RESUMO
(1) Background: The COVID-19 pandemic illuminated vulnerabilities in the Canadian health care system and exposed gaps and challenges across the cancer care continuum. Canada is experiencing significant disruptions to cancer-related services, and the impact these disruptions (delays/deferrals/cancellations) have on the health care system and patients are yet to be determined. Given the potential adverse ramifications, how can Canada's health care systems build resilience for future threats? (2) Methods: To answer this question, CCC facilitated a series of four thought-leadership roundtables, each representing the views of four different stakeholder groups: patients, physicians, health care system leaders, and researchers. (3) Results: Six themes of strength were identified to serve as a springboard for building resilience including, (1) advancing virtual care and digital health technologies to prevent future interruptions in cancer care delivery. (2) developing real-time data metrics, data sharing, and evidence-based decision-making. (3) enhancing public-private-non-profit partnerships to advance research and strengthen connections across the system. (4) advancing patient-centricity in cancer research to drive and encourage precision medicine approaches to care. (5) investing in training and hiring a robust supply of health care human resources. (6) implementing a national strategy and infrastructure to ensure inter-provincial collaborative data sharing (4). Conclusions: A resilient health care system that can respond to shocks and threats is not an emergency system; it is a robust everyday system that can respond to emergencies.
Assuntos
COVID-19 , Neoplasias Colorretais , COVID-19/epidemiologia , Canadá , Neoplasias Colorretais/terapia , Humanos , Liderança , PandemiasRESUMO
The ribonucleolytic exosome complex is central for nuclear RNA degradation, primarily targeting non-coding RNAs. Still, the nuclear exosome could have protein-coding (pc) gene-specific regulatory activities. By depleting an exosome core component, or components of exosome adaptor complexes, we identify â¼2900 transcription start sites (TSSs) from within pc genes that produce exosome-sensitive transcripts. At least 1000 of these overlap with annotated mRNA TSSs and a considerable portion of their transcripts share the annotated mRNA 3' end. We identify two types of pc-genes, both employing a single, annotated TSS across cells, but the first type primarily produces full-length, exosome-sensitive transcripts, whereas the second primarily produces prematurely terminated transcripts. Genes within the former type often belong to immediate early response transcription factors, while genes within the latter are likely transcribed as a consequence of their proximity to upstream TSSs on the opposite strand. Conversely, when genes have multiple active TSSs, alternative TSSs that produce exosome-sensitive transcripts typically do not contribute substantially to overall gene expression, and most such transcripts are prematurely terminated. Our results display a complex landscape of sense transcription within pc-genes and imply a direct role for nuclear RNA turnover in the regulation of a subset of pc-genes.
Assuntos
Exossomos/genética , Genoma Humano/genética , Fases de Leitura Aberta/genética , RNA/genética , Sítio de Iniciação de Transcrição , Regulação da Expressão Gênica/genética , Células HeLa , Humanos , Anotação de Sequência Molecular , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA não Traduzido/genéticaRESUMO
ARS2 is a conserved protein centrally involved in both nuclear RNA productive and destructive processes. To map features of ARS2 promoting RNA decay, we utilized two different RNA reporters, one of which depends on direct ARS2 tethering for its degradation. In both cases, ARS2 triggers a degradation phenotype aided by its interaction with the poly(A) tail exosome targeting (PAXT) connection. Interestingly, C-terminal amino acids of ARS2, responsible for binding the RNA 5'cap binding complex (CBC), become dispensable when ARS2 is directly tethered to the reporter RNA. In contrast, the Zinc-finger (ZnF) domain of ARS2 is essential for the decay of both reporters and consistently co-immunoprecipitation analyses reveal a necessity of this domain for the interaction of ARS2 with the PAXT-associated RNA helicase MTR4. Taken together, our results map the domains of ARS2 underlying two essential properties of the protein: its RNP targeting ability and its capacity to recruit the RNA decay machinery.
Assuntos
Proteínas Nucleares/genética , RNA Helicases/genética , Estabilidade de RNA/genética , RNA Mensageiro/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Células HEK293 , Humanos , Complexo Proteico Nuclear de Ligação ao Cap/genética , Proteínas Nucleares/química , Domínios Proteicos/genética , RNA Helicases/química , RNA Mensageiro/química , RNA Nuclear/química , RNA Nuclear/genéticaRESUMO
The possibility of tuning the nonlinear effective response of composite materials and structures is of great importance for developing new concepts such as soft metamaterials, acoustic diodes, nonlinear waveguides and phononic crystals. In this paper we develop a homogenization technique for dispersions of nonlinear particles in a soft matrix able to take account of second and third order elastic nonlinearities. Based on this method, we prove the possibility to strongly amplify a given particles nonlinearity (either the second or the third one) under specific conditions concerning the linear response of the two constituents (particles and matrix). We finally give a realistic example based on a population of porous polymer particles embedded in a PDMS matrix.
