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- Dynamics and ecology of a multistage expansion of Oropouche virus in BrazilPublication . Tegally, Houriiyah; Dellicour, Simon; Poongavanan, Jenicca; Mavian, Carla; Dor, Graeme; Fonseca, Vagner; Tagliamonte, Massimiliano S.; Dunaiski, Marcel; Moir, Monika; Wilkinson, Eduan; Albuquerque, Carlos Frederico Campelo de; Frutuoso, Livia C. V.; Holmes, Edward C.; Baxter, Cheryl; Lessells, Richard; Kraemer, Moritz U. G.; Lourenco, José; Alcantara, Luiz Carlos Junior; Oliveira, Tulio de; Giovanetti, MartaIn March 2024, Brazil reported an unprecedented Oropouche fever outbreak, driven by the emergence of a reassortant lineage of the Oropouche virus (OROV) expanding beyond the Amazon Basin. To investigate the expansion dynamics of OROV, we implemented complementary phylogeographic and ecological niche modelling approaches that aimed to characterize the environmental factors associated with the range expansion and the risk of local circulation, respectively. Our analyses reveal a multiscale expansion process with both shortand long-distance dispersal events and diffusion velocities in line with air traffic-mediated jumps. We identify banana and cocoa cultivation, temperature, the predicted suitability of the primary vector Culicoides paraensis and human population density as key environmental factors associated with OROV range expansion in new areas. We further show that OROV circulated in areas of enhanced ecological suitability immediately preceding its explosive epidemic expansion in the Amazon. Our study provides valuable insights into the dispersal and ecological dynamics of OROV, highlighting the probable role of human mobility in the long-distance colonization of new areas and raising concern over high viral suitability along the Brazilian coast.
- The emerging role of chemokines and chemokine receptors in the biological and clinical behaviour of pituitary neuroendocrine tumours: an exploratory transcriptomic studyPublication . Silva, Ana Luísa; Barry, Sayka; Hipólito, Ana; Severino, Mariana de Griné; Joaquim, Rita; Hall, Charlotte; Oliveira, Tiago; López-Presa, Dolores; Borrecho, Gonçalo; Tortosa, Francisco; Nobre, Ema; Faria, Claudia C.; Korbonits, Márta; Marques, PedroThe chemokine network in the microenvironment of pituitary neuroendocrine tumours (PitNETs) may modulate tumour biology, aggressiveness, and treatment responses. We aimed to study the role of various chemokines and chemokine receptors in defining PitNET phenotype and clinical outcomes. We included 96 patients (51 females) with available snap-frozen PitNET tissue from surgery between 2014 and 2020. Chemokine and chemokine receptors were studied by RT-qPCR. Fold difference in mRNA expression was calculated using the ΔΔCt method; chemokine and receptor expression levels were normalised to the expression of the control gene TBP, and expressed relative to a reference sample. Ten chemokines and receptors were studied (CCL2, CCL3, CCL4, CXCL8, CX3CL1, CCR2, CCR4, CCR5, CXCR1, CXCR2), and their expression correlated with clinico-pathological and outcome data, as well as other available microenvironment-related data. We found strong positive correlations between all chemokines and chemokine receptors. Higher chemokine and receptor expression levels were seen in patients who had pituitary apoplexy (CCR2, CXCR1), hypopituitarism at diagnosis (CCL2, CCR4), Ki-67 >3% (CCL4, CXCR2), as well as in patients who required re-operation (CCL3, CXCL8, CXCR2), multimodal therapy (CCL2), and had active disease at last-follow-up (CCL2). There was a positive correlation between the number of pituitary surgeries and expression levels of CCL3, CXCL8, CX3CL1, CXCR1, and CXCR2. Compared to nonfunctioning-PitNETs, somatotropinomas had higher expression of CCL2, CCL4, and CCR2, and lower expression of CX3CL1 and CCR4. Expression of CDH1 (encoding E-cadherin) correlated negatively with CCL2, CCL4, CCR2, CCR4, and CXCR2, while the expression of ZEB1 (mesenchymal marker) positively correlated with CCL3, CCL4, and CX3CL1. PitNETs expressing higher levels of CCL4, CX3CL1, CCR4, CCR5, and CXCR1 had more and bigger vessels. Somatotropinomas treated pre-operatively with somatostatin analogues were associated with higher expression of CCL2, CCR4, CXCR1, and CXCR2, while nonfunctioning-PitNETs pre-surgically treated with dopamine agonists were associated with lower expression of CCL3, CCL4, CX3CL1, CCR5, CXCR1, and CXCR2. Our data suggests that chemokines and chemokine receptors may be involved in the modulation of different tumorigenic mechanisms in PitNETs, including tumour proliferation, epithelial-to-mesenchymal transition, and angiogenesis, and may be associated with more aggressive and difficult-to-treat disease.
- Evolutionary dynamics of epitopes of limited variability on the head of influenza H1 haemagglutininPublication . Lourenço, José; Zinad, Hany; Kempton, James; Gupta, SunetraIt is commonly assumed that naturally protective targets of immunity in influenza are highly variable. Theoretical work suggests, by contrast, that influenza evolution is primarily driven by naturally protective responses against epitopes of limited variability (ELV). At least one ELV has been identified on the head region of haemagglutinin of H1 influenza, opening up the possibility of producing a universal influenza vaccine. Here, for the first time, we provide a comprehensive catalogue of ELVs within the head region of H1 haemagglutinin and explain how they arise within its apparently high variable landscape. We show that the head region of H1 haemagglutinin can be decomposed into a number of discrete variable regions (VRs): ELVs tend to include a limited number of VRs compared to other epitopes either because of the smaller footprint of the associated antibody or because they are centred on VRs that are relatively isolated from others. Thus, the variability of an antibody binding site is determined by the number of variable residues included in its footprint rather than the intrinsic entropy of any particular region.
- Discovery and cultivation of prokaryotic taxa in the age of metagenomics and artificial intelligencePublication . Jiménez, Diego Javier; Marasco, Ramona; Schultz, Júnia; Rodríguez, Carlos Andrés Díaz; Nogales, Juan; Rodriguez-R, Luis Miguel; Overmann, Jörg; Rosado, Alexandre SoaresDespite advances in sequencing, microbial genomics, and cultivation techniques, the vast majority of prokaryotic species remain uncultured, which is a persistent bottleneck in microbiology and microbial ecology. This perspective outlines a conceptual framework to improve the transition from genomeresolved metagenomics to the targeted isolation of yet-uncultured prokaryotic taxa. The proposed framework integrates the induced reshaping of microbiomes, genome-based inferences of physiological and phenotypic traits, culture media design, and targeted culturomics, enabling hypothesis-driven cultivation. In addition, this manuscript addresses the critical limitations in the field, including the sequence-to-function gap, and emphasizes the synergistic potential of experimental microbiology, microbial ecology, metagenomics, and artificial intelligence (AI)-based predictions to enhance rational and actionable roadmaps for discovering and cultivating novel prokaryotic lineages.
- Land and climate suitability for West Nile virus in Atlantic archipelagos guided by historical data from EuropePublication . Geraldes, Martim A.; Giovanetti, Marta; Cunha, Mónica V.; Lourenço, JoséWest Nile (WNV) is a zoonotic mosquito-borne virus with an expanding geographical and epidemic activity worldwide. Computational studies have contributed to the understanding of factors driving WNV occurrence, particularly in North America and Europe. Archipelagos have largely been overlooked, despite the risk to unique local avian species and human populations. In this study, we apply an ecological niche approach, trained on WNV occurrence and (a)biotic factors from European countries to project ecological suitability for WNV occurrence across several Atlantic archipelagos. The approach gives weight to the temporal dimension, generating novel insights on seasonality both for Europe and the archipelagos. For European countries, modelling results align with previous findings on spatial hotspots and (a)biotic drivers of WNV occurrence, while further unravelling properties of at-risk human populations within dynamically suitable land areas. For Atlantic archipelagos, results constitute a novel and detailed perspective on local ecological suitability for WNV occurrence, providing a data-driven framework that identifies spatial hotspots, defines seasonal patterns and quantifies the local population at risk. The synthetic data generated in this study supports the development of targeted preparedness, surveillance and mitigation plans tailored to the unique ecological and seasonal dynamics of each region under study.
- Sex-specific transcriptome similarity networks elucidate comorbidity relationshipsPublication . Sánchez-Valle, Jon; Flores-Rodero, María; Costa, Felipe Xavier; Carbonell-Caballero, Jose; Núñez-Carpintero, Iker; Tabarés-Seisdedos, Rafael; Rocha, Luis Mateus; Cirillo, Davide; Valencia, AlfonsoBackground Biological differences between women and men lead to variations in the prevalence and progression of many diseases, influencing diagnosis, management, and treatment outcomes. However, the biological mechanisms that contribute to sex differences in disease co-occurrence remain largely unexplored. This study aims to uncover the molecular processes underlying sex-specific patterns of comorbidity. Methods We analyze gene expression data from over 100 diseases, considering the biological sex of each sample (8906 samples, 43.06% women). For each sex, we construct disease similarity networks based on differential gene expression profiles and identify enriched biological processes. We then compare these networks with epidemiological data from population-level comorbidity studies to assess their concordance. Finally, we investigate drugs associated with sex-specific comorbidities to identify potential differences in therapeutic response. Results We show that 13–16% of transcriptomically similar disease pairs are sex-specific. These similarities recover 53–60% of known comorbidities that differ between women and men. Diseases can co-occur through the differential alteration of biological processes, with immune and metabolic pathways playing a greater role in women, and extracellular matrix organization and signal transduction pathways in men. We also identify drugs differentially linked to comorbid diseases depending on sex, suggesting possible sex-dependent effects on disease co-occurrence. Conclusions Our findings demonstrate that transcriptomic data can reveal sex-specific molecular links between diseases and suggest that biological sex should be considered in the design of therapeutic strategies and drug administration.
- Reemergence of yellow fever virus in forest and periurban settings in BrazilPublication . Andrade, Valnete das Graças Dantas; Adelino, Talita Émile Ribeiro; Fonseca, Vagner; Moreno, Keldenn Melo Farias; Tomé, Luiz Marcelo Ribeiro; Pereira, Luiz Augusto; La-Roque, Debora Glenda Lima de; Filippis, Ana Maria Bispo de; Ramos, Daniel Garkauskas; Ramalho, Dario Brock; Furtado, Kátia Cristina de Lima; Borges, Gleissy Adriane Lima; Martins, Livia Caricio; Frutuoso, Livia C. V.; Lamounier, Ludmila Oliveira; Guimarães, Natália Rocha; Barros, Patrícia Miriam Sayuri Sato; Almeida, Priscila Souza de; Silva, Paulo Eduardo de Souza da; Pinheiro, Rodrigo Giesbrecht; Stabeli, Rodrigo Guerino; Chagas, Shirley Moreira da Silva; Pedroso, Sílvia Helena Sousa Pietra; Kashima, Simone; Penante, Solange Gonçalves; Oliveira, Marília Santini de; Silva, Vinicius Lemes da; Voorhis, Wesley C. Van; Holmes, Edward C.; Lourenço, José; Iani, Felipe Campos de Melo; Júnior, Alberto Simões Jorge; Giovanetti, Marta; Alcantara, Luiz Carlos JuniorBackground: Yellow fever virus remains a major public health threat in Brazil, where recent resurgence risks affecting both forest and periurban populations. Understanding viral movement across ecological settings is critical to support early detection and prevent outbreaks. Methods: We performed genomic surveillance in two Brazilian states, a northern Amazon region and a southeastern region, between 2023 and 2025. Human and non-human primate samples were collected across forest, rural, and urban environments. Viral genomes were generated and analyzed using phylogenetic, phylogeographic, and temporal approaches to reconstruct viral transmission patterns. Results: Here, we show evidence of continued yellow fever virus circulation and diversification in distinct ecological settings. We generate 25 genomes from humans and non-human primates, including the first human-derived genomes from the Amazon region. All genomes fall within the South American lineage. We identify one cluster in the Amazon region consistent with undetected viral persistence and reemergence, and a second cluster in the southeast associated with reintroduction followed by sustained local transmission. Conclusions: These findings demonstrate ongoing yellow fever virus activity in Brazil, with forest regions serving as reservoirs for reemergence and periurban areas supporting continued spread. Strengthened genomic and epizootic surveillance is required to detect viral expansion early and inform targeted prevention strategies across Brazil and the Americas.
- Mechanisms of parasite-mediated disruption of brain vesselsPublication . Loira, Leonor; Arroz-Madeira, Sílvia; Franco, Cláudio A.; Pereira, Sara SilvaThe brain vasculature is a critical barrier to maintain central nervous system (CNS) homeostasis. Parasitic infections can profoundly disrupt the brain vasculature, with consequences ranging from subtle neurological alterations to severe, life-threatening pathologies. In this review, we explore the diverse mechanisms by which endoparasites interact with, modulate and breach CNS blood and lymphatic vessels. We highlight how these pathogens manipulate endothelial function, alter barrier permeability and exploit vascular surface molecules to access or influence the brain. These interactions often trigger local inflammation, endothelial activation and blood–brain barrier breakdown, with significant implications for parasite survival and host pathology. Here, we review the molecular and cellular mechanisms underlying these processes, providing an integrative view of parasite-vascular crosstalk in the brain and identifying emerging research areas. Understanding these interactions offers new insights into brain vascular disease pathogenesis and may inform future strategies for intervention.
- Targeted CRISPR-Cas9 screening identifies core transcription factors controlling murine haemato-endothelial fate commitmentPublication . Teske, Michael; Wertheimer, Tobias; Butz, Stefan; Zwicky, Pascale; Mallona, Izaskun; Nopper, Svenja L.; Münz, Christian; Elling, Ulrich; Lancrin, Christophe; Becher, Burkhard; Grosso, Ana Rita; Baubec, Tuncay; Schmolka, NinaDuring development, blood generation begins in the yolk sac with the differentiation of haemato-endothelial mesoderm forming haematopoietic progenitors. This study aims to identify the crucial molecular regulators of haemato-endothelial mesoderm formation and to extend our knowledge of the process in an unbiased way. We employ a murine embryonic stem cell model that recapitulates embryonic blood development, and perform targeted CRISPR-Cas9 knock out screens focusing on transcription factors and chromatin regulators. We identify the transcription factors ETV2, LDB1, SMAD1, SIX4 and ZBTB7b as regulators of haemato-endothelial mesoderm commitment. Embryonic stem cells lacking these regulators give rise to mesodermal subsets with a defined lineage differentiation bias, while transcriptome analysis of these cells uncovers the precise impact of each factor on gene expression in the developing mesoderm. Our study reveals molecular pathways governing mesodermal development crucial to allow endothelial and haematopoietic lineage specification and paves the way for future advances in haematopoietic stem cell applications.
- Shifting dynamics of Dengue virus serotype 2 and emergence of cosmopolitan genotype, Costa Rica, 2024Publication . González-Elizondo, Mauricio; Soto, Dihala Picado; Laurent, Estela Cordero; Martínez, Francisco Duarte; Alcantara, Luiz Carlos Junior; Fonseca, Vagner; Rico, Jairo Andrés Méndez; Lourenço, José; Franco, Leticia; Giovanetti, Marta; Garita, Claudio SotoDengue remains a major public health challenge. In Costa Rica, we implemented nationwide genomic surveillance to track dengue virus serotype 2 cosmopolitan genotype emergence. Phylogenetic and eco-epidemiologic analyses revealed early detection, climate-driven spread, and spatial heterogeneity. Our findings underscore the need for integrated surveillance to guide adaptive responses to emerging arboviral threats.