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Biomedical subjects

M P Clark

Publications and source records attributed to M P Clark.

13 recordsLinked to original sources
PubMed2001

Total synthesis of cystothiazoles A and C.

An efficient pathway culminating in the enantiocontrolled preparation of cystothiazoles A and C has been described. The cystothiazoles demonstrate potent antifungal activity and function as novel inhibitors of mitochondrial oxidation at a specific site on the cytochrome bc(1) complex. These studies outline a general and flexible plan that can be readily adapted for the synthesis of a variety of related five-membered heterocyclic systems and for biological investigations of structure-activity relationships. The core [2,4']bisthiazole component 8 was prepared in six steps, and the use of the Horner-Emmons olefination to yield the alpha,beta-unsaturated ester 10 set the stage for an asymmetric Evans aldol process, which established the required C(4)/C(5) stereochemistry. Finally the cystothiazoles A and C were prepared via a stereocontrolled O-alkylation of the precursor beta-keto esters 22a and 22b.

Deltaproteobacteria↗
PubMed1998

Multiple domains for initiator binding proteins TFII-I and YY-1 are present in the initiator and upstream regions of the rat XDH/XO TATA-less promoter.

We previously reported that the TATA-less rat xanthine dehydrogenase/oxidase (XDH/XO) promoter is organized with multiple initiator elements (Inr 1, 2, 3 and 4). Additionally, we identified six factor binding footprints in the upstream region of this promoter (FP 1-FP 6), two of which (FP 2 and FP 4) we showed to be C/EBP binding sites. In this report we continue our characterization of the XDH/XO promoter, detailing other cis elements which comprise the Inr and upstream binding factors. Interestingly, multiple binding domains for known initiator binding proteins, YY-1 and USF-related factor/TFII-I, have been identified which potentially play an important role in transcription initiation.

Animals↗
PubMed1998

Correct usage of multiple transcription initiation sites and C/EBP-dependent transcription activation of the rat XDH/XO TATA-less promoter requires downstream elements located in the coding region of the gene.

In the present study, we have shown that a downstream element located in the coding region of the TATA-less rat xanthine dehydrogenase/oxidase (XDH/XO) gene (-7 to +42) plays an important role in transcription initiation and C/EBP transcriptional activation. Previous work from our laboratory has shown that the promoter is organized with multiple initiator elements (Inr 1, 2, 3 and 4) which are important for transcription initiation. Additionally, we had identified two C/EBP binding sites upstream of this promoter. Deletional and mutational studies revealed that C/EBP binding was not essential for the basal level of transcriptional initation. However when XO-luciferase constructs include downstream sequence extending to +42 there is development of C/EBP sensitivity as well as a shift in the initiator usage. In the absence of the downstream element, primer extension analyses reveals Inr 3 and 4 to be the major start sites but in the presence of this additional sequence the usage is shifted to Inr 1 and 2. This shift in Inr usage more closely resembles that seen in intact macrophages or liver cells. Gel mobility shift assays indicate the presence of several binding factors located in this downstream region, one of which has been identified as YY-1. We postulate that YY-1 allows DNA bending which permits the upstream C/EBP elements to exhibit a transcriptional activation which is not seen when the downstream element is absent. This study presents a potential model for regulation of the XDH/XO promoter.

Animals↗
PubMed1998

Function of the nasal muscles in normal subjects assessed by dynamic MRI and EMG: its relevance to rhinoplasty surgery.

The external nose is generally considered to have a relatively static shape. Movement of the nose and the potential for change of external shape and the internal airway have been assessed by (1) cadaver dissection and (2) dynamic studies during a standardized series of facial expressions in 13 subjects; video recording of the movement of skin markers, electromyography, and moving magnetic resonance images. A standard description of muscle anatomy is presented. The dynamic investigations indicated the following. Video analysis showed the components of muscle action: dilatation, constriction of the nostril, depression of the tip, vertical contraction in the bridge, and elevation of the alar, in different expressions. Electromyography confirmed muscle actions during expression and phonation. Magnetic resonance imaging demonstrated large changes in the external shape of the nose and nasal aperture due to muscle actions. Muscle function should be given greater consideration in aesthetic and cleft rhinoplasty.

Electromyography↗
PubMed1998

Wounds of Wewak, Papua New Guinea.

Wounds encountered in the outpatients (A&E) department of Wewak General Hospital in Papua New Guinea were observed during a 3-week visit. A series of 14 accidental wounds and nine resulting from attack were analysed. It was found that there were predisposing social factors of alcohol, conjugal disputes and 'payback' retribution attacks. Physical factors affecting the outcome were nutritional status and a high rate of wound infection. Broken bottles and cans caused some of the injuries. Many aspects of the problem were thus the same as in the UK, but the resources available to help the patients were much more limited.

Adolescent↗
PubMed1996

In vitro transcription in the presence of DNA oligonucleotides can generate strong anomalous initiation sites.

In the present study, we have explored an unexpected observation in transcription initiation that is mediated by single-stranded oligonucleotides. Initially, our goal was to understand the function of different upstream regulatory elements/initiation sites in the rat xanthine dehydrogenase/oxidase (XDH/XO) promoter. We performed in vitro transcription with HeLa nuclear extracts in the presence of different double-stranded oligonucleotides against upstream elements as competitors. A new and unusual transcription initiation site was detected by primer extension. This new initiation site maps to the downstream region of the corresponding competitor. Subsequent analyses have indicated that the induction of a new transcription initiation site is anomalous which is due to the presence of a small amount of single-stranded oligonucleotide in the competitor. We found that this anomalous initiation site is insensitive to the orientation of the promoter and requires only a small amount of single-stranded oligonucleotide (< 2-fold molar excess relative to template). We surmise that a complementary interaction between the single-stranded oligonucleotide and transiently denatured promoter template may be responsible for this sequence-specific transcription initiation artifact. To study the regulation of transcription initiation by in vitro transcription approaches, we propose that one should probe the effect of removing transacting factors by adding an excess of a cognate oligonucleotide which does not bear exact sequence identity to the template.

Animals↗
PubMed1995

Multiple initiators and C/EBP binding sites are involved in transcription from the TATA-less rat XDH/XO basal promoter.

In the present study, we have explored further the organization of the TATA-less rat xanthine dehydrogenase/oxidase gene (XDH/XO). A DNase I hypersensitive site has been identified which it colocalizes with the basal promoter reported previously [Chow et al. (1994) Nucleic Acids Res., 22, 1846-1854]. Gel mobility shift assays indicate the presence of multiple binding factors located in the promoter. At least six footprints were detected of which two have been shown to be C/EBP binding sites. Members of the C/EBP-alpha and C/EBP-beta, but not C/EBP-delta, family are able to bind to these two sites. Deletional and mutational studies revealed that C/EBP binding is not essential for the basal level of transcription initiation of this promoter. Much of the transcriptional activity resides in the -102 to -7 DNA fragment, which contains all initiator activity which acts unidirectionally. Within this fragment, four putative initiator elements could be identified; interestingly, the linear integrity of these initiators is important for efficient transcription of the XDH/XO gene. Separation of the initiators leads to a complete loss of transcription activity; however, this loss could be partially restored by the introduction of an Sp1 binding site upstream of the separated initiators. Despite a difference in usage/frequency of initiation at the various initiators, primer extension analyses reveal similar positions for transcription initiations in both XDH/XO reporter constructs and in the endogenous XDH/XO gene. The differential usage of initiators may imply a possible post-transcriptional regulation for the XDH/XO gene.

Animals↗
PubMed1982

Husband or wife? A multivariate analysis of decision making for voluntary sterilization.

The increasing popularity of sterilization as a contraceptive choice among married couples underscores the need for knowledge about differences between couples choosing male and female procedures. Data from national surveys suggest some sociodemographic differences, but these variables account for only a small amount of the variance. This research looks at other sets of variables--information sources, influence sources, and reasons husbands and wives give for wanting sterilization--in a multivariate analysis of the choice of a male versus a female operation. Particularly for husbands obtaining a vasectomy, the importance of social support is demonstrated.

Behavior↗