No abstract
There is an interest in identifying Anaphase Promoting-Complex/Cyclosome (APC/C) inhibitors that lead to sensitivity to microtubule poisons as a strategy for targeting cancer cells. Using budding yeast Saccharomyces cerevisiae, peptides derived from the Mitotic Arrest Deficient 2 (Mad2)-binding motif of Cell Division Cycle 20 (Cdc20) were observed to inhibit both Cdc20- and CDC20 Homology 1 (Cdh1)-dependent APC/C activity. Over expression of peptides in vivo led to sensitivity to a microtubule poison and, in a recovery from a microtubule poison arrest, delayed degradation of yeast Securin protein Precocious Dissociation of Sisters 1 (Pds1). Peptides with mutations in the Cdc20 activating KILR-motif still bound APC/C, but lost the ability to inhibit APC/C in vitro and lost the ability to induce sensitivity to a microtubule poison in vivo. Thus, an APC/C binding and activation motif that promotes mitotic progression, namely the Cdc20 KILR-motif, can also function as an APC/C inhibitor when present in excess. Another activator for mitotic progression after recovery from microtubule poison is p31comet, where a yeast predicted open-reading frame YBR296C-A encoding a 39 amino acid predicted protein was identified by homology to p31comet, and named Tiny Yeast Comet 1 (TYC1). Tyc1 over expression resulted in sensitivity to microtubule poison. Tyc1 inhibited both APC/CCdc20 and APC/CCdh1 activities in vitro and bound to APC/C. A homologous peptide derived from human p31comet bound to and inhibited yeast APC/C demonstrating evolutionary retention of these biochemical activities. Cdc20 Mad2-binding motif peptides and Tyc1 disrupted the ability of the co-factors Cdc20 and Cdh1 to bind to APC/C, and co-over expression of both together in vivo resulted in an increased sensitivity to microtubule poison. We hypothesize that Cdc20 Mad2-binding motif peptides, Tyc1 and human hp31 peptide can serve as novel molecular tools for investigating APC/C inhibition that leads to sensitivity to microtubule poison in vivo.
Chinese people have a very good mask-wearing culture; it is normal to wear masks to protect their faces from wind and pollution. Thus, they easily accept the wearing of masks to prevent infectious diseases, as seen with the Corona Virus Disease 2019 (COVID-19) in China today. However, Chinese people have a dangerous eating culture: they share foods or soups from the same bowls and pots using their personal chopsticks/spoons and emphasize loud talking when eating at banquets or at homes. We think this eating culture has raised the infection risk of COVID-19 from person to person by contamination. Therefore, in this paper, we propose models to elucidate how people are infected with COVID-19 through droplet transmission when eating with Chinese cultural context to address the urgent need to change Chinese eating culture; we believe these study models can help not only the Chinese people, but also other national people, to raise mindfulness of public health, prevent COVID-19 and other infectious diseases, at the present pandemic and in the future.
BackgroundThe DONATE HCV Trial demonstrated that hearts and lungs can be safely transplanted from HCV-infected donors using a shortened, 4-week, pre-emptive course of direct-acting antivirals (DAA). The 6-month results from that study of 35 patients are encouraging, but longer-term data from a larger cohort are needed to better define the risk–benefit profile.MethodsWe conducted a single-center trial to transplant thoracic organs from HCV viremic donors, irrespective of HCV genotype, to HCV-uninfected adults. Sofosbuvir/velpatasvir, a pan-genotypic DAA, was pre-emptively administered for 4 weeks, beginning within hours of transplant. The primary outcome was a composite of HCV clearance and graft survival at 6 months post-transplant. Secondary outcomes included graft survival and mortality at 12 months and the occurrence of grade 3 or higher adverse events (AEs). This protocol is IRB approved and all participants provided written informed consent (NCT03086044).ResultsBetween March 2017 and March 2019, 57 participants were enrolled: 46 received lung and 11 received heart transplants. The median donor HCV viral load (VL) was 889,817 IU/mL (IQR 212,062–4,641,078). Of the 57 recipients, 53 (93%) had detectable HCV VL immediately after transplant, with median VL of 1,460 IU/mL (IQR 463–6,618). HCV VL became negative by about 2 weeks and subsequently remained undetectable in all participants. Forty-nine of 49 (100%) and 34 of 35 (97%) participants were alive with excellent graft function and an undetectable HCV VL at 6 months and 1-year post-transplant, respectively. No treatment-related serious AEs were identified. Outcomes between transplant recipients from HCV donors vs. non-HCV donors were similar, including the occurrence of renal failure, respiratory failure, and non-HCV infections.ConclusionIn patients who received thoracic organs from HCV viremic donors, a 4-week antiviral treatment course initiated within hours of transplant prevented the establishment of HCV infection. These data demonstrate that thoracic organs from HCV viremic donors can be transplanted safely with excellent graft and recipient survival at 12 months with a similar AE profile compared with transplant recipients who received thoracic organs from non-HCV donors. Two-year outcomes will be available in October 2019.Disclosures All Authors: No reported Disclosures.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.