Our data establish premature senescence of myofibroblasts as an essential antifibrotic mechanism and potential therapeutic target in myocardial fibrosis.

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Background: Negative feedback regulation of insulin signaling involves ubiquitin-dependent degradation of insulin receptor substrate 1 (IRS1). Results: Cullin-RING E3 ubiquitin ligase 7 (CRL7) mediates the ubiquitination of IRS1 in hyperphosphorylated form. Conclusion: Multisite IRS1 phosphorylation triggers interactions with CRL7 for ubiquitin modification. Significance: Insulin signaling is self-restrained when its downstream effector kinases are hyperactivated to trigger the negative feedback inhibition.

OBJECTIVE To determine a just and consistent practice for creating nursing assignments. BACKGROUND Traditional methods of assigning patients to nurses may lead to unbalanced nursing workload. This article describes the ongoing, hospital-wide effort to evaluate and implement a nursing assignment tool based on electronic health record (EHR) functionality and auto-calculated nursing workload scores. METHODS EHR records of individual patient workload scores from all hospital units were collected from August 2017 to June 2018. A nurse-specific total workload score was summed for each staff. Then, each hospital unit's mean nurse workload score and standard deviation, along with the unit's nurse-to-patient ratio, were used to calculate levels of high, medium, and low nursing workload measurement (NWM). RESULTS Mean patient-specific workload scores varied greatly across hospital units. Unit-specific nurse-to-patient ratios were factored into NWM scores to create ranges for assignments that were relatively consistent across the institution. CONCLUSION The use of objective, electronically generated nursing workload scores, combined with traditional nurse-to-patient ratios, provides accurate real-time nurse staffing needs that can inform best practice in staffing. The confirmation of individual patient workload scores and an appreciation for the complexity of EHR vendor rules are necessary for successful implementation. Automation ensures patient safety, staff satisfaction, and optimal resource allocation.

Simian virus 40 (SV40) large tumor antigen (LT) triggers oncogenic transformation by inhibition of key tumor suppressor proteins, including p53 and members of the retinoblastoma family. In addition, SV40 transformation requires binding of LT to Cullin 7 (CUL7), a core component of Cullin-RING E3 ubiquitin ligase 7 (CRL7). However, the pathomechanistic effects of LT-CUL7 interaction are mostly unknown. Here we report both in vitro and in vivo experimental evidence that SV40 LT suppresses the ubiquitin ligase function of CRL7. We show that SV40 LT, but not a CUL7 binding-deficient mutant (LT Δ69-83 ), impaired 26S proteasomedependent proteolysis of the CRL7 target protein insulin receptor substrate 1 (IRS1), a component of the insulin and insulin-like growth factor 1 signaling pathway. SV40 LT expression resulted in the accumulation and prolonged half-life of IRS1. In vitro, purified SV40 LT reduced CRL7-dependent IRS1 ubiquitination in a concentration-dependent manner. Expression of SV40 LT, or depletion of CUL7 by RNA interference, resulted in the enhanced activation of IRS1 downstream signaling pathways phosphatidylinositol-3-kinase/AKT and Erk mitogen-activated pathway kinase, as well as up-regulation of the downstream target gene c-fos. Finally, SV40 LT-positive carcinoma of carcinoembryonic antigen 424/SV40 LT transgenic mice displayed elevated IRS1 protein levels and activation of downstream signaling. Taken together, these data suggest that SV40 LT protects IRS1 from CRL7-mediated degradation, thereby sustaining high levels of promitogenic IRS1 downstream signaling pathways. S tudies with simian virus 40 (SV40), a member of the Polyomaviridae family of tumor viruses, have led to fundamental insights into molecular processes of cell transformation and oncogenesis (1, 2). SV40 encodes the large tumor antigen (LT) with the potential to transform cells in culture and induce tumors in rodents. The tumorigenic features of SV40 have been attributed to binding and deactivation of key tumor suppressor proteins of the host cell including p53 and members of the retinoblastoma (pRB) family (1-3). In addition, SV40 LT was shown to be physically associated with Cullin 7 (CUL7; also named p185 or p193) (4, 5) as well as insulin receptor substrate 1 (IRS1) (6). It has been proposed that the association of SV40 LT with either CUL7 or IRS1 is critical to SV40 oncogenic transformation (7-9). However, the functional effect of LT interaction with CUL7/IRS1 and their pathophysiological interrelation remains mostly unknown.CUL7 is a scaffold protein responsible for assembling the multisubunit Cullin-RING E3 ubiquitin ligase 7 (CRL7) that consists of the RING-finger protein ROC1 and the Skp1-Fbw8 substrate-targeting subunit (10, 11). Genetic studies documented a pivotal growth-regulatory role of CRL7. Both cul7 (12) and fbw8 (13) null mice exhibit intrauterine growth retardation. In addition, CUL7 germ-line mutations were linked to 3-M syndrome, a hereditary disorder characterized by pre-and postnatal growth retardation in hum...

The Feed Materials Production Center, northwest of Cincinnati, processed uranium concentrates and uranium compounds recycled from other stages of nuclear weapons production, as well as some uranium ore and thorium. Particulate releases were primarily uranium (natural, depleted, and slightly enriched. In addition, two large silos containing radium-bearing residues were emission sources of radon and its decay products. The Fernald Dosimetry Reconstruction Project was undertaken to help the Centers for Disease Control and Prevention to evaluate the impact of the Feed Materials Production Center on the public from radionuclides released to the environment from 1951 through 1988. At this point in the study, the project has estimated the quantities of radioactive materials released to air, surface water, and in groundwater; developed the methodology to describe the environmental transport of the materials; developed mathematical models to calculate the resulting radiation doses; and evaluated environmental monitoring data to verify that the estimates of releases and transport are reasonable. Thorough review of historical records and extensive interaction with former and current employees and residents have been the foundation for reconstructing routine operations, documenting accidents, and evaluating unmonitored emission sources. The largest releases of uranium to air and water occurred in the 1950's and 1960's. Radon releases from the silos remained elevated through most of the 1970's. The quantity of uranium released to surface water was much less than that released to air. Best estimates of releases are reported as median values, with associated uncertainties calculated as an integral part of the estimates. Screening calculations showed that atmospheric pathways dominate the total dose from Feed Materials Production Center releases. Accordingly, the local meteorology, effluent particle size and chemical form, and wet and dry deposition, were particularly important in this study. The final goal of the project is the calculation of radiation doses to people living in the study domain, which is represented by a circle with radius of 10 km centered on the Feed Materials Production Center production area.

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Members of the public are becoming increasingly interested in understanding risks associated with their exposure to radionuclides and chemicals in the environment. They also want to be more involved in decision making about future exposures to risks. This paper reviews one community's involvement in decisions about technical methods to calculate soil cleanup criteria for the Rocky Flats Environmental Technology Site near Denver, Colorado. The public anticipated that much of the site would be available for their use following cleanup. Final decisions regarding the future use of the site have yet to be made; however, the soil action levels were developed for this eventuality. When the public expressed considerable concern about cleanup standards for the site in 1996, a community group met to focus efforts on reviewing the cleanup standards. Later, the U.S. Department of Energy officially established the community panel to oversee an independent calculation of radionuclide soil action levels that would be used as the basis for cleanup at Rocky Flats. The primary radionuclide of concern was 239+240Pu. The Radionuclide Soil Action Level Oversight Panel (Panel) was substantively involved in all aspects of the work, from selecting the contractor, approving the computer code that formed the basis of the calculation, and assisting in developing the exposure scenarios, to selecting the values for the numerous input parameters. Communicating the uncertainties to the public, which was a major component of the analysis of soil action levels, presented a unique challenge. Over the course of the 18-mo project, the Panel and interested members of the public gained an understanding of the technical elements of the calculation and the sensitivities of the different parameters. This project serves as an excellent model of the effectiveness of public involvement in science and decision making for the future. It also illustrates the public expectations, difficulties, and time commitments encountered when making scientific decisions in a public forum. Although the process was time consuming for the scientists responsible for the calculations, a more technically defensible as well as publicly acceptable soil action level emerged. The technical approach developed during the project has been recommended for use as a decision-making tool for cleanup of the site.