Biology subjects

Costa, S.

Publications and source records attributed to Costa, S..

11 recordsLinked to original sources

bioRxiv2025

COVID-19 induces persistent transcriptional changes in adipose tissue that are not associated with Long COVID

Long COVID is a heterogeneous condition characterized by a wide range of symptoms that persist for 90 days or more following SARS-CoV-2 infection. Now more than five years out from the onset of the SARS-CoV-2 pandemic, the mechanisms driving Long COVID are just beginning to be elucidated. Adipose tissue has been proposed as a potential reservoir for viral persistence and tissue dysfunction contributing to symptomology seen in Long COVID. To test this hypothesis, we analyzed subcutaneous adipose tissue (SAT) from two cohorts: participants with subacute COVID-19 (28-89 days post-infection) compared to pre-pandemic controls, and participants with Long COVID compared to those with those classified as "indeterminate" based on the RECOVER-Adult Long COVID Research Index (12-47 months post-infection). We found no evidence of persistent SARS-CoV-2 RNA in adipose tissue in any participant. SAT from participants with subacute COVID-19 displayed significant transcriptional remodeling, including depleted immune activation pathways and upregulated Hox genes and integrin interactions, suggesting resident immune cell exhaustion and perturbations in tissue function. However, no consistent changes in gene expression were observed between Long COVID samples and samples from indeterminant participants. Thus, SAT may contribute to inflammatory dysregulation following COVID-19, but does not appear to play a clear role in Long COVID pathophysiology. Further research is needed to clarify the role of adipose tissue in COVID-19 recovery.

immunology↗

bioRxiv2024

Beyond Kaftrio: mechanistic insights to maximize N1303K-CFTR rescue

IntroductionN1303K is the fourth most frequent Cystic Fibrosis (CF) causing mutation. People with CF (pwCF) clinical status can be improved by Elexacaftor(ELX)/Tezacaftor(TEZ)/Ivacaftor (ETI) combotherapy. We investigated the mechanism underlying N1303K-CFTR rescue. MethodsN1303K-CFTR expression and maturation was evaluated by Western Blot in cell lines and Human Nasal Epithelial Primary Cells (HNECs). Cell surface expression was studied by nanoluciferase complementation assay and TurboID proximity labeling. Functional rescue was tested in vitro by YFP-Based Assay and Short Circuit Current. ResultsCorrection by ELX/TEZ increases N1303K-CFTR amounts, but not its maturation in CFTR-expressing HEK and 16HBEge cell lines and in HNECs. In control conditions, N1303K-CFTR is more distributed at the cell surface and significantly more surface partners are identified in the N1303K-CFTR interactome as compared to F508del-CFTR in HEK cells. ELX/TEZ induces a global stabilization of N1303K-CFTR without favoring its plasma membrane relocation in contrast to F508del-CFTR which is redistributed to the membrane. ETI increases N1303K-CFTR activity in HNECs and can be increased by API co-potentiation with a predicted increase in Forced Expiratory Volume in 1 second (ppFEV1) by respectively 13(2)% and 18%(3). This is consistent with a gain in ppFEV1 reported in pwCF carrying the N1303K mutation and additional improvement by API in a patient. ConclusionThese results support the expansion of ETI approval to N1303K mutation but highlight different mechanisms of action than for F508del.

physiology↗

bioRxiv2023

A culture-based approach to study ecological interactions among the microbial species of the human scalp.

The human scalp hosts an unusually low diversity microbiota dominated by three species: Cutibacterium acnes, Staphylococcus epidermidis, and Malassezia restricta, where characteristic shifts in species frequencies are associated with seborrheic dermatitis and dandruff. In order to better understand this important community, here we study the ecological interactions between these scalp species. We establish a new experimental model system that supports the growth of all three species in vitro and allows one to selectively enumerate each species from co-culture. Our work reveals the potential for strong ecological interactions within the scalp community. In particular, C. acnes greatly benefits from the presence of M. restricta, but harms it in return (exploitation), while S. epidermidis suppresses both M. restricta and C. acnes. Our data suggest that the shifts in composition seen in compromised scalps are influenced by ecological interactions between species. We argue that the scalp microbiome should be viewed as an ecological system where species interactions have the potential to contribute to health outcomes. ImportanceOur bodies are home to diverse communities of microorganisms, our microbiome, which can be critical for health and wellbeing. The human scalp hosts a relatively simple community dominated by three species: two bacteria, Cutibacterium acnes and Staphylococcus epidermidis, and one fungus, Malassezia restricta. Both dandruff and seborrheic dermatitis are strongly associated with characteristic shifts in the frequencies of these three species. However, how these species affect one another and behave as a community remains poorly understood. Here, we develop a simple experimental system to empirically study how these three species interact and affect one another for the first time. We find that S. epidermidis greatly suppresses the growth of the other species, while C. acnes specifically exploits M. restricta. Our work suggests that the human scalp is an ecological system in which species interactions have the potential to affect health outcomes.

microbiology↗

bioRxiv2023

Microalgae as a novel biofactory for biocompatible and bioactive extracellular vesicles

Nanoalgosomes are extracellular vesicles (EVs) released by microalgal cells that can mediate intercellular and cross-kingdom communication. In the present study, starting from the optimized nanoalgosome manufacturing from cultures of marine microalgae, we evaluated their innate biological properties in preclinical models. Our investigation of nanoalgosome biocompatibility included toxicological analyses, starting from studies on the invertebrate model organism Caenorhabditis elegans, proceeding to hematological and immunological evaluations in mice and immune-compatibility ex vivo. Nanoalgosome biodistribution was evaluated in mice with accurate space-time resolution, and in C. elegans at cellular and subcellular levels. Further examination highlighted the antioxidant and anti-inflammatory bioactivities of nanoalgosomes. This holistic approach to nanoalgosome functional characterization showcases that nanoalgosomes are innate effectors and potential drug delivery system for novel cosmetic formulations and EV-based therapies.

cell biology↗

bioRxiv2022

Multiple mating rescues offspring sex ratio but not productivity in a haplodiploid exposed to developmental heat stress

O_LIReproduction is generally more sensitive to high temperatures than survival and arguably a better predictor of the response of populations to climate change than survival estimates. Still, how temperature simultaneously impacts male and female reproductive success, the mating system and the operational sex ratio remains an open question. C_LIO_LIHere, we addressed how a sublethal high temperature affects the reproductive system of the haplodiploid spider mite Tetranychus urticae. Males and females maintained at 25{degrees}C or 36{degrees}C during development were paired and the fertility of both sexes, their mating and remating eagerness, and the paternity of the offspring of females with different mating histories were measured. C_LIO_LIFemale and male fertility decreased at 36{degrees}C compared to 25{degrees}C, resulting in lower offspring production and a more male-biased sex ratio, respectively, because of haplodiploidy. However, when females remated, the pattern of first male sperm precedence typically seen in this species was disrupted, with more than one male contributing to the offspring. This was accompanied by reduced mating eagerness in pairs with partially sterile males and increased remating eagerness in pairs in which at least one sex was partially sterile in the first mating. C_LIO_LIThe observed temperature-induced changes in pre- and post-copulatory traits allowed restoring the offspring sex ratio but did not lead to the recovery of offspring number. C_LIO_LIOur results show that temperature induces changes in the spider mite mating behaviour and mating system, with potential impact on sexual selection and sexual conflict. However, such changes may not be sufficient to buffer the impact of extreme temperatures on their populations. C_LI

evolutionary biology↗

bioRxiv2020

In vivo genetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia

An enhanced requirement for extracellular nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy for evaluating dependencies in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a unique vulnerability in this disease. In accord with this transport function, we demonstrate that the SLC5A3 dependency reflects a myo-inositol auxotrophy in AML. Importantly, the commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myoinositol biosynthesis, inositol-3-phosphate synthase 1. We used gain- and loss-of-function experiments to demonstrate a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with the presence of IDH1/IDH2 and CEBPA mutations. Collectively, our findings reveal myo-inositol auxotrophy as a novel form of metabolic dysregulation in AML, which is caused by the aberrant silencing of a biosynthetic enzyme. Statement of significanceHere, we show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically-defined subset of AML.

cancer biology↗

bioRxiv2020

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses

Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Diverse tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from nine renal cell carcinoma patients. We used COSMOS to generate novel hypotheses such as the impact of Androgen Receptor on nucleoside metabolism and the influence of the JAK-STAT pathway on propionyl coenzyme A production. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/057893v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@37d2d7org.highwire.dtl.DTLVardef@f333d4org.highwire.dtl.DTLVardef@cfcac3org.highwire.dtl.DTLVardef@90318_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2020

Trpm8 modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons, and it is involved in the detection of cold temperatures. Increased TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are regulated by rodent housing temperature and brown adipose tissue, suggesting one mediator of this effect may be TRPM8. In order to test whether TRPM8 was involved in the co-regulation of thermogenesis and bone homeostasis, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) and then exposed them to a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Ucp1, Dio2 and Cidea at the end of the study. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but may be required for cold-induced changes in marrow adiposity in males. Furthermore, bone marrow adipose tissue accumulation in females was significantly blunted by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone density and marrow adipose tissue. Identifying mechanisms through which cold temperature and brown adipose tissue influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

physiology↗

bioRxiv2019

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

The I{kappa}B kinase {varepsilon} (IKK{varepsilon}) is a key molecule at the crossroads of inflammation and cancer. Known for its role as an activator of NF{kappa}B and IRF3 signalling leading to cytokine secretion, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKK{varepsilon} remodels cellular metabolism is currently unknown. Here we used a combination of metabolomics and phosphoproteomics to show that IKK{varepsilon} orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and serine biosynthesis. Acting independently of its canonical signalling role, IKK{varepsilon} upregulates the serine biosynthesis pathway (SBP) mainly by limiting glucose and pyruvate derived anaplerosis of the TCA cycle. In turn, this elicits activation of the transcription factor ATF4 and upregulation of the SBP genes. Importantly, pharmacological inhibition of the IKK{varepsilon}-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a set of basal ER negative and highly proliferative human breast cancer tumours, IKK{varepsilon} and PSAT1 expression levels are positively correlated corroborating the link between IKK{varepsilon} and the SBP in the clinical context.

cancer biology↗

bioRxiv2019

Mutational burden of hepatoblastomas: a role for the CX3CL1/CX3CR1 chemokine signaling pathway

BackgroundHepatoblastoma is an embryonal liver tumor supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. CTNNB1 is the only recurrently mutated gene, and this relative paucity of somatic mutations poses a challenge to risk stratification and development of targeted therapies. MethodsIn this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. ResultsOur data disclosed a low mutational background with only three recurrently mutated genes: CTNNB1 and two novel candidates, CX3CL1 and CEP164. The major finding was a recurrent mutation (A235G) identified in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed up-regulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas, with a predominance of these proteins in the cytoplasm of tumor cells. These proteins were not detected in the infiltrated lymphocytes of inflammatory regions of the tumors, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative tumor cells, but strongly positive infiltrated lymphocytes. Our data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, related only with tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. ConclusionsOverall, we present here evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with hepatoblastoma tumorigenesis or progression, besides reporting a novel mutational signature specific to a hepatoblastoma subset.

cancer biology↗

bioRxiv2018

Lack of correlation between number of neurons and behavioral performance in Swiss mice

Neuronal number varies by several orders of magnitude across species, and has been proposed to predict cognitive capability across species. Remarkably, numbers of neurons vary across individual mice by a factor of 2 or more. We directly addressed the question of whether there is a relationship between performance in behavioral tests and the number of neurons in functionally relevant structures in the mouse brain. Naive Swiss mice went through a battery of behavioral tasks designed to measure cognitive, motor and olfactory skills. We estimated the number of neurons in different brain regions (cerebral cortex, hippocampus, olfactory bulb, cerebellum and remaining areas) and crossed the two datasets to test the a priori hypothesis of correlation between cognitive abilities and numbers of neurons. As previous evidence indicates that environmental enrichment may increase neurogenesis and improve neuronal survival, we added a control group that did not undergo cognitive testing to rule out the possibility that our test battery could alter the neuronal number. We found that behavioral testing did not change numbers of neurons in the cerebral cortex and in the hippocampus. Surprisingly, performance in the behavioral tasks did not correlate strongly with number of neurons in any of the brain regions studied. Our results show that whereas neuronal number is a good predictor of cognitive skills across species, it is not a predictor of cognitive, sensory or motor ability across individuals within a species, which suggests that other factors are more relevant for explaining cognitive differences between individuals of the same species.

neuroscience↗