Explore the vast range of titles available.

The small GTPase KRAS is a key driver of carcinogenesis when mutated, and significant progress has been made in targeting KRAS G12C and other oncogenic variants. Building on our previous work demonstrating the potential of nucleotide-based inhibitors with an acrylamide warhead to target KRAS G13C , we designed and synthesized a library of nucleotide-based compounds with cyclic linkers to explore the effect of warhead orientation on reactivity toward Cys13. Using mass spectrometry, kinetic studies, and protein X-ray crystallography, we validated the binding and reactivity of these modulators. In addition, computational predictions of the conformational space of the linkers and warheads provided insights into their reactivity, which agreed well with the experimental data. These findings advance our understanding of the structure-reactivity relationship in these nucleotide-based KRAS inhibitors and will be the basis for further optimization.

The small GTPase KRAS is a key driver of carcinogenesis when mutated, and significant progress has been made in targeting KRAS and other oncogenic variants. Building on our previous work demonstrating the potential of nucleotide-based inhibitors with an acrylamide warhead to target KRAS , we designed and synthesized a library of nucleotide-based compounds with cyclic linkers to explore the effect of warhead orientation on reactivity toward Cys13. Using mass spectrometry, kinetic studies, and protein X-ray crystallography, we validated the binding and reactivity of these modulators. In addition, computational predictions of the conformational space of the linkers and warheads provided insights into their reactivity, which agreed well with the experimental data. These findings advance our understanding of the structure-reactivity relationship in these nucleotide-based KRAS inhibitors and will be the basis for further optimization.

This study evaluated the effect of different cutting intensities and years of harvesting on the morphological characteristics and production of fresh (FMP) and dry matter (DMP) of cactus pear cv. Gigante (Opuntia ficus-indica Mill) under conditions of irrigation, high planting density and fertilization, with 12 months of regrowth. The experimental was completely randomized in a factorial design (3 × 2) with 12 replicates. The treatments were three cutting intensities (preserving the mother cladode (PMC), primary cladodes (PPC), or secondary cladodes (PSC)), and two years of harvesting. The soil was classified as Cambisol Haplicum and the irrigation water was classified as C4S1 (EC 5.25 dS.m-1) density of 50,000 plants ha-1. The research evaluated plant height, number of cladodes per plant (NCP), length, width, perimeter and thickness of the cladodes, cladode area (CA), cladode area index (CAI), FMP and DMP. There was no significant interaction between treatments (P > 0.05) for the variables plant height, NCP, CAI and FMP. The variables related to cladode morphology showed a significant interaction (P < 0.05). The treatment PSC resulted in a greater DMP (P < 0.05) with a mean of 27.17 Mg ha-1 yr-1, compared to PPC (18.58 Mg ha-1 yr-1) or PMC (11.78 Mg ha-1 yr-1). The treatment PSC promoted greater NCP and forage productivity at harvest and can be considered as a management practice for the sustainability of cactus pear cv. Gigante under irrigation. The more important morphological characteristics were also influenced by the lower cutting intensities. RESUMO: A pesquisa objetivou avaliar o efeito de diferentes intensidades de corte e anos de colheita, sobre características morfológicas e produções de matéria verde (PMV) e seca (PMS) da palma forrageira cv. Gigante (Opuntia ficus-indica Mill) sob condições de irrigação, adensamento e adubação, com 12 meses de rebrota. O delineamento experimental foi inteiramente casualizado em esquema fatorial (3 x 2) com 12 repetições. Os tratamentos constaram de três intensidades de corte (preservando o cladódio mãe (PCM), os cladódios primários (PCP) e os secundários (PCS) e dois anos de colheita. Período experimental 24 meses e duas colheitas com intervalos de 12 meses. O solo foi classificado como Cambissolo Háplico e a água de irrigação C4S1 (CE 5,25 dS.m-1) e densidade de 50.000 plantas ha-1. Foram avaliados: altura e número de cladódios por planta (NCP), comprimento, largura, perímetro, espessura e área dos cladódios (AC), índice de área dos cladódios (IAC), PMV e PMS. Não foi observada interação significativa (P>0,05) dos tratamentos para as variáveis altura, NCP, IAC e PMV. Variáveis relacionadas à morfologia dos cladódios apresentaram interação significativa (P<0,05). O tratamento PCS resultou na maior PMS (P<0,05) com produtividade média de 27,2 Mg ha-1 ano-1, quando comparada à PCP (18,6 Mg ha-1 ano-1) ou PCM (11,8 Mg ha-1 ano-1). O tratamento PCS no momento da colheita promoveu maior NCP e maior produtividade de forragem, sendo uma alternativa de manejo com vistas à sustentabilidade da palma cv. Gigante sob irrigação. As características morfológicas mais importantes também foram influenciadas pelas menores intensidades de corte.

Abstract Mutations at both the receptor-binding domain (RBD) and the amino (N)-terminal domain (NTD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike (S) glycoprotein can alter its antigenicity and promote immune escape. We identified that SARS-CoV-2 lineages circulating in Brazil with mutations of concern in the RBD independently acquired convergent deletions and insertions in the NTD of the S protein, which altered the NTD antigenic-supersite and other predicted epitopes at this region. Importantly, we detected the community transmission of different P.1 lineages bearing NTD indels ∆69-70 (which can impact several SARS-CoV-2 diagnostic protocols), ∆144 and ins214ANRN, and a new VOI N.10 derived from the B.1.1.33 lineage carrying three NTD deletions (∆141–144, ∆211, and ∆256–258). These findings support that the ongoing widespread transmission of SARS-CoV-2 in Brazil generates new viral lineages that might be more resistant to antibody neutralization than parental variants of concern.