Biology subjects

Lopez, N.

Publications and source records attributed to Lopez, N..

9 recordsLinked to original sources

bioRxiv2026

Multi-omic characterization of axolotl perilymph-cerebrospinal fluid reveals shifts in composition during limb regeneration

The axolotl salamander can fully regenerate amputated limbs, yet the systemic consequences underlying this process remain largely understudied. Cerebrospinal fluid is an emerging signaling medium capable of communicating with both the central and peripheral nervous systems, but its composition and potential role in salamander limb regeneration have not yet been examined using modern multi-omics techniques. Here, we developed a protocol for extracting mixed perilymph-cerebrospinal fluid (P-CSF) from axolotl and provided the first proteomic and metabolomic characterization of this biological fluid. We identified 2,626 unique proteins and 173 high-confidence metabolites and quantified them across four time points of early limb regeneration. We demonstrated that limb amputation drives progressive shifts in P-CSF proteins, including an elevation of sarcomeric muscle proteins, regeneration-associated factors, and protease/extracellular matrix proteins. We observed shifts in metabolites involved in oxidative stress, polyunsaturated fatty acid oxidation, and histamine metabolism. Injury-comparison experiments revealed that the observed proteomic changes as a result of limb amputation are different than crush injury, denervation, or tail amputation. This study proposes axolotl P-CSF as a reservoir for limb amputation-associated systemic signaling and as a potential conduit of signals involved in limb regeneration.

systems biology↗

bioRxiv2026

Astrocytic morphology in the Medial Habenula: sex differences and modulatory factors

The medial habenula (MHb) is an epithalamic structure involved in aversive processing and emotional regulation, notable for its marked cellular heterogeneity and high astrocyte density. This cellular composition suggests that astrocytes may play an important role in MHb structure and plasticity, potentially contributing to the regulation of emotional states. The aim of this study is to characterize sex-dependent astrocytic morphology in the MHb and determine how it is modulated by peripheral alterations and direct central manipulations. A high-fat diet (HFD) was used as a model of metabolic stress, and systemic lipopolysaccharide (LPS) administration was used to induce a peripheral inflammatory challenge. At the central level, a chemogenetic approach using Gi-DREADDs under the GFAP promoter allowed selective modulation of astrocytic intracellular signalling independently of peripheral influences. Preliminary results indicate sex-dependent morphological differences in MHb astrocytes across all these experimental conditions, supporting the idea that MHb astrocytes are sensitive to both peripheral and central disturbances and may represent a key cellular substrate linking body-brain interactions with emotional regulation.

neuroscience↗

bioRxiv2024

An evolutionarily conserved role for VEGF signaling in the expansion of non-vascular tissue during regeneration.

Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched within tetrapods. Limb regeneration is dependent upon the formation of a blastema, which contains undifferentiated cells capable of giving rise to most cells of the regenerated limb. Innervation is required for regeneration, along with many signaling pathways, including FGF, BMP and Wnt, but the role of VEGF signaling during salamander limb regeneration is not well understood. Here we show that VEGF signaling is essential for limb regeneration and that blastema cells and limb fibroblasts display impaired proliferation in the absence of VEGF signaling. By performing analogous experiments in planaria, which lack vasculature, we show a potential evolutionarily conserved role for VEGF in the expansion of blastema tissues that is separable from angiogenesis. Moreover, loss of VEGF signaling reduces induction of EMT-like processes, suggesting VEGF signaling functions upstream of the expression of EMT transcription factors, including Snai2. These findings highlight potential roles for VEGF signaling during regeneration which may extend beyond typical findings related to angiogenesis.

developmental biology↗

bioRxiv2024

BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression

BackgroundSmooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment. Methods and ResultsWe use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to resolution phase M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect. ConclusionAs BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.

cancer biology↗

bioRxiv2024

Cigarette smoke impairs pulmonary vascular function through nAChR activation

Tobacco smoke is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major health concern worldwide. Despite current therapies alleviate symptoms; there remain some limitations in the efficacy of treatments to curb COPD and its cardiovascular morbidities, particularly pulmonary hypertension. Our previous studies demonstrate that cigarette smoke (CS) has direct effects on pulmonary vascular tone homeostasis and contribute to pulmonary arterial dysfunction. This is in part due to altered activity of the voltage-dependent K+ channel, and to an exacerbated oxidative stress promoting a switch in the sGCs redox state. However, further characterization of the molecular basis of CS-mediated PA dysfunction is needed for more effective targeted treatment and prevention. Our current studies explored these molecular pathways and specifically addressed their contribution to the cellular contractile apparatus within pulmonary arteries. Our results proved deleterious effects on the contractile machinery of pulmonary artery smooth muscle cells. Increased oxidative stress and calcium dysregulation resulting from the activation of acetylcholine receptors (nAChR) in the pulmonary artery led to the manifestation of these effects. This groundbreaking discovery unveiled, for the first time, the expression of these receptors in human pulmonary arteries. Furthermore, we proved that inhibitors directed at these receptors demonstrate efficacy in alleviating various harmful effects of smoking and safeguarding pulmonary artery function from damage. These discoveries hold significant clinical implications, as they suggest that treatment with nAChR-targeted inhibitors could constitute a viable therapeutic option for COPD-related pulmonary hypertension in patients who do not respond to conventional medication.

cell biology↗

bioRxiv2024

Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity

Mimicry of host protein structures ("molecular mimicry") is a common mechanism employed by viruses to evade the hosts immune system. To date, studies have primarily evaluated molecular mimicry in the context of full protein structural mimics. However, recent work has demonstrated that short linear amino acid (AA) molecular mimics can elicit cross-reactive antibodies and T-cells from the host, which may contribute to development and progression of autoimmunity. Despite this, the prevalence of molecular mimics throughout the human virome has not been fully explored. In this study, we evaluate 134 human infecting viruses and find significant usage of linear mimicry across the virome, particularly those in the herpesviridae and poxviridae families. Furthermore, we identify that proteins involved in cellular replication and inflammation, those expressed from autosomes, the X chromosome, and in thymic cells are over-enriched in viral mimicry. Finally, we demonstrate that short linear mimicry from Epstein-Barr virus (EBV) is significantly higher in auto-antibodies found in multiple sclerosis patients to a greater degree than previously appreciated. Our results demonstrate that human-infecting viruses frequently leverage mimicry in the course of their infection, point to substantial evolutionary pressure for mimicry, and highlight mimicrys important role in human autoimmunity. Clinically, our findings could translate to development of novel therapeutic strategies that target viral infections linked to autoimmunity, with the goal of eliminating disease-associated latent viruses and preventing their reactivation.

microbiology↗

bioRxiv2023

Mind the gap: A systematic review and meta-analysisof how social memory is studied

Social recognition is crucial for survival in social species, and necessary for group living, selective reproduction, pair bonding, and dominance hierarchies. Mice and rats are the most commonly used animal models in social memory research, however current paradigms do not account for the complex social dynamics they exhibit in the wild. To assess the range of social memories being studied, we conducted a systematic analysis of neuroscience articles testing the social memory of mice and rats published within the past two decades and analyzed their methods. Our results show that despite these rodents rich social memory capabilities, the majority of social recognition papers explore short-term memories and short-term familiarity levels with minimal exposure between subject and familiar stimuli - a narrow type of social memory. We have identified several key areas currently understudied or underrepresented: kin relationships, mates, social ranks, sex variabilities, and the effects of aging. Additionally, reporting on social stimulus variables such as housing history, strain, and age, is limited, which may impede reproducibility. Overall, our data highlight large gaps in the diversity of social memories studied and the effects social variables have on social memory mechanisms.

neuroscience↗

bioRxiv2021

gp130/STAT3 signaling is required for homeostatic proliferation and anabolism in postnatal growth plate and articular chondrocytes

Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a new molecular circuit that regulates chondrogenic cell maintenance and output and reveals a novel, hitherto unrecognized function of IL-6 cytokines in the skeletal system with direct implications for skeletal development and regeneration.

cell biology↗

bioRxiv2017

DDX3 is exploited by Arenaviruses to suppress type I interferons and favor their replication

Several arenaviruses cause hemorrhagic fever (HF) diseases that are associated with high morbidity and mortality in humans. Accordingly, HF arenaviruses have been listed as top-priority emerging diseases for which countermeasures are urgently needed. Because arenavirus nucleoprotein (NP) plays critical roles in both virus multiplication and immune-evasion, we used an unbiased proteomic approach to identify NP-interacting proteins in human cells. DDX3, a DEAD-box ATP-dependent-RNA-helicase, interacted with NP in both NP-transfected and virus-infected cells. Importantly, DDX3 deficiency compromised the propagation of both Old and New World arenaviruses, including the HF arenaviruses Lassa and Junin viruses. The DDX3 role in promoting arenavirus multiplication correlated with both a previously un-recognized DDX3 contribution to type I interferon suppression in arenavirus infected cells and a positive effect of DDX3 on viral RNA synthesis. Our results uncover novel mechanisms used by arenavirus to exploit the host machinery and subvert immunity, singling out DDX3 as a potential host target for developing new therapies against highly pathogenic arenaviruses.\n\nAUTHOR SUMMARYArenaviruses include severe clinical pathogens causing hemorrhagic fevers and have been recently incorporated by the World Health Organization in a list of critical emerging diseases for which additional research and identification of clinical targets is urgently required. A better understanding of how viral proteins interact with host cellular factors to favor arenavirus multiplication can illuminate novel pipelines on therapeutic strategies. Here we demonstrated that the ATP-dependent RNA helicase DDX3 interacted with the arenavirus nucleoprotein, which displays fundamental functions in different steps of the viral-cycle. Our work also revealed an unexpected new biology on the role that DDX3 might play during viral infections. In sharp contrast to previous studies showing DDX3 enhancement of IFN-I induction, we demonstrated that DDX3 suppressed IFN-I production at late time points after arenavirus infection, contributing to a DDX3 pro-viral effect. We also showed that early after infection, DDX3 pro-viral role was IFN-I independent and was mediated by DDX3 facilitation of viral RNA synthesis without affecting RNA translation. Altogether, our study established DDX3 as a critical host interacting partner of the arenavirus nucleoprotein and demonstrated two previously unrecognized DDX3-dependent strategies by which these deadly viruses exploit the host cellular machinery and suppress immunity.

microbiology↗