Biology subjects

Martins, R.

Publications and source records attributed to Martins, R..

16 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↗

bioRxiv2025

Artificial intelligence-augmented drug discovery identifies gefitinib as a potential treatment for ALS

Amyotrophic lateral sclerosis (ALS) is characterised by motor neuron (MN) death; however, astrocytes play a key role in disease pathogenesis. Developments in the field of artificial intelligence (AI) have the potential to impact drug discovery in multiple ways, including the rapid identification of drug repurposing candidates. A combination of natural language processing and deep learning algorithms was used to generate a knowledge graph based on scientific literature, omics and chemical databases, and other public sources with the aim to identify drug repurposing candidates for ALS. The aim of the study was to determine the effect of a cancer compound identified by AI, gefitinib, on MN survival, and to decipher its mode of action inin vitroandin vivomodels of ALS. We used co-cultures of healthy motor neurons with ALS patient-derived astrocytes (iAstrocytes), obtained through a semi-direct conversion protocol, to assess the neuroprotective properties of gefitinib. Compound treatment led to a significant rescue of MNs cultured with ALS iAstrocytes and a significant reduction in the levels of cleaved TDP-43 fragments in ALS iAstrocytes. Our data suggest that gefitinib-mediated activation of autophagy decreased the 35 kDa fragments of TDP-43. In a proof-of-conceptin vivostudy in SOD1G93Amice, gefitinib treatment significantly delayed the onset of neurological symptoms, thus showing the potential of AI-augmented drug discovery for neurodegenerative disorders.Significance StatementThis study presents an AI-augmented method of identifying potential repurposing candidates for disease with an unprecedented speed. The AI’s results were validatedin vitrousing iAstrocytes differentiated from induced neuronal progenitor cells (iNPCs), which are pathophysiologically relevant models suitable for studying neurodegeneration. iNPCs recapitulate many pathological hallmarks of the disease and they retain the ageing phenotype of the patient that they are obtained from. TDP-43 proteinopathy is one of the disease hallmarks observed in patients and is present in 97% of ALS patients. Here, we show gefitinib, a repurposing candidate identified by AI, improves survival of MNs in a co-culture with patient-derived astrocytes and can modulate TDP-43 proteinopathy.

neuroscience↗

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↗

bioRxiv2025

Linking Transcriptional and Cellular Responses of Human and Murine Pneumococcal Pneumonia

Community-acquired pneumonia (CAP), often caused by Streptococcus pneumoniae, poses a significant global health challenge, especially among high-risk populations. This study investigates the temporal dynamics of pulmonary gene expression during S. pneumoniae-induced pneumonia using a murine model to elucidate host-pathogen interactions and identify potential biomarkers of disease severity. Using bulk RNA sequencing, we analyzed lung tissues at early (1h, 8h) and acute infection (2d, 3d), as well as post-resolution (30d) time-points. At 2 days post-infection, differentially expressed genes (DEGs) revealed heightened innate immune responses, including chemokine and interferon signaling pathways. By 30 days post-infection, gene expression profiles and histological changes normalized, reflecting resolution of inflammation. Stratifying mice into recovered, sick, and moribund phenotypes during the acute infection phase highlighted significant transcriptional distinctions, including upregulated pro-inflammatory genes and Schlafen family members. Arginase 1 emerged as a predictive marker of disease severity, with elevated expression detectable as early as 8 hours post-infection. Comparative analyses revealed significant overlap between transcriptional responses in our model and those from a Gram-negative Acinetobacter baumannii pneumonia model, implicating conserved pathways, such as IL-17 and Toll-like receptor signaling. Additionally, murine DEGs correlated with human plasma proteins associated with severe CAP, including CCL8 and CD14, suggesting translational relevance. This study underscores phase-specific transcriptional reprogramming during pneumococcal pneumonia and identifies potential biomarkers and therapeutic targets for improving outcomes in severe CAP cases.

microbiology↗

bioRxiv2023

Patterned Metal Grids for Flexible and Transparent Neural Microelectrode Arrays

Flexible and transparent microelectrodes can provide large-scale neural recordings with temporal and spatial resolution when used alongside functional calcium imaging. Patterned metal grids defined by direct laser writing (DWL) are a promising approach for these electrodes, as they resort to standard microfabrication processes and materials, allowing the possibility of mass production. For these reasons, a study exploring transparent grid-based electrodes using DWL for measuring electrocorticography signal was performed. Patterned metal grids with 1 m of linewidth and 22 m of spacing between lines showed a sheet resistance of 6 {Omega}/sq and a transmittance of 81% at 550 nm. The grids were transferred to a 5 m Parylene-C membrane using an optimized procedure that involves an oxygen plasma pre-treatment. This procedure ensures mechanical robustness and stability of the grids. Finally, a flexible and transparent prototype was fabricated with a microelectrode array composed by 16 electrodes with 500 m of diameter. These microelectrodes shown an impedance of 10 k{Omega} at 1 kHz in saline solution and they are highly conformal facilitating in vivo implantation and the recording of neural activity in the mouse cerebellum surface. To conclude, patterned metal grids based-electrodes exhibit a promising performance compared to transparent conductive oxides or graphene. Moreover, the introduction of DLW enables easy and fast manipulation of grid shape and dimensions without the need of physical masks, while keeping large scale compatibility, which is important for tools used in neuroscience community.

neuroscience↗

bioRxiv2022

In Vitro Inhibition of SARS-CoV-2 Infection by Bromhexine hydrochloride

The world is enduring the SARS CoV-2 pandemic, and although extensive research has been conducted on the issue, only a few antivirals have been approved to treat patients with COVID-19. Bromhexine hydrochloride was previously identified as a potent inhibitor of TMPRSS2, an essential protease for ACE-2 virus receptor interactions. In the present study, we investigated whether bromhexine treatment could reduce SARS CoV-2 replication in vitro. To evaluate bromhexines effectiveness against SARS COV-2 infection, viral load was measured using Caco-2 cell lines expressing TMPRSS2. Our molecular docking results indicate that bromhexine displays an affinity with the active site of TMPRSS2. The drug significantly inhibited SARS CoV-2, both parental and P1 variant strains, infection in the Caco-2 cell line, reducing about 40% of SARS-CoV-2 entrance and about 90% of viral progeny in the supernatant 48h post-infection. Furthermore, bromhexine did not exhibit any direct virucidal activity on SARS CoV-2. In conclusion, bromhexine hydrochloride efficiently disrupts SARS CoV-2 infection in vitro and has the potential to become an effective antiviral agent in COVID-19 treatment.

pharmacology and toxicology↗

bioRxiv2022

Ultrasound treatment inhibits SARS-CoV-2 in vitro infectivity

The global spreading of SARS-CoV-2 and the emergence of new variants underscore the ongoing need to develop new vaccines and antiviral drugs. While electromagnetic and acoustic waves have well-known virucidal properties, their application in therapeutic settings has been limited due to harming effects in biological matter. Here, we investigates the potential of ultrasound to interfere with SARS-CoV-2. Specifically, we study the effects of acoustic waves in the 1-20 MHz frequency range to determine their impact on the viral envelope of SARS-CoV-2. Our in vitro experiments demonstrate ultrasound exhibits a virucidal effect on SARS-CoV-2 without production of heat or cavitation. This study offers a promising physics-based approach to combat SARS-CoV-2 and potentially other spherical viruses, broadening the scope of antiviral treatments.

biophysics↗

bioRxiv2022

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.

immunology↗

bioRxiv2022

Neuroimaging within the Dominantly Inherited Alzheimer's Network (DIAN): PET and MRI

The Dominantly Inherited Alzheimer Network (DIAN) Observational Study is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). This rare form of Alzheimer disease (AD) is caused by mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. As individuals from these families have a 50% chance of inheriting the familial mutation, this provides researchers with a well-matched cohort of carriers vs non-carriers for case-control studies. An important trait of ADAD is that the age at symptom onset is highly predictable and consistent for each specific mutation, allowing researchers to estimate an individuals point in their disease time course prior to symptom onset. Although ADAD represents only a small proportion (approximately 0.1%) of all AD cases, studying this form of AD allows researchers to investigate preclinical AD and the progression of changes that occur within the brain prior to AD symptom onset. Furthermore, the young age at symptom onset (typically 30-60 years) means age-related comorbidities are much less prevalent than in sporadic AD, thereby allowing AD pathophysiology to be studied independent of these confounds. A major goal of the DIAN Observational Study is to create a global resource for AD researchers. To that end, the current manuscript provides an overview of the DIAN magnetic resonance imaging (MRI) and positron emission tomography (PET) protocols and highlights the key imaging results of this study to date.

neuroscience↗

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

A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

immunology↗

bioRxiv2020

Transparent and flexible ECoG electrode arrays based on silver nanowire networks for neural recordings

This work explored hybrid films of silver nanowires (AgNWs) with indium-zinc oxide (IZO) for developing high-performance and low-cost electrocorticography (ECoG) electrodes. The transparent hybrid films achieved a sheet resistance of 6 {Omega}/sq enabling electrodes with 500 m diameter to reach an impedance of 20 k{Omega} at 1 kHz and a charge storage capacity of 3.2 mC/cm2, an improvement in properties over IZO electrodes, whose performance is on par with the classical tin doped indium oxide (ITO). Characterization of light-induced artifacts was performed showing that light intensities <14 mW/mm2 elicit minimal electrical potential variation, which falls within the magnitude of baseline noise. The validation of electrodes in vivo was achieved by recording electrical neural activity from the surface of rat cortex under anaesthesia. Moreover, the presence of the hybrid films did not cause distortion of light during fluorescence microscopy. This study highlighted the capabilities of the hybrid structure of AgNWs with IZO, that can be fabricated with industrially-established processes at low cost, to be used for transparent ECoG electrodes, offering a new way to record neural electrical activity on a large and fast scale with direct visualization of neurons.

neuroscience↗

bioRxiv2020

Natural infection with Giardia is associated with altered community structure of the human and canine gut microbiome.

Enteric parasitic infections are among the most prevalent infections in lower- and middle-income countries (LMICs), and have a profound impact on global public health. While the microbiome is increasingly recognized as a key determinant of gut health and human development, the impact of naturally-acquired parasite infections on microbial community structure in the gut, and the extent to which parasite-induced changes in the microbiome may contribute to gastrointestinal symptoms, is poorly understood. Enteric parasites are routinely identified in companion animals in the United States, presenting a unique opportunity to leverage this animal model to investigate the impact of naturally-acquired parasite infections on the microbiome. Clinical, parasitological, and microbiome profiling of a cohort of 258 dogs revealed a significant correlation between parasite infection and composition of the bacterial community in the gut. Relative to other enteric pathogens, Giardia was associated with a more pronounced perturbation of the microbiome. Using a database mining approach that allowed us to compare our findings to a large-scale epidemiological study of enteric diseases in humans, we also observed a substantial alteration to microbiome structure in Giardia-infected children. Importantly, infection was associated with a reduction in the relative abundance of potential pathobionts, including Gammaproteobacteria, and an increase in Prevotella - a profile often associated with gut health. Taken together, our data show that widespread Giardia infection in young animals and humans is associated with significant remodeling of the gut microbiome, and provide a possible explanation for the high prevalence of asymptomatic Giardia infections observed across host species. ImportanceWhile enteric parasitic infections are among the most important infections in lower- and middle-income countries, their impact on gut microbiota is poorly understood. We reasoned that clinical symptoms associated with these infections may be influenced by alterations of the microbiome that occur during infection. To explore this notion, we took a two-pronged approach. First, we studied a cohort of dogs naturally infected with various enteric parasites and found a strong association between parasite infection and altered gut microbiota composition. Giardia, one of the most prevalent parasite infections globally, had a particularly large impact on the microbiome. Second, we took a database-driven strategy to integrate microbiome data with clinical data from large human field studies and found that Giardia infection is also associated with marked alteration of the gut microbiome of children, suggesting a possible explanation for why Giardia has been reported to be associated with protection from moderate-to-severe diarrhea.

microbiology↗

bioRxiv2019

Heme induces innate immunity memory

Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in {beta}-glucan-training, the prototype agonist of trained immunity. In sharp contrast to {beta}-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice. In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection.

immunology↗

bioRxiv2019

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity of Gdf15-deficient mice protects against abdominal sepsis

Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth-differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15 and that Gdf15-deficient animals are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.

immunology↗