Biology subjects

Pedroza-Pacheco, I.

Publications and source records attributed to Pedroza-Pacheco, I..

4 recordsLinked to original sources

bioRxiv2026

Sex shapes capillary flows and oxygen extraction in the middle-aged mouse brain

Sex differences in brain aging are well documented, but their origin within the cerebrovascular hierarchy remains unclear. Here we show that cortical blood flow is higher in female than male mice at 15 months of age, at a point when an earlier sex difference in pulsatility and resistance indices has already converged, pial vessel diameter shows no difference between sexes, and estrogen levels are similar between sexes. Using an indicator-dilution and intravascular oxygen measurements using two-photon microscopy, we found that capillary transit-time heterogeneity (CTH) scales more steeply with mean transit time in females, consistent with a passively regulated capillary network, and that this is accompanied by reduced oxygen extraction fraction (OEF) without deficit in arterial oxygen delivery. Spatial transcriptomics reveals that sex differences are organized into distinct regional programs, most prominently in white matter, where a male-associated myelin and axonogenesis signature accompanies reduced white matter volume in females. These molecular and structural differences coincide with elevated hippocampal microglial reactivity and an altered spatial search strategy in females, without any detectable differences in circulating markers of stress, blood-brain barrier integrity, or immunity. Together, these findings indicate that sex differences in the aging brain are expressed at the level of capillary flow regulation and regional tissue programs rather than through bulk cerebral blood flow alone, and that elevated blood flow in females can mask, rather than reflect, adequate tissue oxygenation.

neuroscience↗

bioRxiv2026

TMEM33 deletion potentiates anti-tumor CD8+ T cell immunity

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8+ T cell responses. Constitutive Tmem33-/- mice exhibited delayed melanoma tumor growth and increased CD8+ T cell infiltration. Antigen-specific CD8+ compartments in tumors of Tmem33-/- mice showed TCF-1+PD-1+ progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8+ T cells ex vivo, (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of ex vivo-expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower TMEM33 expression in patient CD8+ T cells significantly correlated with improved survival and elevated TCF-7 (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8+ T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy. One sentence summaryTMEM33 intrinsically limits progenitor exhausted CD8+ T cells, scales anti-tumor responses and predicts melanoma patient survival.

immunology↗

bioRxiv2020

Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication

Human immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks a curative therapy or vaccine. Despite the reduction in AIDS-related deaths achieved by current antiretroviral therapies, drawbacks including drug resistance and the failure to eradicate infection highlight the need to identify new pathways to target the infection. Circadian rhythms are endogenous 24-hour oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components participating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, CLOCK and BMAL1 activate rhythmic transcription of genes including the nuclear receptor REV-ERB, which represses BMAL1 and plays an essential role in sustaining a functional clock. We investigated whether REV-ERB activity regulates HIV-1 replication, and found REV-ERB agonists inhibited HIV-1 promoter activity in cell lines, primary human CD4 T cells and macrophages, whilst antagonism or genetic disruption of REV-ERB increased promoter activity. Furthermore, the REV-ERB agonist SR9009 inhibited promoter activity of different HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic ligands to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock transcription factors in regulating HIV-1 replication.

microbiology↗

bioRxiv2020

cGAMP loading enhances the immunogenicity of VLP vaccines

Cyclic GMP-AMP (cGAMP) is an immunostimulatory second messenger produced by cGAS that activates STING. Soluble cGAMP acts as an adjuvant when administered with antigens. cGAMP is also incorporated into enveloped virus particles during budding. We hypothesised that inclusion of the adjuvant cGAMP within viral vaccine vectors would promote adaptive immunity against vector antigens. We immunised mice with virus-like particles (VLPs) containing the HIV-1 Gag protein and VSV-G. Inclusion of cGAMP within these VLPs augmented splenic VLP-specific CD4 and CD8 T cell responses. It also increased VLP- and VSV-G-specific serum antibody titres and enhanced in vitro virus neutralisation. The superior antibody response was accompanied by increased numbers of T follicular helper cells in draining lymph nodes. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induced high titres of influenza A virus neutralising antibodies and conferred protection following subsequent influenza A virus challenge. Together, these results show that incorporating cGAMP into VLPs enhances their immunogenicity, making cGAMP-VLPs an attractive platform for novel vaccination strategies. Short summarycGAMP is an innate immune signalling molecule that can be transmitted between cells by inclusion in enveloped virions. This study demonstrates enhanced immunogenicity of HIV-derived virus-like particles containing cGAMP. Viral vectors loaded with cGAMP may thus be potent vaccines.

immunology↗