Biology subjects

Pereira, A.

Publications and source records attributed to Pereira, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Intracellular accumulation of AAV6 genomes governs microglia reactivity and the inflammatory response in retinal gene therapy

Adeno-associated viral (AAV) vectors possess immense potential for gene therapy applications. However, microglia can mount an immune response against AAV vectors. Yet, microglia are therapeutic targets since they play a driving role in the progression of neurodegenerative diseases. Thus, it is critical to understand the cellular processes driving the microglia-mediated immune response against AAV vectors. To this end, we modelled AAV6 induced inflammation upon retinal gene therapy in minipigs. Upon AAV6 administration, the IBA1+ cells demonstrated a morphological transition to the amoeboid form, indicating microglial reactivity. We also observed the invasion of peripheral immune cells in the retina. To elucidate the underlying molecular mechanisms, we transduced human iPSC derived microglia-like cells (iMGLs) in vitro with AAV6 and AAV8 respectively. Only AAV6 transduced iMGLs exhibited morphological features and a transcriptomic signature of microglial reactivity. The magnitude of intracellular AAV6 viral genomes was significantly higher as compared to the AAV8 condition. The elevated levels of intracellular AAV6 genomes induced a DNA damage response in AAV6-transduced iMGLs, which is a key feature of neuroinflammation-linked microglial reactivity. Thus, our work highlights the impact of intracellular viral genome accumulation on microglial reactivity and its implications for retinal gene therapy associated inflammation.

neuroscience↗

bioRxiv2026

Conversation in fMRI: DMN Activates During Live Mentalizing

Although language might have evolved in a conversational setting, neural language processing is rarely studied in this setting. It is also important to delineate the roles of networks interacting with the language network, such as the default mode network and networks subserving social cognition or cognitive control. We studied the fundamental question of how conversational production and comprehension processes may differ. By acquiring fMRI data of participants engaging in conversations on ethical dilemmas with a confederate, we aimed to study extra-linguistic areas during live mentalizing, crucially with long (10 min) conversations. A subject-specific network analysis was used to complement group-averaged whole-brain analysis. The results replicate asymmetries between production and comprehension already observed using short conversations. This included left inferior frontal gyrus preferences for production and superior and middle temporal gyri preferences for comprehension. Activation in the posterior dorsal medial prefrontal cortex was specific to production, a result that is stable across conversational durations. Notably, we found preferential activity of the default mode network (DMN) during comprehension, specifically during longer conversations. The frontoparietal network for control (FPN) showed the same pattern, although it was less robust. This might indicate simultaneous self-reflective, Theory of Mind, and/or situational processing during comprehension, potentially due to lower conversational pressures, compared to production. The subnetwork DN-B was more strongly activated than DN-A, across both comprehension and production, suggesting that Theory of Mind remains continuously active throughout conversation. Our findings thus advance the understanding of how several networks contribute to production vs comprehension during conversation.

neuroscience↗

bioRxiv2026

Reusable immobilised quaternary ammonium particles reduce microbial and resistome burdens without promoting resistance selection during wastewater post-treatment.

Wastewater treatment plants act as convergence zones for antibiotic residues, antibiotic-resistant bacteria (ARB), and antimicrobial resistance genes (ARGs), yet conventional processes are not designed to mitigate resistance dissemination from their effluents. While chemical disinfectants are generally effective, soluble quaternary ammonium compounds (QACs) can generate subinhibitory exposure gradients that promote resistance selection and co-selection both during treatment and after release into receiving waters. Here, we evaluate a contact-restricted alternative: benzyldimethyldodecyl ammonium chloride (BDMDAC) immobilised onto hydroxyapatite microparticles as a reusable and retainable post-treatment polishing strategy. Across single-strain assays, treated wastewater exposure, and experimental community evolution, immobilised BDMDAC-functionalised particles (BDMDAC-FPs) achieved concentration-dependent antimicrobial activity without detectable biocide leaching. Optimal exposure (200 mg/L, 4 h) resulted in a ~5.5 log reduction in total bacterial abundance and removal of clinically relevant ARGs. Antimicrobial efficacy was retained after one reuse cycle, supporting operational stability. Plasmid-borne QAC ARGs did not confer protection, and no enrichment of qac-associated or non-QAC ARGs was observed. Conjugation assays demonstrated suppression of horizontal gene transfer even under suboptimal exposure, and mobility-associated markers remained stable or declined during long-term community incubation. Collectively, the data support a contact-restricted mechanism in which antimicrobial pressure is spatially confined to the particle interface, generating high local lethality while limiting diffuse subinhibitory exposure. This spatial confinement decouples antimicrobial efficacy from classical disinfectant-driven resistance selection and mobility amplification. Immobilised BDMDAC-FPs therefore provide a mechanistically distinct and evolution-conscious framework for wastewater polishing technologies.

microbiology↗

bioRxiv2026

Linking Cyanobacterial Genomes to Toxin Dynamics Through Genome-Resolved Metagenomics

Global climate change and nutrient pollution from agricultural systems increase cyanobacterial bloom and toxin release events, and will pose a significant concern for public health and safety over the coming decades. Many in situ studies have focused on environmental, chemical, and microbial community changes and their impact on cyanobacterial bloom frequency and toxicity. However, fine-scale genetic differences in the genomes of bloom-forming cyanobacteria may also impact the quantity and types of toxins produced. Metagenomic approaches allow resolution of strain- and nucleotide-level changes within microbial communities and can improve our understanding of the factors that affect cyanobacterial bloom dynamics and toxicity. Here, we conduct a metagenomic analysis of the bloom-forming cyanobacterial genus Microcystis across a 10-month lake time series from the Valle de Bravo Reservoir, to assess how within-genus genotype-level changes are linked to intracellular toxin production and extracellular toxin release, as well as how single nucleotide variation may affect the types of microcystin toxins produced. Our results demonstrate that the abundances of both toxigenic and non-toxigenic Microcystis genotypes are significantly related to microcystin toxin concentrations. In addition to these genome-wide ("strain"-level) associations, specific single nucleotide variants show strong associations with chemical variants of microcystin in the environment. Our work highlights the importance of fine-scale analysis of microbial community composition for understanding cyanobacterial bloom dynamics and toxin production.

microbiology↗

bioRxiv2025

Joint model shows association of Mapuche genetic ancestry and longitudinal BMI with early menarche

The age at puberty onset varies greatly between individuals and ethnic populations, with significant health implications. Early menarche increases risk for breast cancer, cardiovascular disease, depression, behavioral disorders, diabetes, and all-cause mortality. While genetic factors and higher body mass index (BMI) have been associated with earlier pubertal timing in girls, the effect of Native American genetic ancestry on menarche timing is virtually unknown. We assessed how individual Mapuche Native American genetic ancestry proportions and BMI changes over time influence age at menarche in a cohort of admixed girls with mainly European and Mapuche ancestries. We developed a novel joint statistical model that links a Bernoulli random variable with longitudinal trajectories. The model captures individual-specific BMI trajectory dynamics through individual random effects, linking longitudinal BMI patterns directly to early menarche risk, incorporating the assessment of genetic ancestry effects as well. Two parameter estimation methods were developed, confirming the robustness of the model fit. We found significant ancestry effects, with girls experiencing early menarche having higher mean Mapuche ancestry proportions (47.5% vs 45.1%, p = 0.010). Each 10% increase in Mapuche ancestry substantially increased early menarche risk ({gamma}1 = 3.405, p = 0.010). Childhood BMI growth patterns strongly predicted early menarche: both BMI change rate (1 = 1.189, p < 0.001) and growth acceleration (2 = 9.080, p = 0.003) were significant predictors, while baseline BMI showed no association (p = 0.254). These results demonstrate that higher Mapuche ancestry and accelerating BMI trajectories independently increase early menarche likelihood. Body mass index, early menarche, genetic ancestry, mixed models, joint modeling

genetics↗

bioRxiv2025

Ultrafast tyrosine-based cell membrane modification via diazonium salts: a new frontier for biomedical applications

In this study, we present an ultrafast, efficient, and broadly applicable strategy for cell membrane modification via tyrosine bioconjugation using diazonium salt derivatives. This chemical approach enables both one-step and two-step functionalization of adherent, suspension, and primary cells with diverse ligands, including imaging probes, carbohydrates, biotin, and proteins, without inducing cytotoxicity or immune activation. Membrane engineering through bioconjugation is emerging as a valuable tool in biomedical research, given the cell membranes central role in signaling, transport, and cell-cell interactions. Compared to traditional glyco-engineering methods that often require multiday incubations and can cause cellular stress, our approach achieves precise and high-density grafting in less than one hour, with improved reproducibility and biological compatibility. Importantly, we demonstrate that this strategy can be applied to a variety of cell types, encompassing both immortalized cell lines and primary cells, notably Peripheral Blood Mononuclear Cells (PBMCs) and human effector cells such as natural killer (NK) cells, to enhance their cytotoxic function against EGFR-positive cancer cells via surface-conjugated Nanofitin. Moreover, we show that the bioconjugated signal diminishes over time due to cell division, offering a self-limiting alternative to permanent genetic modifications such as CAR-T, thereby mitigating risks associated with overly prolonged immune activation. Finally, the feasibility of storing pre-functionalized cells at -80 {degrees}C expands the practicality of this platform for future ready-to-use applications. Together, these features make our method a compelling alternative to current technologies for applications in targeted therapy, diagnostics, and cell-based immunotherapy.

bioengineering↗

bioRxiv2025

Spatial genomics of the cardiac sarcomere

Structure-function mapping of proteins has improved our understanding of disease mechanisms and protein domains while human population genetics has provided a window into variational tolerance that can be modeled at a structural level. Here, to reveal novel insight into the cardiac sarcomere, the motor unit of the heart, we develop a novel analytical framework to integrate data from over 17,000 patients with hypertrophic cardiomyopathy (HCM) and combine it with two population-scale genomic databases that incorporate data from more than 800,000 individuals. We integrate in silico genetic predictions of gene variant pathogenicity with 3 dimensional integrative spatial scanning across multiple structural models of cardiac motor proteins. Results reveal both recognized and novel regions of structural variant intolerance across the critical genes of the cardiac sarcomere including novel insights into protein function. We discuss the structural relevance of variant enrichment in the context of sarcomere organization and destabilization of sequestered myosin leading to hypercontractility seen in HCM, by incorporating the recently defined high-resolution structure of human cardiac myosin filament. We extend and validate these findings through pathogenic variant class enrichment and reveal novel associations with the earlier onset of disease in a large clinical cohort. In summary, our study provides a multi-dimensional framework for integrating structural, genomic, and modeling data to reveal novel insight into the cardiac sarcomere.

genomics↗

bioRxiv2024

Cross-species transmission of human hepatitis B virus to wild Neotropical primates

Hepatitis B virus (HBV) infects approximately one-third of the worlds human population and kills over one million people each year. HBV is also prevalent in Old World apes but not in New World primates. Human-to-primate transmission of HBV was suspected in zoo-captive monkeys and Mauritius macaques, but empirical data are scarce. Here, we collected blood and liver samples from 88 monkeys of 27 species in two areas of the Amazon, one with pristine forest and the other highly occupied and deforested by humans. A total of 17 (34.7%) out of 49 specimens from the human-occupied region tested positive for HBV. At this site, there was a positive relationship between human population density in the sampling location and the likelihood of primates being infected by HBV. Conversely, all 39 samples from the pristine forest tested negative for HBV. By sequencing a portion of the HBV S gene in five positive samples, each from a distinct primate genus, we found that four samples were closely related to the globally widespread human HBV-A strain, but not to the Americas-native HBV-F strain. The fifth sample aligned with the human HBV-D type, prevalent in the region where these samples were obtained. To our knowledge, this study represents the first reported cases of HBV in multiple wild New World primate species anywhere in the world. Our results suggest that primates were infected by strains brought into this part of Brazil by human immigrants, where HBV transmission may have been facilitated by the close contact between humans and monkeys due to high human occupation. This shows that the impact of human immigration, occupation and population growth in the Amazon extends beyond habitat loss; it also facilitates cross-species infections, potentially leading to the emergence of new, virulent viral strains that threaten both Amazonian biodiversity and human health. Author SummaryJean P. Boubli: Professor in Primate Ecology and Evolution, School of Science, Engineering and the Environment, University of Salford, Uk Hani R. El Bizri: PhD in Wildlife Conservation with a focus on Amazonian sustainable development. Analyst of Center for International Forestry Research (CIFOR), Bogor, Indonesia Luan F. Botelho-Souza: Masters and doctorate in experimental biology at the Universidade Federal de Rondonia/Brazil, Chrysoula Gubili: Researcher at the Fisheries Research Institute Nea Peramos, Kavala, Greece, specializing in population ecology and conservation genetics. Stephen J. Martin: Professor in Social Insects, School of Science, Engineering and the Environment, University of Salford, Uk Maisa da S. Araujo: Masters and doctorate in experimental biology, at the Universidade Federal de Rondonia/Brazil, Mariluce R. Messias: Professor of Zoology and curator of the Mammalogy Museum at the Universidade Federal de Rondonia/Brazil. Alcione de O. dos Santos: Masters and doctorate in experimental biology at the Universidade Federal de Rondonia/Brazil. Luiz S. Ozaki: Masters degree from Universidade de Brasilia and PhD in Physiological Sciences, Molecular Biology in Fukuoka, Kyushu, Japan. Andre V.C. Pereira: Bachelor in Biology the Universidade Federal de Rondonia/Brazil. Tony H. Katsuragawa: Masters and doctorate in experimental biology, at the Universidade Federal de Rondonia/Brazil. Ana Maisa Passos-Silva: Masters degree in experimental biology from the Federal University of Rondonia/Brazil. Luiz H. S. Gil: Masters in experimental biology, at the Universidade Federal de Rondonia/Brazil. Izeni P. Farias: Professor of Genetics, Universidade Federal do Amazonas, Brazil Juan M.V. Salcedo: Master in Tropical Medicine from the University of Brasilia/Brazil and PhD in Sciences from the University of Sao Paulo/Brazil. Tommy C. Burch: Masters in Biological Sciences and PhD candidate from the University of Salford, UK. Deusilene Vieira: Master in Tropical Medicine from the University of Brasilia/Brazil and PhD in Sciences from the University of Sao Paulo/Brazil.

pathology↗

bioRxiv2024

Spinal Cord Injury Enhances Lung Inflammation and Exacerbates Immune Response After Acute Lung Injury

The severity of spinal cord injury (SCI) is closely tied to pulmonary function, especially in cases of higher SCI levels. Despite this connection, the underlying pathological mechanisms in the lungs post-SCI are not well understood. Previous research has established a connection between disrupted sympathetic regulation and splenocyte apoptosis in high thoracic SCI, leading to pulmonary dysfunction. The aim of this study was to investigate whether mice with low-level SCI exhibit increased susceptibility to acute lung injury by eliciting systemic inflammatory responses that operate independently of the sympathetic nervous system. Here, we employed T9 contusion SCI and exposed mice to aerosolized lipopolysaccharide (LPS) to simulate lung inflammation associated with acute respiratory distress syndrome (ARDS). Twenty-four hours post-LPS exposure, lung tissues and bronchoalveolar lavage (BAL) fluid were analyzed. LPS markedly induced proinflammatory gene expression (SAA3, IRG1, NLRP3, IL-1beta, MCP-1) and cytokine release (IL-1beta, IL-6, MCP-1) in SCI mice compared to controls, indicating an exaggerated inflammatory response. Infiltration of Ly6G/C positive neutrophils and macrophages was significantly higher in SCI mice lungs post-LPS exposure. Interestingly, spleen size and weight did not differ between control and SCI mice, suggesting that T9 SCI alone does not cause spleen atrophy. Notably, bone-marrow-derived macrophages (BMDMs) from SCI mice exhibited hyper-responsiveness to LPS. This study demonstrated an increase in lung inflammation and immune responses subsequent to low-level T9 SCI, underscoring the widespread influence of systemic inflammation post-SCI, especially pronounced in specific organs like the lungs. KEY POINTSO_LISpinal cord injury leads to increased lung permeability following LPS inhalation. C_LIO_LISpinal cord injury amplifies cytokine release after exposure to LPS. C_LIO_LISpinal cord injury affects bone marrow-derived macrophages, showing heightened glycolytic activity and inflammatory conditions. C_LI

immunology↗

bioRxiv2024

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the telencephalic interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic interneurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

neuroscience↗

bioRxiv2024

Role of the NOS-cGMP pathways in time-dependent sensitization of behavioral responses in zebrafish

Nitric oxide (NO) is a molecule involved in plasticity across levels and systems. The role of NOergic pathways in time-dependent sensitization, a behavioral model of translational relevance to trauma and stress-related disorders, was assessed in adult zebrafish. In this model, adult zebrafish acutely exposed to a fear-inducing conspecific alarm substance (CAS) and left undisturbed for an incubation period show increased anxiety-like behavior 24 h after exposure. CAS increased forebrain glutamate immediately after stress and 30 min after stress, an effect that was accompanied by increased nitrite levels immediately after stress, 30 min after stress, 90 min after stress, and 24 h after stress. CAS also increased nitrite levels in the head kidney, where cortisol is produced in zebrafish. CAS-elicited nitrite responses in the forebrain 90 min (but not 30 min) after stress were prevented by a NOS-2 blocker. Blocking NOS-1 30 min after stress prevents TDS; blocking NOS-2 90 min after stress also prevents TDS, as does blocking calcium-activated potassium channels in this latter time window. TDS is also prevented by blocking guanylate cyclase activation in both time windows, and cGMP-dependent channel activation in the second time window. These results suggest that different NO-related pathways converge at different time windows of the incubation period to induce TDS.

neuroscience↗

bioRxiv2023

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing and analyzed 45,559 high quality nuclei targeting the subthalamic nucleus and adjacent structures from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was the top activated pathway in vulnerable cell types. Using immunohistochemistry, we found that activated eIF2 was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2 positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.

neuroscience↗

bioRxiv2023

Conversational production and comprehension: fMRI-evidence reminiscent of the classic Broca-Wernicke model

A key question in neurolinguistics is whether language production and comprehension share neural infrastructure, but this question has not been addressed in the context of actual conversation. We utilized a public fMRI dataset where participants (N=24) engaged in unscripted conversations with a confederate outside the scanner via an audio-video link. We provide evidence indicating that production and comprehension, in a conversational setting, diverge with respect to how they modulate the recruitment of regions in the left-lateralized perisylvian language network. Activity in the left inferior frontal gyrus was stronger in production than in comprehension. Compared to production, comprehension showed stronger recruitment of the left anterior middle temporal gyrus and superior temporal sulcus, but this was not the case for the posterior aspect of these loci. Although our results are reminiscent of the classic Broca-Wernicke model, the anterior temporal activation is a notable difference from that model. This is one of the findings which may be a consequence of the conversational setting, another being that conversational production activated what we interpret as higher-level socio-pragmatic processes. In conclusion, we present evidence supporting that the above-mentioned frontal vs temporal regions in the language network are functionally segregated during conversation.

neuroscience↗

bioRxiv2023

3D printed magneto-active microfiber scaffolds for remote stimulation of 3D in vitro skeletal muscle models

Tunable culture platforms that guide cellular organization and mechanically stimulate skeletal muscle development are still unavailable due to limitations in biocompatibility and actuation triggered without contact. This study reports the rational design and fabrication of magneto-active microfiber meshes with controlled hexagonal microstructures via melt electrowriting (MEW) of a thermoplastic/graphene/iron oxide composite. In situ deposition of iron oxide nanoparticles on oxidized graphene yielded homogeneously dispersed magnetic particles with sizes above 0.5 m and low aspect ratio, preventing cellular internalization and toxicity. With these fillers, homogeneous magnetic composites with very high magnetic filler content (up to 10 wt.%) were obtained and successfully processed in a solvent-free manner for the first time. MEW of magnetic composites enabled the skeletal muscle-inspired design of hexagonal scaffolds with tunable fiber diameter, reconfigurable modularity, and zonal distribution of magneto-active and nonactive material. Importantly, the hexagonal microstructures displayed elastic deformability under tension, mitigating the mechanical limitations due to high filler content. External magnetic fields below 300 mT were sufficient to trigger out-of-plane reversible deformation leading to effective end-to-end length decrease up to 17%. Moreover, C2C12 myoblast culture on 3D Matrigel/collagen/MEW scaffolds showed that the presence of magnetic particles in the scaffolds did not significantly affect viability after 8 days with respect to scaffolds without magnetic filler. Importantly, in vitro culture demonstrated that myoblasts underwent differentiation at similar rates regardless of the presence of magnetic filler. Overall, these innovative microfiber scaffolds were proven as a magnetically deformable platform suitable for dynamic culture of skeletal muscle with potential for in vitro disease modeling.

bioengineering↗

bioRxiv2022

Fin whale singalong: evidence of song conformity

Mechanisms driving song learning and conformity are still poorly known yet fundamental to understand the behavioural ecology of animals. Broadening the taxonomic range of these studies and interpreting song variation under the scope of cultural evolution will increase our knowledge on vocal learning strategies. Here, we analysed changes in fin whale (Balaenoptera physalus) songs recorded over two decades across the Central and Northeast Atlantic Ocean. We found a rapid (over 4 years) replacement of fin whale song types (different inter-note intervals - INIs) that co-existed with hybrid songs during the transition period and showed a clear geographic pattern. We also revealed gradual changes in INIs and note frequencies over more than a decade with all males adopting both rapid and gradual changes. These results provide evidence of vocal learning of rhythm in fin whale songs and conformity in both song rhythm and note frequencies.

animal behavior and cognition↗

bioRxiv2022

Extracellular vesicle formation in Cryptococcus deuterogattii impacts fungal virulence and requires the NOP16 gene

Small molecules are components of fungal extracellular vesicles (EVs), but their biological roles are only superficially known. NOP16 is a eukaryotic gene that is required for the activity of benzimidazoles against Cryptococcus deuterogattii. In this study, during the phenotypic characterization of C. deuterogattii mutants lacking NOP16 expression, we observed that this gene was required for EV production. Analysis of the small molecule composition of EVs produced by wild-type cells and two independent nop16{Delta} mutants revealed that the deletion of NOP16 resulted not only in a reduced number of EVs but also an altered small molecule composition. In a Galleria mellonella model of infection, the nop16{Delta} mutants were hypovirulent. The hypovirulent phenotype was reverted when EVs produced by wild-type cells, but not mutant EVs, were co-injected with the nop16{Delta} cells in G. mellonella. These results reveal a role for NOP16 in EV biogenesis and cargo, and also indicate that the composition of EVs is determinant for cryptococcal virulence.

microbiology↗

bioRxiv2022

Transcriptional and cell type profiles of cortical brain regions showing ultradian cortisol rhythm dependent responses to emotional face stimulation

The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling - the ANXA1 gene and retrograde endocannabinoid signaling - show top differential expression and the most significant enrichment. Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies.

neuroscience↗

bioRxiv2021

Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

Understanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using an unbiased correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expression of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.

neuroscience↗