecule chromatin profiling across all centromeres, revealing that along single chromatin fibers, CENP-A, the histone variant specifying centromere identity, forms multiple discrete subdomains within hypomethylated centromere dip regions (CDRs) that are flanked by H3K9me3-enriched heterochromatin. Despite underlying sequence variation, CDRs localize to sequence-homogeneous domains and maintain relatively balanced CENP-A dosage and aggregate length across all chromosomes and between haplotypes. Further, we show that bidirectional changes to centromeric and pericentromeric DNA methylation are accompanied by changes to centromeric chromatin architecture. In passaged cells with centromeric hypomethylation, subdomain boundaries are eroded, and adjacent CENP-A domains tend to merge and expand. Conversely, in pluripotent stem cells with centromeric hypermethylation, CDRs are fundamentally reorganized, such that discrete hypomethylated domains are frequently consolidated into broader contiguous tracts. These methylation-associated CDR restructuring events suggest that DNA methylation acts as a principal regulator of human centromere organization, with implications for understanding centromere plasticity, epigenetic inheritance, and chromosomal instability in development and disease.

genomics↗

bioRxiv2025

Task engagement differentially drives hippocampal and neocortical neural codes

Sensory inputs are progressively transformed into internal representations of the environment along the cortical hierarchy. How does the behavioral relevance of these inputs affect this encoding? Using two-photon calcium imaging in mice navigating virtual-reality environments, we found that visual cortex maintained high sensory discrimination regardless of behavioural engagement, whereas the hippocampal dentate gyrus required active navigation for effective discrimination. These findings suggest that sensory cortices act as general-purpose sensory discriminators, while the hippocampus filters information based on task relevance.

neuroscience↗

bioRxiv2022

Esr1+ hypothalamic-habenula neurons shape aversive states.

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity.

neuroscience↗

bioRxiv2022

An unwanted association: the threat to papaya crops by a novel potexvirus in northwest Argentina

An emerging virus isolated from papaya (Carica papaya) crops in northwestern (NW) Argentina was sequenced and characterized using next-generation sequencing. The resulting genome is 6,667-nt long and encodes five open reading frames in an arrangement typical of other potexviruses. This virus appears to be a novel member within the genus Potexvirus. Blast analysis of RNA-dependent RNA polymerase (RdRp) and coat protein (CP) genes showed the highest amino acid sequence identity (67% and 71%, respectively) with pitaya virus X. Based on nucleotide sequence similarity and phylogenetic analysis, the name papaya virus X is proposed for this newly characterized potexvirus that was mechanically transmitted to papaya plants causing chlorotic patches and severe mosaic symptoms. RT-PCR based detection of papaya virus X (PapVX) revealed that it is widely present in papaya crops from NW Argentina. The prevalence of PapVX, which seems to be restricted to the NW region of Argentina, and the fact that it has only been detected in this region could be associated with a recent emergence or adaptation of this virus to papaya in NW Argentina.

microbiology↗

bioRxiv2022

M2-polarized macrophages control LSC fate by enhancing stemness, homing, immune evasion and metabolic reprogramming

While it is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones, the tumor microenvironment (TME) in acute myeloid leukemias (AML) remains poorly understood. Here, we uncover the functional and prognostic relevance of an M2-polarized macrophage compartment. Intra bone marrow co-injection of M2d-macrophages together with leukemic blasts that fail to engraft on their own now induce fatal leukemia in mice. Even a short-term two-day in vitro exposure to M2d macrophages can "train" leukemic blasts after which cells are protected against phagocytosis, display increased mitochondrial metabolism and improved in vivo homing, resulting in full-blown leukemia. Single-cell RNAseq analysis of AML associated macrophages revealed metabolic-related pathways such as Fatty Acid Oxidation and NAD+ generation as therapeutical targetable vulnerabilities. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for effective targeting strategies.

cancer biology↗

bioRxiv2022

Dynamic human liver proteome atlas reveals functional insights into disease pathways

Deeper understanding of liver pathophysiology would benefit from a comprehensive quantitative proteome resource at cell-type resolution to predict outcome and design therapy. Here, we quantify more than 150,000 sequence-unique peptides aggregated into 10,000 proteins across total liver, the major liver cell types, time-course of primary cell cultures and liver disease states. Bioinformatic analysis reveals that half of hepatocyte protein mass is comprised of enzymes and 23% of mitochondrial proteins, twice the proportion of other liver cell types. Using primary cell cultures, we capture dynamic proteome remodeling from tissue states to cell line states, providing useful information for biological or pharmaceutical research. Our extensive data serves as spectral library to characterize a human cohort of non-alcoholic steatohepatitis and cirrhosis. Dramatic proteome changes in liver tissue include signatures of stellate cell activation resembling liver cirrhosis and providing functional insights. We built a web-based dashboard application for the interactively exploration of our resource. HighlightsO_LICell-type resolved liver proteome with copy numbers for 10,500 proteins C_LIO_LITime-course of human liver primary cells uncovers functional proteome shifts C_LIO_LIA human cohort study reveals liver proteome changes in NASH and cirrhosis C_LIO_LIAn interactive web portal integrates the results for easy exploration C_LI

systems biology↗

bioRxiv2021

Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

Progressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study. This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.

molecular biology↗

bioRxiv2021

Inhibitory control of synaptic signals preceding motor action in mouse frontal cortex

Preparatory activity in the frontal cortex preceding movement onset is thought to represent a neuronal signature of motor planning. However, how excitatory and inhibitory synaptic inputs to frontal neurons are integrated during movement preparation remains unclear. Here we address this question by performing in vivo whole-cell patch-clamp recordings in the secondary motor cortex (MOs) of head-fixed mice moving on a treadmill. We find that both superficial and deep principal neurons show slowly increasing (~10 s) membrane potential and spike rate ramps preceding the onset of spontaneous, self-paced running periods. By contrast, in animals trained to perform a goal-directed task, both membrane potential and spike ramps are characterized by larger amplitudes and accelerated kinetics during preparation of goal-driven movement. To determine the role of local inhibitory neurons in shaping these task-dependent preparatory signals, we chemogenetically suppressed the activity of specific interneuron subpopulations in untrained animals. Inactivation of parvalbumin-positive (PV+) interneurons leads to depolarized membrane potential ramps with increased amplitudes during preparation of movement, while inactivation of somatostatin-positive (SOM+) interneurons abolishes membrane potential ramps. A computational model of the local MOs circuit shows that SOM+-mediated inhibition of PV+ interneurons in conjunction with recurrent connectivity among the principal neurons can reproduce slow ramping signals, while plasticity of excitatory synapses on SOM+ interneurons can explain the acceleration of these signals in trained animals. Together, our data reveal that local inhibitory neurons play distinct roles in controlling task-dependent preparatory ramping signals when MOs neurons integrate external inputs during motor planning. HighlightsO_LIPrincipal neurons in MOs show slow preparatory membrane potential and firing rate ramps preceding the onset of spontaneous, self-paced running periods. C_LIO_LIIn animals trained to perform a goal-directed task, both membrane potential and spike ramps are faster and larger in amplitude. C_LIO_LIInactivation of PV+ interneurons disinhibits MOs principal neurons and increases the amplitude of membrane potential ramps, while inactivation of SOM+ interneurons abolishes membrane potential ramps. C_LIO_LIOur modeling results suggest that the concerted action of external inputs and local inactivation shapes task-dependent preparatory motor signals in MOs neurons. C_LI

neuroscience↗

bioRxiv2020

Replicability of spatial gene expression atlas data from the adult mouse brain

BackgroundSpatial gene expression is particularly interesting in the mammalian brain, with the potential to serve as a link between many data types. However, as with any type of expression data, cross-dataset benchmarking of spatial data is a crucial first step. Here, we assess the replicability, with reference to canonical brain sub-divisions, between the Allen Institutes in situ hybridization data from the adult mouse brain (ABA) and a similar dataset collected using Spatial Transcriptomics (ST). With the advent of tractable spatial techniques, for the first time we are able to benchmark the Allen Institutes whole-brain, whole-transcriptome spatial expression dataset with a second independent dataset that similarly spans the whole brain and transcriptome. ResultsWe use LASSO, linear regression, and correlation-based feature selection in a supervised learning framework to classify expression samples relative to their assayed location. We show that Allen reference atlas labels are classifiable using transcription, but that performance is higher in the ABA than ST. Further, models trained in one dataset and tested in the opposite dataset do not reproduce classification performance bi-directionally. Finally, while an identifying expression profile can be found for a given brain area, it does not generalize to the opposite dataset. ConclusionsIn general, we found that canonical brain area labels are classifiable in gene expression space within dataset and that our observed performance is not merely reflecting physical distance in the brain. However, we also show that cross-platform classification is not robust. Emerging spatial datasets from the mouse brain will allow further characterization of cross-dataset replicability.

genomics↗

bioRxiv2020

Causal evidence for the adaptive benefits of social foraging in the wild

Sociality is a fundamental organizing principle across taxa, thought to come with a suite of adaptive benefits. However, making causal inferences about these adaptive benefits requires experimental manipulation of the social environment, which is rarely feasible in the field. Here we manipulated the number of conspecifics in Trinidadian guppies (Poecilia reticulata) in the wild, and quantified how this affected a key benefit of sociality, social foraging, by investigating several components of foraging success. As adaptive benefits of social foraging may differ between sexes, we studied males and females separately, expecting females, the more social and risk-averse sex, to benefit more from conspecifics than males. Conducting over 1,600 foraging trials, we found that in both sexes, increasing the number of conspecifics led to faster detection of novel food patches and a higher probability of feeding following detection of the patch, resulting in greater individual resource consumption. The slope of the latter relationship differed between the sexes, with males unexpectedly exhibiting a stronger social benefit. Our study provides rare causal evidence for the adaptive benefits of social foraging in the wild, and highlights that sex differences in sociality do not necessarily imply an unequal ability to profit from the presence of others.

animal behavior and cognition↗

bioRxiv2019

Molecular Atlas Of The Adult Mouse Brain

Brain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain organization based on unbiased extraction of spatially-defining features. Applying whole-brain spatial transcriptomics, we captured the gene expression signatures to define the spatial organization of molecularly discrete subregions. We found that the molecular code contained sufficiently detailed information to directly deduce the complex spatial organization of the brain. This unsupervised molecular classification revealed new area- and layer-specific subregions, for example in isocortex and hippocampus, and a new division of striatum. The whole-brain molecular atlas further supports the identification of the spatial origin of single neurons using their gene expression profile, and forms the foundation to define a minimal gene set - a brain palette - that is sufficient to spatially annotate the adult brain. In summary, we have established a new molecular atlas to formally define the identity of brain regions, and a molecular code for mapping and targeting of discrete neuroanatomical domains.

neuroscience↗

bioRxiv2019

High circulating elafin levels are associated with Crohn’s disease-associated intestinal strictures

ObjectiveNearly 33% of Crohns disease (CD) patients develop intestinal strictures. Antimicrobial peptide or protein expression is associated with disease activity in inflammatory bowel disease (IBD) patients. Circulating blood cells and intestine of IBD patients have abnormal expression of elafin, a human elastase-specific protease inhibitor and antimicrobial peptide. However, the association between elafin and CD-associated intestinal stricture is unknown. We hypothesize the elafin expression in stricturing CD patients is abnormal. We determined the expression of elafin in blood, intestine, and mesenteric fat in IBD patients.\n\nMethodsHuman colonic and mesenteric fat tissues and serum samples were collected from the Cedars-Sinai Medical Center and UCLA, respectively.\n\nResultsHigh serum elafin levels were associated with a significantly elevated risk of intestinal stricture in CD patients. Machine learning algorithm using serum elafin levels and clinical data identified stricturing CD patients with high accuracy. Serum elafin levels had weak positive correlation with clinical disease activity (Partial Mayo Score and Harvey Bradshaw Index) in IBD patients. Ulcerative colitis (UC) patients had high serum elafin levels, but the increase was not associated with endoscopic Mayo score. Colonic elafin mRNA and protein expression were not associated with clinical disease activity in IBD patients, while stricturing CD patients had low colonic elafin expression. Mesenteric fat in stricturing CD patients had significantly increased elafin mRNA expression, which may contribute to high circulating elafin level.\n\nConclusionHigh serum elafin levels and adipose elafin expression are associated with intestinal strictures, which may help identify intestinal strictures in CD patients.

molecular biology↗