The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type ...Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.
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•Mice expressing analog-sensitive Cdk1 allow identification of Cdk1 substrates•Many Cdk1 substrates in ESCs are chromatin-bound at poised or transcribed genes•Cdk1 phosphorylates a large number of epigenetic regulators•Cdk1 phosphorylates and inactivates H3K79 methyltransferase Dot1l
Cdk1 drives mitotic entry and progression. Michowski et al. generated mice expressing analog-sensitive Cdk1. The authors found that in embryonic stem cells, Cdk1 phosphorylates a large number of epigenetic regulators and controls the global epigenetic landscape. Decreased Cdk1 activity during differentiation allows coordinated expression of differentiation genes.
Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs ...(miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.
•Characterization of human microRNAs which target the cell-cycle machinery•Profiling cell-cycle-targeting miRNAs against 122 human cancer cell lines from CCLE•Algorithm to predict the response of tumors to cell-cycle-targeting miRNAs•In vivo delivery of cell-cycle-targeting miRNAs inhibits cancer growth
By performing screens for miRNAs targeting cell-cycle proteins, Hydbring et al. identify a class of miRNAs that target multiple cyclins and CDKs. Nanoparticle delivery of these miRNAs inhibits tumor growth in several xenograft models, including treatment-refractory patient-derived xenografts.
E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by ...activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin Emight represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.
Objectives:
Early in the COVID-19 pandemic, several outbreaks were linked with facilities employing essential workers, such as long-term care facilities and meat and poultry processing facilities. ...However, timely national data on which workplace settings were experiencing COVID-19 outbreaks were unavailable through routine surveillance systems. We estimated the number of US workplace outbreaks of COVID-19 and identified the types of workplace settings in which they occurred during August–October 2021.
Methods:
The Centers for Disease Control and Prevention collected data from health departments on workplace COVID-19 outbreaks from August through October 2021: the number of workplace outbreaks, by workplace setting, and the total number of cases among workers linked to these outbreaks. Health departments also reported the number of workplaces they assisted for outbreak response, COVID-19 testing, vaccine distribution, or consultation on mitigation strategies.
Results:
Twenty-three health departments reported a total of 12 660 workplace COVID-19 outbreaks. Among the 12 470 workplace types that were documented, 35.9% (n = 4474) of outbreaks occurred in health care settings, 33.4% (n = 4170) in educational settings, and 30.7% (n = 3826) in other work settings, including non–food manufacturing, correctional facilities, social services, retail trade, and food and beverage stores. Eleven health departments that reported 3859 workplace outbreaks provided information about workplace assistance: 3090 (80.1%) instances of assistance involved consultation on COVID-19 mitigation strategies, 1912 (49.5%) involved outbreak response, 436 (11.3%) involved COVID-19 testing, and 185 (4.8%) involved COVID-19 vaccine distribution.
Conclusions:
These findings underscore the continued impact of COVID-19 among workers, the potential for work-related transmission, and the need to apply layered prevention strategies recommended by public health officials.
Standards for burn nursing practice Bayley, E W; Braun, A E; D'Italia, J G ...
Journal of burn care & rehabilitation,
1989 Jul-Aug, Letnik:
10, Številka:
4
Journal Article
Social anxiety disorder (SAD) is highly prevalent yet largely undetected and untreated in adolescents despite the availability of effective treatments. Implementing interventions in schools enhances ...recognition and access to treatment for SAD. However, without reliable means to accurately identify youth in need of services, school-based interventions are not feasible. The purpose of this study is to evaluate the utility of a two-step, school-based screening approach to identify youth with SAD. Students at three public high schools were screened with self-report questionnaires or nominated by school personnel. Subsequently, a brief telephone assessment of student symptoms was completed with students’ parents. Results showed that using both questionnaires and telephone assessments yielded acceptable detection rates, while school staff nominations were not beneficial. This study provides support for the use of a two-step screening procedure consisting of student self-reports followed by brief parent telephone interviews to identify youth with clinically impairing social anxiety. Implications for enhancing school-based detection of and intervention for socially anxious adolescents are discussed.
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