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S Westin

Publications and source records attributed to S Westin.

At least 19 recordsLinked to original sources
PubMed1998

Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis and which depends on interactions with co-activators, including steroid receptor co-activating factor-1 (SRC-1). Here we present the X-ray crystal structure of the human apo-PPAR-gamma ligand-binding domain (LBD), at 2.2 A resolution; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-gamma. We also describe the ternary complex containing the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 A resolution. Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a 'charge clamp' that contacts backbone atoms of the LXXLL helices of SRC-1. These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.

Amino Acid Sequence↗
PubMed1998

Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators.

Retinoic-acid receptor-alpha (RAR-alpha) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are members of the nuclear-receptor superfamily that bind to DNA as heterodimers with retinoid-X receptors (RXRs). PPAR-RXR heterodimers can be activated by PPAR or RXR ligands, whereas RAR-RXR heterodimers are selectively activated by RAR ligands only, because of allosteric inhibition of the binding of ligands to RXR by RAR. However, RXR ligands can potentiate the transcriptional effects of RAR ligands in cells. Transcriptional activation by nuclear receptors requires a carboxy-terminal helical region, termed activation function-2 (AF-2), that forms part of the ligand-binding pocket and undergoes a conformational change required for the recruitment of co-activator proteins, including NCoA-1/SRC-1. Here we show that allosteric inhibition of RXR results from a rotation of the RXR AF-2 helix that places it in contact with the RAR coactivator-binding site. Recruitment of an LXXLL motif of SRC-1 to RAR in response to ligand displaces the RXR AF-2 domain, allowing RXR ligands to bind and promote the binding of a second LXXLL motif from the same SRC-1 molecule. These results may partly explain the different responses of nuclear-receptor heterodimers to RXR-specific ligands.

Allosteric Regulation↗
PubMed1998

[Surgeons on trial].

Explore the source record for details and available documents.

Cardiac Surgical Procedures↗
PubMed1997

The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function.

The functionally conserved proteins CBP and p300 act in conjunction with other factors to activate transcription of DNA. A new factor, p/CIP, has been discovered that is present in the cell as a complex with CBP and is required for transcriptional activity of nuclear receptors and other CBP/p300-dependent transcription factors. The highly related nuclear-receptor co-activator protein NCoA-1 is also specifically required for ligand-dependent activation of genes by nuclear receptors. p/CIP, NCoA-1 and CBP all contain related leucine-rich charged helical interaction motifs that are required for receptor-specific mechanisms of gene activation, and allow the selective inhibition of distinct signal-transduction pathways.

Amino Acid Sequence↗
PubMed1997

CYP2C7 expression in rat liver and hepatocytes: regulation by retinoids.

Rats deficient in vitamin A express low levels of P4502C7 mRNA in the liver. Administration of all-trans retinoic acid (at-RA) or growth hormone (GH) to deficient animals only partially restored the expression whereas the combined treatment returned the P4502C7 mRNA levels to that observed in normal rats. That a retinoid is the predominant inducer of P4502C7 at the cellular level is evident from studies performed with primary hepatocytes, but it became clear that GH is a prerequisite for the vitamin A effect in vivo. The at-RA induction of P4502C7 mRNA in primary rat hepatocytes was inhibited by ketoconazole, an inhibitor of P450 activity, and by cycloheximide, blocking ongoing protein synthesis. In contrast, the at-RA induction of RAR-beta2 mRNA was not affected by any of these compounds. This could indicate previously not recognized mechanisms of at-RA action. Interestingly, at-4-oxo-RA, an at-RA metabolite formed by a P450 catalyzed reaction, also induced P4502C7 mRNA. Induction of P4502C7 mRNA by the retinoic acid receptor (RAR) selective agonist TTNPB indicated that this pathway is preferred over the retinoid X receptor (RXR) pathway. In addition, analysis of RA metabolites in liver cell extracts revealed the formation of several as yet unidentified metabolites. The formation of some of these metabolites was inhibited by ketoconazole and they could therefore constitute potential inducers of CYP2C7. We suggest that metabolism of at-RA, possibly by a P450 enzyme, is an important step in the at-RA induction of P4502C7.

Animals↗
PubMed1996

[An outcome of water-borne gastroenteritis in Klaebu].

In November 1994 a major outbreak of acute gastroenteritis was experienced in the municipality of Klaebu (4,486 inhabitants). To investigate the course and extent of the epidemic, a questionnaire was mailed to all 1,573 households. The returned questionnaires covered 2,943 persons, of whom 1,640 (56%) were reported ill with the following most common symptoms: Nausea (83%), vomiting (78%), diarrhoea (72%) and abdominal pain (70%). The epidemic curve was typical of a common source epidemic. The incidence of vomiting turned out to have three distinct peaks with an interval of 26 hours, probably due to secondary infections. Two specimens that were examined by electron microscope showed typical Norwalk virus structures, and this virus was assumed to be the etiologic agent. The actual cause of this common-source epidemic was found to be inadequate chlorination. The onset of symptoms in different parts of the municipality showed that time taken for the infection to be transported from the reservoir to the consumers was longer than expected. Such delays allow for information on preventive measures to be communicated via the radio and other media.

Adolescent↗
PubMed1996

[What is the situation for rehabilitation money recipients after the support ceases?].

The objective was to follow up clients who had reached the newly imposed 52-week limit for medical rehabilitation benefits in order to clarify future main sources of income. The setting was five municipalities in the county of Sør-Trøndelag in Norway, including the city of Trondheim. The study was carried out as a two-year historic prospective study of a sample of recipients of medical rehabilitation benefits, based on follow-up data from local National Insurance of offices. Among a sample of 260 clients on medical rehabilitation per 30 June 1993, 250 were available for analysis in June 1995. After two years' follow-up, 12% were occupationally active while nearly half the sample had been granted a disability pension. A major change of status occurred during the last three months before July 1994. After two years of follow-up, nine out of ten clients were still receiving support from the National Insurance Scheme. 37% were still on time-limited benefits. These data provide little support for limiting the time on rehabilitation benefits with the objective of getting people back to work.

Adolescent↗
PubMed1996

Methods for quality assessment in general practice.

BACKGROUND AND OBJECTIVES: There is now a wide variety of methods available to general practitioners who want to engage in quality assessment, quality assurance, or quality improvement activities in their practices. These methods require some kind of performance review, or at least the collection of some performance-related data. As in traditional research, the choice of methods depends on what research questions one wants to address. This paper elaborates on some key concepts related to the choice of methods, making a distinction between whether any method actually covers performance (what a doctor does in daily practice) or competence (what a doctor is capable of doing) as well as a distinction between whether a method is direct (patient-doctor contact is observable) or is indirect. METHOD: An overview frame will be presented of the methods most commonly used for data collection within quality assessment. These methods are discussed on their validity, reliability, feasibility and acceptability. Direct methods aimed at recording performance are assumed to hold the highest validity, but practical, economic and logistic factors may favour less ambitious methods for audit or quality improvement activities. CONCLUSIONS: One crucial element in all methods is creating a set of empirical data, as a basis for comparisons, reflection, dialogue and discussions among colleagues.

Data Collection↗