Biology subjects

Medrano, J.

Publications and source records attributed to Medrano, J..

4 recordsLinked to original sources

bioRxiv2026

Transformation and recombination of neural information in a brain network

Mammalian brain function relies on integrated interactions among interconnected neural structures. The principles by which regional activity is transformed into projection-specific signals and then recombined at targets elsewhere in the brain are fundamental to brain processing, but remain poorly understood. Here we study these phenomena using a genetically encoded probe that provides neurophysiological readouts from virally labeled projections on a brain-wide scale via functional magnetic resonance imaging (fMRI). By analyzing outputs from thalamic and cortical somatosensory processing regions in rats, we find that projection-specific neural population activity undergoes shifts in tuning and temporal characteristics as it emanates from source regions. Patterns of neural information flow to targeted brain structures reconfigure under different conditions of stimulation and rest, contrasting with intrinsic fMRI functional connectivity profiles, which remain constant. Excitatory and inhibitory projections are coactivated during stimulation, but their relative response amplitudes change dynamically between stimulus conditions and across repeated stimuli, suggesting mechanistic roles for network-wide shifts in excitation/inhibition balance. Our results thus reveal how information flow throughout a neural system reshapes to promote stimulus selectivity and provide underpinnings of large-scale brain phenomena.

neuroscience↗

bioRxiv2025

Genome-wide CRISPR screen reveals Wnt signaling defects regulate lipid accumulation in APOE4 oligodendrocytes

APOE4 is the largest genetic risk factor for late-onset Alzheimers disease, but the cellular mechanisms by which APOE variants influence risk of disease remain incompletely understood. We have previously found that APOE4 expression led to the intracellular accumulation of lipid droplets in oligodendrocytes, causing decreased myelination. However, the mechanisms by which APOE4 alters lipid metabolism are not fully understood. Here, we leveraged a genome-wide CRISPR screen and ATAC-sequencing in human induced pluripotent stem cell (iPSC)-derived oligodendrocytes to dissect APOE4s lipid-associated mechanisms of action. Using these approaches, we identified decreased Wnt signaling, and overactive GSK3b activity, as regulators of lipid droplet accumulation in oligodendrocytes. Genetic and pharmacological inhibition of GSK3b reduced lipid droplets in APOE4 oligodendrocytes, and increased myelination in three-dimensional iPSC-derived brain organoids. Finally, we show that pharmacological inhibition of GSK3b reduces lipid droplets and improves myelination in APOE4;PS19 Tau transgenic mice. Together, our results provide a framework for understanding the mediation of APOE4-related changes to oligodendrocyte lipid metabolism and myelination.

neuroscience↗

bioRxiv2025

Antiretroviral treatment does not prevent extrapulmonary tuberculosis during SIV/Mtb co-infection in macaques

Co-infection with both HIV and M. tuberculosis (Mtb) results in disseminated tuberculosis (TB) and accelerated progression of HIV. Despite greater access to antiretroviral treatment (ART), it remains unclear whether suppression of HIV replication protects against severe Mtb infection. Here, using a macaque model of SIV/Mtb coinfection, we investigated whether treatment of SIV infection with ART influenced control of a subsequent Mtb challenge compared to SIV infected macaques who were not treated with ART. Using a macaque model of simian immunodeficiency virus (SIV)-Mtb co-infection, macaques were first infected with SIVB670, SIVB670 with ART, or saline followed by a low-dose Mtb inoculation with serial clinical, microbiological, PET CT imaging, and immunologic assessments. At necropsy, gross pathology, viremia, bacterial burden, and immunologic parameters were compared. SIV-TB animals had greater gross pathology and total bacterial burden than TB only and SIV/ART/TB groups. However, despite normal blood CD4 counts and undetectable SIV RNA, SIV/ART/TB macaques showed similar clinical parameters and extrapulmonary involvement as SIV/TB animals. Analysis of barcoded-Mtb suggests ART control of SIV replication does not prevent Mtb extrapulmonary dissemination. These data indicate that people living with HIV on ART remain at high risk of bacterial dissemination and extrapulmonary TB disease, particularly when methods to identify extrapulmonary disease are inconsistent. This highlights the importance of understanding the mechanism of extrapulmonary spread and disease severity in HIV/TB co-infected individuals.

immunology↗

bioRxiv2024

Environmental sphagnum-associated fungi target thiol homeostasis to compete with Mycobacterium tuberculosis.

Mycobacterial species in nature are found in abundance in sphagnum peat bogs where they compete for nutrients with a variety of microorganisms including fungi. We screened a collection of fungi isolated from sphagnum bogs by co-culture with Mycobacterium tuberculosis (Mtb) to look for inducible expression of antitubercular agents and identified five fungi that produced cidal antitubercular agents upon exposure to live Mtb. Whole genome sequencing of these fungi followed by fungal RNAseq after Mtb exposure allowed us to identify biosynthetic gene clusters induced by co-culture. Three of these fungi induced expression of patulin, one induced citrinin expression and one induced the production of nidulalin A. The biosynthetic gene clusters for patulin and citrinin have been previously described but the genes involved in nidulalin A production have not been described before. All three of these potent electrophiles react with thiols and treatment of Mtb cells with these agents followed by Mtb RNAseq showed that these natural products all induce profound thiol stress suggesting a rapid depletion of mycothiol. The induction of thiol-reactive mycotoxins through three different systems in response to exposure to Mtb suggests that fungi have identified this as a highly vulnerable target in a similar microenvironment to that of the caseous human lesion.

microbiology↗