Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the discovery of a short-lived chaperone that is required for the correct maturation of the eukaryotic 20S proteasome and is destroyed at a specific stage of the assembly process. The S. cerevisiae Ump1p protein is a component of proteasome precursor complexes containing unprocessed beta subunits but is not detected in the mature 20S proteasome. Upon the association of two precursor complexes, Ump1p is encased and is rapidly degraded after the proteolytic sites in the interior of the nascent proteasome are activated. Cells lacking Ump1p exhibit a lack of coordination between the processing of beta subunits and proteasome assembly, resulting in functionally impaired proteasomes. We also show that the propeptide of the Pre2p/Doa3p beta subunit is required for Ump1p's function in proteasome maturation.
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PMID:Ump1p is required for proper maturation of the 20S proteasome and becomes its substrate upon completion of the assembly. 949 90

This article has summarized research and policy activities undertaken in Washington State over the past several years to identify the key problems that result in poor quality and excessive disability among injured workers, and the types of system and delivery changes that could best address these problems in order to improve the quality of occupational health care provided through the workers' compensation system. Our investigations have consistently pointed to the lack of coordination and integration of occupational health services as having major adverse effects on quality and health outcomes for workers' compensation. The Managed Care Pilot Project, a delivery system intervention, focused on making changes in how care is organized and delivered to injured workers. That project demonstrated robust improvements in disability reduction; however, worker satisfaction suffered. Our current quality improvement initiative, developed through the Occupational Health Services Project, synthesizes what was learned from the MCP and other pilot studies to make delivery system improvements. This initiative seeks to develop provider incentives and clinical management processes that will improve outcomes and reduce the burden of disability on injured workers. Fundamental to this approach are simultaneously preserving workers' right to choose their own physician and maintaining flexibility in the provision of individualized care based on clinical need and progress. The OHS project then will be a "real world" test to determine if aligning provider incentives and giving physicians the tools they need to optimize occupational health delivery can demonstrate sustainable reduction in disability and improvements in patient and employer satisfaction. Critical to the success of this initiative will be our ability to: (1) enhance the occupational health care management skills and expertise of physicians who treat injured workers by establishing community-based Centers of Occupational Health and Education; (2) design feasible methods of monitoring patient outcomes and satisfaction with the centers and with the providers working with them in order to assess their effectiveness and value; (3) establish incentives for improved outcomes and worker and employer satisfaction through formal agreements with the centers and providers; and (4) develop quality indicators for the three targeted conditions (low back sprain, carpal tunnel syndrome, and fractures) that serve as the basis for both quality improvement processes and performance-based contracting. What lessons or insights does our experience offer thus far? The primary lesson is the importance of making effective partnerships and collaborations. Our policy and research activities have benefited significantly from the positive relationship the DLI established with the practice community through the Washington State Medical and Chiropractic Associations and from the DLI's close association with the Healthcare Subcommittee of the Workers' Compensation Advisory Committee. This committee is established by state regulation and serves as a forum for dialogue between the committee and the employer and labor communities. Our experience thus underscores the importance of establishing broad-based support for delivery system innovations. Our research activities have also benefited from the close collaboration between DLI program staff and UW health services researchers. The DLI staff brought important program and policy experience, along with an appreciation of the context and environment within which the research, policy, and R&D activities were conducted. The UW research team brought scientific rigor and methodological expertise to the design and implementation of the research and policy activities. In Washington State, the DLI represents a "single payer" for the purposes of workers' compensation. As discussed earlier, Washington State, along with five other states, has a state-fund system that requires all employers that are not self-insured to purchase workers' compensation insurance through the state fund. No matter what one feels about the merits or drawbacks of a single-payer system of health care financing, the fact is that such a system creates important opportunities for policy initiatives and for research and evaluation. Our ability to access population-based data on injured workers and to develop policy initiatives through innovation and pilot testing to assess whether proposed changes are really improvements has been critical. Understanding what works within the constraints and complexities of the system on a small scale is critical in order to bring forth policy and processes that will be of value systemwide. Finally, we note that general medical care faces many of the same quality-related problems and challenges as occupational health care. Medical care for chronic diseases, such as diabetes, is often fragmented and uncoordinated. (ABSTRACT TRUNCATED)
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PMID:Improving the quality of workers' compensation health care delivery: the Washington State Occupational Health Services Project. 1128 95

The present study has been designed to investigate the potential role of ubiquitin proteasome system and other proteases in acute as well as delayed aspects of ischemic preconditioning induced reversal of ischemia-reperfusion injury in mouse brain. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24 h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using elevated plus-maze test. Rota rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min (ischemic preconditioning) both immediately before (for acute preconditioning) and 24 h before (for delayed preconditioning) global cerebral ischemia prevented markedly ischemia-reperfusion-induced cerebral injury as measured in terms of infarct size, loss of memory and motor coordination. Z-Leu-Leu-Phe-Chinese hamster ovary (CHO) (2 mg/kg, intraperitoneally (i.p.)), an inhibitor of ubiquitin proteasome system and other proteases attenuated the neuroprotective effect of both the acute as well as delayed ischemic preconditioning. It is concluded that the neuroprotective effect of both the acute as well as delayed phases of ischemic preconditioning may be due to the activation of ubiquitin proteasome system and other proteases.
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PMID:Possible involvement of ubiquitin proteasome system and other proteases in acute and delayed aspects of ischemic preconditioning of brain in mice. 2113 32

More studies are required to develop therapeutic agents for treating spinocerebellar ataxia type 3 (SCA3), which is caused by mutant polyglutamine-expanded ataxin-3 and is the most prevalent subtype of spinocerebellar ataxias. T1-11 [N6-(4-Hydroxybenzyl) adenosine], isolated from a Chinese medicinal herb Gastordia elata, is an adenosine A2A receptor agonist. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. T1-11 exerted a therapeutic effect on HD transgenic mouse by decreasing protein level of polyglutamine-expanded huntingtin in the striatum. In the present study, we test the possibility that T1-11 or JMF1907 [N6-(3-Indolylethyl) adenosine], a synthetic analog of T1-11, alleviates pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom in the SCA3 transgenic mouse expressing HA-tagged polyglutamine-expanded ataxin-3-Q79 (ataxin-3-Q79HA). Daily oral administration of T1-11 or JMF1907 prevented neuronal death of pontine nuclei in the SCA3 mouse with a dose-dependent manner. Oral application of T1-11 or JMF1907 reversed mutant ataxin-3-Q79-induced cerebellar transcriptional repression in the SCA3 transgenic mouse. T1-11 or JMF1907 ameliorated the symptom of motor incoordination displayed by SCA3 mouse. Oral administration of T1-11 or JMF1907 significantly decreased protein level of ataxin-3-Q79HA in the pontine nuclei or cerebellum of SCA3 mouse. T1-11 or JMF1907 significantly augmented the chymotrypsin-like activity of proteasome in the pontine nuclei or cerebellum of SCA3 mouse. Our results suggests that T1-11 and JMF1907 alleviate pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom of SCA3 transgenic mouse by augmenting the proteasome activity and reducing the protein level of polyglutamine-expanded ataxin-3-Q79 in the pontine nuclei and cerebellum.
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PMID:T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. 2625 60