Biology subjects

Lopez, I.

Publications and source records attributed to Lopez, I..

10 recordsLinked to original sources

bioRxiv2026

Preserved brain function and reversible cognitive adaptation duringendurance exercise

Endurance exercise imposes extreme metabolic demands on the adult human brain, raising the question of how core brain function is preserved under physiological challenge. We previously showed that marathon running induces reversible reductions in myelin within specific white-matter tracts, suggesting adaptive structural change under metabolic stress. Here, we asked whether this process is functionally tolerated. Neurophysiological recordings revealed maintained conduction latencies across motor, somatosensory, visual, and auditory pathways within 48 hours after race completion, indicating intact axonal signal transmission despite reduced myelin content. Cognitive testing revealed selective and transient modulation of higher-order processing, including attenuated practice-related gains in processing speed and short-lived increases in interference, whereas visuomotor speed and executive flexibility were preserved. All cognitive measures normalized one month after the race, supporting an adaptive framework linking myelin change with preserved brain function under extreme metabolic stress.

neuroscience↗

bioRxiv2026

Chemical Probes in Scientific Literature: Expanding and Validating Target-Disease Evidence

Chemical probes are indispensable tools for validating therapeutic hypotheses, yet their broader impact on early-stage drug discovery remains unquantified. To our knowledge, this study represents the first systematic, large-scale investigation of the chemical probe literature. By screening over 18 million articles using a high-quality dictionary of 561 chemical probes, we identified 20,000 articles mentioning a chemical probe which resulted in 5,558 unique target-disease (T-D) associations. Our analysis yields four principal findings that redefine the utility of these chemicals: First, we show that chemical probe evidence typically precedes the appearance of structured data in major knowledge bases by 1-7 years, providing a crucial lead time for target prioritisation. Second, we identified 353 T-D pairs (6.4%) with no prior evidence in the Open Targets Platform, highlighting the approachs discovery potential. Third, the application of strict novelty filters uncovered 135 new high-confidence associations between targets and diseases, revealing distinct opportunities for therapeutic repurposing in non-oncological, rare autoimmune diseases, and diseases without effective therapies due to complex biology or high treatment resistance. Finally, we demonstrate that chemical probes are essential for strengthening evidence, providing functional validation for associations previously supported only by weaker, correlative data such as RNA expression or animal models. Collectively, these findings illustrate that chemical probes catalyse early therapeutic discovery, emphasising the importance of cataloguing existing probes and identifying new ones.

bioinformatics↗

bioRxiv2025

A Reference Atlas of the Human Dorsal Root Ganglion

Somatosensory perception largely emerges from diverse peripheral sensory neurons whose cell bodies reside in dorsal root ganglia (DRG). Damage or dysfunction of DRG neurons is a major cause of chronic pain and sensory loss. In mice, deep single-cell transcriptomic profiling and genetically defined models have offered important clues into DRG function, but in humans, the cellular and molecular landscape of DRG neurons remains less understood. Here, we constructed a reference cell atlas of the human DRG by profiling transcriptomes of cells and nuclei from 126 donors sampled across cervical, thoracic, and lumbar DRGs. This atlas resolves 22 neuronal subtypes, including known and previously unrecognized subtypes linked to nociception, mechanosensation, thermosensation, and proprioception, as well as 10 types of non-neuronal cells. Cross-species integration, spatial transcriptomics, and microneurography enabled cell-type-specific comparisons of soma size and conduction velocity between species. Human DRG somata are larger across all cell types than their mouse counterparts, and the conduction velocities of human hair follicle innervating A-fibers are faster than in mice, suggesting a functional shift in rapid mechanical detection in humans. This integrated human DRG reference cell atlas provides a resource for exploring new molecular and physiological features of human DRG, which could help identify new strategies for treating chronic pain and other diseases of the peripheral nervous system.

neuroscience↗

bioRxiv2025

African Green Monkeys Respond to Synthetic AB Oligomers with Persistent Alzheimers-like Activation

Wild African green monkeys (AGMs) provide a promising alternative to congenic rodent models because of their closer evolutionary relationship to humans and natural genetic variation. They share key physiological and biochemical traits with humans, including lifespan, neuroanatomy, vascular structure, and inflammatory responses. Unlike rodents, AGMs naturally develop Alzheimers-like amyloid-{beta} (A{beta}) plaques and tau tangles with age. Immunohistochemical studies further show that AGMs inoculated with synthetic A{beta} oligomers (A{beta}O) exhibit hyperphosphorylated tau and neuroinflammation one year later, in the absence of overt neurodegeneration. The AGM body size permits collection of cerebrospinal fluid (CSF) and CSF derived extracellular vesicles (EV) from living individuals, which are key sources of Alzheimers disease biomarkers that can be monitored during disease progression. Here, we evaluate A{beta}O treated AGMs at the systems level using proteomics of CSF and phosphatidylserine affinity isolated EVs (EVps). We optimized a workflow to obtain paired CSF and EVps proteomics from <1 mL volumes, i.e. comparable to human liquid biopsy. Our measurements reveal robust, persistent AD-like responses at the biochemical level without overt loss of cognitive function. As such, these findings in AGMs suggest potential alternatives for disease tracking or point to protective mechanisms for limiting disease progression in AD. HighlightsO_LIDual proteomics of African green monkeys transiently challenged with synthetic A{beta} oligomers (A{beta}O) C_LIO_LIPhosphotidylserine (TIM4) based workflow enables CSF and EV profiling using clinical volumes C_LIO_LIOne year post-A{beta}O: vascular-inflammatory pathways rise; neuronal-axonal pathways fall C_LIO_LIA{beta}Os drive human-AD-like proteome shifts on time scales shorter than cognitive decline C_LI In briefWild African green monkeys (AGMs) offer a translational model for early Alzheimers biology, with physiology more similar to humans. We transiently exposed AGMs to synthetic A{beta} oligomers and, 12 months later, profiled paired proteomes from whole CSF and a CSF subcompartment enriched for extracellular vesicles. Despite no overt cognitive decline, AGM proteomes showed persistent Alzheimers-like remodeling, particularly in vascular, inflammatory, and neuronal systems. Parallel analysis of the CSF subcompartment revealed proteins and pathways under-represented in bulk CSF, sharpening disease-relevant signals and candidate biomarkers. This systems-level, longitudinal study establishes AGMs as a powerful platform for liquid biopsy discovery and illuminates basic biology of molecular responses to soluble A{beta} oligomers accompany and potentially protect against neurodegeneration.

systems biology↗

bioRxiv2025

RetiGene, a comprehensive gene atlas for inherited retinal diseases (IRDs)

Inherited retinal diseases (IRDs) are rare disorders, typically presenting as Mendelian traits, that result in stationary or progressive visual impairment. They are characterized by extensive genetic heterogeneity, possibly the highest among all human genetic diseases, as well as diverse inheritance patterns. Despite advances in gene discovery, limited understanding of gene function and challenges in accurately interpreting variants continue to hinder both molecular diagnosis and genetic research in IRDs. One key problem is the absence of a comprehensive and widely accepted catalogue of disease genes, which would ensure consistent genetic testing and reliable molecular diagnoses. With the rapid pace of IRD gene discovery, gene catalogues require frequent validation and updates to remain clinically and scientifically useful. To address these gaps, we developed RetiGene, an expert-curated gene atlas that integrates variant data, bulk and single-cell RNA sequencing, and functional annotations. Through the integration of diverse data sources, RetiGene supports candidate gene prioritization, functional studies, and therapeutic development in IRDs.

genetics↗

bioRxiv2025

Protocol Optimization Improves the Performance of Multiplexed RNA Imaging

Spatial transcriptomics has emerged as a powerful tool to define the cellular structure of diverse tissues. One such method is multiplexed error robust fluorescence in situ hybridization (MERFISH). MERFISH identifies RNAs with error tolerant optical barcodes generated through sequential rounds of single-molecule fluorescence in situ hybridization (smFISH). MERFISH performance depends on a variety of protocol choices, yet their effect on performance has yet to be systematically examined. Here we explore a variety of properties to identify optimal choices for probe design, hybridization, buffer storage, and buffer composition. In each case, we introduce protocol modifications that can improve performance, and we show that, collectively, these modified protocols can improve MERFISH quality in both cell culture and tissue samples. As RNA FISH-based methods are used in many different contexts, we anticipate that the optimization experiments we present here may provide empirical design guidance for a broad range of methods.

genomics↗

bioRxiv2024

Cellular behavior analysis from live-cell imaging of TCR T cell-cancer cell interactions

T cell therapies, such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cells, are a growing class of anti-cancer treatments. However, expansion to novel indications and beyond last-line treatment requires engineering cells dynamic population behaviors. Here we develop the tools for cellular behavior analysis of T cells from live-cell imaging, a common and inexpensive experimental setup used to evaluate engineered T cells. We first develop a state-of-the-art segmentation and tracking pipeline, Caliban, based on human-in-the-loop deep learning. We then build the Occident pipeline to collect a catalog of phenotypes that characterize cell populations, morphology, movement, and interactions in co-cultures of modified T cells and antigen-presenting tumor cells. We use Caliban and Occident to interrogate how interactions between T cells and cancer cells differ when beneficial knock-outs of RASA2 and CUL5 are introduced into TCR T cells. We apply spatiotemporal models to quantify T cell recruitment and proliferation after interactions with cancer cells. We discover that, compared to a safe harbor knockout control, RASA2 knockout T cells have longer interaction times with cancer cells leading to greater T cell activation and killing efficacy, while CUL5 knockout T cells have increased proliferation rates leading to greater numbers of T cells for hunting. Together, segmentation and tracking from Caliban and phenotype quantification from Occident enable cellular behavior analysis to better engineer T cell therapies for improved cancer treatment.

cell biology↗

bioRxiv2024

Survival cost sharing among altruistic full siblings in Mendelian population

BackgroundWe focus on Haldanes familial selection in monogamous families in a diploid population, where the survival probability of each sibling is determined by altruistic food sharing with its siblings during starvation. An autosomal recessive-dominant or intermediate allele pair uniquely determines the altruistic or selfish behavior, which are coded by homozygotes. We focus on the case when additive cost and benefit functions determine the survival probability of each full sibling. ResultsWe provide conditions for the existence of the altruistic and selfish homozygote. We show that the condition of evolutionary stability of altruism depends on the genotype-phenotype mapping. Furthermore, if the offspring size increases then the condition of evolutionary stability of altruism becomes stricter. Contrary to that, for the evolutionary stability of selfish behavior it is enough if the classical Hamiltons rule does not hold. Moreover, when the classical Hamiltons rule holds and the condition of evolutionarily stability of altruism does not hold, then the selfish and altruistic phenotypes coexist. ConclusionsIn summary, the classical Hamiltons rule is a sufficient condition for the existence of altruism, but it alone does not imply the evolutionary stability of the pure altruistic homozygote population when the altruistic siblings share the cost of altruism.

evolutionary biology↗

bioRxiv2023

Extracellular release of damaged mitochondria induced by cytotoxic conditioning exacerbates GVHD

Despite therapeutic advancements, GVHD is a major complication of HSCT. In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing Pathogen Associated Molecular Patterns (PAMPs), result in activation of host antigen-presenting cells (APC) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APC. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of MHC-II, co-stimulatory CD86, and pro-inflammatory cytokines, resulting in increased donor T cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggests that pre-HSCT conditioning results in extracellular release of damaged mitochondria which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria following conditioning could serve as a novel strategy for GVHD prevention.

immunology↗

bioRxiv2023

Systematic assessment of the contribution of structural variants to inherited retinal diseases

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY, and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads, and discordant read pairs. PCR followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. In total, sixteen candidate pathogenic SVs were identified in sixteen families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive, and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS, PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions.

genetics↗