Henrique Roman Ramos

L‐tryptophan (Trp) metabolism through the L‐kynurenine (Kyn) pathway contributes to immune escape in neoplasms, including bladder cancer (BC). Indoleamine 2,3‐dioxygenase‐1 (IDO1) is a key enzyme, and its catabolites—Kyn, 3‐hydroxykynurenine (3HK), and 3‐hydroxyanthranilate (3HAA)—depend on other enzymes and play a crucial role in immunomodulation. Objectives: We investigated the association between Kyn pathway enzyme expression and BC prognostic factors. Methods: Data from 165 bc patients in the GEO DataSets were analyzed, comparing staging, tumor grade, progression, and recurrence with the expression of IDO1, arylformamidase (AFMID), kynurenine–oxoglutarate transaminase (KAT), kynureninase (KYNU), kynurenine 3‐monooxygenase (KMO), 3‐hydroxyanthranilate 3,4‐dioxygenase (HAAO), and aminocarboxymuconate‐semialdehyde decarboxylase (ACMSD). Predictive genes were further evaluated in RT4 (low‐grade, non‐invasive) and T24 (high‐grade, invasive) BC cells treated with IFN‐gamma and the IDO1 inhibitor INCB024360. Trp catabolites were quantified in the supernatant. Results: Enzyme expression varied widely, especially for IDO1, AFMID, KAT, KMO, and KYNU. IDO1 correlated positively with KMO and negatively with KAT. High IDO1 and KMO levels were linked to advanced‐stage disease, while KAT and KYNU were associated with earlier stages and lower tumor grade. RT4 and T24 cells showed distinct basal enzyme expression, with T24 cells being more responsive to IFN‐gamma, increasing IDO1 and KYNU while decreasing KAT and KMO. These effects were inhibited by INCB024360. High Trp consumption increased Kyn and 3HAA but not 3HK. Conclusions: Kyn pathway enzyme expression varies with disease progression and may indicate immune activity by influencing tumor microenvironment catabolites. BC cell sensitivity to immune stimuli differs, potentially shaping distinct immune escape mechanisms.

Background: Three-finger toxins (3FTxs) are a major axis of functional diversification in advanced snake venoms, with canonical paralytic activity mediated through muscle-type nicotinic acetylcholine receptors (nAChRs) and a broader set of non-nicotinic targets. This review integrates evidence bearing on coevolution between 3FTxs and target receptors, spanning toxin origin, diversification, receptor evolution, and ecological context. Methods: The synthesis draws on comparative genomic and transcriptomic studies of 3FTx gene-family evolution, codon-model analyses of selection, structural characterisation of toxin–receptor interfaces, and functional assays (including receptor-mimicking peptide binding) that link sequence variation to binding and toxicity. Results: Across lineages, 3FTx diversification is repeatedly structured by strong constraint on the disulphide-rich scaffold with accelerated change concentrated in solvent-exposed loops, alongside birth–death dynamics and exon/segment-level innovation that expand binding specificity. On the receptor side, resistance-associated variation is most intensively characterised for the nAChR α₁ orthosteric site and includes convergent, mechanistically distinct solutions such as electrostatic repulsion and glycosylation-mediated steric interference. Within the predominantly elapid systems currently examined, integrative datasets indicate that prey-selective binding and geographically variable susceptibility can arise from modest substitutions at toxin–receptor interfaces, but they also reveal substantial taxonomic and target-specific biases. Conclusions: Current evidence supports adaptive diversification in both toxins and receptors, while broader evolutionary interpretations are limited by uneven sampling and the frequent lack of matched toxin and receptor variants analysed within a common evolutionary framework. Development of predictive models will require joint pipelines linking genomics, structure-informed evolutionary inference, scalable functional assays, and explicit ecological network context.

Introduction: This research, conducted between August and October 2021, investigates the prevalence of hypercholesterolemia in the Brazilian scenario, examining the relationship between lipid levels, sedentary lifestyle, diet, psychological factors, and integrative practices performed during the COVID-19 pandemic. Methods: The 139 participants in the study were divided into two groups, one group with 38 participants who attended the "I Symposium on Combating High Cholesterol in the Pandemic" and another group with 101 participants who did not attend the "I Symposium on Combating High Cholesterol in the Pandemic". Results: The results indicated that both groups recognize the risks associated with dietary habits, with only the symposium participants demonstrating slightly deeper knowledge about foods rich in Omega-3 (ω-3). Discussion: Although sports practice has maintained its relevance, a decrease in compliance with WHO guidelines was observed. Additionally, the results highlight growing concerns about mental health during the pandemic period. Conclusion: This study highlighted, in addition to analyses regarding hypercholesterolemia, challenges in event adherence, suggesting the need for more effective educational strategies. The option for an online research method, although theoretically accessible, had a low adherence rate, suggesting the need for reflections on the effectiveness of research methods, as well as pointing to the importance of approaches more in line with the profile and needs of the target audience.

This comprehensive review explores the cutting-edge advancements in snake venom research, focusing on the integration of proteomics, genomics, transcriptomics, and bioinformatics. Highlighting the transformative impact of these technologies, the review delves into the genetic and ecological factors driving venom evolution, the complex molecular composition of venoms, and the regulatory mechanisms underlying toxin production. The application of synthetic biology and multi-omics approaches, collectively known as venomics, has revolutionized the field, providing deeper insights into venom function and its therapeutic potential. Despite significant progress, challenges such as the functional characterization of toxins and the development of cost-effective antivenoms remain. This review also discusses the future directions of venom research, emphasizing the need for interdisciplinary collaborations and new technologies (mRNAs, cryo-electron microscopy for structural determinations of toxin complexes, synthetic biology, and other technologies) to fully harness the biomedical potential of venoms and toxins from snakes and other animals.

Coralsnakes (Micrurus spp.) are the only elapids found throughout the Americas. They are recognized for their highly neurotoxic venom, which is comprised of a wide variety of toxins, including the stable, low-mass toxins known as three-finger toxins (3FTx). Due to difficulties in venom extraction and availability, research on coralsnake venoms is still very limited when compared to that of other Elapidae snakes like cobras, kraits, and mambas. In this study, two previously described 3FTx from the venom of M. corallinus, NXH1 (3SOC1_MICCO), and NXH8 (3NO48_MICCO) were characterized. Using in silico, in vitro, and ex vivo experiments, the biological activities of these toxins were predicted and evaluated. The results showed that only NXH8 was capable of binding to skeletal muscle cells and modulating the activity of nAChRs in nerve–diaphragm preparations. These effects were antagonized by anti-rNXH8 or antielapidic sera. Sequence analysis revealed that the NXH1 toxin possesses eight cysteine residues and four disulfide bonds, while the NXH8 toxin has a primary structure similar to that of non-conventional 3FTx, with an additional disulfide bond on the first loop. These findings add more information related to the structural diversity present within the 3FTx class, while expanding our understanding of the mechanisms of the toxicity of this coralsnake venom and opening new perspectives for developing more effective therapeutic interventions.

Context: Although rare, coral snake envenomation is a serious health threat in Brazil, because of the highly neurotoxic venom and the scarcely available antivenom. The major bottleneck for antivenom production is the low availability of venom. Furthermore, the available serum is not effective against all coral snake species found in Brazil. An alternative to circumvent the lack of venom for serum production and the restricted protection of the actually available antivenom would be of great value. We compared the Brazilian coral snake and mono and polyvalent Australian antivenoms in terms of reactivity and protection. Methods: The immunoreactivity of venoms from 9 coral snakes species were assayed by ELISA and western blot using the Brazilian Micrurus and the Australian pentavalent as well as monovalent anti-Notechis, Oxyuranus and Pseudechis antivenoms. Neutralization assays were performed in mice, using 3 LD₅₀ of the venoms, incubated for 30 minutes with 100 μL of antivenom/animal. Discussion: All the venoms reacted against the autologous and heterologous antivenoms. Nevertheless, the neutralization assays showed that the coral snake antivenom was only effective against M. corallinus, M. frontalis, M. fulvius, M. nigrocinctus and M. pyrrhocryptus venoms. On the other hand, the Australian pentavalent antivenom neutralized all venoms except the one from M. spixii. A combination of anti-Oxyuranus and Pseudechis monovalent sera, extended the protection to M. altirostris and, partially, to M. ibiboboca. By adding Notechis antivenom to this mixture, we obtained full protection against M. ibiboboca and partial neutralization against M. lemniscatus venoms. Conclusions: Our findings confirm the limited effectiveness of the Brazilian coral snake antivenom and indicate that antivenoms made from Australian snakes venoms are an effective alternative for coral snake bites in South America and also in the United States were coral snake antivenom production has been discontinued.

Envenoming by coral snakes (Elapidae: Micrurus), although not abundant, represent a serious health threat in the Americas, especially because antivenoms are scarce. The development of adequate amounts of antielapidic serum for the treatment of accidents caused by snakes like Micrurus corallinus is a challenging task due to characteristics such as low venom yield, fossorial habit, relatively small sizes and ophiophagous diet. These features make it difficult to capture and keep these snakes in captivity for venom collection. Furthermore, there are reports of antivenom scarcity in USA, leading to an increase in morbidity and mortality, with patients needing to be intubated and ventilated while the toxin wears off. The development of an alternative method for the production of an antielapidic serum, with no need for snake collection and maintenance in captivity, would be a plausible solution for the antielapidic serum shortage. In this work we describe the mapping, by the SPOT-synthesis technique, of potential B-cell epitopes from five putative toxins from M. corallinus, which were used to design two multiepitope DNA strings for the genetic immunisation of female BALB/c mice. Results demonstrate that sera obtained from animals that were genetically immunised with these multiepitope constructs, followed by booster doses of recombinant proteins lead to a 60% survival in a lethal dose neutralisation assay. Here we describe that the genetic immunisation with a synthetic multiepitope gene followed by booster doses with recombinant protein is a promising approach to develop an alternative antielapidic serum against M. corallinus venom without the need of collection and the very challenging maintenance of these snakes in captivity. Coral snakes are a group of deadly venomous snakes that exhibit a characteristic red, yellow/white, and black coloured banding pattern. Accidents involving these snakes tend to be very severe or even lethal, causing peripheral nervous system depression with muscle paralysis and vasomotor instability. The only acceptable medical treatment for snakebite accidents is the administration of an antivenom, generally produced by immunising horses with the snake venom. Nonetheless, for what concerns the antielapidic serum production in Brazil, the total amount of venom available for horse immunisations is insufficient. This is mainly due to the small size of coral snake glands, their underground life style, combined with its very low survival rates in captivity. Moreover, cases of patients being intubated and ventilated as a consequence of antivenom shortage in USA have also been registered. In this work, we present an alternative method for the development of antielapidic serum, which does not rely upon snake capture. This serum was produced by a heterologous DNA prime—with a multiepitope DNA string coding for the most reactive epitopes from the most abundant toxins of M. corallinus, a coral snake which occupy highly populated areas in Brazil—followed by recombinant multiepitope protein boost immunisation of mice.

Introdução: o desenvolvimento de uma vacina contra a esquistossomose será um importante avanço no controle desta doença crônica e muitas vezes debilitante, afetando milhões de pessoas em todo o mundo....