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Biomedical subjects

L J Burke

Publications and source records attributed to L J Burke.

At least 19 recordsLinked to original sources
PubMed2000

Transcriptional repression by the insulator protein CTCF involves histone deacetylases.

The highly conserved zinc-finger protein, CTCF, is a candidate tumor suppressor protein that binds to highly divergent DNA sequences. CTCF has been connected to multiple functions in chromatin organization and gene regulation including chromatin insulator activity and transcriptional enhancement and silencing. Here we show that CTCF harbors several autonomous repression domains. One of these domains, the zinc-finger cluster, silences transcription in all cell types tested and binds directly to the co-repressor SIN3A. Two distinct regions of SIN3A, the PAH3 domain and the extreme C-terminal region, bind independently to this zinc-finger cluster. Analysis of nuclear extract from HeLa cells revealed that CTCF is also capable of retaining functional histone deacetylase activity. Furthermore, the ability of regions of CTCF to retain deacetylase activity correlates with the ability to bind to SIN3A and to repress gene activity. We suggest that CTCF driven repression is mediated in part by the recruitment of histone deacetylase activity by SIN3A.

3T3 Cells↗
PubMed2000

Co-repressors 2000.

In the last 5 years, many co-repressors have been identified in eukaryotes that function in a wide range of species, from yeast to Drosophila and humans. Co-repressors are coregulators that are recruited by DNA-bound transcriptional silencers and play essential roles in many pathways including differentiation, proliferation, programmed cell death, and cell cycle. Accordingly, it has been shown that aberrant interactions of co-repressors with transcriptional silencers provide the molecular basis of a variety of human diseases. Co-repressors mediate transcriptional silencing by mechanisms that include direct inhibition of the basal transcription machinery and recruitment of chromatin-modifying enzymes. Chromatin modification includes histone deacetylation, which is thought to lead to a compact chromatin structure to which the accessibility of transcriptional activators is impaired. In a general mechanistic view, the overall picture suggests that transcriptional silencers and co-repressors act in analogy to transcriptional activators and coactivators, but with the opposite effect leading to gene silencing. We provide a comprehensive overview of the currently known higher eukaryotic co-repressors, their mechanism of action, and their involvement in biological and pathophysiological pathways. We also show the different pathways that lead to the regulation of co-repressor-silencer complex formation.

Chromatin↗
PubMed2000

Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains.

Rev-erbA/RVR are closely related orphan nuclear receptors (NRs) functioning as dominant transcriptional silencers through an association with the nuclear receptor corepressor N-CoR. In contrast with ligand-regulated NRs, Rev-erbA/RVR lack the ligand-binding domain (LBD) C-terminal activation helix, H12. In the case of retinoid acid receptor and thyroid hormone receptor, ligand binding is thought to reposition H12, causing corepressor dissociation and coactivator recruitment, thus leading to transcriptional activation. Here we present homology models of the Rev-erbA/RVR LBDs, which show that the putative ligand cavity is occupied by side chains, suggesting the absence of endogenous ligands. Modeling also revealed a very hydrophobic surface due to the absence of H12, exposing residues from H3, loop 3-4, H4, and H11. Mutation of specific residues from this surface severely impaired the in vitro and in vivo interaction of the Rev-erbA/RVR LBD with the receptor-interacting domain of the corepressors N-CoR or its splice variant RIP13delta1, reinforcing the view of the physical association of N-CoR with a LBD surface encompassing H3-H4 and H11. Furthermore, mutations in the LBD surface significantly reduced the ability of Rev-erbA and RVR to function as repressors of transcription. Interestingly, a hydrophobic surface comprised of H3-H4 and H12 in liganded NRs mediates the interaction with coactivators. Hence, it appears that corepressors and coactivators bind to overlapping surfaces of NR LBDs, the conformational change associated with H12 upon ligand binding resulting in a switch from a corepressor- to a coactivator-binding surface.

Amino Acid Sequence↗
PubMed1999

Strategic planning for research use in nursing practice.

BACKGROUND/OBJECTIVE: To prepare for a culture change to integrate research utilization into daily nursing practice, the authors conducted a descriptive survey of all registered nurses (RNs) in an integrated healthcare delivery system. The purposes of this study were to assess RNs' knowledge, attitudes, and practices (KAP) of nursing research activities, assess factors that support a research environment, and determine facilitating and challenging factors related to conducting regional nursing research. METHODS: A 33-item survey based on the Iowa Model for Evidence-Based Practice was developed, validated, and determined to be reliable by the authors. Site coordinators organized and managed the orientation, administration, and collection of data from the 2,736 registered nurses who worked in 6 hospitals, 65 affiliated clinics, and 3 business units. Narrative notes taken by study investigators were analyzed for themes to determine challenging and facilitating factors for conducting regional research. RESULTS: Education and job title significantly predicted knowledge and ability to perform research activities but was not related to willingness to engage in research activities. Several environmental factors were associated with knowledge of, willingness to engage in, and ability to perform research utilization activities. Challenging and facilitating factors to conducting regional research were identified. CONCLUSIONS/IMPLICATIONS: Our research environment is changing to value research as shown in the philosophy, conceptual framework, and bylaws for the professional nursing staff. Novice-to-expert research utilization expectations are included in the promotional model for nursing. All RN job descriptions and the annual performance tool were revised to include responsibilities related to research activities. The Iowa Model for Evidence-Based Practice was adopted as the method for creating practice validation and change. Train-the-trainer educational and experiential sessions are being designed for nurse leaders; all new RN employees complete a self-assessment tool of research utilization knowledge and the nursing division strategic goals incorporate research utilization expectations. The elements of this plan may be useful for nurse executives. Healthcare systems are restructuring throughout the world and within the United States. These changes are occurring to better meet the evolving healthcare needs of the population through cost-effective approaches. Within the United States, emerging organized healthcare systems require research related to patient care outcomes and the health systems that can best address them.

Adult↗
PubMed1998

The corepressor N-CoR and its variants RIP13a and RIP13Delta1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70.

Repression of transcription by the classical nuclear receptors (e.g. TR, RAR), the orphan nuclear receptors (e.g. Rev-erbAalpha/beta), Mxi-1 and Mad bHLH-zip proteins and the oncoproteins PLZF and LAZ3/BCL6 is mediated by the corepressors N-CoR and SMRT. The interaction of the corepressors with the components involved in chromatin remodelling, such as the recruiting proteins Sin3A/B and the histone deacteylases HDAc-1 and RPD3, has been analysed in detail. The N-CoR/Sin3/HDAc complexes have a key role in the regulation of cellular proliferation and differentiation. However, the interaction of these corepressors with the basal transcriptional machinery has remained obscure. In this study we demonstrated that the N-terminalrepression domains and the receptor interactiondomains (RID) of N-CoR and its splice variants, RIP13a and RIP13Delta1, directly interact with TAFII32 in vivo and in vitro . We show that interaction domain II within the N-CoR and RIP13a RID is required for the interaction with TAFII32. We also observed that N-CoR directly interacts with each of the basal factors, TFIIB and TAFII70, and can simultaneously interact with all three basal factors in a non-competitive manner. Furthermore, we provide evidence that suggests the RVR/Rev-erbbeta-corepressor complex also interacts with the general transcriptional machinery, and that the physicalassociation of TFIIB with N-CoR also occurs in the presence of Sin3B and HDAc-1. Interestingly, we observed that N-CoR expression ablated the functional interaction between TFIIB and TAFII32 that is critical to the initiation of transcription. In conclusion, this study demonstrates that the N-terminal repressor region and the C-terminal RIDs are part of the corepressor contact interface that mediates the interaction with the general transcription factors, and demonstrates that TAFs can also directly interact with corepressors to mediate signals from repressors to the basal machinery. We also suggest that N-CoR interacts with the central components of the transcriptional initiation process (TFIIB, TAFs) and locks them into a non-functional complex or conformation that is not conducive to transcription.

Animals↗
PubMed1998

Implementing the differentiated pay structure model. Process and outcomes.

OBJECTIVE: A salaried Differentiated Pay Structure (DPS) model based on the work of Dr. Virginia Cleland was tested on two units. The project objectives were to: 1) create a budget-neutral compensation distinction for different competencies and educational levels; 2) evaluate the effect of the new salaried model on unit costs and pay; 3) determine the effect of the DPS model on job satisfaction, organizational commitment, and anticipated turnover; and 4) assess the impact of professional commitment, professional practice climate, perception of staffing adequacy, and dispositional optimism on job satisfaction, organizational commitment, and anticipated turnover. BACKGROUND: Although there has been long-standing interest in salaried models and reward methodologies, there is a dearth of systematic research associated with specific compensation models. METHODS: A quasi-experimental, non-equivalent control group design was used to examine the effects of the DPS model. RESULTS: Findings demonstrated that nurses were paid more under the DPS model, and that they were paid for more hours than they actually worked (N = 68). No difference in job satisfaction was found between experimental and control groups. For all nurses (N = 232) dispositional optimism was associated with all job satisfaction subscales except pay. Organizational commitment, professional commitment, professional practice climate, and staffing adequacy were also correlated with job satisfaction, perceptions of care quality and anticipated turnover. Older nurses who had worked longer in nursing, and who had more tenure were less satisfied with their coworkers and care quality. CONCLUSION: Further longitudinal research with larger experimental samples is required in order to fully understand the effects of the DPS model in nursing.

Adult↗
PubMed1998

Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha.

Rev-erbA alpha and RVR are orphan nuclear receptors that function as dominant transcriptional silencers. Ligand-independent repression of transcription by Rev-erbA alpha and RVR is mediated by the nuclear receptor corepressors, N-CoR and its variants RIP (RXR interacting protein) 13a and RIP13 delta 1. The physical association between the corepressors and Rev-erbA alpha and RVR is dependent on the presence of a receptor interaction domain (RID) in the N-CoR family. Our previous study demonstrated that the E region of RVR and Rev-erbA alpha is necessary and sufficient for the in vivo interaction with the nuclear receptor corepressor, RIP13 delta 1. The present investigation demonstrates that two corepressor interaction regions, CIR-1 and CIR-2, separated by approximately 150 amino acids in the E region of RVR, are required for the interaction with N-CoR, RIP13a, and RIP13 delta A. The D region is not required for the physical interaction. In contrast, the D and E regions of Rev-erbA alpha were necessary for the interaction with the N-CoR and RIP13a-RIDs in vivo, suggesting that RIP13 delta 1 and N-CoR/RIP13a differentially interact with Rev-erbA alpha. Mutagenesis of CIR-1, a novel domain that is highly conserved between RVR and Rev-erbA alpha, demonstrated that the N-terminal portion of helix 3 plays a key role and is absolutely necessary for the interaction with RIP13 delta 1, RIP13a, and N-CoR. The phenylalanine residues, F402 and F441, in RVR and Rev-erbA alpha, respectively, were critical residues in supporting corepressor interaction. Cotransfection studies demonstrated that repression of a physiological target, the human Rev-erbA alpha promoter, by RVR was significantly impaired by mutation of CIR-1 or deletion of CIR-2. Furthermore, overexpression of either the N-CoR/RIP13a or RIP13 delta 1-RIDs alleviated RVR-mediated repression of the Rev-erbA alpha promoter, demonstrating that corepressor binding mediates the repression of a native target gene by RVR. A minimal region containing juxtapositioned CIR-1 and CIR-2 was sufficient for corepressor binding and transcriptional repression. In conclusion, our study has identified a new corepressor interaction region, CIR-1, in the N terminus of helix 3 in the E region of RVR and Rev-erbA alpha, that is required for transcriptional silencing. Furthermore, we provide evidence that CIR-1 and CIR-2 may form a single corepressor interaction interface.

Amino Acid Sequence↗
PubMed1997

Research-based planning for change: assessing nurses' attitudes toward governance and professional practice autonomy after hospital acquisition.

OBJECTIVE: This article describes one medical center's experience in using research to plan for nursing staff integration after hospital acquisition. BACKGROUND: Resistance to new policies, procedures, and standards; passive acceptance of new leadership; limited support for management plans; and failure to integrate with new nursing units are common staff reactions after acquisitions. Little has been written regarding which key staff variables to assess after acquisitions and how to use this data to plan for change. Structural contingency and attribution theory were used to guide leadership staff's assessment of acquired staff attributes to determine their congruence with concepts valued by the acquiring organization. METHODS: Qualitative and quantitative data were collected using a survey method. All 141 registered nurses and licensed practical nurses of the acquired medical center received a mailed survey. Sixty-six completed surveys were returned through the U.S. mail. No identifying information was placed on the survey to assure anonymity. RESULTS: The survey results described nurses perceptions of the advantages, concerns, and suggestions for a smooth transition after acquisition. In addition, the results clarified that nurses in the newly acquired hospital preferred a shared governance structure (congruent with the acquiring medical center's values) and the nurses perceived professional nursing autonomy was similar to that of nurses who worked at the acquiring medical center. CONCLUSIONS: By sharing the findings, both staffs were sensitized to the similarities among the staff as well as to their differences. Transition strategies were planned to capitalize on this knowledge. This process may be useful for other nurse executives to replicate as they guide their organizations through similar transitions.

Adult↗
PubMed1996

Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors.

Rev-erbA alpha and RVR/Rev-erb beta/BD73 are orphan steroid receptors that have no known ligands in the 'classical sense'. These 'orphans' do not activate transcription, but function as dominant transcriptional silencers. The thyroid hormone receptor (TR) and the retinoic acid receptor (RAR) act as transcriptional silencers by binding corepressors (e.g. N-CoR/RIP13 and SMRT/TRAC-2) in the absence of ligands. The molecular basis of repression by orphan receptors, however, remains obscure, and it is unclear whether these corepressors mediate transcriptional silencing by Rev-erbA alpha and RVR. Recently, two new variants of N-CoR have been described, RIP13a and RIP13delta1. The characterisation of these splice variants has identified a second receptor interaction domain (ID-II), in addition to the previously characterised interaction domain (ID-I). This investigation utilised the mammalian two hybrid system and transfection analysis to demonstrate that Rev-erbA alpha and RVR will not efficiently interact with either ID-I or ID-II separately from RIP13a or RIP13delta1. However, they interact efficiently with a domain composed of ID-I and ID-II from RIP13a. Interestingly, the interaction of Rev-erbA alpha and RVR is strongest with ID-I and ID-II from RIP13delta1. Detailed deletion analysis of the orphan receptor interaction with RIP13/N-CoR rigorously demonstrated that the physical association was critically dependent on an intact E region of Rev-erbA alpha and RVR. Over-expression of the corepressor interaction domains (i.e. dominant negative forms of N-CoR/RIP13) could alleviate orphan receptor-mediated repression of transactivation by GALVP16. This demonstrated that these regions could function as anti-repressors. In conclusion, these data from two independent approaches demonstrate that repression by Rev-erbA alpha and RVR is mediated by an interaction of ID-I and ID-II of N-CoR, RIP13a and delta1 with the putative ligand binding domain of the orphan receptors.

DNA-Binding Proteins↗
PubMed1996

Transcriptional repression by Rev-erbA alpha is dependent on the signature motif and helix 5 in the ligand binding domain: silencing does not involve an interaction with N-CoR.

Rev-erbA alpha is an orphan nuclear receptor that functions as a dominant transcriptional repressor. Tissue culture and in situ hybridisation studies indicated that Rev-erbA alpha plays an important role in mammalian differentiation and development. Previous studies have localised the silencing domain of Rev-erbA alpha to the D/E region of the orphan receptor. This study utilised the GAL4 hybrid system to demonstrate that efficient repression is mediated by 34 amino acids (aa) between aa 455 and 488 in the E region of the receptor. This domain contains the ligand binding domain (LBD)-signature motif [(F/W)AKxxxxFxxLxxxDQxxLL] and a region that, according to the recently published crystal structures of steroid receptors, would be predicted to form helix 5 of the canonical LBD structure. Fine deletions and site-specific mutagenesis indicated that both the LBD signature motif and helix 5 were necessary for efficient silencing. Utilising mammalian two hybrid technology, we have also demonstrated that Rev-erbA alpha does not associate with the interaction domain (aa 2218-2451) of the nuclear receptor corepressor, N-CoR, that is known to interact with the thyroid hormone and retinoic acid receptors. This suggested that transcriptional repression by Rev-erbA alpha is not mediated through an interaction with N-CoR. In conclusion, we have identified and characterised the minimal domain of Rev-erbA alpha, that mediates transcriptional repression by this orphan receptor.

Amino Acid Sequence↗
PubMed1996

The clinical practice developmental model: the transition process.

The authors report their hospital's experience in replicating Benner's novice-to-expert clinical nursing practice model, called the Clinical Practice Developmental Model. The authors describe the outcomes of an exploratory, qualitative study conducted to understand staff nurses' perceptions of their transition experience from a traditional clinical ladder for advancement and recognition to the theoretically based clinical practice developmental model. The findings of this study identify critical factors that influenced nurses' perceptions and describe positive and negative outcomes of transition. Specific recommendations to facilitate organizational changes for the nurse executive and the individual nurse are discussed.

Adult↗
PubMed1992

Living with recurrent ventricular dysrhythmias.

The number of patients who live with recurrent ventricular dysrhythmias is increasing as medical advances such as pharmacologic and electrical therapies decrease mortality rates in this population. As a result, nurses frequently encounter patients who are trying to learn to live with chronic aspects of recurrent life-threatening dysrhythmias. The findings of this study provide an important beginning description of strategies used by patients to address their concerns. The RVD patients in this study reported using a variety of strategies to manage their physiologic and psychosocial concerns. Their responses described a continuum of strategies to handle concerns that ranged from "compensate for the concern" to "unable to handle the concern." These findings suggest several implications for nursing. Careful assessment of all patients with RVD is appropriate to detect areas where patients perceive a need for additional strategies to manage their concerns, require support for existing self-reliance strategies, and need identification of additional nursing interventions. Individualized or group programs may be appropriate interventions to assist some patients. Strategies to support patients who report an inability to manage specific concerns need clarification. Ideally, as further research defines the processes patients with RVD use to manage their concerns, high-risk patients can be discovered and provided with interventions to promote their adjustment to living with life-threatening dysrhythmias.

Adaptation, Psychological↗
PubMed1986

Nursing diagnoses, indicators, and interventions in an outpatient cardiac rehabilitation program.

This study identified two nursing diagnoses used in an outpatient cardiac rehabilitation program. The indicators and interventions for these diagnoses were also identified. We feel that nurses in cardiac rehabilitation programs will find these diagnostic labels to be clinically useful. The indicators may also help nurses decide when to use the diagnostic labels. The interventions will provide direction on how to treat these nursing diagnoses. The use of nursing diagnoses in this setting helps clarify nursing's unique role in a multidisciplinary team providing services to participants in outpatient cardiac rehabilitation programs.

Adult↗