Contact coral dermatitis affecting the ankle.
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Adult↗
Biomedical subjects
S Dalton
Publications and source records attributed to S Dalton.
Problem-based learning: a method that encourages critical thinking.
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Dietetics↗
The dietitians' philosophy and practice in multidisciplinary weight management.
Dietitians are developing a philosophy and a practice protocol of weight management. A professional philosophy of weight management addresses questions about the social, psychological, and biological spectra of weight management: Should overweight be considered in terms of size acceptance or gluttony and sloth? How should emotional overeating and obsessive restriction be managed? Should obesity be considered a chronic disease, or should the idea that health at every size is possible be espoused? A professional practice protocol addresses another set of questions: Is obesity to be viewed as a short-term and long-term health challenge? Regarding the spectrum of antiobesity agents and antidieting approaches of weight management, what professional position and individual practice will be adopted? Should professional contact with patients be continuous or aimed toward self-care? What measures of successful outcomes will be used: weight change or life quality improvement? How should professional responsibility be balanced with personal concerns about eating and health behaviors that affect body weight? What are examples of closing the gap between the vision and the reality of the roles and goals of the dietitian on a weight management team? Dietitians are translating philosophy into practice. Because dietary control alone has a record of limited success in weight loss and less success in maintaining weight loss, the dietitian's expanded role includes helping patients manage weight with coping skills, motivation techniques, physical activity, and food behavior change. The challenge is integrating functional components of practice with dietitians' unique food and nutrition skills that include selection of alternative foods, portion control, and preparing acceptable, tasty foods for lifelong weight management.
Dietary Services↗
Lithium intolerance in a medical-psychiatric population.
This pilot study was designed to explore the tolerance and efficacy of lithium as an adjunctive prophylactic agent when added to maintenance antidepressant regimens following an episode of depression in an older medical-psychiatric population. In a randomized controlled trial, 27 depressed patients had either lithium carbonate or placebo added to their maintenance antidepressant (AD) regimen following an index episode of depression. Of 17 patients who received lithium carbonate, 76% (13/17) were unable to tolerate this agent for the duration of the study because of side effects (e.g., gastrointestinal disturbances or tremor). The four patients who tolerated lithium were monitored for relapse of depression over a 15-month follow-up period, and one relapsed (after a 49-week remission) whereas 60% (6/10) of the placebo patients relapsed. Cognitive functioning was stable in the lithium-treated patients who remained on therapy. The high rate of lithium intolerance in this study indicates that lithium dosing and serum levels must be conservatively managed in this clinical population.
Adjuvants, Pharmaceutic↗
Recovery and relapse in geriatric depression after treatment with antidepressants and ECT in a medical-psychiatric population.
The objective of this naturalistic, longitudinal treatment outcome study was to determine relapse rates in geriatric depression following treatment with antidepressants and electroconvulsive therapy in a medical-psychiatric population. Thirty-nine elderly patients (average age 71 years) with unipolar major depression were treated with either antidepressants (AD) or, if resistant to AD treatment, ECT followed by maintenance antidepressants. Patients were monitored over 18 months, and relapse rates were closely determined using the Longitudinal Interval Follow-up Evaluation (LIFE) and the 21-item Hamilton Depression Rating Scale. Although 90% of patients recovered from their index episode of depression, relapse rates were approximately 29%. These results indicate that in spite of high chances of recovery from geriatric depression, intensive psychopharmacologic and psychotherapeutic strategies are needed to decrease relapse rates in geriatric depression.
Aged↗
Cell cycle control of chromosomal DNA replication.
Accurate replication and segregation of chromosomal DNA is essential for high-fidelity transmission of genetic information from generation to generation. Eukaryotic cells typically replicate by first duplicating their chromosomes during the S phase followed by their segregation between two daughter cells during the M phase. Over recent years, advances in our understanding of this process at the molecular level have been incredibly rapid. The present review will focus on molecular control of DNA replication and the mechanisms which operate to ensure that once replicated, chromosomes are not rereplicated in the same cell cycle.
Cell Cycle↗
Characterization of Cdc47p-minichromosome maintenance complexes in Saccharomyces cerevisiae: identification of Cdc45p as a subunit.
Cdc47p is a member of the minichromosome maintenance (MCM) family of polypeptides, which have a role in the early stages of chromosomal DNA replication. Here, we show that Cdc47p assembles into stable complexes with two other members of the MCM family, Cdc46p and Mcm3p. The assembly of Cdc47p into complexes with Cdc46p does not appear to be cell cycle regulated, making it unlikely that these interactions per se are a rate-limiting step in the control of S phase. Cdc45p is also shown to interact with Cdc47p in vivo and to be a component of high-molecular-weight MCM complexes in cell lysates. Like MCM polypeptides, Cdc45p is essential for the initiation of chromosomal DNA replication in Saccharomyces cerevisiae; however, Cdc45p remains in the nucleus throughout the cell cycle, whereas MCMs are nuclear only during G1. We characterize two mutations in CDC47 and CDC46 which arrest cells with unduplicated DNA as a result of single base substitutions. The corresponding amino acid substitutions in Cdc46p and Cdc47p severely reduce the ability of these polypeptides to assemble in a complex with each other in vivo and in vitro. This argues that assembly of Cdc47p into complexes with other MCM polypeptides is important for its role in the initiation of chromosomal DNA replication.
Amino Acid Sequence↗
Phosphorylation of MCM4 by cdc2 protein kinase inhibits the activity of the minichromosome maintenance complex.
In eukaryotes, tight regulatory mechanisms ensure the ordered progression through the cell cycle phases. The mechanisms that prevent chromosomal DNA replication from taking place more than once each cell cycle are thought to involve the function of proteins of the minichromosome maintenance (MCM) family. Here, we demonstrate that Xenopus MCM4, a member of the MCM protein family related to Spcdc21/ ScCDC54, is part of a large protein complex comprising several other MCM proteins. MCM4 undergoes cell cycle-dependent phosphorylation both in cleaving embryos and in cell-free extracts. MCM4 phosphorylation starts concomitantly with the clearing of the MCM complex from the chromatin during S phase. Phosphorylation is carried out by cdc2/cyclinB protein kinase, which phosphorylates MCM4 in vitro at identical sites as the ones phosphorylated in vivo. Phosphorylation is specific for cdc2 protein kinase since MCM4 is not a substrate for other members of the cdk family. Furthermore, phosphorylation of MCM4 dramatically reduces its affinity for the chromatin. We propose that the cell cycle-dependent phosphorylation of MCM4 is a mechanism which inactivates the MCM complex from late S phase through mitosis, thus preventing illegitimate DNA replication during that period of the cell cycle.
Animals↗
Cdc45p assembles into a complex with Cdc46p/Mcm5p, is required for minichromosome maintenance, and is essential for chromosomal DNA replication.
We report the isolation and characterization of CDC45, which encodes a polypeptide of 650 amino acids that is essential for the initiation of chromosomal DNA replication in the budding yeast, Saccharomyces cerevisiae. CDC45 genetically interacts with at least two members of the MCM (minichromosome maintenance) family of replication genes, CDC46 and CDC47, which are proposed to perform a role in restricting initiation of DNA replication to once per cell cycle. Like mutants in several MCM genes, alleles of CDC45 also show a severe minichromosome maintenance defect. Together, these observations imply that Cdc45p performs a role in the control of initiation events at chromosomal replication origins. We investigated this possibility further and present evidence demonstrating that Cdc45p is assembled into complexes with one MCM family member, Cdc46p/Mcm5p. These observations point to a role for Cdc45p in controlling the early steps of chromosomal DNA replication in conjunction with MCM polypeptide complexes. Unlike the MCMs, however, the subcellular localization of Cdc45p does not vary with the cell cycle, making it likely that Cdc45p interacts with MCMs only during the nuclear phase of MCM localization in G1.
Amino Acid Sequence↗
Cell cycle-regulated nuclear import and export of Cdc47, a protein essential for initiation of DNA replication in budding yeast.
The CDC47 gene was isolated by complementation of a cdc47 temperature-sensitive mutant in Saccharomyces cerevisiae and was shown to encode a predicted polypeptide, Cdc47, of 845 aa. Cdc47 belongs to the Cdc46/Mcm family of proteins, previously shown to be essential for initiation of DNA replication. Using indirect immunofluorescence microscopy and subcellular fractionation techniques, we show that Cdc47 undergoes cell cycle-regulated changes in its subcellular localization. At mitosis, Cdc47 enters the nucleus, where it remains until soon after the initiation of DNA replication, when it is rapidly exported back into the cytoplasm. Cdc47 protein levels do not vary with the cell cycle, but expression of CDC47 and nascent synthesis of Cdc47 occur late in the cell cycle, coinciding with mitosis. Together, these results show that Cdc47 is not only imported into the nucleus at the end of mitosis but is also exported back into the cytoplasm at the beginning of S phase. The observation that Cdc47 is exported from the nucleus at the beginning of S phase has important implications for how initiation of DNA replication is controlled.
Amino Acid Sequence↗
Cdc54 belongs to the Cdc46/Mcm3 family of proteins which are essential for initiation of eukaryotic DNA replication.
CDC54 is a gene essential for initiation of DNA replication in Saccharomyces cerevisiae, and which is known to genetically interact with other regulators of the S-phase, including CDC46. We describe the isolation and sequencing of CDC54 and show that it encodes a protein structurally related to Cdc46p, Mcm2p and Mcm3p by the presence of a conserved domain of 145 amino acids which is internal to each polypeptide. This conserved domain resembles the DEAD box of RNA helicases and is similar to the conserved domain associated with a group of transcription and replication factors with known or assumed DNA-dependent ATPase activity, suggesting it may be involved in nucleic-acid recognition. Comparison of Cdc54p to related proteins from other species revealed that it closely resembles cdc21p from Schizosaccharomyces pombe.
Amino Acid Sequence↗
The yeast tribrid system--genetic detection of trans-phosphorylated ITAM-SH2-interactions.
Protein-protein interactions are often dependent on the post-translational modification of one component of a complex. To facilitate the study of these interactions in signal transduction, we have developed the yeast tribrid system, a modification of the yeast two-hybrid system. We demonstrate that the interactions are dependent upon the presence of a tyrosine kinase, an SH2 domain and a tyrosine containing substrate. Using the gamma subunit of the high-affinity IgE receptor, Fc epsilon RI, this approach has been used to isolate a novel SH2-containing family member. The mRNA encoding this novel protein is differentially expressed in rat tissues. The yeast tribrid system can be readily adapted for the characterization of novel tyrosine kinases or substrates, as well as the study of protein-protein interactions which involve other post-translational modifications.
Adaptor Proteins, Signal Transducing↗
Cell cycle-regulated transcription of the CLB2 gene is dependent on Mcm1 and a ternary complex factor.
Clb2 is the major B-type mitotic cyclin required for entry into mitosis in the budding yeast Saccharomyces cerevisiae. We showed that accumulation of CLB2 transcripts in G2 cells is controlled at the transcriptional level and identified a 55-bp upstream activating sequence (UAS) containing an Mcm1 binding site as being necessary and sufficient for cell cycle regulation. Sequences within the cell cycle-regulated UAS were shown to bind Mcm1 in vitro, and mutation which abolished Mcm1-dependent DNA binding activity eliminated cell cycle-regulated transcription in vivo. A second protein with no autonomous DNA binding activity was also recruited into Mcm1-UAS complexes, generating a ternary complex. A point mutation in the CLB2 UAS which blocked ternary complex formation, but still allowed Mcm1 to bind, resulted in loss of cell cycle regulation in vivo, suggesting that the ternary complex factor is also important in control of CLB2 transcription. We discuss the possibility that the CLB2 gene is coregulated with other genes known to be regulated with the same periodicity and suggest that Mcm1 and the ternary complex factor may coordinately regulate several other G2-regulated transcripts.
Base Sequence↗
Human shoulder tendon biopsy samples in organ culture produce procollagenase and tissue inhibitor of metalloproteinases.
OBJECTIVE: To investigate the production of the matrix metalloproteinase (MMP), collagenase (MMP-1), and its natural inhibitor, the tissue inhibitor of metalloproteinases (TIMP) by diseased human tendon samples in organ culture. METHODS: Portions of tendons were excised from the shoulders of patients undergoing shoulder surgery, classified as either proximal to the lesion (abnormal) or distal to the lesion (normal) according to their macroscopic appearance at surgery, and placed in organ culture for periods of up to 28 days. The release of collagenase and TIMP activity in the conditioned culture medium was measured. RESULTS: Procollagenase and TIMP were both produced by all the tendon samples for an extended period of time. The levels of enzyme and inhibitor varied between patients, but in most of them TIMP levels were greater than collagenase levels. In one sample of calcified tendon, procollagenase levels were greater than those of TIMP. The mean level of collagenase produced by tendon proximal to the lesion and tendon distal to the lesion were not significantly different (95.2 (SD 106.8) U/g and 34.0 (45.3) U/g, respectively), while the corresponding figures for TIMP were 109.7 (62.3) U/g and 53.0 (27.9) U/g (p = < 0.05), although there was considerable variation in some samples. Western blotting and collagen fragment analysis confirmed that the collagenolytic activity detected was attributable to the metalloproteinase fibroblast collagenase (MMP-1). CONCLUSIONS: Tendon tissue can actively secrete procollagenase, an enzyme that, once activated, is capable of remodelling collagen, the major connective tissue component of tendon. Collagenase is produced even in unstimulated cultures, although the concentrations of TIMP are usually greater than that of collagenase in most samples. Some activation of collagenase appeared to have occurred. These results indicate that tendon tissue cells are capable of producing a remodelling response, even in end stage tendon disease.
Adult↗
Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element.
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Amino Acid Sequence↗
Mapping of the human SAP1 (SRF accessory protein 1) gene and SAP2, a gene encoding a related protein, to chromosomal bands 1q32 and 12q23, respectively.
SAP1, SAP2, and ELK1 form a related subgroup of ETS-domain proteins that can form ternary complexes with the transcription factor SRF at the c-fos serum response element (SRE). SAP1 was identified by a genetic screen for proteins interacting with SRF expressed in yeast, and SAP2 by its homology with SAP1; ELK1 was previously identified by its homology to the ETS domain. cDNA probes were used to isolate cosmid and phage clones harboring genes encoding SAP1 and SAP2. These clones were subsequently used to map the genes to 1q32 and 12q23, respectively, by fluorescence in situ hybridization.
Chromosome Mapping↗
Isolation and characterization of SRF accessory proteins.
Many genes which are regulated by growth factors contain a common regulatory element, the serum response element (SRE). Activation of transcription by the SRE involves a ternary complex formed between a ubiquitous factor, serum response factor (SRF), and a second protein, p62/TCF. We used a yeast genetic screen to isolate cDNAs encoding a protein, SAP-1, with the DNA binding properties of p62/TCF. The SAP-1 sequence contains three regions of homology to the previously uncharacterized Elk-1 protein, which also acts as an SRF accessory protein. Only two of these regions are required for cooperative interactions with SRF in the ternary complex. The third contains several conserved sites for the MAP kinases, whose activity is regulated in response to growth factor stimulation. We discuss the potential role of these proteins in regulation of the c-fos SRE.
Amino Acid Sequence↗