Biology subjects

Navarro, J.

Publications and source records attributed to Navarro, J..

10 recordsLinked to original sources

bioRxiv2026

Tau isoforms modulate the axon initial segment controlling axonal trafficking and neuronal excitability

The axon initial segment (AIS) is a specialized neuronal compartment integrating action potential initiation with selective control of axonal trafficking. The microtubule associated protein tau is a central regulator of cytoskeletal organization and transport, yet how distinct tau isoforms contribute to AIS development and function remains unclear. Here, we examined the role of tau isoform relative abundance in regulating AIS establishment, maturation, excitability, and transport selectivity using murine primary neurons and human induced pluripotent stem cell (hiPSC)-derived neurons combined with super resolution imaging, electrophysiology, and live trafficking assays. We found that tau expression levels and isoform content modulate the timing and robustness of AIS maturation. In murine neurons, tau deficiency or predominance of 3 repeat (3R) tau delays Ankyrin G accumulation and AIS stabilization without preventing AIS formation. hiPSC-derived neurons display an intrinsic AIS developmental program accompanied by progressive changes in tau isoform content. Super resolution DNA PAINT reveals that endogenous tau decorates axonal microtubules in discrete nanoclusters with compartment specific distributions. Modulation of the endogenous 3R/4R tau balance in hiPSC-derived neurons shows that isoform composition, independently of tau levels, regulates AIS positioning and Ankyrin G organization. Functionally, shifts towards 3R-tau reduce sodium currents, impair action potential firing, and alter lysosomal transport dynamics within the AIS. Together, these findings identify tau isoform balance as a developmental regulator of AIS maturation, linking cytoskeletal organization to neuronal excitability and transport gating. Because the aberrant alternative tau splicing of exon 10 is a defining feature of primary tauopathies, our results provide mechanistic insight into how imbalanced tau isoforms may contribute to neuronal dysfunction.

cell biology↗

bioRxiv2025

Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimers disease brain

The mechanism(s) whereby redox stress mediates aberrant immune signaling in age-related neurological disorders remains largely unknown. Normally, the innate immune system mounts a robust response to infectious stimuli. However, unintentional activation by host-derived factors, such as aggregated proteins associated with neurodegenerative disorders or by cytoplasmic genomic or mitochondrial DNA, can elicit aberrant immune responses. One such immune response is represented by the cytosolic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Using redox chemical biology and mass spectrometry approaches, we identified S-nitrosylation of STING cysteine 148 as a novel posttranslational redox modification underlying aberrant type 1 interferon signaling in Alzheimers disease (AD). Critically, we observed S-nitrosylated STING (SNO-STING) in postmortem human AD brains, in hiPSC-derived microglia (hiMG) exposed to amyloid-{beta} (A{beta})/-synuclein (Syn) aggregates, and in 5xFAD transgenic mice. Mechanistically, our findings reveal that STING S-nitrosylation is critical in initiating signaling cascades by promoting the formation of disulfide-bonded STING oligomers. This leads to neuroinflammation early in the course of disease in vivo in 5xFAD mice with consequent synaptic loss. Collectively, our research supports the role of SNO-STING in neuroinflammation associated with AD, and points to a novel druggable cysteine residue in STING to prevent this S-nitrosylation reaction with its inherent inflammatory response. One Sentence SummaryS-Nitrosylation of STING triggers activation of cGAS-STING signaling in Alzheimers disease brain and subserves a novel link between excessive nitrosative stress and dysregulated innate immunity, thus contributing to disease progression.

neuroscience↗

bioRxiv2025

Phylogenetic diversity and species diversity are decoupled under experimental warming and cooling in Rocky Mountain plant communities

AimNearly 8% of species could go extinct from climate change; many organisms are already experiencing declines in abundance, local extinction, and range shifts. How such changes impact community diversity is an open question in most systems. Whether changes in phylogenetic diversity parallel those in traditional diversity metrics is also often unknown. We used experimentally transplanted plant communities to ask how different aspects of community diversity change with environmental factors across elevation, and whether phylogenetic relationships predict individual species responses to change. LocationWe experimentally transplanted subalpine plant communities down and upslope across 400 m of elevation at the Rocky Mountain Biological Laboratory, Gothic, CO, USA, to simulate climate warming and cooling. MethodsWe identified how experimental warming and cooling impacted community diversity by testing for differences in species richness, Shannon diversity, and phylogenetic diversity among transplant treatments. We tested for phylogenetic signal in each species change in percent cover among treatments. Finally, we assessed if aspects of species rarity (and thus their putative extinction risk) predicted post-transplant change independently or in addition to their phylogenetic relationship within the community. ResultsWe found that species richness and Shannon diversity decreased in cooled treatments and increased in some warmed treatments. In contrast, phylogenetic diversity increased in the cooled treatment and did not change in the warmed treatments. Individual species changes in response to warming and cooling were not correlated with phylogeny or aspects of rarity. Main conclusionsOur results suggest that species losses in cooled treatments are phylogenetically dispersed, increasing phylogenetic diversity, even as richness and Shannon diversity decline. Increasing richness and Shannon diversity in warmed treatments suggests that new species from across the phylogeny can colonize after transplantation, leading to stability in phylogenetic diversity under warming at this time scale, with further change likely as extinction debts are paid.

ecology↗

bioRxiv2025

Induction of Resident Memory CD8+T cell Phenotypes to Eliminate the HIV reservoir

During analytical treatment interruption (ATI), failure to contain tissue HIV reservoirs remains a major barrier to remission. We conditioned peripheral blood mononuclear cells with cues that promote tissue-resident memory differentiation, aiming to reprogram HIV-specific CD8+T cells for these tissue microenvironments. Sequential IL-15/TGF-{beta}1-stimulation expanded proliferative CD103+CD39+ effector populations and restored polyfunctional HIV-specific CD8+T cell responses, irrespective of CD39 or PD-1 expression. Cytokine-stimulated CD8+T cells enhanced ex vivo elimination of the HIV reservoir, and within the induced effector pool, only CD69+ subsets expressing CD103+ or CD39+ eliminated intact HIV-1 genomes. Single-cell transcriptomics showed that IL-15/TGF-{beta}1 stimulation increased clonotypic diversity and expanded resident-like effector clusters with reduced immune-checkpoint receptor expression and augmented mitochondrial function, findings confirmed by flow cytometry. Engrafted recipients from a humanized mouse ATI model more effectively eliminated HIV+-reactivated cells after adoptive transfer of sequentially-treated CD8+T cells. Thus, IL-15/TGF-{beta}1-mediated CD8+T cell reprogramming represents a promising immunotherapy to enable immune control after ATI.

immunology↗

bioRxiv2024

Indicators to assess interannual variability in marine connectivity processes: a semi-theoretical approach

Oceanographic connectivity in an effective network of protected areas is crucial for restoring and stabilising marine populations. However, temporal variability of connectivity is rarely considered as a criterion in designing and evaluating marine conservation planning. In this study, indicators were defined to characterise occurrence, strength and frequency of the temporal variability in connectivity in a northwestern Mediterranean Sea area. Indicators were tested on semi-theoretically-estimated connections provided by the runs of a passive particle transport model in a climatological year and in three years between 2006 - 2020, showing large deviation from the climatological year. The indicators compared the temporal variability in connectivity of four zones, highlighting differences in connectivity due to their locations and the mesoscale hydrodynamics, and identifying areas that require further investigation. The three indicators also showed that the temporal variability in connectivity was influenced by the duration and depth of particle transport, although no consistent pattern was observed in the indicator variations of the compared zones. Provided that specific objectives will be given when parameterising transport models (i.e., selection of focus species and time period), indicators of temporal variability in connectivity have potential to support, and correctly implement, spatial conservation planning, prioritise the protection of marine resources, and measure the effectiveness of Marine Protected Areas, in line with a long-term vision of ocean management.

ecology↗

bioRxiv2022

Identification of HIV-Reservoir Cells with Reduced Susceptibility to Antibody-Dependent Immune Response

HIV establishes a persistent infection in heterogeneous cell reservoirs, which can be maintained by different mechanisms including cellular proliferation, and represent the main obstacle to curing the infection. The expression of the Fc{gamma} receptor CD32 has been identified as a marker of the active cell reservoirs in people on antiretroviral therapy, but if its expression has any role in conferring advantage for viral persistence is unknown. Here, we report that HIV-infected cells expressing CD32 have reduced susceptibility to natural killer (NK) antibody-dependent cell cytotoxicity (ADCC) by a mechanism compatible with the suboptimal binding of HIV-specific antibodies. Infected CD32 cells have increased proliferative capacity in the presence of immune complexes, and are more resistant to strategies directed to potentiate NK function. Remarkably, reactivation of the latent reservoir from antiretroviral-treated people living with HIV increases the pool of infected CD32 cells, which are largely resistant to the ADCC immune mechanism. Thus, we report the existence of reservoir cells that evade part of the NK immune response through the expression of CD32. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2022

CDMAP/CDVIS: Context-dependent Mutation Analysis Package and Visualization Software

The Context-dependent Mutation Analysis Package and Visualization Software (CDMAP/CDVIS) is an automated, modular toolkit used for analysis and visualization of context-dependent mutation patterns (site-specific variation in mutation rate from neighboring-nucleotide effects). The CDMAP algorithm calculates context-dependent mutation rates in chromosomes or replichores, and can generate high-resolution figures to analyze variation in mutation rate across spatiotemporal scales. Output from CDMAP can be integrated into CDVIS, an interactive database for visualizing mutation patterns across multiple taxa simultaneously.

bioinformatics↗

bioRxiv2020

Crosstalk between invadopodia and the extracellular matrix

The scaffold protein Tks5 is required for invadopodia-mediated cancer invasion both in vitro and in vivo. We have previously also revealed a role for Tks5 in tumor cell growth using three-dimensional (3D) culture model systems and mouse transplantation experiments. Here we use both 3D and high-density fibrillar collagen (HDFC) culture to demonstrate that native type I collagen, but not a form lacking the telopeptides, stimulated Tks5-dependent growth, which was dependent on the DDR collagen receptors. We used microenvironmental microarray (MEMA) technology to determine that laminin, collagen I, fibronectin and tropoelastin also stimulated invadopodia formation. A Tks5-specific monoclonal antibody revealed its expression both on microtubules and at invadopodia. High- and super-resolution microscopy of cells in and on collagen was then used to place Tks5 at the base of invadopodia, separated from much of the actin and cortactin, but coincident with both matrix metalloprotease and cathepsin proteolytic activity. Inhibition of the Src family kinases, cathepsins or metalloproteases all reduced invadopodia length but each had distinct effects on Tks5 localization. These studies highlight the crosstalk between invadopodia and extracellular matrix components, and reveal the invadopodium to be a spatially complex structure.

cancer biology↗

bioRxiv2020

Hedgehog Signalling Modulates Glial Proteostasis and Lifespan.

The conserved Hedgehog (Hh) signaling pathway has a well-established role in animal development, however its function during adulthood remains largely unknown. Here, we investigated whether the Hh signaling pathway is active during adult life in Drosophila melanogaster and uncovered a protective function for Hh signaling in coordinating correct proteostasis in glial cells. Adult-specific depletion of Hh reduces lifespan, locomotor activity and dopaminergic neuron integrity. Conversely, increased expression of Hh extends lifespan and improves fitness. Moreover, Hh pathway activation in glia rescues the lifespan and age-associated defects of hedgehog (hh) mutants. At the molecular level, the Hh pathway regulates downstream chaperones, principally hsp40 and hsp68, whose overexpression in glial cells rescues the shortened lifespan and proteostasis defects of hh mutants. Finally, we demonstrate the protective ability of Hh signalling in a Drosophila Alzheimers disease model expressing human Amyloid Beta (A{beta}1-42) in the glia. Overall, we propose that Hh signalling is requisite for lifespan determination and correct proteostasis in glial cells and may have potential in ameliorating a wide range of degenerative diseases.

neuroscience↗

bioRxiv2018

Host genetic associations with the gut microbiota in HIV-1-infected subjects: a pilot exploratory study

The impact of host genetics on gut microbial dynamics is debated. No study to date has investigated the possible role of host genetics in shaping the gut microbiota in HIV-1 infected subjects. With the aim of generating preliminary data to inform future host genetic studies, we performed an exploratory host exome analysis of 147 subjects either infected or at risk of becoming infected with HIV-1 from the MetaHIV cohort in Barcelona. Using a DNA microarray chip, we sought to identify host genetic variants associated to three specific microbial features with a potentially inheritable component, and which were previously found to be associated with gut dysbiosis in HIV infection, i.e.: gut enterotype, presence of methanogenic archaea and microbial gene richness. After correction for multiple comparisons, we did not observe any statistically significant association between the hosts genetic landscape and the explored gut microbiome traits. These findings will help design future, adequately-powered studies to assess the influence of host genetics in the microbiome of HIV-1-infected subjects.

genomics↗