NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis

Aims  NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. Methods and results  In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed ‘transient inward current’ events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. Conclusion  The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes

Novos critérios de renda para concessão do benefício de prestação continuada da assistência social sob a ótica da dignidade da pessoa humana

O presente artigo aponta para necessidade de regulamentação do artigo 203, inciso V, da Constituição Federal de 1988, tendo em vista que, em decisão recente, o Supremo Tribunal Federal declarou a norma existente inconstitucional, pois o critério de renda para concessão do benefício, qual seja, famílias com idosos ou portadores de deficiência cuja renda familiar per capita é inferior a 1/4 do salário mínimo vigente, foi considerado defasado. Necessária é então a estipulação de um novo critério, sempre sob a ótica da dignidade da pessoa humana e analisando o impacto econômico gerado pelo número maior de beneficiados. São apresentados dois novos e hipotéticos critérios, 1/3 e 1/2 do salário mínimo per capita, fazendo a análise de ambos com base em dados do censo 2010 e outros autores e chega-se a conclusão de que o critério de renda de 1/2 per capita é o mais apropriado para a realidade brasileira atual

Cluster and virial expansions for the multi-species tonks gas

We consider a mixture of non-overlapping rods of different lengths ℓk moving in R or Z. Our main result are necessary and sufficient convergence criteria for the expansion of the pressure in terms of the activities zk and the densities ρk. This provides an explicit example against which to test known cluster expansion criteria, and illustrates that for non-negative interactions, the virial expansion can converge in a domain much larger than the activity expansion. In addition, we give explicit formulas that generalize the well-known relation between non-overlapping rods and labelled rooted trees. We also prove that for certain choices of the activities, the system can undergo a condensation transition akin to that of the zero-range process. The key tool is a fixed point equation for the pressure

Multivalent glycoconjugates as vaccines and potential drug candidates

Pathogens adhere to the host cells during the first steps of infection through multivalent interactions which involve protein–glycan recognition. Multivalent interactions are also involved at different stages of immune response. Insights into these multivalent interactions generate a way to use suitable carbohydrate ligands that are attached to a basic scaffold consisting of e.g., dendrimer, polymer, nanoparticle, etc., with a suitable linker. Thus a multivalent architecture can be obtained with controllable spatial and topology parameters which can interfere with pathogen adhesion. Multivalent glycoconjugates bearing natural or unnatural carbohydrate antigen epitopes have also been used as carbohydrate based vaccines to stimulate an innate and adaptive immune response. Designing and synthesizing an efficient multivalent architecture with optimal ligand density and a suitable linker is a challenging task. This review presents a concise report on the endeavors to potentially use multi- and polyvalent glycoconjugates as vaccines as well as anti-infectious and anti-inflammatory drug candidates

Catálogo Taxonômico da Fauna do Brasil: setting the baseline knowledge on the animal diversity in Brazil

The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others

Neurological Disorders and Risk of Arrhythmia

Neurological disorders including depression, anxiety, post-traumatic stress disorder (PTSD), schizophrenia, autism and epilepsy are associated with an increased incidence of cardiovascular disorders and susceptibility to heart failure. The underlying molecular mechanisms that link neurological disorders and adverse cardiac function are poorly understood. Further, a lack of progress is likely due to a paucity of studies that investigate the relationship between neurological disorders and cardiac electrical activity in health and disease. Therefore, there is an important need to understand the spatiotemporal behavior of neurocardiac mechanisms. This can be advanced through the identification and validation of neurological and cardiac signaling pathways that may be adversely regulated. In this review we highlight how dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, autonomic nervous system (ANS) activity and inflammation, predispose to psychiatric disorders and cardiac dysfunction. Moreover, antipsychotic and antidepressant medications increase the risk for adverse cardiac events, mostly through the block of the human ether-a-go-go-related gene (hERG), which plays a critical role in cardiac repolarization. Therefore, understanding how neurological disorders lead to adverse cardiac ion channel remodeling is likely to have significant implications for the development of effective therapeutic interventions and helps improve the rational development of targeted therapeutics with significant clinical implications

Benefícios da fisioterapia no pós-operatório de câncer de mama: estudo de caso

Introdução: O câncer de mama é o tipo de câncer mais comum entre as mulheres, porém se diagnosticado e tratado oportunamente apresenta um prognóstico relativamente bom. Mesmo com as significativas mudanças nas técnicas de tratamento ainda são muitas as consequências físicas e emocionais encontradas nestes pacientes. Por isso, a abordagem multidisciplinar é fundamental, e a fisioterapia representa um importante papel nestes casos preservando e restaurando a integridade cinético-funcional dos órgãos e sistemas. Objetivos: Verificar os benefícios proporcionados por um programa de fisioterapia em uma paciente no pós-operatório de câncer de mama, buscando uma melhora do quadro álgico, da amplitude de movimento e da força muscular. Materiais e métodos: O presente estudo foi delineado pelo método qualiquantitativo em saúde, do tipo estudo de caso, realizado na Clínica Escola de Fisioterapia da URI – campus de Erechim, com uma paciente de 60 anos que se encontrava no segundo mês de pós-operatório de câncer de mama direita. Resultados: Ao primeiro encontro a paciente relatou dores em região axilar e de membro superior direito e cervical, além disso, verificou-se diminuição da amplitude de movimento de membros superiores e diminuição de força muscular do membro superior homolateral à cirurgia. O protocolo fisioterapêutico realizado foi baseado nas limitações funcionais avaliadas, e teve duração de 12 sessões. Conclusão: Após esse período se verificou que o protocolo de tratamento fisioterapêutico foi eficaz no pós-operatório de câncer de mama, proporcionando diminuição da dor, prevenção do linfedema, aumento da amplitude de movimento de membros superiores, sem alteração na força muscular.