Biology subjects

Paixao, T.

Publications and source records attributed to Paixao, T..

13 recordsLinked to original sources

bioRxiv2026

Distinct regulation across the transcription cycle drives mitotic transcriptional silencing

In most organisms, as cells enter mitosis, transcription is globally silenced. While individual studies have shown that each stage of the transcription cycle can be modulated during mitosis, how initiation, elongation, and termination are temporally and kinetically regulated to ensure transcriptional silencing remains unclear. Here, we combine real-time quantitative imaging of ongoing transcription in early Drosophila embryos with mathematical modelling to systematically dissect how transcriptional kinetics change as cells progress into mitosis. We found that transcription initiation undergoes a gradual repression starting in prophase, while elongation rates remain unaltered. After nuclear envelope breakdown, an abrupt mechanism causes premature termination of elongating RNA, driven at least in part by the SNF-helicase-like protein Transcription Termination factor 2 / Lodestar (TTF2/Lds). Our study provides a quantitative framework for understanding how transcription is modulated across the cell cycle, demonstrating that mitotic repression arises from multiple processes with different dynamics that collectively ensure the precise shutdown of gene expression.

cell biology↗

bioRxiv2026

Tissue lamination state switches neuronal translocation from active to passive in the vertebrate retina

Neuronal migration is essential for establishing functional tissue architecture in the developing central nervous system. While cell-intrinsic mechanisms driving neuronal movement have been identified, how migratory strategies adapt to dynamic developmental tissue changes remains less understood. Here, we address this question using retinal bipolar cells generated across unlaminated and laminated stages. This enables direct comparison of neuronal translocation across tissue states. Combining quantitative live imaging with targeted perturbations, we show that the migration mode of bipolar cells switches depending on tissue lamination state. Bipolar cells born before photoreceptor layer formation undergo directed, microtubule-dependent somal translocation. In contrast, later-born cells exhibit passive, non-directed displacement driven by collective tissue movements. Interference with tissue-wide movements impairs this displacement, while disrupting photoreceptor layer formation restores directed translocation. Independent of strategy, cells achieve accurate laminar positioning, indicating that tissue context determines neuronal migration mode, a principle likely relevant across the developing neural and other tissues.

developmental biology↗

bioRxiv2026

Age-dependent disease tolerance to SARS-CoV-2 infection

Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations. One-Sentence SummarySARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.

immunology↗

bioRxiv2025

Limited bone marrow chimerism impairs thymic cell competition and causes leukemia

Cell competition in the thymus is a critical tumor suppressor process that prevents leukemia. We show that suboptimal bone marrow correction of {gamma}c-deficient mice disrupts this process, inducing thymus autonomy and promoting T cell acute lymphoblastic leukemia (T-ALL). {gamma}c-deficiency causes severe combined immunodeficiency in mice and humans and is treated by hematopoietic stem and progenitor cell (HSPC) transplantation. However, inefficient correction led to intermittent thymic activity, consistent with sporadic thymus seeding. This was accompanied by altered thymocyte composition and the emergence of an aberrant TCR{beta}{square}CD4{square}CD8{square} population that preceded overt leukemia. Leukemia incidence and latency were exacerbated when HSPCs were pre-cultured under conditions mimicking gene-editing protocols, whereas delaying thymopoietic support in the host mitigated disease. Critically, the extent of bone marrow reconstitution determined the ability to suppress thymus autonomy and leukemia development. Together, these findings demonstrate that inadequate bone marrow correction directly compromises thymic cell competition, creating a permissive niche for malignant transformation. Our work highlights thymus autonomy as a risk in immunodeficiency treatment and underscores the need to ensure robust hematopoietic reconstitution to prevent leukemogenesis.

immunology↗

bioRxiv2025

A critical role for the ER Membrane Complex (EMC) in lipid droplet homeostasis

The ER Membrane complex (EMC) facilitates insertion of multiple classes of integral membrane protein into the lipid bilayer of the endoplasmic reticulum (ER). Recent years have seen significant progress in understanding the structural aspects of EMC function, but the client protein/s enforcing its evolutionary conservation throughout eukaryotic kingdoms remain to be determined. Given reported role/s for the EMC in lipid homeostasis, we deleted the essential EMC3 subunit in the liver and adipose tissues of mice and examined the impact of EMC loss in a range of metabolic models. Intriguingly, absence of EMC3 in either the liver or adipose tissues results in defective storage of triglycerides and perturbations in lipid droplet (LD) homeostasis. EMC-deficient mouse adipose tissues were defective in their ability to mediate fat storage in response to a high fat diet and were unable to support non-shivering thermogenesis. Proteomic analyses of EMC3-deficient tissues found reduced levels of FITM2, a key regulator of LD biogenesis and ER homeostasis, identifying it as a novel EMC client. Strikingly, deletion of the EMC3 homolog dPob in the Drosophila fat body, which shares overlapping functions with mammalian liver/adipose tissues, revealed similar defects in LD homeostasis. Together, our results indicate that the EMC plays a key evolutionarily conserved role in biogenesis of machinery maintaining triglyceride storage in metazoans.

biochemistry↗

bioRxiv2025

A Metabolite-Based Resistance Mechanism Against Malaria

Whether jaundice, a common presentation of Plasmodium (P.) falciparum malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood (1-3). We found that asymptomatic P. falciparum infection was associated with a >10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (5), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasites food vacuole. In conclusion, jaundice represents a metabolic response to Plasmodium spp. infection that limits malaria severity.

immunology↗

bioRxiv2024

Optimistic and pessimistic cognitive judgement bias modulates the stress response and cancer progression in zebrafish

Cognitive judgement bias in decision-making under ambiguity occurs both in animals and humans, with some individuals interpreting ambiguous stimulus as positive (optimism) and others as negative (pessimism). We hypothesize that judgement bias is a personality trait and that individuals with a pessimistic bias would be more reactive to stressors and therefore more susceptible to stress-related diseases than optimistic ones. Here, we show that zebrafish judgment bias is a consistent behavioral trait over time, and that pessimistic and optimistic fish express phenotype-specific neurogenomic responses to stress. Furthermore, both phenotypes show differential activation of the hypothalamic-pituitary-interrenal axis in response to chronic stress, suggesting that optimists have a lower stress reactivity. Accordingly, optimists seem to be more resilient to disease than pessimists, as shown by a lower tumorigenesis in a zebrafish melanoma line [Tg(mtifa:HRAS-GFP)]. Together these results indicate that judgement bias is paralleled by differences in the stress response with implications for disease resilience.

animal behavior and cognition↗

bioRxiv2024

Life history traits influence the dynamics of genetic diversityin a refugium population undergoing expansion andcontraction

Species ranges are dynamic, experiencing expansions, contractions or shifts as a response to habitat changes induced by extrinsic factors such as climate change and, more recently, human activities. While the scientific literature has explored the genetic effects of spatial processes, published studies rarely incorporate life-history traits to study the effect of such changes on species living in the same environments. There is thus a gap in our understanding regarding the variation in genetic diversity patterns among species with distinct life-history traits such as growth rates and generation times, experiencing the same habitat change scenarios. In this study, we first used spatial simulations to investigate the temporal dynamics of genetic diversity within refugium populations experiencing a range expansion followed by a stationary and a contraction period. We explored different scenarios, varying both the speed of contraction and the life-history traits of the simulated species. In addition, we used a simpler panmictic model for which we derived analytical results. Altogether, we identified three temporal dynamics of genetic diversity in the refugium population during the contraction phase: scenarios where genetic diversity i) decreased throughout the contractions, ii) increased for periods that could be greater than thousands of years before plateauing and then decreasing or iii) followed a persistent increasing trend, without any visible effect of the expansion or contraction. We show that these different temporal dynamics can be predicted by comparing the observed expected heterozygosity (He) to the values expected if the species were at equilibrium within the refuge (He refuge) and within the whole landscape (He landscape). We also observe that there are scenarios where a rapid contraction maintains more diversity just at the end of the contraction, as widely believed and as reported in a previous simulation study. However, we also observe the opposite pattern for a wide range of parameters. The widespread idea that observing high diversity levels in a refugium population is due to a recent and rapid habitat loss is thus not necessarily true and will depend on various life history traits and how they relate to habitat change dynamics.

evolutionary biology↗

bioRxiv2023

Adaptation to oral infection in D. melanogaster through evolution of both resistance and disease tolerance mechanisms

Pathogens exert strong selection on hosts, that evolve and deploy different defensive strategies, namely minimizing pathogen exposure (avoidance), directly promoting pathogen elimination (resistance), and/or managing the deleterious effects of illness (disease tolerance). However, how the response to pathogens partitions across these processes has never been directly assessed in a single system, let alone in the context of known adaptive trajectories under controlled selection regimes. Here, an experimental evolution system composed of D. melanogaster and its natural pathogen P. entomophila is used to independently assess the role of behavioural traits, and of resistance and disease tolerance mechanisms on host evolution. We compare one replicate of a population adapted to oral infection with P. entomophila (BactOral) to a replicate of its control population to find no evidence for behavioural change but measurable differences in both resistance and disease tolerance. In BactOral, we identify a relative decrease in bacterial loads correlated with an increase in gut production of specific AMPs, but no differences in bacterial intake, in gut cell renewal rate, or in the rate of bacterial defecation, pointing to a strengthening in resistance. Additionally, we posit that disease tolerance also contributes to the adaptive response of the BactOral population through a tighter control of its immune response and of the deleterious effects of exposure. This study reveals a genetically complex and mechanistically multi-layered response, possibly reflecting the structure of adaptation to infection in natural populations.

evolutionary biology↗

bioRxiv2022

A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia

Anemia is a clinical hallmark and independent risk factor of malaria mortality, the disease caused by Plasmodium spp. infection. While malarial anemia arises from parasite-induced hemolysis, whether and how host metabolic adaptation to malaria regulates anemia severity is less understood. Here we demonstrate that reprogramming of organismal iron (Fe) metabolism by the kidneys is a central component of the host metabolic response regulating the pathogenesis of life-threatening malarial anemia. Renal proximal tubule epithelial cells (RPTEC) are the main cell compartment responsible for Fe storage and recycling during Plasmodium infection in mice. Transcriptional reprogramming of RPTEC couples immune resistance to Plasmodium infection to renal Fe export via the induction of the cellular Fe exporter SLC40A1/ferroportin 1. This integrated defense strategy is essential to deliver Fe to erythroblasts and support compensatory erythropoiesis to prevent the development of life-threatening anemia. Failure to mobilize Fe from RPTEC causes acute kidney injury (AKI) and is associated with life-threatening anemia in P. falciparum-infected individuals. These findings reveal an unexpected role of the kidneys in the control of organismal Fe metabolism and anemia severity during malaria.

pathology↗

bioRxiv2021

Phenotypic architecture of sociality and its associated genetic polymorphisms in zebrafish

Sociality is often seen as a single phenotypic trait, but it relies on motivational and cognitive components implemented by specific causal mechanisms. Hence, these components may have evolved independently, or may have been linked by phenotypic correlations driven by a shared selective pressure for increased social competence. Furthermore, these components may be domain-specific or of general domain across social and non-social contexts. Here we have characterized the phenotypic architecture of sociality in zebrafish, which has been increasingly used as a model organism in social neuroscience. For this purpose, we have behaviorally phenotyped zebrafish from different wild type lines in four tests: social tendency, social and non-social recognition, and open-field test. Our results indicate that: (1) sociality has two main components that are independent from each other (social tendency and social recognition), hence not supporting the occurrence of a sociality syndrome; (2) both social traits are phenotypically linked to non-social traits (non-social exploration and non-social memory, respectively), forming two general behavioral modules, general inspection and general recognition, and suggesting that sociality traits have been co-opted from general-domain motivational and cognitive traits. Moreover, the study of the association between genetic polymorphisms (i.e. single nucleotide polymorphisms, SNPs) and each behavioral module further supports this view, since several SNPs from a list of candidate "social" genes, are statistically associated with the general inspection (motivational), but not with a general recognition (cognitive), behavioral module. The SNPs associated with general inspection are widespread across different chromosomes and include neurotransmitters, neuromodulators, and synaptic plasticity genes, suggesting that this behavioral module is regulated by multiple genes, each of them with small effects. Together, these results support the occurrence of general domain motivational and cognitive behavioral modules in zebrafish, which have been co-opted for the social domain. Author summarySocial living has been considered one of the major transitions in evolution and it has been considered to act as a major selective force shaping the evolution of brain and behavior in animals. Sociality relies on two basic behavioral mechanisms: (1) the willingness to approach and be near others (aka social tendency); and (2) the ability to distinguish between others (aka social recognition) in order to adjust the behavior expressed during social interactions according to the identity of the interactant. There is an ongoing debate on to what extent these social abilities have specifically evolved in response to social living and are domain specific, or if they were selected as a broad response to cognitive demands and are of general domain. Here, we used zebrafish to test the domain-specific vs. general domain hypotheses and to assess the association of social tendency and social recognition with a set of candidate "social" genes (i.e. genes that have been linked to social behavior in other studies with different vertebrate species). We found that both social traits are not correlated to each other and are of general domain, and that only social tendency is associated with candidate "social" genes, suggesting that social tendency and social recognition are independent behavioral modules that rely on separate genetic architectures and that can evolve separately.

animal behavior and cognition↗

bioRxiv2021

Local genetic context shapes the function of a gene regulatory network

Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions, such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks remains a major challenge. Here, we use a well-defined synthetic gene regulatory network to study how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one gene regulatory network with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Our results demonstrate that changes in local genetic context can place a single transcriptional unit within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual transcriptional units, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of gene regulatory networks.

molecular biology↗

bioRxiv2020

Self-renewal capacity of double negative 3 (DN3) early thymocytes preserves thymus autonomous function but compromises the β-selection checkpoint

T lymphocyte differentiation in the thymus relies on high cellular turnover, and cell competition enforces thymocyte replenishment. If deprived of competent progenitors, the thymus can maintain thymopoiesis autonomously for several weeks but this bears a high risk of leukemia. Here we show that double negative 3 early (DN3e) thymocytes can acquire stem cell like properties, which enables them to maintain thymopoiesis. Specifically, DN3e proved to be long-lived, they proliferated and differentiated in vivo, were necessary for autonomous thymopoiesis, and included DNA-label-retaining cells. Single cell RNAseq revealed a transcriptional program of thymopoiesis similar in autonomy and the controls. Nevertheless, a new population was identified in thymus autonomy that was enriched for an aberrant Notch target gene signature and bypassed the {beta}-selection checkpoint. In sum, DN3e have the potential to self-renew and differentiate in vivo if cell competition is compromised but this enables the accumulation of atypical cells, probably leading to leukemia.

immunology↗