Atomoxetine: toxicological aspects of a new treatment for Attention Deficit Hyperactivity Disorder in Brazil.

Atomoxetine is a drug widely used for the treatment of the attention deficit hyperactivity disorder (ADHD) with reduced risk of adverse motor reactions and chemical dependence. However, the pharmacokinetics characteristics as well as the toxicological risk of atomoxetine deserves further investigation to comprehensively analyze the therapeutic and safety aspects of this drug. This study aimed to predict the physicochemical profile and medicinal chemistry characteristics of atomoxetine, alongside its pharmacokinetic properties-namely absorption, distribution, metabolism, and excretion-as well as its toxicology (ADMET) potential through the utilization of web-based in silico tools. This research emphasizes predicted physicochemical, medicinal chemistry, and absorption parameters of atomoxetine that could influence the efficacy and safety of this drug for ADHD treatment. Additionally, atomoxetine also presents noteworthy predicted risks of hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, respiratory system toxicity, skin toxicity, and carcinogenicity. These findings underscore the necessity for further assessments of atomoxetine's safety profile, particularly considering different patient populations and durations of drug treatment. The data reported here from in silico predictions suggest that closer monitoring is warranted when atomoxetine is administered to patients with ADHD. Moreover, controlled studies detailing reliable protocols for personalized dosing, considering the multifactorial variability in metabolism efficiency and toxicological potential, would enable a more comprehensive assessment of atomoxetine's safety profile.

Quantum mechanics insights into melatonin and analogs binding to melatonin MT1 and MT2 receptors.

Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

Advancing molecular modeling and reverse vaccinology in broad-spectrum yellow fever virus vaccine development.

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant ( ß -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.

Identification of Helicobacter pylori-carcinogenic TNF-alpha-inducing protein inhibitors via daidzein derivatives through computational approaches.

Gastric cancer is considered a class 1 carcinogen that is closely linked to infection with Helicobacter pylori (H. pylori), which affects over 1 million people each year. However, the major challenge to fight against H. pylori and its associated gastric cancer due to drug resistance. This research gap had led our research team to investigate a potential drug candidate targeting the Helicobacter pylori-carcinogenic TNF-alpha-inducing protein. In this study, a total of 45 daidzein derivatives were investigated and the best 10 molecules were comprehensively investigated using in silico approaches for drug development, namely pass prediction, quantum calculations, molecular docking, molecular dynamics simulations, Lipinski rule evaluation, and prediction of pharmacokinetics. The molecular docking study was performed to evaluate the binding affinity between the target protein and the ligands. In addition, the stability of ligand-protein complexes was investigated by molecular dynamics simulations. Various parameters were analysed, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM). The results has confirmed that the ligand-protein complex CID: 129661094 (07) and 129664277 (08) formed stable interactions with the target protein. It was also found that CID: 129661094 (07) has greater hydrogen bond occupancy and stability, while the ligand-protein complex CID 129664277 (08) has greater conformational flexibility. Principal component analysis revealed that the ligand-protein complex CID: 129661094 (07) is more compact and stable. Hydrogen bond analysis revealed favourable interactions with the reported amino acid residues. Overall, this study suggests that daidzein derivatives in particular show promise as potential inhibitors of H. pylori.

Computational antigenic insights into the novel NADC-34-like Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) isolate YC-2020.

In this computational study, we advanced the understanding of the antigenic properties of the NADC-34-like isolate of the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), named YC-2020, relevant in veterinary pathology. We utilized sequence comparison analyses of the M and N proteins, comparing them with those of NADC34, identifying substantial amino acid homology that allowed us to highlight conserved epitopes and crucial variants. Through the application of Clustal Omega for multiple sequence alignment and platforms like Vaxijen and AllerTOP for predicting antigenic and allergenic potential, our analyses revealed important insights into the conservation and variation of epitopes essential for the development of effective diagnostic tools and vaccines. Our findings, aligned with initial experimental studies, underscore the importance of these epitopes in the development of targeted immunodiagnostic platforms and significantly contribute to the management and control of PRRSV. However, further studies are required to validate the computational predictions of antigenicity for this new viral isolate. This approach underscores the potential of computational models to enable ongoing monitoring and control of PRRSV evolution in swine. While this study provides valuable insights into the antigenic properties of the novel PRRSV isolate YC-2020 through computational analysis, it is important to acknowledge the limitations inherent to in silico predictions, specifically, the absence of laboratory validation.

A robust computational quest: Discovering potential hits to improve the treatment of pyrazinamide-resistant Mycobacterium tuberculosis.

The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through in vitro and in vivo experiments.

Non-pharmacological therapies for pain management in paediatric intensive care units: a protocol for a scoping review.

INTRODUCTION: In critically ill children, pain management is complex owing to cognitive development and the nature of hospitalisation in paediatric intensive therapy units. Although there are many protocols and guidelines for pain control via pharmacological interventions, non-pharmacological practices should also be explored and disseminated for their potential benefit. METHODS AND ANALYSIS: A systematic literature search will be performed using the following databases: Academic Search Premier, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Excerpta Medica Database, Virtual Health Library, Medical Literature Analysis and Retrieval System Online, ScienceDirect, Scopus, Web of Science Core Collection, Theses from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Dart Europe, Open Access Theses and Dissertations and grey literature from Google Scholar. The research will consider quantitative and qualitative studies, mixed-method studies, systematic reviews, text articles, opinion articles, letters to editors and editorials in any language and from any database. The following will be eligible for inclusion: (1) newborns, infants, children and adolescents; and (2) non-pharmacological therapies used for pain in paediatric intensive care. ETHICS AND DISSEMINATION: This study does not require ethical approval. The results of this research will be disseminated through social media channels and podcasts about pain in children. TRIAL REGISTRATION NUMBER: This protocol has been registered with the Open Science Framework (DOI 10.17605/OSF.IO/DZHKT).

Quantum biochemical analysis of the binding interactions between a potential inhibitory drug and the Ebola viral glycoprotein.

Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD.Communicated by Ramaswamy H. Sarma.

Prevalência e fatores pessoais associados à violência autoprovocada em adolescentes / Prevalence and personal factors associated with self-harm in adolescents / Prevalencia y factores personales asociados a la violencia autoinflingida en adolescentes

RESUMO Objetivo: identificar a prevalência e os fatores pessoais associados à violência autoprovocada em adolescentes. Método: estudo observacional analítico, do tipo transversal. A população foi composta pelas notificações de violência interpessoal ou autoprovocada em adolescentes no Brasil, oriundas do Sistema de Informação de Agravos de Notificação. Foram incluídas as notificações ocorridas entre 2009 e 2021 no Brasil, em adolescentes de 10 a 19 anos. Os dados foram analisados com estatística descritiva e inferencial. Resultados: a prevalência de violência autoprovocada foi de 27,39% no Brasil. Adolescentes pretos aumentam a prevalência de violência autoprovocada em 3%, e os pardos e indígenas em 2%; mais de 8 anos de escolaridade constitui fator de proteção em relação à violência autoprovocada, reduzindo em 12% a prevalência de violência autoinfligida. Conclusão: os resultados indicam a necessidade de que sejam traçadas políticas e estratégias eficazes que auxiliem no cuidado a esse público.

ABSTRACT Objective: To identify the prevalence and personal factors associated with self-harm in adolescents. Method: A cross-sectional analytical observational study. The population consisted of notifications of interpersonal or self-harm violence in adolescents in Brazil from the Notifiable Diseases Information System. Notifications between 2009 and 2021 in Brazil were included in adolescents aged 10 to 19. The data was analyzed using descriptive and inferential statistics. Results: The prevalence of self-harm was 27.39% in Brazil. Black adolescents increase the prevalence of self-harm violence by 3% and brown and indigenous adolescents by 2%; more than eight years of schooling is a protective factor in relation to self-harm violence, reducing the prevalence of self-inflicted violence by 12%. Conclusion: The results indicate the need for effective policies and strategies to help care for this public.

RESUMEN Objetivo: identificar la prevalencia y los factores personales asociados a la violencia autoinfligida en adolescentes. Método: estudio observacional, analítico, transversal. La población estuvo constituida por notificaciones de violencia interpersonal o autoinfligida entre adolescentes de Brasil, provenientes del Sistema de Información de Enfermedades De Declaración Obligatoria. Se incluyeron las notificaciones ocurridas entre 2009 y 2021 en Brasil, en adolescentes de 10 a 19 años. Los datos fueron analizados con estadística descriptiva e inferencial. Resultados: la prevalencia de violencia autoinfligida fue del 27,39% en Brasil. Los adolescentes negros aumentan la prevalencia de la violencia autoinfligida en un 3%, y los pardos e indígenas en un 2%; más de 8 años de escolaridad constituye un factor protector en relación a la violencia autoinfligida, reduciendo en un 12% la prevalencia de la violencia autoinfligida. Conclusión: los resultados indican la necesidad de diseñar políticas y estrategias efectivas para ayudar a la atención de esta población.

O cuidar do adolescente com obesidade na atenção primária à saúde: perspectivas de gestores e profissionais / The care of obese adolescents in primary health care: perspectives of managers and professionals / Atención a adolescentes con obesidad en atención primaria de salud: perspectivas de gestores y profesionales

RESUMO Objetivo: Descrever e explorar, sob a perspectiva de gestores e profissionais de saúde, o cuidado ofertado ao adolescente com obesidade no âmbito da Atenção Primária à Saúde. Método: Estudo de caso, realizado em município do estado do Ceará-Brasil. A coleta de dados ocorreu em 2022, por meio de entrevistas semiestruturadas. Os dados foram examinados através da Análise de conteúdo de Bardin. Resultados: O cuidado ao adolescente com obesidade é fragmentado, cada profissional atua conforme decisão própria, pois o município não utiliza protocolos que subsidiem a prática assistencial. Foram elencadas potencialidades para o cuidado, sendo a principal a equipe multiprofissional. Quanto às dificuldades, destacou-se a procura do serviço de saúde pelo adolescente. Conclusão: Faz-se necessária uma (re)organização do modelo de atenção ao adolescente com obesidade no município. Além disso, o estudo ressalta a necessidade de maior atenção a obesidade na adolescência e provoca reflexões acerca do cuidado dispensado a este adolescente.

ABSTRACT Objective: Describe and explore, from the perspective of managers and health professionals, the care offered to adolescents with obesity in the context of Primary Health Care. Method: A case study conducted in a municipality in the state of Ceará-Brazil. Data collection took place in 2022 through semi-structured interviews. The data were examined using Bardin Content Analysis. Results: The care of obese adolescents is fragmented, and each professional acts according to their own decision, as the municipality does not use protocols that subsidize the practice of care. Potentials for care were listed, the main one being the multidisciplinary team. Regarding the difficulties, the adolescent's demand for health services was highlighted. Conclusion: It is necessary to (re) organize the care model for obese adolescents in the municipality. In addition, the study highlights the need for greater attention to adolescent obesity and causes reflections on the care provided to this adolescent.

RESUMEN Objetivo: Describir y explorar, desde la perspectiva de los gestores y profesionales sanitarios, la atención ofrecida a los adolescentes con obesidad en el ámbito de la Atención Primaria de Salud. Método: Estudio de caso, realizado en un municipio del estado de Ceará-Brasil. Los datos se recogieron en 2022 mediante entrevistas semiestructuradas. Los datos se analizaron mediante el análisis de contenido de Bardin. Resultados: La atención a los adolescentes con obesidad está fragmentada, y cada profesional actúa según su propia decisión, ya que el municipio no utiliza protocolos para subvencionar la práctica asistencial. Se enumeraron las potencialidades asistenciales, siendo la principal el equipo multiprofesional. En cuanto a las dificultades, se destaca la búsqueda del servicio sanitario por parte del adolescente. Conclusión: Es necesario (re)organizar el modelo de atención a los adolescentes con obesidad en el municipio. Además, el estudio pone de manifiesto la necesidad de prestar más atención a la obesidad en la adolescencia y suscita reflexiones sobre la atención prestada a este adolescente.

Phase synchronization in a sparse network of randomly connected neurons under the effect of Poissonian spike inputs.

This article investigates the emergence of phase synchronization in a network of randomly connected neurons by chemical synapses. The study uses the classic Hodgkin-Huxley model to simulate the neuronal dynamics under the action of a train of Poissonian spikes. In such a scenario, we observed the emergence of irregular spikes for a specific range of conductances and also that the phase synchronization of the neurons is reached when the external current is strong enough to induce spiking activity but without overcoming the coupling current. Conversely, if the external current assumes very high values, then an opposite effect is observed, i.e., the prevention of the network synchronization. We explain such behaviors considering different mechanisms involved in the system, such as incoherence, minimization of currents, and stochastic effects from the Poissonian spikes. Furthermore, we present some numerical simulations where the stimulation of only a fraction of neurons, for instance, can induce phase synchronization in the non-stimulated fraction of the network, besides cases in which for larger coupling values, it is possible to propagate the spiking activity in the network when considering stimulation over only one neuron.

In silico design of an epitope-based vaccine against PspC in Streptococcus pneumoniae using reverse vaccinology.

BACKGROUND: Streptococcus pneumoniae is a major pathogen that poses a significant hazard to global health, causing a variety of infections including pneumonia, meningitis, and sepsis. The emergence of antibiotic-resistant strains has increased the difficulty of conventional antibiotic treatment, highlighting the need for alternative therapies such as multi-epitope vaccines. In this study, immunoinformatics algorithms were used to identify potential vaccine candidates based on the extracellular immunogenic protein Pneumococcal surface protein C (PspC). METHOD: The protein sequence of PspC was retrieved from NCBI for the development of the multi-epitope vaccine (MEV), and potential B cell and T cell epitopes were identified. Linkers including EAAAK, AAY, and CPGPG were used to connect the epitopes. Through molecular docking, molecular dynamics, and immunological simulation, the affinity between MEV and Toll-like receptors was determined. After cloning the MEV construct into the PET28a ( +) vector, SnapGene was used to achieve expression in Escherichia coli. RESULT: The constructed MEV was discovered to be stable, non-allergenic, and antigenic. Microscopic interactions between ligand and receptor are confirmed by molecular docking and molecular dynamics simulation. The use of an in-silico cloning approach guarantees the optimal expression and translation efficiency of the vaccine within an expression vector. CONCLUSION: Our study demonstrates the potential of in silico approaches for designing effective multi-epitope vaccines against S. pneumoniae. The designated vaccine exhibits the required physicochemical, structural, and immunological characteristics of a successful vaccine against SPN. However, laboratory validation is required to confirm the safety and immunogenicity of the proposed vaccine design.

Repercussões e fatores preponderantes da atuação de enfermeiras especialistas: visão de gestores / Repercussions and preponderant factors of the performance of specialist nurses: view of managers / Repercusiones y factores preponderantes de la actuación de enfermeros especialistas: visión de los directivos

Objetivo: analisar a visão dos gestores sobre as repercussões e fatores preponderantes da atuação de enfermeiras especialistas em hospitais universitários federais. Método: estudo descritivo-exploratório, com abordagem qualitativa, realizado com gestores de hospitais universitários do Nordeste brasileiro, no período de outubro a novembro de 2021, após aprovação em Comitê de Ética e Pesquisa. As análises ocorreram através do software Atlas.ti® e do referencial teórico de Bardin. Resultados: neste estudo, em entrevistas realizadas com cinco gestores, duas categorias foram identificadas e analisadas, sendo a primeira sobre as repercussões e a segunda sobre os fatores preponderantes no mercado de trabalho da atuação de enfermeiras especialistas. Conclusão: os gestores relacionam positivamente a contratação de enfermeiras especialistas, uma vez que, agregam qualidade à assistência, embora existam fatores dificultadores, como a inflexibilidade de remanejamento, adoecimento e perfil feminino da classe de enfermagem(AU)

Objective: to analyze the view of managers on the repercussions and preponderant factors of the performance of specialist nurses in university hospitals. Method: descriptive-exploratory study, with a qualitative approach, carried out with managers of university hospitals in northeastern Brazil, from october to november 2021, after approval by the Ethics and Research Committee. Analyzes performed using the Atlas.ti® software and Bardin's theoretical framework. Results: in this study, in interviews carried out with five managers, two categories were identified and analyzed, the first on the repercussions, and the second on the preponderant factors in the labor market of the performance of specialist nurses. Conclusion: managers positively perceive the hiring of specialist nurses, as they add quality to the care, although there are complicating factors such as the inflexibility of relocation, illness and the female profile of the nursing class(AU)

Objetivo: analizar la visión de los directivos sobre las repercusiones y factores preponderantes de la actuación de los enfermeros especialistas en hospitales federales universitarios. Método: estudio de investigación descriptivo-exploratorio, con enfoque cualitativo, realizado junto a directivos de hospitales universitarios del Nordeste de Brasil, de octubre a noviembre de 2021, previa aprobación del Comité de Ética en Investigación. Los análisis se realizaron por medio del software Atlas.ti® y del marco teórico de Bardin. Resultados: en este estudio, en entrevistas realizadas a cinco directivos, se identificaron y analizaron dos categorías: la primera sobre las repercusiones y la segunda sobre los factores preponderantes en el mercado laboral de la actuación de los enfermeros especialistas. Conclusión: los directivos perciben positivamente la contratación de enfermeras especialistas, ya que agregan calidad a la atención, aunque existen factores que complican, como la inflexibilidad de reubicación, las enfermedades y el perfil femenino de la clase de enfermería(AU)

Advances of Reverse Vaccinology for mRNA Vaccine Design against SARS-CoV-2: A Review of Methods and Tools.

mRNA vaccines are a new class of vaccine that can induce potent and specific immune responses against various pathogens. However, the design of mRNA vaccines requires the identification and optimization of suitable antigens, which can be challenging and time consuming. Reverse vaccinology is a computational approach that can accelerate the discovery and development of mRNA vaccines by using genomic and proteomic data of the target pathogen. In this article, we review the advances of reverse vaccinology for mRNA vaccine design against SARS-CoV-2, the causative agent of COVID-19. We describe the steps of reverse vaccinology and compare the in silico tools used by different studies to design mRNA vaccines against SARS-CoV-2. We also discuss the challenges and limitations of reverse vaccinology and suggest future directions for its improvement. We conclude that reverse vaccinology is a promising and powerful approach to designing mRNA vaccines against SARS-CoV-2 and other emerging pathogens.

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective.

Malaria is a parasitic disease that, in its most severe form, can even lead to death. Insect-resistant vectors, insufficiently effective vaccines, and drugs that cannot stop parasitic infestations are making the fight against the disease increasingly difficult. It is known that the enzyme dihydroorotate dehydrogenase (DHODH) is of paramount importance for the synthesis of pyrimidine from the Plasmodium precursor, that is, for its growth and reproduction. Therefore, its blockade can lead to disruption of the parasite's life cycle in the vertebrate host. In this scenario, PfDHODH inhibitors have been considered candidates for a new therapy to stop the parasitic energy source. Given what is known, in this work, we applied molecular fractionation with conjugated caps (MFCC) in the framework of the quantum formalism of density functional theory (DFT) to evaluate the energies of the interactions between the enzyme and the different triazolopyrimidines (DSM483, DMS557, and DSM1), including a complex carrying the mutation C276F. From these results, it was possible to identify the main features of each system, focusing on the wild-type and mutant PfDHODH and examining the major amino acid residues that are part of the four complexes. Our analysis provides new information that can be used to develop new drugs that could prove to be more effective alternatives to present antimalarial drugs.

Smooth muscle contraction of the fundus of stomach, duodenum and bladder from mice exposed to a stress-based model of depression.

Several reports have demonstrated that depressive disorder is related to somatic symptoms including gastrointestinal or genitourinary alterations. The pathophysiological mechanisms underlying the gastrointestinal or genitourinary alterations associated with the depression are still not fully understood. Therefore, this study aimed to evaluate the motor activity of gastrointestinal (fundus of stomach and duodenum) and genitourinary tract (bladder) in a stress-based animal model of depression. Adult male mice were submitted to uncontrollable and unpredictable stress (learned helplessness model), controllable stress and non-stressful situations (control). Then, animals were euthanized and the fundus of stomach, duodenum segments or whole bladder were isolated and mounted in a standard organ bath preparation. We evaluated the contractile effects induced by KCl 80 mM for 5 min or carbachol (acetylcholine receptor agonist). The relaxant effects of isoproterenol (ß-adrenoceptor agonist) were also checked. Animals submitted to the learned helplessness model developed a helpless (depressive-like behavior) or resilient (does not exhibit depressive-like behavior) phenotype. The contractions induced by carbachol were diminished in fundus of stomach isolated from helpless and resilient animals. The isoproterenol-induced fundus of stomach relaxation was reduced in resilient but not helpless mice. The contractions/relaxation of duodenum segments isolated from helpless or resilient animals were not altered. Both helpless and resilient animals showed an increase in the bladder contractions induced by carbachol while the relaxant effects of isoproterenol were reduced when compared to control. Conversely, mice underwent a controllable stress situation did not exhibit alterations in the fundus of stomach or duodenum contraction/relaxation induced by pharmacological agents although a decrease in the bladder contraction induced by carbachol was found. In conclusion, incontrollable and unpredictable stress and not depressive phenotype (helpless animals) or controllable stress could be related to the alterations in motor activity of the fundus of stomach and bladder.

Refugees and access to employment in Brazil: implications for health and sociability.

This is a reflective study with the objective of analyzing the possibilities of access to employment by refugees in the Brazilian territory, in view of the socio-legal conditions in Brazil, understanding the relationship between work and health. Refugees experience the penalty of restricted access to employment, which has a significant impact on their lives. By remaining disconnected from work, they are pushed to the margins of society. In addition to this, they face difficulties in accessing adequate housing, healthcare services, education, healthy food, among others, all of which deeply affect their way of life in a foreign country with a different culture. The work becomes relevant in the discussion about access to health, goods and services necessary to live with dignity, and its implications in the work-health-disease relationship. Collaborative actions at a global level are necessary to ensure that employment opportunities are available for refugees. In this regard, this reflection articulates two basic ideas: the recognition of the importance of work in social life and living conditions, and the understanding that the determination of the health-disease process goes beyond the biological and individual choices, having historicity and a social and cultural character.

Spike protein mutations and structural insights of pangolin lineage B.1.1.25 with implications for viral pathogenicity and ACE2 binding affinity.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID -19, is constantly evolving, requiring continuous genomic surveillance. In this study, we used whole-genome sequencing to investigate the genetic epidemiology of SARS-CoV-2 in Bangladesh, with particular emphasis on identifying dominant variants and associated mutations. We used high-throughput next-generation sequencing (NGS) to obtain DNA sequences from COVID-19 patient samples and compared these sequences to the Wuhan SARS-CoV-2 reference genome using the Global Initiative for Sharing All Influenza Data (GISAID). Our phylogenetic and mutational analyzes revealed that the majority (88%) of the samples belonged to the pangolin lineage B.1.1.25, whereas the remaining 11% were assigned to the parental lineage B.1.1. Two main mutations, D614G and P681R, were identified in the spike protein sequences of the samples. The D614G mutation, which is the most common, decreases S1 domain flexibility, whereas the P681R mutation may increase the severity of viral infections by increasing the binding affinity between the spike protein and the ACE2 receptor. We employed molecular modeling techniques, including protein modeling, molecular docking, and quantum mechanics/molecular mechanics (QM/MM) geometry optimization, to build and validate three-dimensional models of the S_D614G-ACE2 and S_P681R-ACE2 complexes from the predominant strains. The description of the binding mode and intermolecular contacts of the referenced systems suggests that the P681R mutation may be associated with increased viral pathogenicity in Bangladeshi patients due to enhanced electrostatic interactions between the mutant spike protein and the human ACE2 receptor, underscoring the importance of continuous genomic surveillance in the fight against COVID -19. Finally, the binding profile of the S_D614G-ACE2 and S_P681R-ACE2 complexes offer valuable insights to deeply understand the binding site characteristics that could help to develop antiviral therapeutics that inhibit protein-protein interactions between SARS-CoV-2 spike protein and human ACE2 receptor.