Biology subjects

Figueiredo, A.

Publications and source records attributed to Figueiredo, A..

14 recordsLinked to original sources

bioRxiv2026

Ferroptosis is a Physiologic Vulnerability of Iron-Recycling Macrophages

Iron deficiency anemia affects one-third of the global human population. Paradoxically, the daily iron required to fuel the production red blood cell (RBC) and prevent anemia is provided through its recycling from senescent RBC. This is achieved by splenic red pulp macrophages (RPM) that extract iron from the heme groups of hemoglobin (Hb). How these professional erythrophagocytic macrophages prevent intracellular iron flux from inducing cell death via ferroptosis is unknown. Here we show that SPI-C, the master transcriptional regulator of the erythrophagocytic lineage, orchestrates two redundant anti-ferroptosis pathways. One supports glutathione synthesis, via NF-E2-related factor 2 (NRF2), and the other relies on bilirubin production by biliverdin reductase A (BVRA). Genetic ablation of both pathways, but not either alone, sensitizes erythrophagocytic macrophages to ferroptosis, depletes RPM and increases the severity of iron deficiency anemia in mice. These findings reveal a central physiologic role of ferroptosis in the control of macrophage function, iron homeostasis and iron-deficiency anemia. HighlightsO_LISPI-C enforces the antioxidant metabolic program of RPM. C_LIO_LISPI-C controls bilirubin production by biliverdin reductase A. C_LIO_LIBilirubin protects erythrophagocytic macrophages from ferroptosis. C_LIO_LIFerroptosis protection supports iron-recycling macrophages and limit iron deficiency anemia. C_LI

immunology↗

bioRxiv2026

Age-Group Differences in Skeletal Age, Anabolic Hormones, and Physical Fitness in Elite Youth Football Players from Under-13 to Under-16

ObjectivesFootball players between the ages of 13 and 16 were the subjects of this study to (i) compare skeletal age, growth hormone (GH), insulin-like growth factor-1 (IGF-1), VO2max, countermovement jump (CMJ) performance, and playing time across four consecutive age groups (under-13 to under-16), and (ii) investigate correlations between these metrics within each age group. Designcross-sectional research study. MethodsThe U13, U14, U15, and U16 groups included 122 elite male youth football players (14.13 {+/-} 1.14 years; 169.39 {+/-} 9.82 cm; 55.56 {+/-} 10.10 kg). The Fels method was used to determine skeletal age. Anthropometric measures included height, weight, and sitting height. The CMJ and Yo-Yo (VO2max) tests were used to assess physical fitness. GH and IGF-1 were measured in blood samples. Pearson correlation and one-way ANOVA were used. ResultsAnthropometric assessment, skeletal age, VO2max, CMJ, IGF-1, football training, and minutes playing all showed significant group differences, with the U16 group demonstrating the highest values and the U13 group the lowest (p < 0.001). There were no significant differences in GH (p = 0.172). Although there were no consistent relationships between GH or IGF-1 and height or weight, these variables did correlate with other factors; however, these associations varied by group. ConclusionsAcross the under-13 to under-16 span, skeletal age, physical fitness, and IGF-1 increased progressively between age groups, whereas GH did not differ. The impact of biological maturation on performance was demonstrated by the fact that older, more experienced players performed better than younger ones. The absence of a between-group difference in GH, despite progressive changes in the other measures, points to maturity-driven adaptations rather than a uniform hormonal response.

Developmental Biology↗

bioRxiv2025

Biliverdin Reductase Catalytic Activity Is Essential for Malaria Resistance

Jaundice, a condition characterized by elevated levels of circulating bilirubin, is an adaptive response to malaria sustained through bilirubin production by biliverdin reductase A (BVRA). Beyond its enzymatic activity, BVRA acts as a protein kinase and as a transcription factor. To disentangle the contribution of BVRA catalytic activity over its non-canonical functions we generated BlvraG17A and BlvraE97A mice harboring G17A and E97A missense mutations in the BVRA NAD(P)H-binding domain and reductase motif, respectively. Both BlvraG17A and BlvraE97Amice presented a reduction in enzymatic activity and succumbed to malaria, otherwise non-lethal to wild-type (BlvraWT) mice. Quantification of circulating unconjugated bilirubin revealed a dose response effect whereby the mutant strains failed to reach a threshold of circulating bilirubin required to support its protective effect. These findings establish the antimalarial effect of the enzymatic activity of BVRA and define a concentration threshold of bilirubin required for malaria protection, informing therapeutic development and biomarker-guided malaria treatment strategies. Highlights- Establishment of catalytic deficient BVRA mouse mutants; - Anti-malarial effect of BVRA relies on its catalytic activity; - A minimal bilirubin threshold for parasite control; - A minimal bilirubin threshold for malaria resolution;

pathology↗

bioRxiv2025

Monocyte control of organismal energy homeostasis

Multicellular organisms rely on inter-organ communication networks to maintain vital parameters within a dynamic physiological range. Macrophages are central to this homeostatic control system, sensing deviations of those parameters and responding accordingly to support tissue function and organismal homeostasis. Here we demonstrate that dysregulation of iron metabolism in parenchyma cells, imposed by the deletion of ferritin H chain, is sensed by monocyte-derived macrophages. In response, macrophages derived from circulating monocytes support tissue function, energy metabolism and thermoregulation, as demonstrated in bone marrow chimeric and parabiotic mice. This salutary effect is contingent on a transcriptional program, controlled in macrophages by the transcription factor A mitochondria. This transcriptional response acts in a non-cell autonomous manner to support the mitochondria of parenchyma cells, irrespectively of mitochondrial transfer. In conclusion, monocyte-derived macrophages cross-regulate Fe and energy metabolism to support tissue function and organismal homeostasis.

immunology↗

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↗

bioRxiv2023

A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations

Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to the transformation of a capillary into a shunt remain unclear and how shunts can be reverted into capillaries is poorly understood. Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in endothelial cell (EC) volume of venous origin (hypertrophic venous cells) are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signaling cell-autonomously regulates EC volume, demonstrating that our discoveries link with hereditary hemorrhagic telangiectasia (HHT)-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. We demonstrate that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocates for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.

cell biology↗

bioRxiv2022

A shift in the pathotype diversity and complexity of Phytophthora sojae, causal agent of root and stem rot of soybean, in Brazil

Soybean root rot disease caused by the oomycete Phytophthora sojae is particularly destructive, once it is a host-specific pathogen that can infect and kill soybean plants at any stage of growth. The use of resistant cultivars is the most effective method of controlling the disease. Therefore, monitoring changes in the adaptability of P. sojae population to resistance genes (Rps) is extremely important not only from an epidemiological point of view but mainly for the management of the disease and durability of the Rps genes. We investigated the pathotypes of 40 isolates of P. sojae, sampled from the region with a higher incidence of soybean root rot in Brazil, using a set of 14 soybean differentials. The first study investigating pathotype diversity in Brazil was published in 2013. A decade later, we are reporting a major shift in pathotype diversity and complexity. This information can be useful for breeding programs aiming at developing soybean cultivars with resistance to root and stem rot and optimize the usage of genes and germplasm.

microbiology↗

bioRxiv2022

Grapevine leaf MALDI-MS imaging reveals the localisation of a putatively identified sucrose metabolite associated to Plasmopara viticola development

Despite well-established pathways and metabolites involved in grapevine-Plasmopara viticola interaction, information on the molecules involved in the first moments of pathogen contact with the leaf surface and their specific location is still missing. To understand and localise these molecules, we analysed grapevine leaf discs infected with P. viticola with MSI. Plant material preparation was optimised, and different matrices and solvents were tested. Our data shows that trichomes hamper matrix deposition and the ion signal. Results show that putatively identified sucrose presents a higher accumulation and a non-homogeneous distribution in the infected leaf discs in comparison with the controls. This accumulation was mainly on the veins, leading to the hypothesis that sucrose metabolism is being manipulated by the development structures of P. viticola. Up to our knowledge this is the first time that the localisation of a putatively identified sucrose metabolite was shown to be associated to P. viticola infection sites.

plant biology↗

bioRxiv2022

Evolution of the quorum sensing systems in Pseudomonas aeruginosa can involve both loss of regulon function and network modulation

Pseudomonas aeruginosa populations evolving in cystic fibrosis (CF) lungs, animal infection models, natural environments or in vitro undergo extensive genetic adaption and diversification. A common mutational target is the quorum sensing (QS) regulon, a three-unit regulatory system that controls the expression of a suite of virulence factors and secreted public goods. Three scenarios have been advocated to explain selection for QS mutants, which include (I) disuse of the regulon, (II) cheating on public goods, or (III) modulation of the network. Here, we test these scenarios by examining a set of 61 QS mutants from an experimental evolution study. We observed non-synonymous mutations in all three QS systems - Las, Rhl and PQS. Most Las mutants carried large deletions, resulting in loss of QS function, and the inability to produce QS-regulated traits (scenario I or II). Conversely, phenotypic and gene expression analyses of Rhl mutants support network modulation (scenario III), as these mutants overexpressed the Las and Rhl regulators and showed an altered QS-regulated trait production portfolio. PQS mutants also showed patterns of network modulation (scenario III), spurring strain diversification and phenotypic trade-offs, where the upregulation of certain QS traits is associated with the downregulation of others. Overall, our results indicate that mutations in different QS systems lead to diverging effects on the social portfolio of bacterial populations. These mutations might not only affect the plasticity and diversity of evolved populations but could also impact bacterial fitness and virulence in infections. ImportancePseudomonas aeruginosa uses quorum sensing (QS), a three-unit multi-layered network, to coordinate expression of traits for growth and virulence in the context of infections. Despite its importance for bacterial fitness, the QS regulon appears to be a common mutational target during long-term adaptation of P. aeruginosa in the host, natural environments and experimental evolutions. This raises the questions why such an important regulatory system is under selection and how mutations change the portfolio of QS-regulated traits. Here, we examine a set of 61 naturally evolved mutants to address these questions. We found that mutations involving the master regulator, LasR, resulted in an almost complete breakdown of QS, while mutations in RhlR and PqsR resulted in modulations of the QS regulon, where both the QS regulon structure and the QS-regulated trait portfolio changed. Our work reveals that natural selection drives diversification in QS activity patterns in evolving populations.

microbiology↗

bioRxiv2021

Revealing the secrets beneath grapevine and Plasmopara viticola early communication: a picture of host and pathogen proteomes

Plant apoplast is the first hub of plant-pathogen communication where pathogen effectors are recognized by plant defensive proteins and cell receptors and several signal transduction pathways are activated. As a result of this first contact, the host triggers a defence response that involves the modulation of several extra and intracellular proteins. In grapevine-pathogen interactions, little is known about the communication between cells and apoplast. Also, the role of apoplastic proteins in response to pathogens still remains a blackbox. In this study we focused on the first 6 hours after Plasmopara viticola inoculation to evaluate grapevine proteome modulation in the apoplastic fluid (APF) and whole leaf tissue. Plasmopara viticola proteome was also assessed enabling a deeper understanding of plant and pathogen communication. Our results showed that oomycete recognition, plant cell wall modifications, ROS signalling and disruption of oomycete structures are triggered in Regent after P. viticola inoculation. Our results highlight a strict relation between the apoplastic pathways modulated and the proteins identified in the whole leaf proteome. On the other hand, P. viticola proteins related to growth/morphogenesis and virulence mechanisms were the most predominant. This pioneer study highlights the early dynamics of extra and intracellular communication in grapevine defence activation that leads to the successful establishment of an incompatible interaction.

plant biology↗

bioRxiv2021

Monoclonal antibodies against cell wall chitooligomers as accessory tools for the control of cryptococcosis

Therapeutic strategies against systemic mycoses can involve antifungal resistance and significant toxicity. Thus, novel therapeutic approaches to fight fungal infections are urgent. Monoclonal antibodies (mAbs) are promising tools to fight systemic mycoses. In this study, mAbs of the IgM isotype were developed against chitin oligomers. Chitooligomers derive from chitin, an essential component of the fungal cell wall and a promising therapeutic target, as it is not synthesized by humans or animals. Surface plasmon resonance (SPR) assays and cell-binding tests showed that the mAbs recognizing chitooligomers have high affinity and specificity for the chitin derivatives. In vitro tests showed that the chitooligomer mAbs increased the fungicidal capacity of amphotericin B against Cryptococcus neoformans. The chitooligomer-binding mAbs interfered with two essential properties related to cryptococcal pathogenesis: biofilm formation and melanin production. In a murine model of C. neoformans infection, the combined administration of the chitooligomer-binding mAb and subinhibitory doses of amphotericin B promoted disease control. The data obtained in this study support the hypothesis that chitooligomer antibodies are of great potential as accessory tools in the control of cryptococcosis.

microbiology↗

bioRxiv2020

Endothelial cell invasiveness is controlled by myosin IIA-dependent inhibition of Arp2/3 activity

Sprouting angiogenesis is fundamental for development and contributes to multiple diseases, including cancer, diabetic retinopathy and cardiovascular diseases. Sprouting angiogenesis depends on the invasive properties of endothelial tip cells. However, there is very limited knowledge on the mechanisms that endothelial tip cells use to invade into tissues. Here, we prove that endothelial tip cells use long lamellipodia projections (LLPs) as the main cellular protrusion for invasion into non-vascular extracellular matrix. We show that LLPs and filopodia protrusions are balanced by myosin-IIA (MIIA) and actin-related protein 2/3 (Arp2/3) activity. Endothelial cell-autonomous ablation of MIIA promotes excessive LLPs formation in detriment of filopodia. Conversely, endothelial cell-autonomous ablation of Arp2/3 prevents LLPs development and leads to excessive filopodia formation. We further show that MIIA inhibits Rac1-dependent activation of Arp2/3, by regulating the maturation state of focal adhesions. Our discoveries establish the first comprehensive model of how endothelial tip cells regulate its protrusive activity and will pave the way towards new strategies to block invasive tip cells during sprouting angiogenesis.

cell biology↗

bioRxiv2020

A fast genetically encoded fluorescent sensor for faithful in vivo acetylcholine detection in mice, fish, worms and flies

Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice and in vivo preparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals.

neuroscience↗

bioRxiv2018

Spider mites escape bacterial infection by avoiding contaminated food

To fight infection, arthropods rely on the deployment of an innate immune response but also upon physical/chemical barriers and avoidance behaviours. However, most studies focus on immunity, with other defensive mechanisms being relatively overlooked.\n\nWe have previously shown that the spider mite Tetranychus urticae does not mount an induced immune response towards systemic bacterial infections, entailing very high mortality rates. Therefore, we hypothesized that other defence mechanisms may be operating to minimize infection risk. Here, we test (a) if spider mites are also highly susceptible to other infection routes - spraying and feeding - and (b) if they display avoidance behaviours towards infected food. Individuals sprayed with or fed on Escherichia coli or Pseudomonas putida survived less than the control, pointing to a deficient capacity of the gut epithelium, and possibly of the cuticle, to contain bacteria. Additionally, we found that spider mites prefer uninfected food to food contaminated with bacteria, a choice that probably does not rely on olfactory cues.\n\nOur results suggest that spider mites may rely mostly on avoidance behaviours to minimize bacterial infection and highlight the multi-layered nature of immune strategies present in arthropods.

ecology↗