Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity.

The development of novel antivirals is crucial not only for managing current COVID-19 infections but for addressing potential future zoonotic outbreaks. SARS-CoV-2 main protease (Mpro) is vital for viral replication and viability and therefore serves as an attractive target for antiviral intervention. Herein, we report the optimization of a cyclic peptide inhibitor that emerged from an mRNA display selection against the SARS-CoV-2 Mpro to enhance its cell permeability and in vitro antiviral activity. By identifying mutation-tolerant amino acid residues within the peptide sequence, we describe the development of a second-generation Mpro inhibitor bearing five cyclohexylalanine residues. This cyclic peptide analogue exhibited significantly improved cell permeability and antiviral activity compared to the parent peptide. This approach highlights the importance of optimizing cyclic peptide hits for activity against intracellular targets such as the SARS-CoV-2 Mpro.

Financial forecasts accuracy in Brazil's social security system.

Long-term social security statistical forecasts produced and disseminated by the Brazilian government aim to provide accurate results that would serve as background information for optimal policy decisions. These forecasts are being used as support for the government's proposed pension reform that plans to radically change the Brazilian Constitution insofar as Social Security is concerned. However, the reliability of official results is uncertain since no systematic evaluation of these forecasts has ever been published by the Brazilian government or anyone else. This paper aims to present a study of the accuracy and methodology of the instruments used by the Brazilian government to carry out long-term actuarial forecasts. We base our research on an empirical and probabilistic analysis of the official models. Our empirical analysis shows that the long-term Social Security forecasts are systematically biased in the short term and have significant errors that render them meaningless in the long run. Moreover, the low level of transparency in the methods impaired the replication of results published by the Brazilian Government and the use of outdated data compromises forecast results. In the theoretical analysis, based on a mathematical modeling approach, we discuss the complexity and limitations of the macroeconomic forecast through the computation of confidence intervals. We demonstrate the problems related to error measurement inherent to any forecasting process. We then extend this exercise to the computation of confidence intervals for Social Security forecasts. This mathematical exercise raises questions about the degree of reliability of the Social Security forecasts.

The doublecortin gene family and disorders of neuronal structure.

The doublecortin gene family is associated with subcortical band heterotopia, lissencephaly, epilepsy, developmental dyslexia and retinitis pigmentosa. At least 11 genes homologous to the doublecortin gene exist in humans and mice. Cellular processes regulated by different members of the doublecortin family involve neuronal migration, neurogenesis and eye receptor development. Underlying mechanisms include regulation of cytoskeletal structure and microtubule-based transport. Through their doublecortin-domains, doublecortin proteins can bind microtubules and regulate microtubule-dependent processes. However, this regulation is complex and involves many interacting proteins. Moreover, different spatiotemporal expression patterns and the generation of splice variants further contribute to this complexity. The doublecortin-like kinase 1 gene in particular, produces splice variants with different protein domains such as doublecortin-domains, a serine, threonine and proline-rich domain and a serine/threonine kinase-domain. Here, we review our current knowledge on the doublecortin gene family with an emphasis on proteins interacting with doublecortin domains and other domains. In addition, to generate new hypotheses for further research, we analyzed the serine, threonine and proline-rich domain for predicted protein interactions.

Alterações morfométricas em músculo respiratório de ratos submetidos à imobilização de pata / Morphometric alterations in respiratory muscle of rats submitted to paw immobilization

A imobilização é um recurso frequentemente utilizado na prática clínica, sendo comum em patologias álgicas e nas fraturas. O objetivo deste estudo foi analisar a influência do processo de imobilização em músculo do sistema respiratório, o diafragma. O experimento foi efetuado com 12 ratos Wistar machos divididos em dois grupos, controle e imobilizado. O procedimento de imobilização foi realizado através de um método alternativo de imobilização por fita adesiva, sendo mantida por duas semanas. Analisou-se a morfometria das fibras do diafragma com coloração de hematoxilina e eosina. Ao compararmos o diâmetro médio das fibras musculares do diafragma dos animais imobilizados (47,15μm ± 0,329μm) em relação ao controle (54,67μm ± 0,396μm), encontramos diferença estatística entre os grupos (p < 0,0001). Considerando os dados encontrados, foi possível concluir que a imobilização de pata, no modelo utilizado, foi capaz de gerar hipotrofia da musculatura respiratória, assim como um quadro geral de redução de massa corporal do animal.

Immobilization is a frequently used procedure in clinical practice and common in pain diseases and fractures. This study examined the influence of immobilization in a muscle-related respiratory system, the diaphragm. This experiment was conducted with twelve male rats divided into two groups, control and immobilized with an alternative method of restraining by tape, kept for two weeks. We analyzed the morphometry of the diaphragm muscle fibers with hematoxylin/eosin staining. Statistical difference was found (p < 0.0001) when the average diameter of the diaphragm muscle fibers of immobilized animals (47.15μm ± 0.329μm) was compared to the ones in the control group (54.67μm ± 0.396μm). Considering the results, it can be concluded that the immobilization of the animal paw in the used model was able to produce hypotrophy of respiratory musculature, as well as a general framework for reducing the mass of the animal.