Altering the GTP binding site of the DNA/RNA-binding protein, Translin/TB-RBP, decreases RNA binding and may create a dominant negative phenotype.

The DNA/RNA-binding protein, Translin/Testis Brain RNA-binding protein (Translin/TB-RBP), contains a putative GTP binding site in its C-terminus which is highly conserved. To determine if guanine nucleotide binding to this site functionally alters nucleic acid binding, electrophoretic mobility shift assays were performed with RNA and DNA binding probes. GTP, but not GDP, reduces RNA binding by approximately 50% and the poorly hydrolyzed GTP analog, GTPgammaS, reduces binding by >90% in gel shift and immunoprecipitation assays. No similar reduction of DNA binding is seen. When the putative GTP binding site of TB-RBP, amino acid sequence VTAGD, is altered to VTNSD by site directed mutagenesis, GTP will no longer bind to TB-RBP(GTP) and TB-RBP(GTP) no longer binds to RNA, although DNA binding is not affected. Yeast two-hybrid assays reveal that like wild-type TB-RBP, TB-RBP(GTP) will interact with itself, with wild-type TB-RBP and with Translin associated factor X (Trax). Transfection of TB-RBP(GTP) into NIH 3T3 cells leads to a marked increase in cell death suggesting a dominant negative function for TB-RBP(GTP) in cells. These data suggest TB-RBP is an RNA-binding protein whose activity is allosterically controlled by nucleotide binding.

Trax (translin-associated factor X), a primarily cytoplasmic protein, inhibits the binding of TB-RBP (translin) to RNA.

Trax (Translin-associated factor X) has been shown to interact with TB-RBP/Translin by its coimmunoprecipitation and in yeast two-hybrid assays. Here we demonstrate that Trax is widely expressed, does not bind to DNA or RNA, but forms heterodimers with TB-RBP under reducing conditions. The heterodimer of TB-RBP and Trax inhibits TB-RBP binding to RNA, but enhances TB-RBP binding to specific single stranded DNA sequences. The in vitro interactions between TB-RBP and Trax are confirmed by similar interactions in the yeast two-hybrid system. Cell fractionation and confocal microscope studies reveal that Trax is predominantly cytoplasmic. In contrast, TB-RBP is present in both the nuclei and cytoplasm of transfected cells and uses a highly conserved nuclear export signal to exit nuclei. In addition to a leucine zipper, two basic domains in TB-RBP are essential for RNA binding, but only one of these domains is needed for DNA binding. Trax restores DNA binding to TB-RBP containing an altered form of this domain. These data suggest that Trax-TB.RBP interactions modulate the DNA- and RNA-binding activity of TB-RBP.

New oxidative transformations of phenolic and indolic oxazolines: an avenue to useful azaspirocyclic building blocks.

The oxidative cyclization of a phenolic amide to a spirolactam has long been regarded as an "impossible" reaction, because exposure of the substrates to a variety of oxidants results in formation of spirolactones with consequent loss of the amine segment. We recently communicated that this heretofore unknown transformation may be achieved by oxidation of oxazoline analogues of phenolic and indolic amides. Herein, we provide full details of our work.

Severe systemic sclerosis with anti-topoisomerase I antibodies is associated with an HLA-DRw11 allele.

SSc is an autoimmune connective tissue disease in which strong HLA associations have not been described. Anti-topo I antibodies are recognized, in general, in SSc patients with diffuse cutaneous involvement, whereas anti-ACAs are found in individuals with limited cutaneous involvement. We studied 95 Caucasian SSc patients, 44 with anti-topo I antibodies and 51 with neither anti-topo I nor ACA, for HLA-DR associations by using DNA typing techniques. We analyzed 181 normal Caucasian individuals in the same fashion. A significant association was observed in the anti-topo-I-positive patients with DRw11 (p = 1.7 x 10(-6), RR 4.2). The distribution of DRw11 alleles in these patients was significantly different from that observed in controls and could be accounted for by an increase in the frequency of the DRB1*1104 allele (p = 1.2 x 10(-9), RR 9.5). The DRw11 alleles were also associated with SSc with more tendon friction rubs (p = 0.006), which is a marker of more severe disease. In addition, a strong association was observed with anti-topo I antibodies and a particular sequence (aa 71-77) of the DQB1 chain (p = 0.02, RR 2.2). HLA associations in the case of SSc patients with anti-topo I antibodies are complex and involve at least two genes: HLA-DRw11, which appears to play a major role in determining the severity of the disease, and a DQ sequence, which associates with the development of the anti-topo I antibodies.

A multidisciplinary public-academic liaison to improve public mental health services in South Carolina.

The state of South Carolina is in the process of transforming its core services for people with severe and persistent mental illnesses to a community-based model. This paper describes the planning and on-going implementation of an alliance of academic programs, mental health advocates, and service providers forged by the state department of mental health in 1990. Goals of the consortium are to develop graduates who possess the needed knowledge, skills, and attitudes to work in the public sector; to undertake collaborative research to improve services in that sector; and to maintain the effectiveness and satisfaction of current workers in the public system. The authors describe activities of the consortium to achieve these goals and give examples of enhanced academic involvement in the public mental health system as a result of the consortium's activities.

State-university collaboration in psychiatry: the Pew Memorial Trust Program.

This contribution summarizes the background leading up to the goals of and the experience gained from a major national initiative to expand and improve collaborative activities between state departments of mental health and university departments of psychiatry through regional conferences, national workshops, ongoing consultations, and awards. It details the problems of the public system and how successful collaborative efforts have improved the situation, cites the role of one such a program (in Maryland), recounts the process of holding a national invitational conference and the subsequent "Call to Action," and summarizes what the Pew Project is intended to do and how the project is progressing.

Family members' opinions about civil commitment.

As part of a survey of 260 Oregon family members with mentally ill relatives, respondents were asked about their experiences with civil commitment and their opinions about proposed modifications in the commitment statutes. Family members typically described their mentally ill relative as a schizophrenic man in his thirties who had had six psychiatric hospitalizations and was currently being treated with medications at a community mental health center. Three-fourths of the relatives had been committed. A majority (57 percent) of the respondents were in favor of mandatory outpatient treatment and medication after involuntary hospitalization but were not enthusiastic about outpatient commitment without hospitalization. Family members also wanted more education about mental illness, more information about the commitment process, and assignment of a professional to help in the commitment process.

Chronic mental illness and the criminal justice system.

A total of 260 family members responded to a survey seeking information about their mentally ill relatives' contacts with the criminal justice system. Reports by family members indicated that the mentally ill relatives were mainly men in their early thirties with a diagnosis of schizophrenia or bipolar disorder; they had had an average of four admissions to a state mental hospital. The majority had been arrested, but only a fifth had been convicted of a crime. Substance abuse and noncompliance with psychiatric medications were significant predictors of arrest. Family members overwhelmingly attributed the arrests to psychiatric crises, and in about half the cases a failed attempt at commitment had preceded the arrest. However, only a minority of the mentally ill relatives were taken to a hospital at the time of the arrest. The findings highlight the need for closer collaboration between mental health specialists and law enforcement personnel.

The evolution of Oregon's Public Psychiatry Training Program.

Public psychiatry training in Oregon traces its roots to the community mental health movement of the 1960s and now includes a focus on training in the community and in state hospitals.

Investigators' and judges' opinions about civil commitment.

As part of our work with the Oregon Task Force on Civil Commitment, we surveyed the judges and commitment investigators involved in the state's involuntary treatment program. In Oregon the investigators recommend whether or not a commitment hearing should be held. These mental health professionals indicated that current confidentiality laws restrict their access to important information. The investigators also expressed concern about the lack of resources with which to divert clients out of the commitment system. Judges too felt that relaxing the rules of evidence would improve the quality of commitment hearings. Regarding changes in the system, investigators and judges indicated that outpatient treatment (including compliance with medications) should be required of committed patients. These professionals noted that involuntary outpatient treatment could only be enforced if the system included a mechanism for hospitalizing patients who were noncompliant. Although the investigators believed commitment criteria should be broadened so that their clients could receive treatment before becoming dangerous, judges did not generally endorse this view. We discuss the implications of these findings for new civil commitment legislation.

Psychiatric manpower and services in a community mental health system.

Executive directors of Oregon's 36 community mental health programs were surveyed in the fall of 1983 to determine the nature of psychiatric services offered and the roles played by psychiatrists. The study showed that a total of 18.2 full-time-equivalent psychiatrists were working in the community system, a mean of .5 per program, considerably below the national average. None of the responding directors were psychiatrists, and only six employed psychiatrists as medical directors. The directors valued psychiatrists most highly for their skills in educating, supervising, and consulting with staff; for their unique clinical skills; and for medication management. They considered the biggest disadvantage of employing psychiatrists to be the expense. The authors discuss factors that contribute to psychiatrists' satisfaction with work in community mental health programs and strategies for recruiting and retaining psychiatrists in the programs.

Academic, community and state mental health program collaboration: the Oregon experience.

The authors review the relationship that has evolved over the years between the Department of Psychiatry at Oregon Health Sciences University and Oregon's community and state mental health programs. They describe the compatibility that exists between the basic requirements of academic psychiatry departments and public mental health programs and demonstrate how these organizations have been able to fulfill one another's needs in Oregon. Specific examples of successful collaborations in the areas of education, administration, research, and service are presented to illustrate how relationships that have been designed to meet specific requirements of one organization can fulfill many requirements of both. Suggestions are provided for those organizations contemplating similar collaborative endeavors.