CBR - Contribuições em Revistas Científicas / Contribution to Journals
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- Insights into the mechanism of action of the bipartite fusion module of SARS-CoV-2 spike proteinPublication . Buga, Carolina C.; Valerio, Mariana; Alenquer, Marta; Miranda, Marta Pires de; Melo, Manuel N.; Castanho, Miguel A. R. B.; Amorim, Maria João; Soares, Cláudio M.; Vicente, João B.; Veiga, Ana Salomé; Lousa, DianaSARS-CoV-2 entry into host cells is mediated by the spike glycoprotein, which promotes fusion between viral and host membranes. Despite its importance, the precise location and mode of action of the fusion peptide, a key spike region that inserts into and perturbs the host membrane, remain elusive. Two regions have been proposed as fusion peptides: one located at the N-terminus of the protein (nFP) and the other at an internal position (iFP). Here, we combine computational and experimental approaches to characterize their roles and impact on membrane fusion. Molecular dynamics (MD) simulations indicated that the nFP interacts mostly at the membrane surface. Consistently, experimental biophysical assays revealed that the nFP exhibits low affinity and weak perturbing effects on lipid vesicles. In contrast, the iFP exhibits stronger membrane binding and induces stronger perturbation in vitro. MD simulations show that the iFP inserts deeply into and strongly affects the membrane, inducing lipid tail protrusion and increased water flux through the bilayer. Moreover, spike-pseudotyped lentiviruses carrying mutations in the iFP region showed that residues Y873, F888, and F906 are required for viral entry. Together, our findings suggest that SARS-CoV-2 uses a bipartite fusion module in which the nFP establishes initial contact with the host membrane and primes the bilayer, enabling subsequent deep insertion and further membrane destabilization promoted by the iFP. Given that FPs are conserved across viral families, a similar fusion module may be present in other coronaviruses, making this region a promising target for the development of broad-range antiviral therapeutics.
- Infiltrative and inflammatory systemic disorders involving the pituitary glandPublication . Biagetti, Betina; Marques, Pedro; Sarria-Estrada, Silvana; Puig-Domingo, Manel; Araujo-Castro, Marta; Marazuela, MónicaThe hypothalamic-pituitary region can be affected by a wide and heterogeneous group of infiltrative and inflammatory disorders, including granulomatous, histiocytic, storage, infectious, non-pituitary neoplastic, and autoimmune or inflammatory conditions collectively grouped as hypophysitis. Although individually rare, these disorders are increasingly recognized due to growing awareness, wider use of pituitary imaging, and the emergence of immune checkpoint inhibitor-induced hypophysitis. They typically present with hypopituitarism (often including arginine vasopressin deficiency, which, particularly when accompanied by pituitary stalk thickening, is highly suggestive of a non-adenomatous lesion) together with mass effect symptoms and, in many cases, systemic manifestations reflecting extrapituitary organ involvement. Neuroimaging findings, while rarely pathognomonic, can narrow the differential diagnosis, particularly when pituitary stalk involvement is present: symmetric stalk/gland enlargement with homogeneous enhancement suggests lymphocytic, IgG4-related, or granulomatous hypophysitis, whereas rim enhancement, necrosis, or bone-destructive lesions point toward infectious or neoplastic causes. A structured diagnostic work-up, combining clinical history, hormonal evaluation, targeted laboratory testing, pituitary and systemic imaging, and, when necessary, histopathological confirmation, is essential to establish an accurate diagnosis before committing patients to long-term immunosuppression or unnecessary pituitary surgery. Management requires two parallel strategies: prompt hormone replacement therapy, with urgent attention to corticotroph deficiency, and disease-specific treatment tailored to the underlying etiology, ranging from glucocorticoids and immunosuppressants to antimicrobial therapy, targeted oncologic agents, or surgery. Because pituitary deficits are frequently irreversible and several of these disorders follow a relapsing course, long-term multidisciplinary follow-up is warranted. This review summarizes the pathophysiology, clinical presentation, diagnostic approach and neuroimaging features, for infiltrative and inflammatory hypothalamic-pituitary disorders, aiming to facilitate their timely recognition and appropriate management.
- Climate-driven spatiotemporal dynamics of Aedes infestation and dengue transmission in Porto Alegre, Southern BrazilPublication . Silva, Adryan Aparecido da; Ferreira, Álvaro Gil Araujo; Lourenço, José; Freitas, Amanda Cupertino deDengue transmission is strongly influenced by climatic conditions that affect mosquito population dynamics and virus circulation. In Southern Brazil, where dengue historically occurred at low levels, recent climatic anomalies may be contributing to the expansion of Aedes vectors and increased local dengue incidence. This study investigated the spatiotemporal association between climatic variables, Aedes infestation and dengue cases in Porto Alegre (Southern Brazil, from 2018 to 2025). Entomological, surveillance and climatic data were analyzed using Moran’s I and LISA for spatial association, Kendall correlation, polynomial regression and LASSO to identify relevant drivers and develop predictive models of mosquito infestation and dengue incidence. Strong spatial association between Aedes aegypti and Aedes albopictus was observed, with persistent local clusters detected across all years. Annual climatic variables were associated with mosquito abundance in several districts. Overall, rainfall frequency had a stronger effect on Ae. aegypti abundance than accumulated rainfall. Temperature and lagged infestation indices showed strong associations with both species and dengue incidence, with lag effects detected up to eight weeks. Predictive models demonstrated good agreement between observed and predicted values, particularly at low to moderate infestation levels. Lagged variables were consistently retained in both mosquito abundance and dengue incidence models, highlighting the importance of temporal predictors in anticipating vector dynamics and dengue risk. This approach is broadly applicable for predicting Aedes infestation and disease incidence and it underscores the importance of integrating entomological and climatic surveillance data to enhance anticipation and early detection of dengue risk periods in large urban settings and inform more effective public health interventions.
- Design, synthesis, and antimalarial evaluation of novel quinazolin-4(3H)-one derivatives with molecular modeling insights into target selectivityPublication . Nascimento, Igor José dos Santos; Menezes, Karla Joane da Silva; Leonardo, Margarida Cochicho; Morais, Inês; Vieira, Carolina Silva Dias; Pereira, Sara Silva; Cortes, Sofia; Moreira, Rui; Nogueira, Fatima; Olimpio de Moura, RicardoMalaria is a tropical disease caused by protozoa of the genus Plasmodium and is responsible for several deaths worldwide. Current therapies are limited by the high incidence of adverse effects and the rising prevalence of parasite drug resistance, underscoring the need for research into new chemical scaffolds that can overcome these limitations and for the identification of novel drug targets to advance antimalarial development. In this context, quinazolines show promising potential as new antimalarials. Therefore, in this study, a new series of quinazolin-4(3H)-one analogs was synthesized and evaluated for antiplasmodial activity. As a result, 36 compounds were synthesized and characterized, of which 3d, 3e, 4a, and 4e showed promising activity in assays against P. falciparum-3D7HT-GFP (IC50 = 4.36, 2.26, 1.70, and 4.10 μM) with no cytotoxicity (CC50 = 44.56, 22.91, 26.42, and 48.15 μM) and acceptable selectivity indexes (10.22, 10.14, 15.55, and 11.75). The compounds were evaluated against Leishmania donovani and Trypanosoma congolense but did not inhibit these parasites, suggesting that this chemical scaffold is selective for plasmodial targets. Accordingly, molecular modeling proposed Nmyristoyltransferase (NMT) as a potential target and identified the specific binding mode of compound 4a for P. falciparum NMT (PfNMT) relative to L. donovani NMT (LdNMT), T. congolense NMT (TcNMT), and Homo sapiens NMT (HsNMT). It was found that the presence of Leu411, Leu369, Ser337, and Phe336 in PfNMT, substituted by Met412, Val370, Val338, and Tyr337 in LdNMT, and Met445, Tyr370, Ile371, and Tyr370 in TcNMT, may be related to the predicted target selectivity and the greater affinity of 4a for PfNMT. Finally, molecular dynamics simulations suggest that 4a is most stable against PfNMT, and MM-PBSA calculations indicate a binding energy for this target (ΔGbinding = −130.873 kJ/mol). These findings corroborate the promising potential of 4a and support its proposed selectivity against PfNMT, yielding a scaffold that can be explored in subsequent optimization studies.
- Aquaporin-1 sustains lymphangiogenic responses in hyperosmotic inflammatory microenvironmentsPublication . Roci, Irena; Kim, Jaeryung; Korodi, Kelly de; Wyss, Tania; Bernier-Latmani, Jeremiah; Arroz-Madeira, Silvia; González-Loyola, Alejandra; Bovay, Esther; Grenningloh, Nadia; Schoofs, Hans; Jeon, Noo Li; Giampietro, Costanza; Mäkinen, Taija; Noël, Agnès; Petrova, Tatiana V.Intestinal lymphatic vessels are essential for dietary lipid absorption and immune cell trafficking. Villus lymphatic capillaries, lacteals, undergo continuous VEGF-C–dependent renewal to function in a hyperosmolar, inflammatory environment exposed to dietary and microbial by-products. To define mechanisms underlying this adaptation, we integrated new and published single-cell RNA-sequencing datasets of murine small intestinal lymphatic endothelial cells (LECs). Lacteal LECs resembled Ptx3+ immune-interacting LECs and were characterized by high expression of water channel AQP1. LEC-specific Aqp1 deletion reduced lacteal length, impaired lipid uptake, and limited weight gain on a high-fat diet, while mosaic deletion revealed a cell-autonomous requirement for AQP1 in LEC positioning at hyperosmolar tip regions. AQP1 promoted LEC migration under hyperosmotic stress by preserving cytoskeletal and junctional remodeling and alleviating osmotic stress–induced transcriptional programs. AQP1 was upregulated during inflammatory remodeling in lymphedema and lymphatic malformations, but not during embryonic lymphangiogenesis. These findings link lacteal regeneration to inflammatory lymphatic remodeling and highlight tissue osmolarity as a biophysical determinant of postnatal lymphangiogenesis.
- Acromegaly and cardiovascular disease: mechanisms, clinical impact, and evolving managementPublication . Araujo-Castro, Marta; Marques, Pedro; Cardoso, Luis Miguel; Pascual-Corrales, Eider; Refardt, Julie; Neggers, Sebastian J. C. M. M.; Cassinello, José María Jiménez; Marazuela, Mónica; Puig-Domingo, Manel; Biagetti, BetinaCardiovascular disease is one of the most common and serious complications of acromegaly and a leading contributor to reduced life expectancy in affected individuals. This review examines the prevalence, mechanisms, diagnosis, and management of cardiovascular complications in patients with acromegaly. Growth hormone and insulin-like growth factor 1 excess promotes a range of cardiovascular disturbances, including structural heart changes, arrhythmias, vascular dysfunction, and an increased burden of traditional cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia. Early recognition and targeted treatment of these complications are critical to reducing cardiovascular morbidity and mortality. While surgery and medical therapies for acromegaly aimed at normalizing hormone levels may lead to partial or full reversal of some cardiovascular alterations, many patients require continued management of comorbid conditions to control their overall cardiometabolic risk. Advances in diagnostic strategies and therapeutic options have contributed to improved survival, yet gaps remain in our understanding of how best to prevent or reverse cardiovascular damage in this population. Multidisciplinary care and individualized risk assessment are essential components of modern acromegaly management.
- Glucocorticoid-induced arginine vasopressin deficiency and neurohypophyseal T1-hyperintensity transient switch-offPublication . Marques, Pedro; Neto, Lia; Fontes, Luísa; Sapinho, Inês
- Protocol for evaluating ChatGPT in biomedical association generation and verification using a RAG enabled, cross-model majority voting workflowPublication . Hamed, Ahmed Abdeen; Rocha, Luis M.We present a protocol to evaluate ChatGPT’s ability to generate disease-centric biomedical associations. It outlines how we generate the associations, validate the biological entities using biomedical ontologies, and verify associations using literature. The protocol includes a self-consistency strategy to assess generative reliability across ChatGPT models. To address ontology exact-match limitations, we provide a use case performing semantic verification through a workflow enabled by Retrieval-Augmented Generation (RAG) powered by open-source large language models (LLMs). This enables LLMs to establish truth over content generated by other LLMs and expose hallucination.
- Glucocorticoid-induced arginine vasopressin deficiency and neurohypophyseal T1-hyperintensity transient switch-offPublication . Marques, Pedro; Neto, Lia; Fontes, Luísa; Sapinho, Inês
- Protocol for evaluating ChatGPT in biomedical association generation and verification using a RAG enabled, cross-model majority voting workflowPublication . Hamed, Ahmed Abdeen; Rocha, Luis M.We present a protocol to evaluate ChatGPT’s ability to generate disease-centric biomedical associations. It outlines how we generate the associations, validate the biological entities using biomedical ontologies, and verify associations using literature. The protocol includes a self-consistency strategy to assess generative reliability across ChatGPT models. To address ontology exact-match limitations, we provide a use case performing semantic verification through a workflow enabled by Retrieval-Augmented Generation (RAG) powered by open-source large language models (LLMs). This enables LLMs to establish truth over content generated by other LLMs and expose hallucination.