Sao Carlos Institute of Physics, University of Sao Paulo, Sao Carlos, Brazil. Electronic address:
Published: March 2023
AI Article Synopsis
Article Abstract
SARS-CoV-2 is the causative agent of COVID-19. The main viral protease (M) is an attractive target for antivirals. The clinically approved drug nirmatrelvir and the clinical candidate ensitrelvir have so far showed great potential for treatment of viral infection. However, the broad use of antivirals is often associated with resistance generation. Herein, we enzymatically characterized 14 naturally occurring M polymorphisms that are close to the binding site of these antivirals. Nirmatrelvir retained its potency against most polymorphisms tested, while mutants G143S and Q189K were associated with diminished inhibition constants. For ensitrelvir, diminished inhibition constants were observed for polymorphisms M49I, G143S, and R188S, but not for Q189K, suggesting a distinct resistance profile between inhibitors. In addition, the crystal structures of selected polymorphisms revealed interactions that were critical for loss of potency. In conclusion, our data will assist the monitoring of potential resistant strains, support the design of combined therapy, as well as assist the development of the next generation of M inhibitors.
Learning new categories is fundamental to cognition, occurring in daily life through various sensory modalities. However, it is not well known how acquiring new categories can modulate the brain networks. Resting-state functional connectivity is an effective method for detecting short-term brain alterations induced by various modality-based learning experiences.
It is now understood that brain metastases do not occur randomly but have distinct spatial patterns depending on the origin of the cancer. According to the "seed and soil" hypothesis, the final colonization of metastatic cells is the result of their adaptation to the altered environment. To investigate the most favorable microenvironment for brain metastasis, we analyzed neuroimaging data from 177 patients with breast cancer brain metastasis and 548 patients with lung cancer brain metastasis to create a replicable probabilistic map of metastatic locations.
Division of Cardiology, Department of Medicine, Warren Alpert Medical School of Brown University, and Lifespan Cardiovascular Institute, Providence, Rhode Island, USA.
This state-of-the-art review describes the potential etiologies, pathophysiology, and management of mixed shock in the context of a proposed novel classification system. Cardiogenic-vasodilatory shock occurs when cardiogenic shock is complicated by inappropriate vasodilation, impairing compensatory mechanisms, and contributing to worsening shock. Vasodilatory-cardiogenic shock occurs when vasodilatory shock is complicated by myocardial dysfunction, resulting in low cardiac output.
Background: Measles is a very contagious illness that can be clinically diagnosed and intervened quickly. It is caused by the measles virus Morbillivirus. The disease has a case fatality rate of 5% to 10% in the sub-Saharan region.
