Biology subjects

Gonzalez, L.

Publications and source records attributed to Gonzalez, L..

At least 19 recordsLinked to original sources

bioRxiv2026

SEX-DEPENDENT MODULATION OF WHOLE BRAIN cFOS EXPRESSION BY LIGHT AND MELANOPSIN IN THE MOUSE

Light is a fundamental feature of the environment, signaling time of day, weather changes, approaching predators, and other survival cues. The extensive projections from the retina to the brain provide an anatomical substrate for light to adaptively tune circuit function based on changing environmental light. Yet we understand little about the scope and functional impact of light outside of visual and circadian circuits. To address this, we created a whole-brain atlas of light-induced cFos expression in the mouse brain. This approach yielded a strikingly broad pattern of light-driven cFos activation throughout the brain that extended beyond canonical visual circuits, with unexpectedly strong modulation of neuromodulatory centers. These patterns differed starkly in males and females, and were dependent primarily on melanopsin-expressing, intrinsically photosensitive retinal ganglion cells. These findings uncover surprising brainwide patterns of light modulation and are shared as an interactive resource so that they can inspire new, future studies.

neuroscience↗

bioRxiv2026

Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4C2) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2 has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2 phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2 phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G4C2, where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.

molecular biology↗

bioRxiv2026

The SMYD1 p.Asn101Ser is a partial loss-of-function variant that impairs mitochondrial function and leads to early-onset cardiomyopathy.

Infantile cardiomyopathies are rare, life-threatening disorders for which genetic diagnosis has been accelerated by next-generation sequencing approaches, including gene panel, exome, and genome sequencing. However, determining the functional consequences of identified variants remains a major challenge. Variants in SMYD1, a striated muscle-specific lysine methyltransferase critical for cardiac development and mitochondrial function, have only recently been linked to human cardiomyopathy. Here, we functionally characterize a homozygous SMYD1 variant (c.302A>G; p.Asn101Ser) identified in a patient with severe early-onset cardiomyopathy requiring cardiac transplantation. Structural modeling predicts that the N101S substitution perturbs a highly conserved residue near the cofactor binding pocket within SMYD1s catalytic domain, disrupting local interactions and modestly destabilizing the protein. Consistent with these predictions, in vitro studies demonstrate that the N101S variant impairs mitochondrial respiratory capacity in myocytes. Quantification of SMYD1 protein levels in patient cardiac tissue revealed increased SMYD1 abundance, suggesting that the N101S variant results in functional impairment rather than protein instability and may trigger compensatory upregulation of SMYD1 expression. Together, these findings support a hypomorphic mechanism in which the N101S variant disrupts SMYD1 activity, leading to mitochondrial dysfunction and cardiomyopathy. This study provides mechanistic insight into SMYD1-associated cardiomyopathy and highlights the importance of integrating genetic, structural, and functional analyses to establish the pathogenicity of rare variants. New & NoteworthyThis study provides the first functional characterization of the cardiomyopathy-associated SMYD1 N101S variant identified in a child with severe infantile cardiomyopathy. Structural modeling predicts reduced protein stability, while cellular assays demonstrate impaired mitochondrial respiratory function, supporting a hypomorphic effect. These findings establish a mechanistic link between SMYD1 dysfunction and infantile cardiomyopathy and highlight the importance of integrating genomic and functional approaches in rare cardiovascular disease.

cell biology↗

bioRxiv2026

Culsma: A Formal Language for Laboratory Protocols

Laboratory protocols are commonly communicated in natural language, leaving room for variation in how experimental commitments are understood and carried out. We present Culsma, an executable specification language in which protocols are written as programs. The same program is legible to bench scientists and directly machine-readable by software that checks and runs it. It serves as the protocol's operational specification, making experimental commitments explicit for checking before execution and retaining them in results. Culsma addresses how experimental procedures are modeled: it defines operations by the experimental changes and relationships they establish, giving a fine-grained, compositional basis whose technique- and device-specific realizations remain extensible. We examine this boundary in workflows spanning molecular and cell biology, protein biochemistry, and immunoassays, which combine material handling, separation, and measurement differently, asking which distinctions the operation interface preserves. A maintained, source-linked benchmark broadens this evaluation with versioned checks of source-step correspondence and software execution.

bioinformatics↗

bioRxiv2025

UC Irvine Brain Initiative Cell Atlas Network (BICAN) Brain Procurement Program for the Center for Multiomic Human Brain Cell Atlas Project

High-quality neurotypical postmortem human brain tissue is essential but difficult to obtain for constructing comprehensive human brain cell atlases. Here we describe the establishment of UC Irvines Brain Procurement Program, a coordinated initiative to collect and process neurotypical donor brains for multiomic mapping studies within the NIH BRAIN Initiative Cell Atlas Network (BICAN) consortium. Through partnerships with the Orange County Coroners Office, the UC Irvine Willed Body Program, UCI Medical Center, and the Childrens Hospital of Orange County, we have developed standardized workflows encompassing donor identification, postmortem brain recovery and processing, region-of-interest dissection, neurotypical donor selection, and data management. Our experience demonstrates the feasibility of a community-based, multi-institutional procurement framework while highlighting challenges in recruiting neurotypical donors and ensuring demographic representation reflective of Southern California. We further identify opportunities to strengthen outreach and donation pathways. This program provides a scalable model for advancing population-reflective, high-quality human brain cell atlas efforts. HighlightsO_LIEstablish a multi-site pipeline for procuring high-quality neurotypical human brains. C_LIO_LIDemonstrate feasibility of donor collection across childhood to adulthood. C_LIO_LIIdentify barriers and propose strategies to improve broad donor recruitment. C_LI

neuroscience↗

bioRxiv2025

Fronto-Parietal Oscillatory Dynamics of Emotion Regulation as a Function of Adult Attachment Orientations

Emotion regulation enables individuals to modulate emotional experiences and behaviors according to situational demands. Within attachment theory, individual differences in attachment anxiety and avoidance are conceived as interpersonal dispositions that influence the quality and efficiency of emotion regulation strategies, potentially shaping the underlying neural dynamics. This study examined cortical oscillatory activity during two regulation strategies--cognitive reappraisal and expressive suppression--focusing on theta (4-8 Hz) and beta (15-30 Hz) bands at the source level. Forty adults (21 male, 18 female, 1 gender-unspecified; M = 27.58 years, SD = 8.71) performed an emotion regulation task involving emotionally evocative images from the International Affective Picture System (IAPS) while EEG was recorded. Cortical sources were reconstructed using standardized low-resolution brain electromagnetic tomography (sLORETA). Linear mixed-effects models (LMMs) assessed the effects of condition, region of interest (ROI), and attachment orientations on oscillatory power. Results showed that higher attachment anxiety predicted reduced theta power in the right dorsolateral prefrontal cortex (dlPFC) during reappraisal, indicating attenuated recruitment of cognitive control mechanisms. In the beta band, suppression reduced activity in the right parietal lobe/precuneus -- a region involved in self-referential and attentional processes -- across participants, while during reappraisal, attachment anxiety was linked to lower beta power and attachment avoidance to higher beta power in the left dlPFC. Together, these findings indicate that cognitive reappraisal and expressive suppression engage distinct cortical oscillatory systems, and that interpersonal dispositions modulate their neural implementation. Frontal theta appears to index top-down control during reappraisal, whereas beta activity shows a dual pattern: frontal beta variations reflect differences in control stability associated with attachment orientations, and parietal beta decreases during suppression suggest attentional disengagement from self-referential processing.

neuroscience↗

bioRxiv2025

Tree microbiomes and methane emissions in upland forests

RationaleUpland forest trees emit CH , but whether emissions derive from internal microbial production or soil-derived transport remains debated. Methanogens have been detected in heartwood of several species, yet the prevalence of wood-associated methanogenesis, its metabolic basis, and its relationship to co-occurring methanotrophy are poorly understood. MethodsWe measured 1,148 stem fluxes and 276 soil fluxes, sampled internal stem gases including {delta}{superscript 1}3CH , quantified methanogens and methanotrophs via ddPCR in 564 samples, characterized communities via 16S rRNA sequencing, and upscaled fluxes. Key resultsMethanogens were detected in 97% of heartwood samples (up to 10 copies g {superscript 1}) at concentrations exceeding soil by [~]2 orders of magnitude; methane consumers were likewise near-ubiquitous across forest compartments. Wood harbored distinct microbial communities dominated by hydrogenotrophic Methanobacteriaceae, corroborated by depleted {delta}{superscript 1}3CH . Vertical flux profiles indicated soil transport only in wet microsites, with uniform emissions across height consistent with internal production across most upland species. Species-level methanogen:methanotroph ratios predicted emissions (R{superscript 2} = 0.51), indicating net flux reflects the balance between production and oxidation. Main conclusionMethane-cycling microbes are widespread in upland trees, and net methane flux reflects the species-level balance between production and consumption. Internal methanogenesis contributes widely to upland tree emissions; resolving ecosystem-scale magnitude requires improved quantification of woody surface area and vertical flux variability.

ecology↗

bioRxiv2025

Systematic cross-study assessment of RNA-Seq experimental workflows for plasma cell-free transcriptome profiling

Plasma cell-free RNA (cfRNA) is a promising source of non-invasive biomarkers, but its clinical translation is hindered by technical challenges and a lack of protocol standardization, which compromises reproducibility and comparability across studies. There is a need for a systematic evaluation of existing cfRNA-Seq workflows to understand the drivers of technical variability. Here, we address this gap by performing a comprehensive cross-study analysis of 2,166 cfRNA-Seq samples from 15 published studies and an in-house generated dataset, applying a uniform bioinformatics pipeline to enable a controlled comparison of experimental workflows. Our analysis reveals that the donor phenotype typically explains a negligible fraction of the transcriptomic variation, whose main determinants are technical - principally protocol choice, genomic DNA contamination levels and library diversity. Remarkably, this technical noise is so profound that variation within plasma cfRNA samples exceeds that found across a wide range of human tissues. Finally, we demonstrate that critical pre-analytical factors are often confounded with patient phenotypes, jeopardizing the validity of biomarker discovery efforts. Our work serves as a comprehensive benchmark of current cfRNA-Seq methodologies and provides evidence-based guidelines to improve experimental design. By highlighting the dominance of controllable technical factors, we offer a path towards more robust and reproducible cfRNA research.

bioinformatics↗

bioRxiv2025

Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling

Influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies cis-aconitate (cis-aco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. Cis-aco impairs viral polymerase activity, suppressing viral mRNA expression and protein synthesis to inhibit replication across a range of influenza subtypes. This antiviral efficacy is confirmed in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, cis-aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, cis-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu(R) is no longer effective. These findings position cis-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe.

immunology↗

bioRxiv2025

Multidimensional characterization of cellular ecosystems in Hodgkin lymphoma

The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.

cancer biology↗

bioRxiv2025

HP1-enhanced chromatin compaction stabilizes a synthetic metabolic circuit in yeast

Chromatin compaction defines genome topology, evolution, and function. The Saccharomycotina subphylum, including the fermenting yeast Saccharomyces cerevisiae have a decompacted genome, possibly because they lost two genes mediating a specific histone lysine methylation and histone binding protein heterochromatin protein 1 (HP1). This decompaction may result in the higher-than-expected mutation and meiotic recombination rates observed in this species. To test this hypothesis, we retro-engineered S. cerevisiae to compact the genome by expressing the HP1 homologue of Schizosaccharomyces pombe SpSwi6 and H3K9 methyltransferase SpClr4. The resulting strain had significantly more compact chromatin and reduced rates of mutation and meiotic recombination. The increased genomic stability significantly prolongs the optogenetic control of an engineered strain designed to grow only in blue light. This result demonstrates the potential of our approach to enhance the stability of strains for metabolic engineering and other synthetic biology applications, which are prone to lose activities due to genetic instability.

synthetic biology↗

bioRxiv2025

MAIT cells protect in severe pneumococcal pneumonia by regulating neutrophil/macrophage antimicrobial activities

Mucosal-Associated Invariant T (MAIT) cells populate the lung tissue where they contribute to defense against respiratory infections. While MAIT cells have been implicated in host resistance to infections caused by Gram-negative bacteria, their contribution in immunity against Gram-positive bacteria-driven pneumonia is still enigmatic. Here, we demonstrate that both mouse and human MAIT cells are activated during severe infection caused by Streptococcus pneumoniae, the major cause of community-acquired bacterial pneumonia. Upon infection, lung MAIT cells undergo a transcriptional reprogramming associated with acquisition of potent antimicrobial properties. MAIT cell-deficient mice are more susceptible to pneumococcal pneumonia, including higher mortality, uncontrolled bacterial growth and dissemination, and impaired neutrophil and interstitial macrophage activity. Moreover, prophylactic stimulation of MAIT cells using cognate antigen protects from pneumococcus-induced lethal pneumonia. These findings demonstrate that MAIT cells are key cellular actors during Gram-positive bacterial infections.

immunology↗

bioRxiv2025

Jack of all trades and master of most: Carpobrotus taxa show no trade-off in reproductive strategies

O_LIThe ability to reproduce via multiple strategies is crucial for the invasion success of alien plant species. Here, we use Carpobrotus taxa (species and hybrids) to explore how trade-offs between and within these strategies may influence plant invasion dynamics. Native to South Africa, Carpobrotus plants are globally prominent in coastal ecosystems, reproducing by seed and clonally, and frequently hybridizing in both native and introduced regions. Three genetically distinct clusters were previously identified, with evidence of hybridization within and between these clusters in native and non-native ranges. C_LIO_LIWe collected fruit samples from populations representing the genetic clusters and their hybrids across native and non-native ranges (i.e., Europe, California, and New Zealand). These genetic clusters reflect the complex taxonomy of Carpobrotus, where species boundaries are unclear due to hybridization and morphological similarity. We then assessed seed set, seed mass, germination rates, and early growth under varying abiotic conditions alongside genetic estimates of clonality. C_LIO_LIGermination rates were influenced by temperature, moisture, and nutrient levels. Non-native populations demonstrated higher seed set, seed mass, and germination success compared to native populations, indicating a stronger investment in sexual reproduction. These populations also showed higher levels of clonality, shown by lower genotypic richness, suggesting that both reproductive strategies enhance invasive potential. C_LIO_LIHigh-clonality populations produced more seeds, demonstrating that the two reproductive strategies are not mutually exclusive. These results highlight the importance of multiple reproductive strategies for the establishment and spread of Carpobrotus taxa and provide insights into the mechanisms driving their global success. C_LI

plant biology↗

bioRxiv2024

Hyperballistic intercellular signaling through growth assisted positive feedback

Intercellular signaling in bacteria is often mediated by small molecules secreted by cells. These small molecules disperse via diffusion which limits the speed and spatial extent of information transfer in spatially extended systems. Theory shows that a secondary signal and feedback circuits can speed up the flow of information and allow it to travel further. Here, we construct and test several synthetic circuits in Escherichia coli to determine to what extent a secondary signal and feedback can improve signal propagation in bacterial systems. We find that positive feedback-regulated secondary signals propagate further and faster than diffusion-limited signals. Additionally, the speed at which the signal propagates can accelerate in time, provided the density of the cells within the system increases. These findings provide the foundation for creating fast, long-range signal propagation circuits in spatially extended bacterial systems.

synthetic biology↗

bioRxiv2024

The predominant binding mode of Palmatine to DNA

Palmatine is a protoberberine alkaloid, which may produce singlet oxygen under visible light irradiation and binds to DNA. The fact that singlet oxygen activation in palmatine may be triggered by environmental conditions, and in particular its interaction with nucleic acids, makes it a most suitable candidate for photodynamic therapy and DNA-targeted non-invasive anticancer strategies. Despite these remarkable properties the actual binding mode between palmatine and DNA has not been resolved, yet. Its elucidation has, indeed, led to contrasting hypothesis. In this contribution by using long-range molecular dynamic simulations and enhanced sampling approaches, we unequivocally identify that intercalation is the dominant binding mode of palmatine with DNA, from either a thermodynamic and kinetic point of view. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/613446v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1f30e43org.highwire.dtl.DTLVardef@2d5e04org.highwire.dtl.DTLVardef@776b2aorg.highwire.dtl.DTLVardef@1ca206_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Genetic landscape of an in vivo protein interactome

Protein-protein interaction (PPI) networks accurately map environmental perturbations to their molecular consequences in cells, but effects of genome-wide genetic variation on PPIs remain unknown. We hypothesized that PPI networks integrate genetic and environmental effects, potentially defining biochemical mechanisms underlying complex polygenic traits. Here, we measured 61 PPIs in inbred strains of Saccharomyces cerevisiae with [~]12,000 single-nucleotide polymorphisms (SNPs) across the genome. Unlike mRNA expression and protein abundance that are primarily affected by SNPs local (in "cis") to a gene, PPIs are predominantly affected by SNPs far (in "trans") to the genomic loci of the interacting proteins. However, consistent with the PPI networks small-world characteristic, these transacting SNPs are in neighboring genes in the network. We likewise discovered SNPs in non-coding RNAs and post-transcriptional regulators (3 UTRs) with, counterintuitively, larger PPI-modulating effects than SNPs within protein-coding regions. Finally, we inferred known and novel mechanisms of action for yeast and human drugs. HIGHLIGHTSO_LIProtein-interaction quantitative trait locus ("piQTL") mapping reveals sensitivity of in vivo PPIs to polymorphisms across the yeast genome C_LIO_LITrans-piQTLs significantly outnumber and are stronger than cis-piQTLs C_LIO_LISNPs in non-coding RNAs and 3 UTRs have comparable effects to PPI as SNPs in coding regions C_LIO_LIpiQTL mapping reveals known and novel mechanism of yeast and human drugs C_LI

genomics↗

bioRxiv2023

IFN-γ primes bone marrow neutrophils to acquire regulatory functions in severe viral respiratory infections

Neutrophil subsets endowed with regulatory/suppressive properties are widely regarded as deleterious immune cells that can jeopardize antitumoral response and/or antimicrobial resistance. Here, we describe a sizeable fraction of neutrophils characterized by the expression of Programmed death-ligand 1 (PD-L1) in biological fluids of humans and mice with severe viral respiratory infections (VRI). Biological and transcriptomic approaches indicated that VRI-driven PD-L1+ neutrophils are endowed with potent regulatory functions and reduced classical antimicrobial properties, as compared to their PD-L1- counterpart. VRI-induced regulatory PD-L1+ neutrophils were generated in the bone marrow in an IFN-{gamma}-dependent manner and were quickly mobilized into the inflamed lungs where they fulfilled their maturation. Neutrophil depletion and PD-L1 blockade during experimental VRI resulted in higher mortality, increased local inflammation and reduced expression of resolving factors. These findings suggest that PD-L1+ neutrophils are important players in disease tolerance by mitigating local inflammation during severe VRI and that they may constitute relevant targets for future immune interventions.

immunology↗

bioRxiv2023

A Foundational Large Language Model for Edible Plant Genomes

Significant progress has been made in the field of plant genomics, as demonstrated by the increased use of high-throughput methodologies that enable the characterization of multiple genome-wide molecular phenotypes. These findings have provided valuable insights into plant traits and their underlying genetic mechanisms, particularly in model plant species. Nonetheless, effectively leveraging them to make accurate predictions represents a critical step in crop genomic improvement. We present AO_SCPLOWGROC_SCPLOWNT, a foundational large language model trained on genomes from 48 plant species with a predominant focus on crop species. We show that AO_SCPLOWGROC_SCPLOWNT can obtain state-of-the-art predictions for regulatory annotations, promoter/terminator strength, tissue-specific gene expression, and prioritize functional variants. We conduct a large-scale in silico saturation mutagenesis analysis on cassava to evaluate the regulatory impact of over 10 million mutations and provide their predicted effects as a resource for variant characterization. Finally, we propose the use of the diverse datasets compiled here as the Plants Genomic Benchmark (PGB), providing a comprehensive bench-mark for deep learning-based methods in plant genomic research. The pre-trained AO_SCPLOWGROC_SCPLOWNT model is publicly available on HuggingFace at https://huggingface.co/InstaDeepAI/agro-nucleotide-transformer-1b for future research purposes.

genomics↗