The long-term goals of the proposal are to determine the steps in metabolism of histone mRNA and how these different steps are regulated. Histone mRNA levels are controlled in parallel with DNA synthesis and many anti-metabolite chemotherapy drugs directly impact histone nRNA levels. This proposal focuses on the mechanism of regulation of histone nRNA degradation, the process of transcription termination and transport of histone mRNA from the nucleus to the cytoplasm, and the role of the coding region in expression of the histone H3 gene. Steps will be taken to further map the complete mouse histone gene cluster. The 3' stem-loop structure interacts with a specific protein in the polysomes and in the nucleus. This protein will be isolated in the presence and absence of inhibitors of DNA synthesis to assess whether alterations of the binding activity play a positive or negative role in regulating the histone mRNA degradation. The cDNA encoding the protein will be isolated. The step- loop structure appears to be a dominant signal for mRNA transport and the exact structural requirements will be explored using site-specific mutagenesis. Nuclear factors which interact with the stem-loop will be characterized and the relationship to the cytoplasmic factor determined. A transcription termination site which lies between two highly expressed histone genes will be further characterized to precise define the sequence requirements for transcription termination. Factors which interact either with the DNA or RNA transcript in this region will be characterized. Finally the mechanism by which a small coding region fragment increases the steady-state level of histone nRNA will be determined. Using site- specific mutagenesis the sequence requirements for its activity, including position and orientation effects will be determined and the trans-acting factors involved in the coding region activity characterized. R18MH47634 A services research demonstration project is proposed having two major goals: 1) provide nontraditional residential psychiatric crisis care alternatives to at least 240 persons in Harris County, Texas, and 2) expand the research knowledge base about the relative costs of, efficacy of, and consumer satisfaction with a variety of alternative residential acute care modalities. The project is a collaborative effort involving: 1) the Texas Department of Mental Health and Mental Retardation, 2) the Harris County Mental Health and Mental Retardation Authority, 3) the University of Texas Health Sciences Center, and 4) the University of Texas Medical Branch at Galveston. The population to be studied are individuals in Harris County with the most severe and persistent mental illness based on criteria that include: dangerousness to themselves or others, plus 1) are either homeless or at substantial risk of homelessness, or 2) have frequent contact with law enforcement, or 3) are high utilizers of emergency services, and have demonstrated prior reluctance to be successfully engaged in traditional clinic-based treatment programs. The study population includes significant numbers of minority group members and substance abusers. The project utilizes a 2 x 2 x 2 factorial experimental design with random assignment of consumers to either one of eight experimental groups, or to a control group that receives traditional inpatient hospital care followed by traditional aftercare. Experimental interventions include two levels of hospitalization (very brief and none), two levels of where the alternative community-based residential care is provided (in vivo pre-crisis residence versus crisis apartments) and two levels of who provides the alternative community-based care (non-consumer paraprofessionals versus consumer/ex-consumer paraprofessionals). The effects of these interventions will be measured in terms of the level of decompensation relative to a pre-crisis baseline, and the relative amount of recompensation over multiple points in time following the cessation of the crisis. Dependent variables include: 1) symptom measures as well as global and specific functioning measures, 2) measures of the satisfaction of both primary and secondary consumers with crisis services provided (including measures of burden on secondary consumers, and 3) crisis and post-crisis aftercare service costs.
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