In silico mapping of essential residues in the catalytic domain of PDE5 responsible for stabilization of its commercial inhibitors

Phosphodiesterase type 5 (PDE5) is an important enzyme associated with the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). Due to the relevant role of second messenger cGMP as a mediator in many physiological processes, efforts have been converged to find a safe pharmacological approach, seeking a specific, selective and potent inhibitor of the PDE5 enzyme. There are five commercial drugs with potential for clinical use: tadalafil, sildenafil, avanafil, udenafil and vardenafil. Here, we applied molecular modeling to obtain different profiles of protein-ligand interactions by adopting distinct PDE5 structures, specifically PDBid:1XOZ and two extracted from molecular dynamics (MD) simulations. The results generated by molecular docking showed several possibilities for inhibitor interactions with the catalytic pocket. Tadalafil, sildenafil and vardenafil were clearly stabilized by Gln817 via a well-oriented hydrogen bond. Another set of different interactions, such as polar, hydrophobic, pi-stacking, metal-ligand and electrostatic, were responsible for accommodating avanafil and udenafil. All of the ligands are discussed in detail with consideration of the distinct protein structures, and a profile of the probability of residue-ligand contact is suggested, with the most frequently observed being: Tyr612, His613, Ser661, Thr723, Asp724, Asp764, Leu765, Val782 and Phe786. The molecular interactions displayed herein confirm findings achieved by previous authors and also present new contacts. In addition, the discussion can help researchers obtain a molecular basis for planning new selective PDE5 inhibitors, as well as explain an inhibitor's experimental assays by considering the specific interactions occurring at the catalytic site874CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP470374/2013-62010/16947-9; 2013/05475-7; 2013/08293-7; 2013/22360-9; 2017/26687-3; 2017/02201-

A FUNÇÃO CONTROLE EM UMA INSTITUIÇÃO FEDERAL DE ENSINO SUPERIOR: UM ESTUDO DE CASO DA AUDITORIA INTERNA

O artigo aborda a atuação da Auditoria Interna de uma Instituição Federal de Ensino Superior - IFES na percepção dos seus gestores e auditores em relação às atividades desenvolvidas no apoio à gestão, evidenciando o resgate histórico da implantação da unidade de controle interno na Instituição. A pesquisa, um estudo de caso único, foi realizada por meio de metodologia qualitativa, utilizando para a coleta de dados, documentos da Instituição, questionários e entrevistas. O resultado da pesquisa concluiu que a percepção geral é de que a unidade contribui para a gestão, embora se entenda que há necessidade de aprimorar o relacionamento interno e de apoio à gestão, havendo necessidade de pró-atividade, voltar-se para o controle de resultados, promover cursos sobre as atividades de controle e aperfeiçoar a divulgação de suas atividades a fim de oportunizar uma cultura mais propícia aos controles de modo geral

A Terapia Cognitiva de Aaron Beck como Reflexividade na Alta Modernidade:: Uma Sociologia do Conhecimento

A sociology of knowledge interprets the knowledge production as tied to social situations. Leaving from this epistemological premise, our paper objectified to interpret the Aaron Beck cognitive therapy as a knowledge that is both constructed and constructor of the phenomenon of reflexivity in high modernity, as interpreted by Anthony Giddens. Our hypothesis is that the reorientation of the customer’s beliefs system, proposed by the cognitive therapy, is a form of reflexive reconstruction of self-identity aiming to surpass typical conflicts of the instability in high modernity. We designate some aspects in the cognitive therapy that identify it with reflexivity, over all the idea that the self-identity’s construction is a task in which the individual engages reflexively.Uma sociologia do conhecimento interpreta a produção do conhecimento como vinculada a situações sociais. Partindo dessa premissa epistemológica, nosso artigo objetivou interpretar a terapia cognitiva de Aaron Beck como conhecimento construído e construtor do fenômeno de reflexividade da alta modernidade, conforme interpretada por Anthony Giddens. Nossa hipótese é que a reorientação do sistema de crenças do cliente, proposta pela terapia cognitiva, é uma forma de reconstrução reflexiva da autoidentidade, visando superar conflitos típicos da instabilidade da alta modernidade. Assinalamos aspectos na terapia cognitiva que a identificam com a reflexividade, sobretudo a ideia de que a construção da autoidentidade é uma tarefa na qual o indivíduo se engaja reflexivamente

Feasibility of reducing frailty components in older adults with Alzheimer's dementia:a randomized controlled home-based exercise trial (AD-HOMEX)

Objectives: There is a need for interventions to reduce frailty in older people with Alzheimer's dementia (AD). The purpose of this study was to investigate the effect of a home-based multimodal exercise program for older adults with AD (AD-HOMEX) on frailty. Design: A parallel single-blind randomized controlled trial comparing a home-based exercise program and usual care. Setting and participants: A home-based program in Brazil. Forty individuals aged 65 years or older with mild to moderate AD. Methods: The intervention group (IG) participated in a 16-week protocol involving three 60-minute sessions per week of progressive individualized physical exercises supervised by a physical therapist. The participants in the control group (CG) maintained their usual care. Frailty was assessed using the FRAIL questionnaire, the Edmonton Frail Scale (EFS) and a subjective assessment by the evaluator (SAE) at baseline and follow-up. Per-protocol analysis was performed. Results: Thirty-five participants completed the program (IG = 16; CG = 19). Frailty improved in the IG based on the EFS (P = .004) and FRAIL (P Conclusions and implications: AD-HOMEX seems to reduce frailty and improve frailty transition patterns. Our findings provide a further theoretical basis for designing home-based physical interventions as routine practice for older frail adults with AD

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit