Biology subjects

Xavier, J.

Publications and source records attributed to Xavier, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Restoration of E-cadherin Expression Alters Metastatic Organotropism in Invasive Lobular Breast Carcinoma Models

Invasive lobular carcinoma (ILC) is the most frequently diagnosed special histological subtype of invasive breast cancer and accounts for 10 - 15% of all cases. The pathognomonic hallmark of ILC is the genetic loss of E-cadherin (CDH1) causing the disruption of adherens junctions and resulting in discohesive, linear growth. To better understand the role of E-cadherin in ILC metastasis, we generated three ILC cell lines, MDA-MB-134-VI, SUM44PE, and BCK4, with inducible E-cadherin expression, resulting in successful restoration of functional adherens junctions. E-cadherin expression reduced growth in 2D culture, and that effect was even greater in 3D ultra-low attachment (ULA) conditions where increased cell death was consistent with the previously described role of E-cadherin in anoikis. E-cadherin expression did not rescue the lack of migration and invasion of ILC cell line models; however, it decreased haptotaxis and increased adherence to Collagen I in SUM44 cells. There was no significant effect of E-cadherin expression on primary orthotopic tumor growth, but spontaneous metastasis to the reproductive tract, brain, and GI tract was reduced. Inhibition of metastasis to the reproductive tract and brain was also seen after tail vein injection of MDA-MB-134 E-cadherin-expressing cells. In summary, overexpression of functional E-cadherin in ILC models has some, but limited, effects on 2D growth in vitro and primary tumor growth in vivo, but there are pronounced effects on 3D ULA growth and metastases in vivo, with stronger effects on metastatic sites enriched in patients with ILC, especially the reproductive and GI tracts.

cancer biology↗

bioRxiv2026

A Cherry-Flavoured E-Cigarette Adduct, BPGA, Reprograms Alveolar Epithelial Cell Fate Through Epithelial-to-Mesenchymal Transition and Evasion of Apoptosis

E-cigarettes have attracted significant attention as a safer substitute for conventional tobacco smoking. However, they have introduced new inhalable toxicants, including benzaldehyde-propylene glycol acetal (BPGA)--a chemical adduct produced by cherry-flavoured e-cigarettes. The health risks associated with such flavour-derived acetals remain insufficiently elucidated at the cellular level. This study investigated the role of BPGA in the progression of epithelial-to-mesenchymal transition (EMT)-like changes in alveolar epithelial cells (A549 cells). A549 cells exposed to various concentrations of BPGA were analysed for cell viability, morphology, mitochondrial function, lysosomal health, and cytoskeletal integrity using viability assays and fluorescence imaging. Intracellular reactive oxygen species (ROS) production was quantified using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Antioxidant enzyme expression, inflammatory responses, and EMT-associated phenotypic alterations were evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence (IF) assays. Exposure of alveolar epithelial cells to BPGA caused a concentration-dependent decrease in cell viability. BPGA exposure resulted in mitochondrial membrane depolarisation, lysosomal damage, cytoskeletal changes, and stress fibre formation, which altered cell morphology. It significantly increased intracellular ROS production. As a result, antioxidant enzyme levels were upregulated as a protective response. However, during severe oxidative stress, this response was overwhelmed. Excess ROS disrupted cellular homeostasis and initiated apoptosis, though not completely. ROS also acted as a signalling molecule, promoting the upregulation of inflammatory mediators. These changes were associated with altered EMT marker expression, suggesting that BPGA might drive EMT-like remodelling. In conclusion, BPGA, a chemical adduct from e-cigarette vapour, induces alveolar injury by promoting oxidative stress, inflammation, and EMT-related changes, which may explain a mechanism by which e-cigarette exposure could lead to lung injury and pulmonary fibrosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/724520v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@2e9797org.highwire.dtl.DTLVardef@e2543eorg.highwire.dtl.DTLVardef@108bb1aorg.highwire.dtl.DTLVardef@33e710_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

pharmacology and toxicology↗

bioRxiv2026

Metabiosis underlies a microbiota permissive to Pseudomonadota and increases the risk of gut-borne bloodstream infection

The gut microbiota contains trillions of bacteria essential to health, but also harbors potential pathogens. The phylum Pseudomonadota, which includes Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, typically composes <1% of the microbiota but causes disproportionate numbers of gut-borne bloodstream infections. Identifying the ecological dependencies that enable Pseudomonadota to cause gut-borne disease is important for human health. Here, we studied microbiota dynamics in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) to find that microbiota compositions permissive to Pseudomonadota had, following antibiotic prophylaxis, high levels of Bacteroides--a major reservoir of polysaccharide utilization loci (PULs). We tested the causality of this clinical association in a mouse co-colonization model and discovered that Bacteroides fragilis promotes Pseudomonas gut colonization and survival to ciprofloxacin, a drug commonly used as prophylactic in allo-HCT. In vitro experiments revealed a general mechanism by which diverse Pseudomonadota species depend on Bacteroides polysaccharide breakdown to grow better, form more biofilm, and survive ciprofloxacin treatment under anaerobic conditions, a type of ecological dependency termed metabiosis. Guided by this insight, we used metagenomics to identify the PUL-encoded functions underlying the metabiotic potential of a patients microbiota and establish a link to gut-derived Gram-negative bacteremia in allo-HCT. Together, our findings translate mechanistically based microbiome ecology into a clinically actionable framework for early risk stratification and intervention.

microbiology↗

bioRxiv2026

A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8+ T cell antitumor immunity

Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8 T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8 T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response. SignificanceTDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8 T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.

cancer biology↗

bioRxiv2025

Perturbation-Aware Neural ODE (pNODE) Learns Microbiome Dynamics from Clinical Data and Predicts Gut-Borne Bloodstream Infections in Patients Receiving Cancer Treatment

Disruption of the gut microbiota during cancer treatment, particularly in allogeneic hematopoietic cell transplantation (allo-HCT), contributes to adverse clinical outcomes, including gut-borne bloodstream infections. Accurately forecasting microbial population dynamics under clinical perturbations, such as antibiotic administration, could inform treatment strategies to reduce infection risk. However, traditional models like the Generalized Lotka-Volterra (gLV), which consider only pairwise interactions with constant sign and magnitude, are limited in capturing the real-world nonlinear dynamics of multispecies microbiomes following ecosystem disturbances. Here, we introduce a perturbation-augmented Neural Ordinary Differential Equation (pNODE) framework that flexibly models microbial population dynamics in continuous time, integrating both microbial abundances and time-resolved antibiotic perturbations. Using synthetic and real clinical data from over 1,000 allo-HCT patients, we show that pNODEs outperform gLV in predictive accuracy, robustness to noise, and forecasting critical events, such as the intestinal expansion of an opportunistic pathogen. Notably, we demonstrate that running a pre-trained pNODE in generative mode to simulate prospective Enterococcus abundance trajectories from an initial sample and antibiotic timeline yields scores that accurately predict subsequent bloodstream infections in held-out cohorts, outperforming baseline and ground-truth-based predictors. Our findings demonstrate the potential of pNODEs as a next-generation tool for modeling clinical microbiome dynamics, with applications for predicting infections in immunocompromised patients hospitalized for cancer treatment.

bioinformatics↗

bioRxiv2025

Airway smooth muscle--on-a-chip: a microfluidic approach to study alveolar smooth muscle remodelling

Respiratory illnesses, like chronic obstructive pulmonary disease (COPD) and asthma, pose significant global health challenges due to their chronic nature and limited treatment options. Airway smooth muscle (ASM) plays a vital role in respiratory diseases, particularly in airway remodelling and obstruction. ASM, which encircles the bronchial tree and extends to the trachea, plays a vital yet not fully understood role in lung physiology. However, its dysfunction is strongly associated with asthma and COPD progression, leading to excessive contraction, increased inflammatory mediator release, and ASM hypertrophy. However, identifying its precise function is challenging due to limitations in existing research models for assessing ASM contraction. In vivo models offer a comprehensive physiological perspective but possess ethical concerns and they do not allow for the direct measurement of ASM contraction. Meanwhile, ex vivo and in vitro models provide a more direct assessment; however, they lack crucial physiological factors. Understanding how ASM cells interact with their surroundings is essential for gaining deeper insights into respiratory disorders. To address this gap, we aimed to mimic the human airway smooth muscle-on-a-chip model, incorporating ASM cells in a 3D microenvironment. This microfluidic platform provides a physiologically relevant environment, allowing for studying complex mechanisms that drive airway remodelling and dysfunction in respiratory diseases. The ASM-on-a-chip is designed for long-term 3D cell culture of ASM cells that reorient itself to form a smooth muscle fibre. The design provides side channels for manipulating the constituent of the hydrogel to study the effect of compounds on AMS remodelling.

bioengineering↗

bioRxiv2025

A rapidly prototyped, simple yet versatile dynamic breathing Exposure-on-a-Chip for investigating nanoparticle deposition in the alveoli

We developed and characterized a three-layer microfluidic Exposure-on-a-Chip (EOC) model to replicate the alveolar microenvironment and simulate breathing motions, offering a physiologically relevant platform for studying inhaled nanomedicines. The EOC chip, fabricated from biocompatible polydimethylsiloxane (PDMS), features a fluidic chamber for cell culture, a pneumatic chamber for pressure application, and a thin PDMS membrane (150 {micro}m) separating the chambers to support cell growth and enable mechanical stretching. Xurography and 3D printing were validated as efficient and reproducible fabrication methods. Mechanical characterization, using fluorescent bead tracing, confirmed that the PDMS membrane accurately mimics alveolar breathing motions under physiological conditions (1-8% strain). Biological validation showed that alveolar epithelial and endothelial cells cultured on the EOC formed functional monolayers, maintaining barrier integrity under cyclic and static stretching, separately. To study nanoparticle behavior, we examined the deposition of nanoparticles under dynamic stretching versus static conditions. Significantly fewer nanoparticles accumulated in cells under continuous dynamic exposure with stretching compared to static culture, highlighting the critical role of mechanical forces in nanoparticle-cell interactions. The EOC platform provides a robust and scalable tool for evaluating nanomedicine efficacy in dynamic environments, representing a significant advancement in alveolus-on-chip technology.

bioengineering↗

bioRxiv2024

Hope for Others: Research Results from the University of Pittsburgh Rapid Autopsy Program for Breast Cancer

Breast cancer affects 1/8 of women throughout their lifetimes, with over 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research. Here, we describe our protocol and processes for establishing and improving the US-based Hope for OTHERS (Our Tissue Helping Enhance Research and Science) program for organ donation in metastatic breast cancer. As of August 2024, we consented 114 patients and performed 37 autopsies, from which we collected 551 unique metastatic frozen tumor samples, 1244 FFPE blocks, 90 longitudinal liquid biopsy samples and developed 14 patient-derived organoid and 8 patient-derived xenograft models. We report in-depth clinical and histopathological information and discuss extensive new research and novel findings in patient outcomes, metastatic phylogeny, and factors in successful living model development. Our results reveal key logistical and protocol improvements that are uniquely beneficial to certain programs based on identifiable features, such as working closely with patient advocates, methods to rescue RNA quality in cases where tissue quality may degrade due to time delays, as well as guidelines and future expansions of our program. Statement of SignificanceRapid autopsy programs are unique research settings with huge potential for studying metastatic cancer, however, they have complex research challenges. Our work provides a valuable resource in advancing this field of research.

cancer biology↗

bioRxiv2024

Developmental and transcriptomic responses of Hawaiian bobtail squid early stages to ocean warming and acidification

1Cephalopods play a central ecological role across all oceans and realms. However, under the current climate crisis, their physiology and behaviour are impacted, and we are beginning to comprehend the effects of environmental stressors at a molecular level. Here, we study the Hawaiian bobtail squid (Euprymna scolopes), known for its specific binary symbiosis with the bioluminescent bacterium Vibrio fischeri acquired post-hatching. We aim to understand the response (i.e., developmental and molecular) of E. scolopes after the embryogenetic exposure to different conditions: i) standard conditions (control), ii) increased CO2 ({Delta}pH 0.4 units), iii) warming (+3{o}C), or iv) a combination of the two treatments. We observed a decrease in hatching success across all treatments relative to the control. Using transcriptomics, we identified a potential trade-off in favour of metabolism and energy production, at the expense of development under increased CO2. In contrast, elevated temperature shortened the developmental time and, at a molecular level, showed signs of alternative splicing and the potential for RNA editing. The data also suggest that the initiation of the symbiosis may be negatively affected by these environmental drivers of change in the biosphere, although coping mechanisms by the animal may occur.

ecology↗

bioRxiv2024

TGF-β induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis

The heterogeneity of epithelial-to-mesenchymal transition (EMT) programs is manifest in the diverse EMT-like phenotypes occurring during tumor progression. However, little is known about the mechanistic basis and functional role of specific forms of EMT in cancer. Here we address this question in lung adenocarcinoma (LUAD) cells that enter a dormancy period in response to TGF-{beta} upon disseminating to distant sites. LUAD cells with the capacity to enter dormancy are characterized by expression of SOX2 and NKX2-1 primitive progenitor markers. In these cells, TGF-{beta} induces growth inhibition accompanied by a full EMT response that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGF-{beta} induces this transition by driving the expression of the actin-depolymerizing factor gelsolin, which changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors, protecting them from killing by mechanosensitive cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Inhibiting this actin depolymerization process clears tissues of dormant metastatic cells. Thus, LUAD primitive progenitors undergo an atypical EMT as part of a strategy to evade immune-mediated elimination during dormancy. Our results provide a mechanistic basis and functional role of this atypical EMT response of LUAD metastatic progenitors and further illuminate the role of TGF-{beta} as a crucial driver of immune evasive metastatic dormancy.

cancer biology↗

bioRxiv2023

Self-generating autocatalytic networks: structural results, algorithms, and their relevance to evolutionary processes

The concept of an autocatalytic network of reactions that can form and persist, starting from just an available food source, has been formalised by the notion of a Reflexively-Autocatalytic and Food generated (RAF) set. The theory and algorithmic results concerning RAFs have been applied to a range of settings, from metabolic questions arising at the origin of life, to ecological networks, and cognitive models in cultural evolution. In this paper, we present new structural and algorithmic results concerning RAF sets, by studying more complex modes of catalysis that allow certain reactions to require multiple catalysts (or to not require catalysis at all), and discuss the differing ways catalysis has been viewed in the literature. We then focus on the structure and analysis of minimal RAFs, and derive structural results and polynomial-time algorithms, with applications to metabolic network data described briefly.

evolutionary biology↗

bioRxiv2023

Machine learning of cellular metabolic rewiring

Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here, we introduce MetaboLiteLearner, a machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry (GC/MS) to predict abundance changes in metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. The model learned captures shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting potential organ-tailored cellular adaptations. Integrating machine learning and metabolomics paves the way for new insights into complex cellular adaptations. SignificanceMetabolic rewiring--the cellular adaptation to shifts in environment and nutrients--plays key roles in many contexts, including cancer metastasis. Traditional metabolomics often falls short of capturing the nuances of these metabolic shifts. This work introduces MetaboLiteLearner, a machine learning approach that harnesses the rich fragmentation patterns from electron ionization collected in scan mode during gas chromatography/mass spectrometry, paving the way for new insights into metabolic adaptations. Demonstrating its robustness on a breast cancer model, we highlight MetaboLiteLearners potential to reshape our understanding of metabolic rewiring, with implications in diagnostics, therapeutics, and basic cell biology.

bioinformatics↗

bioRxiv2022

Relative enrichment of oral bacteria in feces indicates loss of intestinal commensals with implications for host health

The increased relative abundance of oral bacteria detected in fecal samples has been associated with intestinal diseases and digestive disorders. This observation raises two competing hypotheses: either oral bacteria invade the gut bacterial population and expand in the intestine (the Expansion hypothesis), or oral bacteria transit through and their relative increase in feces marks a depletion of the gut bacterial population (the Marker hypothesis). To address this, we conducted a comprehensive analysis of quantitative microbiome data from mouse experiments and diverse patient cohorts. Our findings consistently support the Marker hypothesis as the primary explanation. We further establish a robust inverse correlation between the total fraction of oral bacteria and decreased total bacterial abundance in feces. This correlation underlies the associations between the oral bacterial fraction and multiple patient outcomes consistent with a depleted gut microbiota. By distinguishing between the two hypotheses, our study guides the interpretation of microbiome compositional data and their links with human health.

microbiology↗

bioRxiv2022

Low polyethylene glycol (PEG) concentration contributes to photoprotection in Chlamydomonas reinhardtii under highlight stress.

The highlight is one of the major problems encountered by all the autotrophs in the natural environment, as it affects the photosynthetic performance of these organisms, they were equipped themself with the diverse photoprotective mechanism. However, the drastic climate change in recent years had a more lethal effect on these organisms as it is beyond their threshold to withstand. In the past decade, scientists have unravelled many photoprotective mechanisms like qE, qZ, qT and qI (NPQ) used by autotrophs to combat highlight stress and the thirst for discovering such a new mechanism remains constant. In this regard, we studied the effect of mild osmotic stress (2%PEG) in alleviating high-light stress using Chlamydomonas (C) reinhardtii as a model system. The cells were grown in low Polyethylene glycol (PEG)-induced osmotic stress at varying light intensities; their response to these treatments had been examined via biochemical and biophysical approaches. The PEG-treated cells showed better growth and photosynthetic efficiency even at highlight than control, but their NPQ level is lesser than control, suggesting a unique or novel photoprotective mechanism is operating in PEG-treated samples. The Circular dichroism and ATG8 localization assay suggest that supercomplexes organization is not much disturbed in PEG-treated samples irrespective of light intensity. Also, the latter indicates that PEG-treated cells were healthier than the control at the highlight. This result is promising as we can improve the algal biomass under natural environmental conditions with fluctuating light intensity. As algal biomass has immense commercial importance in biofuel production, cosmetics and pharmaceutical application. This mechanism can be exploited to promote the socio-economic status of our nation. HighlightsO_LIPEG application triggers ROS accumulations, stimulating signalling cascade and overcoming highlight-induced compromise in biomass. C_LIO_LIUnder highlight, the photosynthetic pigment (chlorophyll and carotenoid) constantly increased with PEG except for C-250. Specifically, the photoprotective pigment like violaxanthin and lutein has been increased. C_LIO_LIPEG shielding stabilizes pigment-protein interaction, confirming that the supercomplex organization is in its native state. C_LIO_LIPEG keeps low ATG8 accumulation, preventing cells and enabling it to combat highlights more effectively. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/505872v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1bef077org.highwire.dtl.DTLVardef@9d45bcorg.highwire.dtl.DTLVardef@14d7366org.highwire.dtl.DTLVardef@1d3617f_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2021

A compilation of fecal microbiome shotgun metagenomics from hospitalized patients undergoing hematopoietic cell transplantation

Hospitalized patients receiving hematopoietic cell transplants provide a unique opportunity to study how the human gut microbiome changes in response to perturbations, and how the resulting changes in the microbiome feedback on its living host. We previously compiled a large-scale longitudinal dataset of stool microbiome compositions from these patients and associated metadata1. In that dataset the microbiome analysis was limited to the taxonomic composition of the bacterial population obtained from 16S rRNA gene sequencing. Here, we augment those data with shotgun metagenomic sequences from a nested subset of 395 stool samples. We provide accession numbers that link each sample to the paired-end sequencing files deposited in a public repository, which can be directly accessed by the online services of PATRIC2 to be analyzed without the users having to download or transfer the files. We provide examples that show how shotgun sequencing enriches microbiome analyses beyond the taxonomic composition such as the analysis of gene functions including virulence factors and antibiotic resistances, and the assembly of genomes from metagenomic data.

systems biology↗

bioRxiv2021

Ecological dynamics of the gut microbiome in response to dietary fiber

Dietary fibers are generally thought to benefit intestinal health. Their impacts on the composition and metabolic function of the gut microbiome, however, vary greatly across individuals. Previous research showed that each individuals response to fibers depends on their baseline gut microbiome, but the ecology driving microbiota remodeling during fiber intake remained unclear. Here, we studied the long-term dynamics of gut microbiome and short-chain fatty acids (SCFAs) in isogenic mice with distinct microbiota baselines fed with the fermentable fiber inulin compared to the non-fermentable fiber cellulose. We found that inulin produced generally rapid response followed by gradual stabilization to new equilibria, and those dynamics were baseline-dependent. We parameterized an ecology model from the timeseries data, which revealed a group of bacteria whose growth significantly increases in response to inulin. and whose baseline abundance and interspecies competition explains the baseline-dependence of microbiome density and community composition dynamics. Fecal levels of of SCFAs, such as propionate, is associated with the abundance of inulin responders, yet inter-individual variation of gut microbiome impedes the prediction of SCFAs by machine learning models. Finally, we showed that our methods and major findings are generalizable to dietary resistant starch. This study emphasizes the importance of ecological modeling to understand microbiome responses to dietary changes and the need for personalized interventions.

ecology↗

bioRxiv2021

Chikungunya virus ECSA lineage reintroduction in the northeasternmost region of Brazil

The Northeast region of Brazil registered the second highest incidence proportion of chikungunya fever in 2019. In that year an outbreak consisting of patients presented with febrile disease associated with joint pain were reported by the public primary health care service in the city of Natal, Rio Grande do Norte state, in March 2019. At first, the aetiological agent of the disease was undetermined. Since much is still unknown about chikungunya virus (CHIKV) genomic diversity and evolutionary history in this northeasternmost state, we used a combination of portable whole genome sequencing, molecular clock, and epidemiological analyses that revealed the re-introduction of the CHIKV East-Central-South-African (ECSA) lineage into Rio Grande do Norte. We estimated CHIKV ECSA lineage was first introduced into Rio Grande do Norte in early June 2014, while the 2019 outbreak clade diverged around April 2018 during a period of increased chikungunya incidence in the Southeast region, which might have acted as a source of virus dispersion towards the Northeast region. Together, these results confirm the ECSA lineage continues to spread across the country through interregional importation events likely mediated by human mobility. HIGHLIGHTSCHIKV ECSA lineage introduction into Rio Grande do Norte state, Northeast Brazil, was estimated to early June 2014 At least two CHIKV importation events occurred in Rio Grande do Norte state, Brazil The 2019 chikungunya outbreak in Rio Grande do Norte was likely caused by a second event of CHIKV introduction imported from Rio de Janeiro state.

genomics↗

bioRxiv2020

Metabolic homeostasis controls the diversity of cooperative swarming in pathogenic bacteria

Microbes have disproportionate impacts on the macroscopic world. This is in part due to their ability to grow to large groups and cooperatively secrete massive amounts of secondary metabolites that impact their environment. Yet, the conditions enabling secondary metabolism without compromising primary needs remain unclear. Here we investigated the biosynthesis of rhamnolipids, a secondary metabolite that Pseudomonas aeruginosa makes to decrease the surface tension of surrounding liquid. Using a combination of genomics, metabolomics, transcriptomics, and mathematical modeling we show that biosynthesis of rhamnolipids from glycerol varies inconsistently across the phylogenetic tree; instead, non-producer lineages are also those worse at reducing the oxidative stress of primary glycerol metabolism. The link to oxidative stress explains the inconsistent distribution across the P. aeruginosa tree, adding a new layer to the regulation of rhamnolipids--a microbial secondary metabolite important for fitness in natural and clinical settings. SignificanceThe bacterium Pseudomonas aeruginosa is a major source of hospital-acquired infections. This pathogens knack for virulence relies on its ability to multiply and secrete massive amounts of substances that overwhelm microbial competitors and weaken host defenses. It remains unclear how the bacteria conciliate their need to grow and multiply--a need at the individual-level-- with their ability to secrete products--a need of the population. Here we combined genomics, metabolomics and mathematical modeling to study the biosynthesis of rhamnolipids, a surfactant that P. aeruginosa makes to reduce the surface tension of surrounding liquids. Our study reveals a new link between oxidative stress and rhamnolipid synthesis, which helps explain how this important bacterial product has evolved and how it persists in many lineages of pathogens.

systems biology↗