Biology subjects

Nunez, J.

Publications and source records attributed to Nunez, J..

8 recordsLinked to original sources

bioRxiv2025

Galectin-3 is a Nanotherapeutic Target in Graft-versus-Host Disease Mediated Kidney Injury

Kidney injury is a frequent and serious complication of allogeneic hematopoietic cell transplantation (HCT), yet its pathophysiology remains poorly understood and effective treatments are lacking. Through analysis of kidney tissue from HCT recipients, we identified substantial acute tubular injury and T cell infiltration that correlated with extra-renal graft-versus-host disease (GVHD) severity, linking systemic alloreactivity and post-transplant renal pathology. In murine models, GVHD was similarly associated with acute kidney injury, renal Th1-type T cell infiltration, and hyperactivation of NF-{kappa}B and JAK-STAT signalling. Notably, galectin-3, a damage-associated lectin, was upregulated in both patient biopsies and experimental GVHD target organs. Leveraging this pathological feature, we engineered galectin-3-targeted lipid nanoparticles for tissue-specific delivery of ruxolitinib, an approved GVHD therapy. Galectin-3 upregulation was also identified in canonical acute GVHD target organs including the liver and intestinal tract, and nanoparticle-delivered ruxolitinib substantially enhanced renal function, reduced systemic GVHD, and minimized hematologic toxicity compared to conventional drug administration. Our findings demonstrate renal involvement in acute GVHD and establish a nanoparticle-based strategy for precision delivery of immunomodulatory therapies to affected tissues.

bioengineering↗

bioRxiv2025

Precursors of Sea Star Wasting: Immune and Microbial Disruption During Initial Disease Outbreak in Southeast Alaska

Sea Star Wasting Disease (SSW) has devastated sea star populations along the North American Pacific coast since 2013, yet the mechanisms of disease progression, particularly in natural environments, remain unclear. Here we integrate transcriptomic and microbial data from wild Pycnopodia helianthoides sampled across sites affected and unaffected by SSW in southeast Alaska during the initial outbreak recorded in the region in 2016. Individuals exposed to SSW but lacking visible symptoms showed elevated expression of complement system components, pathogen recognition genes, immune regulatory and cell death pathways. Alongside signs of immune activation, genes involved in maintaining extracellular matrix composition, tissue remodeling, and cell adhesion were differentially expressed, indicating early disruption of tissue homeostasis preceding visible wasting symptoms. Gene ontology analysis revealed enrichment of immune response, cell-cell adhesion, response to oxygen levels and nervous system regulatory pathways. Furthermore, network analyses revealed differentially abundant microbes in Exposed individuals--notably Vibrio spp.--were highly correlated with immune response, tissue integrity, stress and detoxification genes in network modules. Together, our findings offer insight into early host-pathogen dynamics in wild populations, underscoring putative links between immune activation and microbial community shifts with the onset of SSW disease.

ecology↗

bioRxiv2024

Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

Developmental and Epileptic Encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Nav) regulator, we observed no effect of Fgf13 ablation in interneurons on Navs but rather a marked reduction in K+ channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K+ channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets.

neuroscience↗

bioRxiv2024

Neural space-time model for dynamic scene recovery in multi-shot computational imaging systems

Computational imaging reconstructions from multiple measurements that are captured sequentially often suffer from motion artifacts if the scene is dynamic. We propose a neural space-time model (NSTM) that jointly estimates the scene and its motion dynamics. Hence, we can both remove motion artifacts and resolve sample dynamics. We demonstrate NSTM in three computational imaging systems: differential phase contrast microscopy, 3D structured illumination microscopy, and rolling-shutter DiffuserCam. We show that NSTM can recover subcellular motion dynamics and thus reduce the misinterpretation of living systems caused by motion artifacts.

biophysics↗

bioRxiv2023

Zona incerta dopamine neurons encode motivational vigor in food seeking

Energy deprivation triggers food seeking to ensure homeostatic consumption, but the neural coding of motivational vigor in food seeking during physical hunger remains unknown. Here, we report that ablation of dopamine (DA) neurons in zona incerta (ZI) but not ventral tegmental area potently impaired food seeking after fasting. ZI DA neurons were quickly activated for food approach but inhibited during food consumption. Chemogenetic manipulation of ZI DA neurons bidirectionally regulated feeding motivation to control meal frequency but not meal size for food intake. In addition, activation of ZI DA neurons and their projections to paraventricular thalamus transited positive-valence signals to promote acquisition and expression of contextual food memory. Together, these findings reveal that ZI DA neurons encode motivational vigor in food seeking for homeostatic eating. One Sentence SummaryActivation of ZI DA neurons vigorously drives and maintains food-seeking behaviors to ensure food consumption triggered by energy deprivation through inhibitory DAZI-PVT transmissions that transit positive-valence signals associated with contextual food memory.

neuroscience↗

bioRxiv2022

STAMP-Based Digital CRISPR-Cas13a (STAMP-dCRISPR) for Amplification-Free Quantification of HIV-1 Plasma Viral Load

The development of new nucleic acid techniques to quantify HIV RNA in plasma is critical for identifying the disease progression and monitoring the effectiveness of antiretroviral therapy. While RT-qPCR has been the gold standard for HIV viral load quantification, digital assays could provide an alternative calibration-free absolute quantification method. Here, we report the development of a self-digitalization through automated membrane-based partitioning (STAMP) technique to digitalize the CRISPR-Cas13 assay (dCRISPR) for amplification-free and absolute quantification of HIV-1 viral RNAs. The analytical performances of STAMP-dCRISPR were evaluated with synthetic HIV-1 RNA, and it was found samples spanning 4 orders of dynamic range between 100 aM to 1 pM can be quantified as fast as 30 min. We also examined the overall assay from RNA extraction to STAMP-dCRISPR quantification with spiked plasma samples. The overall assay showed a resolution of 42 aM at a 90% confidence level. Finally, a total of 20 clinical plasma samples from patients were evaluated with STAMP-dCRISPR. The obtained results agreed well with the RT-qPCR. Our result demonstrates a new type of easy-to-use, scalable, and highly specific digital platform that would offer a simple and accessible platform for amplification-free quantification of viral RNAs, which could be exploited for the quantitative determination of viral load for an array of infectious diseases.

bioengineering↗

bioRxiv2021

BRD2 inhibition blocks SARS-CoV-2 infection in vitro by reducing transcription of the host cell receptor ACE2

SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required for ACE2 transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous ACE2 expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a novel therapeutic target for COVID-19.

cell biology↗

bioRxiv2018

Speciation in a biodiversity hotspot: phylogenetic relationships, species delimitation, and divergence times of the Patagonian ground frogs of Eupsophus roseus group (Alsodidae)

The alsodid ground frogs genus Eupsophus is divided into the roseus (2n=30) and vertebralis (2n=28) groups, distributed throughout the temperate Nothofagus forests of South America. Currently, the roseus group is composed by four species, while the vertebralis group consists of two. Phylogenetic relationships and species delimitation within each group are controversial. In fact, previous analyses considered that roseus group was composed between four to nine species. In this work, we evaluated phylogenetic relationships, diversification times, and species delimitation within roseus group using a multi-locus dataset. For this purpose, mitochondrial (D-loop, Cyt b, and COI) and nuclear (POMC and CRYBA1) partial sequences, were amplified from 164 individuals, representing all species. Maximum Likelihood (ML) and Bayesian approaches were used to reconstruct phylogenetic relationships. Species tree was estimated using BEAST and singular value decomposition scores for species quartets (SVDquartets). Species limits were evaluated with six coalescent approaches. Diversification times were estimated using mitochondrial and nuclear rates with LogNormal relaxed clock in BEAST. Nine well-supported monophyletic lineages were recovered in Bayesian, ML, and SVDquartets, including eight named species and a lineage composed by specimens from Villarrica population (Bootstrap: >90, PP:> 0.9). Single-locus species delimitation analyses overestimated the species number in E. migueli, E. calcaratus and E. roseus lineages, while multi-locus analyses recovered as species the nine lineages observed in phylogenetic analyses (>0.95). It is hypothesized that Eupsophus diversification occurred during Mid-Pleistocene (0.42-0.14 Mya), with most species originated after of the Last Southern Patagonian Glaciation (0.18 Mya). Our results revitalize the hypothesis that E. roseus group is composed by eight species and support to Villarrica lineage as a new putative species.

zoology↗