Biology subjects

Mendoza, M.

Publications and source records attributed to Mendoza, M..

At least 19 recordsLinked to original sources

bioRxiv2026

A Bioactive Phospholipid Promotes Rapid Progenitor Lung Progenitor Activation via AP-1

Upon injury to the distal lung, alveolar type 2 cells (AT2s) must make a discrete switch from surfactant factories to stem cells capable of regeneration, which involves both proliferation and differentiation into oxygen-exchanging alveolar type 1 (AT1) cells. However, the discrete signals and molecular pathways facilitating this fundamental switch in AT2 functionality are uncertain. Here we demonstrate that the bioactive lipid lysophosphatidic acid (LPA), typically associated with driving fibrosis, is an extremely efficient inducer of this state change in comparison to previously implicated signals IL-1{beta} and p53 stabilization. We observed endogenous production and accumulation of LPA in influenza-injured murine lungs, creating a microenvironment that facilitates AT2 progenitor switching. Multiple transcriptomic approaches reveal elevation of Fosl1 and Jun, core members of the Activator Protein 1 (AP-1) transcription factor family, in response to LPA. Using novel genetic models combined with influenza injury, we demonstrate that AP-1 activity in AT2s is necessary for effective alveolar regeneration at both the cellular and physiologic levels. These findings unveil a critical relationship between paracrine LPA and cell-intrinsic AP-1 in facilitating effective lung alveolar regeneration. HighlightsO_LILPA facilitates progenitor switching in lung regeneration via initiation of a discrete transcriptomic state C_LIO_LILPA promotes AT2 state switching via Jun (AP-1) C_LIO_LIImpaired AP-1 signaling significantly restricts recovery from influenza infection C_LI

cell biology↗

bioRxiv2026

Trophotypes of the human gut microbiome: discrete energetic states under a macroecological framework

A central prediction of complex-systems ecology is that strongly interacting communities settle into a limited number of recurrent configurations -- attractors of their internal energy-flow dynamics -- rather than spreading continuously across the space of possible compositions. This has been confirmed in terrestrial mammals, in birds and mammals combined at global scale, and in marine communities, using guild richness as a state descriptor that integrates long-term energetic capacity. Here I extend the framework to the human gut microbiome. Using 8,960 faecal samples from the American Gut Project described by the richness of twelve metabolic guilds, I apply Average Membership Degree analysis (AMD) and identify four discrete Trophotypes separated by sparsely populated regions of the functional space. Principal component analysis, applied independently to the same matrix, identified the same three guilds --- primary generalist degraders, butyrate producers, and acetate producers --- as the main axes of variation, together accounting for 78% of total variance; a diagnostic random forest recovered the same partition structure. The four Trophotypes occupy the four quadrants of the energetic plane defined by input through primary degradation and retention through butyrate production, in a topology consistent with multiple stable configurations sustained by stoichiometric constraints. Host-level metadata predict membership weakly across three independent algorithms (Cohens {kappa} between 0.09 and 0.13). The human gut microbiome organises into a small set of recurrent functional states aligned with broad energetic axes, consistent with the multistability expected in systems governed by nonlinear network interactions. ImportanceThe human gut microbiome does not exist in a single state: different individuals harbour communities with qualitatively different functional organisations. Understanding why requires knowing how many distinct configurations exist and what governs them. This study applies a geometric framework previously used to characterise trophic structures of bird and mammal communities at global scale to a large cohort of human faecal microbiomes. Four discrete functional configurations emerge, defined by variation in the capacity to input energy through primary polysaccharide degradation and to retain it through butyrate and acetate production -- the two macroscopic axes that current theory identifies as the organising dimensions of the colonic fermentative network. Self-reported host metadata predict configuration membership only weakly, indicating either that the relevant control variables are not captured by survey data or that the configurations represent genuinely multistable attractors of the system.

microbiology↗

bioRxiv2026

Influenza-induced tuft cell expansion alters ILC-mediated inflammation

Tuft cells act as sentinels that amplify type 2 inflammation primarily by activating type 2 innate lymphoid cells (ILC2s). Although normally absent from the distal lung, ectopic tuft cells form after severe lung injury including influenza infection in mice. Here, we investigated the function of these ectopic tuft cells in shaping innate immunity following influenza injury. We observed that IFN{gamma} restrains tuft cell differentiation, whereas ILC2s drive tuft cell expansion, establishing a reciprocal regulatory axis. Tuft cell-deficient mice exhibited reduced eosinophilic inflammation and expansion of ILC1s and ILC3s after influenza injury resolution. Single-cell RNA-seq of influenza infected whole lung revealed transcriptional signatures consistent with type 1 pathway activation, type 2 suppression and oxidative stress. Following influenza injury and subsequent Alternaria alternata challenge, tuft cell-deficient mice also showed neutrophilic and ILC3 expansion. Together, these data identify a distal-airway tuft-cell-ILC2 circuit that helps maintain a balanced inflammatory environment in response to viral injury and aeroallergens.

molecular biology↗

bioRxiv2026

Automated behavioral segmentation and markerless pose tracking of mice during spaceflight

The NASA Rodent Habitat aboard the International Space Station enabled long-duration studies of behavioral responses to spaceflight, but video-based behavioral analysis has relied on laborious manual annotation. No study has tested whether deep learning tools can automate this analysis under the demanding imaging conditions of orbital vivaria. We applied pose estimation (SLEAP) and behavioral segmentation (DeepEthogram) to archival footage from the Rodent Research-1 mission. Nine labelers annotated 3,249 pose labels across 2,063 frames, and three behaviorists labeled 411,194 frames across 66 videos. Pose tracking accuracy approximated human inter-annotator variability despite progressive lens soiling, grid occlusions, and spherical aberration. Behavioral classification across eight categories achieved accuracy of 0.86-0.90 and suggests progressive behavioral adaptations to microgravity. Kinematic reconstruction of circling estimated centripetal accelerations periodically approaching 1g. This is the first application of deep learning-based pose estimation and behavioral segmentation to rodents in spaceflight, establishing benchmarks for future monitoring systems. One-Sentence SummaryDeep learning-based pose estimation and behavioral segmentation of ISS video reveal progressive behavioral adaptations of mice to microgravity

neuroscience↗

bioRxiv2026

Dysplastic Epithelial Repair Propagates Chronic Pathology Through the Paracrine Transformation of Pulmonary Fibroblasts

Severe lung injury promotes the ectopic accumulation of basal cells in the alveoli and the presence of these dysplastic epithelial cells are strongly associated with regions of pulmonary fibrosis (PF) in diseased lungs. Recent studies have identified a unique subset of "inflammatory" fibroblasts expressing pro-inflammatory genes, especially cytokines involved in monocyte recruitment, that are also enriched in disease and thought to contribute to the onset and progression of PF. Here we show that these two injury-induced cell types are intricately connected, in that dysplastic basal cells generate diffusible signals to robustly induce the inflammatory phenotype in pulmonary fibroblasts. Capitalizing on transcriptomic analysis, we identify the enriched inflammatory signaling pathways in treated fibroblasts and specifically demonstrate that IL-1 secreted by dysplastic basal cells is responsible for this fibroblastic transformation. IL-1 neutralization in vivo is sufficient to significantly reduce the inflammatory fibroblast burden in regions of alveolar bronchiolization, and the resolution of inflammatory fibroblasts in turn reduces CCR2+ immune cell recruitment to these areas. These results suggest dysplastic basal cells play an indirect role in chronic inflammation and fibrotic remodeling through the induction of a proinflammatory fibroblast phenotype and subsequent recruitment of immune cells, establishing a chronic wound healing microenvironment that prolongs localized pathologic remodeling.

cell biology↗

bioRxiv2026

Hunting for microsatellite instability in long-read data with Owl

Microsatellite instability (MSI) is a key biomarker of mismatch repair deficiency and response to immunotherapy, yet most existing genomic detection methods are optimized for short-read sequencing and rely on small panels of homopolymer markers, limiting the ability to characterize genome-wide and motif-specific patterns of instability. Here we present Owl, a bioinformatic tool for quantifying MSI from long-read (PacBio) genomic data. Owl leverages a genome-wide marker set of more than 140,000 microsatellite repeats ranging from 1-6 bp in length to measure MSI across a phased genome. Using a wrap-around alignment algorithm, Owl constructs repeat-length distributions at each marker site and flags somatic instability using the coefficient of variation. We applied Owl to screen for markers with stable coverage, phasing, and baseline variation across 131 diverse genomes from the Human Pangenome Reference Consortium, where Owl scores ranged from 1.4% to 5.4% of markers exceeding the instability threshold. When applied to 19 cancer cell lines and one diffuse astrocytoma tumor-normal pair, Owl identified five MSI-high genomes with 15-18% unstable markers and showed close concordance with an Illumina DRAGEN MSI assay for the astrocytoma sample. Motif-level analyses revealed shared enrichment of short homopolymer and dinucleotide (A- and AT-rich) repeats across MSI-high cancers, and additionally uncovered a distinct pattern of elevated GGAA microsatellite instability in Ewing sarcoma cell lines, consistent with the known role of the EWS::FLI1 fusion protein at GGAA-rich regulatory elements. Owl is implemented in Rust and integrated into the PacBio HiFi Somatic workflow, providing a scalable framework for MSI analysis from long-read sequencing focused on repeat instability specifically in tumor samples.

bioinformatics↗

bioRxiv2026

Modafinil Modulation of Oscillatory and Aperiodic Brain Activity in Rats Across Wakefulness and Subsequent Sleep

Cortical states shape sensory processing, decision-making, and behavior, and are characterized by distinct patterns of neuronal oscillatory activity. Pharmacological agents can modulate these states and their underlying electrophysiological signatures. Modafinil is a widely used wake-promoting agent and cognitive enhancer, but its effects on cortical oscillations are not fully understood. In this study, we evaluated the effect of modafinil on cortical activity during wakefulness and subsequent sleep. Ten male Wistar rats were implanted with electrocorticographic electrodes and recorded following oral administration of modafinil or its vehicle. Our results show that modafinil increased wakefulness in a dose-dependent manner, with doses of 200 and 300 mg/kg producing prolonged wake episodes and reducing hypnogram complexity. During wakefulness, modafinil enhanced gamma-band power in anterior cortices, an effect primarily driven by increases in the aperiodic rather than oscillatory components. Although no sleep rebound was observed, subsequent NREM sleep exhibited increased delta power, particularly in anterior regions, indicating heightened sleep pressure. In conclusion, our findings demonstrate that modafinil-induced wakefulness is associated with an enhanced aperiodic gamma band component at the anterior cortices in the EEG. Furthermore, modafinil modulates sleep homeostasis by enhancing NREM sleep intensity rather than extending its duration.

neuroscience↗

bioRxiv2025

Early Sleep-Dependent Sensory Gating in the Olfactory System

Disconnection from the external world is a defining feature of sleep. Although most models attribute sensory gating to thalamocortical mechanisms, the olfactory system--bypassing the thalamus--offers a unique window into earlier stages of sensory disconnection. Here, we combine chronic and acute recordings in rodents to test whether nasal sensory inputs are internalized during sleep. We show that respiration-locked potentials and gamma activity in the olfactory bulb are strongly modulated by brain state: they diminish during sleep and reappear during wakefulness and cortical activation. This gating occurs independently of respiratory dynamics and arises near the first synapse of the olfactory pathway. Finally, we find that neocortical slow-wave activity correlates with reduced connectiveness, with coupling progressively vanishing as sleep deepens. These findings reveal a sleep-dependent sensory gating mechanism at early stages of a non-thalamic pathway, providing new insights into the neural substrates of sensory disconnection during sleep.

neuroscience↗

bioRxiv2025

The SHR/Akr Y chromosome reveals repeated turnover of the rat pseudoautosomal region

Crossing-over between Chr X and Chr Y was first observed 90 years ago, in the brown rat, Rattus norvegicus. However, the sequence of the rat pseudoautosomal region (PAR) has remained a mystery. We produced a near-complete sequence of Chr Y from the SHR strain, along with nearly a megabase of sequence from both telomeres of Chr X. Both telomeric ends of Chr Y display extensive homology to Chr X, but no homology to the ancestral PAR of placental mammals. Using rat Y BACs probes for FISH on meiotic cells, we show that pairing almost always occurs between the tips of Yq and Xp, which are virtually identical in nucleotide sequence, but contain no protein-coding genes. Homology at the other ends of Chr X and Chr Y is likely the result of a recent transposition of five genes from Xq to Yp. These sequences are only 99.5% identical and pair infrequently, but show signs that it may have been pseudoautosomal in the ancestor of the rat genus. The rat Chr Y sequence presents opportunities for experimental studies of meiotic phenomena in a tractable model organism. The short PAR, with a correspondingly high recombination rate, represents a unique substrate for molecular studies of crossing-over. Likewise, the absence of extensively co-amplified testis gene families on the rat X and Y suggests they might serve as control for the intense competition between selfish elements that completely remodeled the mouse sex chromosomes.

genomics↗

bioRxiv2024

Chromatin Compaction Follows a Power Law Scaling with Cell Size from Interphase Through Mitosis

Coordination of mitotic chromosome compaction with cell size is crucial for proper genome segregation during mitosis. During development, DNA content remains constant but cell size evolves, necessitating a mechanism that scales chromosome compaction with cell size. In this study, we examined chromatin compaction in the developing Drosophila nervous system by analyzing the large neuronal stem cells and their smaller progeny, the ganglion mother cells. Using super-resolution 3D Stochastic Optical Reconstruction Microscopy and quantitative time-lapse fluorescence microscopy, we observed that nanoscale chromatin density during interphase scales with nuclear volume according to a power law. This scaling relationship is disrupted by inhibiting histone deacetylase activity, indicating that molecular cues rather than mechanical constraints primarily regulate chromatin compaction. Notably, this power law dependency is maintained into mitosis but the scaling exponent decreases, suggesting phase separation of chromatin events during mitotic compaction. We propose that the scaling of mitotic chromosome size relative to cell size depends on the power law behaviour of interphase chromatin volume, and that scaling of mitotic chromatin compaction is an emergent property of linear polymers undergoing phase separation with their solvent. Statement of SignificanceUnderstanding how chromatin compaction changes with cell size is essential for understanding the mechanisms ensuring accurate genome segregation during cell division. In this study, we combine Voronoi tessellation analysis of Stochastic Optical Reconstruction Microscopy and image processing methods based on fluorescence intensity spectrum analysis of live confocal images to measure chromatin volume in interphase and mitosis in cells of different sizes. This work reveals that chromatin density in Drosophila neuronal cells follows a power law relationship with nuclear volume from interphase through mitosis, suggesting a fundamental principle underlying chromosome scaling across different cell sizes. We show that this scaling is regulated by molecular cues, such as histone deacetylase activity, and is conserved through a potential phase separation during mitosis, providing new insights into the biophysical processes that govern chromatin organization. This work broadens our understanding of chromosome biology and will have implications for understanding size-dependent chromatin dynamics in other organisms.

cell biology↗

bioRxiv2024

Srs2/PARI DNA helicase mediates abscission inhibition in response to chromatin bridges in yeast and human cells

The coordination of chromosome segregation with cytokinesis is crucial for maintaining genomic stability. Chromatin bridges, arising from DNA replication stress or catenated chromosomes, can interfere with this process, leading to genomic instability if not properly managed. Here, we uncover that the budding yeast DNA helicase Srs2 and its human homolog PARI delay the timing of abscission events in the presence of chromatin bridges. We demonstrate that Srs2 is essential for delaying abscission in yeast cells with chromatin bridges, and preventing their damage by cytokinesis. In human cells, PARI similarly plays a key role in delaying abscission events, such as midbody severing and actin patch disassembly during cytokinesis, in response to chromatin bridges caused by topoisomerase II inhibition. Our results also show that PARI functions within the Aurora B-mediated abscission checkpoint pathway. These findings reveal an evolutionarily conserved role of the Srs2/PARI DNA helicase in maintaining genomic integrity by modulating abscission timing in response to chromatin bridge formation.

cell biology↗

bioRxiv2024

Disruption of Immune Responses By Type I Diabetes Exacerbates SARS-CoV-2 Mediated Lung Injury

COVID-19 commonly presents as pneumonia, with those most severely affected progressing to respiratory failure. Patient responses to SARS-CoV-2 infection are varied, with comorbidities acting as major contributors to varied outcomes. Focusing on one such major comorbidity, we assessed whether pharmacological induction of Type I Diabetes Mellitus (T1DM) would increase the severity of lung injury in a murine model of COVID-19 pneumonia utilizing wild type mice infected with mouse-adapted SARS-CoV-2. Hyperglycemic mice exhibited increased weight loss and reduced blood oxygen saturation in comparison to their euglycemic counterparts, suggesting that these animals indeed experienced more severe lung injury. Transcriptomic analysis revealed a significant impairment of the adaptive immune response in the lungs of diabetic mice compared to those of control. In order to expand the limited options available for tissue analysis due to biosafety restrictions, we also employed a novel technique to digest highly fixed tissue into a single cell suspension, which allowed for flow cytometric analysis as well as single cell RNA sequencing. Flow immunophenotyping and scRNA-Seq confirmed impaired recruitment of T cells into the lungs of T1DM animals. Additionally, scRNA-Seq revealed a distinct, highly inflammatory macrophage profile in the diabetic cohort that correlates with the more severe infection these mice experienced clinically, allowing insight into a possible mechanism for this phenomenon. Recognizing the near certainty that respiratory viruses will continue to present significant public health concerns for the foreseeable future, our study provides key insights into how T1DM results in a much more severe infection and identifies possible targets to ameliorate comorbidity-associated severe disease. NEW AND NOTEWORTHYWe define the exacerbating effects of Type I Diabetes Mellitus (T1DM) on COVID-19 pneumonia severity in mice. Hyperglycemic mice experienced increased weight loss and reduced oxygen saturation. Transcriptomic analysis revealed impaired immune responses in diabetic mice, while flow cytometry and single-cell RNA sequencing confirmed reduced T cell recruitment and an inflammatory macrophage profile. Additionally, we introduced a novel technique for tissue analysis, enabling flow cytometric analysis and single-cell RNA sequencing on highly fixed tissue samples.

immunology↗

bioRxiv2024

ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer's disease

Dysregulation of histone acetylation in the brain has emerged as a major contributor to human Alzheimers disease (AD). The mechanisms by which these protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is chromatin-associated in neurons. ACSS2 is recruited to specific promoters and generates a local pool of acetyl-CoA from acetate, thereby fueling histone acetylation and driving the expression of neuronal genes that regulate learning and memory. Here, we examine the contribution of ACSS2-mediated histone acetylation to AD-related molecular and behavioral outcomes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. Further, we identify Cajal-Retzius neurons as a critical hippocampal neuronal population affected, exhibiting the largest epigenetic and transcriptional dysregulation. Overall, these results reveal ACSS2 as a key neuroprotective metabolic enzyme, dysregulation of which might play an important role in the etiology of human AD, and guide the development of future therapies for AD and related dementia.

neuroscience↗

bioRxiv2024

Gene-specific RNA homeostasis revealed by perturbation of the NuA4/Tip60 acetyltransferase complex

Transcript buffering entails the reciprocal modulation of mRNA synthesis and degradation rates to maintain stable RNA levels under varying cellular conditions. Current research supports a global, non-sequence-specific connection between mRNA synthesis and degradation, but the underlying mechanisms are still unclear. In this study, we investigated changes in RNA metabolism following acute depletion of TIP60/KAT5, the acetyltransferase subunit of the NuA4 transcriptional coactivator complex, in mouse embryonic stem cells. By combining RNA sequencing of nuclear, cytoplasmic, and newly synthesised transcript fractions with biophysical modelling, we demonstrate that TIP60 predominantly enhances transcription of numerous genes, while a smaller set of genes undergoes TIP60-dependent transcriptional repression. Surprisingly, transcription changes caused by TIP60 depletion were offset by corresponding changes in RNA nuclear export and cytoplasmic stability, indicating gene-specific buffering mechanisms. Similarly, disruption of the unrelated ATAC coactivator complex also resulted in gene-specific transcript buffering. These findings reveal that transcript buffering functions at a gene-specific level and suggest that cells dynamically adjust RNA splicing, export, and degradation in response to individual RNA synthesis alterations, thereby sustaining cellular homeostasis.

genomics↗

bioRxiv2023

In utero pulse injection of isotopic amino acids quantifies protein turnover rates during murine fetal development

Protein translational control is highly regulated step in the gene expression program during mammalian development that is critical for ensuring that the fetus develops correctly and that all of the necessary organs and tissues are formed and functional. Defects in protein expression during fetal development can lead to severe developmental abnormalities or premature death. Currently, quantitative techniques to monitor protein synthesis rates in a developing fetus (in utero) are limited. Here, we developed a novel in utero stable isotope labeling approach to quantify tissue-specific protein dynamics of the nascent proteome during mouse fetal development. Fetuses of pregnant C57BL/6J mice were injected with isotopically labeled lysine (Lys8) and arginine (Arg10) via the vitelline vein at various gestational days. After treatment, fetal organs/tissues including brain, liver, lung, and heart were harvested for sample preparation and proteomic analysis. We show that the mean incorporation rate for injected amino acids into all organs was 17.50 {+/-} 0.6%. By analyzing the nascent proteome, unique signatures of each tissue were identified by hierarchical clustering. In addition, the quantified proteome-wide turnover rates (kobs) were calculated between 3.81E-5 and 0.424 hour-1. We observed similar protein turnover profiles for analyzed organs (e.g., liver versus brain), however, their distributions of turnover rates vary significantly. The translational kinetic profiles of developing organs displayed differentially expressed protein pathways and synthesis rates which correlated with known physiological changes during mouse development.

systems biology↗

bioRxiv2023

A transient dermal niche and dual epidermal programs underlie sweat gland development

Eccrine glands are mammalian skin appendages indispensable for human thermoregulation. Like all skin-derived appendages, eccrine glands form from multipotent progenitors in the basal skin epidermis. It remains unclear how epidermal progenitors progressively specialize to specifically form eccrine glands, precluding efforts to regenerate these vital organs. Herein, we applied single nucleus transcriptomics to compare the expression content of wildtype, eccrine-forming mouse skin to that of mice harboring a skin-specific disruption of Engrailed 1 (En1), a transcription factor that promotes the formation of eccrine glands in both humans and mice. We identify two concurrent epidermal transcriptomes in the earliest eccrine anlagen: a predominant transcriptome that is shared with hair follicles, and a vastly underrepresented transcriptome that is En1-dependent and eccrine-specific. We demonstrate that differentiation of the eccrine anlage requires the induction of a transient and transcriptionally unique dermal niche that forms around each developing gland in humans and mice. Our study defines the transcriptional determinants underlying eccrine identity in the epidermis and uncovers the dermal niche required for eccrine developmental progression. By identifying these defining components of the eccrine developmental program, our findings set the stage for directed efforts to regenerate eccrine glands for comprehensive skin repair.

developmental biology↗

bioRxiv2022

Transcriptome landscape of kleptoplastic sea slug Elysia viridis

Certain sacoglossan sea slugs can sequester and maintain photosynthetically active chloroplasts through algae feeding, a phenomenon called kleptoplasty. The period while these plastids remain active inside the slugs body is species- and environment-dependent and can span from a few days to more than three weeks. Here we report for the first time the transcriptome of sea slug Elysia viridis (Montagu, 1804), which can maintain kleptoplasts for more than two weeks and is distributed along all the Atlantic European coastline. The obtained transcriptome of E. viridis comprised 12,884 protein-coding sequences (CDS). The shortest one was 261bp, and the longest 8,766bp; the whole transcriptome has a total length of 9.3Mb (Table S4 and Fig. S2). Analysing these CDS, we identified 9,422 different proteins, with best hits mainly from two genera: Elysia (87.2%), and Plakobranchus (11.0%) (Fig. S2); the other 2.3% corresponded to multiple genera of sea slugs and snails (Tectipleura) (Kano et al., 2016). We got the functional annotation (Gene Ontologies, GO) corresponding to 9,333 CDS: 4,755 CDS associated with 2,583 Biological Process (BP); 5,466 CDS linked to 683 Cellular Components (CC); and 6,693 related to 1,606 Molecular Functions (MF). We identified 201 CDS related to response to stress (GO:0006950) and 10 CDS associated with the regulation of response to stress (GO:0080134). Focussing on the ROS-quenching toolkit, we found 24 CDS related to oxidoreductase complex (GO:1990204) and 560 annotated with oxidoreductase activity (GO:0016491) acting in a large number of donors, e.g., CH-OH, CH=O, C=O, CH and CH2. In addition, we found 39 CDS with antioxidant activity (GO:00162099) and other CDS with ROS-quenching function: superoxide dismutase (GO:0004784), peroxidase (GO:0004601), glutathione oxidoreductase (GO:0097573) and peroxidase (GO:0004602); and thioredoxin peroxidase (GO:0008379) activity. Furthermore, we found 8 CDS related to the symbiont response (GO:0140546) and nine related to the pattern recognition receptor signalling pathway (GO:0002221).

evolutionary biology↗

bioRxiv2022

Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation

Histone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.

neuroscience↗