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Biomedical subjects

J F Martin

Publications and source records attributed to J F Martin.

At least 19 recordsLinked to original sources
PubMed1992

Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system.

Members of the helix-loop-helix (HLH) family of proteins bind DNA and activate transcription as homo- and heterodimers. Myogenin is a muscle-specific HLH protein that binds DNA in vitro as a heterodimer with several widely expressed HLH proteins, such as the E2A gene products E12 and E47. We describe a method for detection of protein-protein interactions among HLH proteins in vivo in which dimerization through the HLH motif reconstructs a hybrid transcription factor containing the DNA-binding domain of yeast GAL4 linked to one HLH motif and the activation domain of VP-16 linked to another. We have used this assay to investiagate whether myogenin forms homomeric or heteromeric complexes in vivo and to determine whether growth factors and oncogenes that inhibit myogenesis influence myogenin's ability to dimerize. The results show that myogenin heterodimerizes with E12 and E47 in vivo, but it does not homodimerize to a measurable extent. Peptide growth factors, as well as the immediate early gene products c-Jun, v-Fos, and c-Myc, inhibit the activity of myogenin through a mechanism independent of its association with E2A products.

Adenovirus Early Proteins↗
PubMed1992

Repression of myogenin function by TGF-beta 1 is targeted at the basic helix-loop-helix motif and is independent of E2A products.

The muscle-specific helix-loop-helix (HLH) proteins myogenin, MyoD, myf5, and MRF4 form hetero-oligomers with ubiquitous HLH proteins encoded by the E2A gene and activate muscle transcription by binding to a DNA sequence known as an E-box (CANNTG). Transforming growth factor-beta (TGF-beta) can inhibit muscle differentiation by silencing the transcription-activating potential of myogenic HLH proteins without affecting their ability to bind DNA. We show that repression by TGF-beta is directed at the basic-HLH motif of myogenin and is independent of E2A products. Using a series of reporter genes as targets for trans-activation by myogenin, transcriptional repression by TGF-beta is also shown to map to the E-box motif and to not require heterologous DNA sequence elements. These results demonstrate that TGF-beta represses muscle-specific transcription through a post-translational mechanism that renders the basic-HLH regions of the myogenic regulators nonfunctional. The selective repression of myogenic HLH proteins by TGF-beta indicates that the TGF-beta signaling system can discriminate between different classes of HLH proteins and implies that myogenic HLH proteins activate muscle-specific transcription through a unique mechanism.

Cells, Cultured↗
PubMed1992

Improved safety and efficacy in adaptive control of arterial blood pressure through the use of a supervisor.

This paper presents a dual approach to adaptive control of arterial blood pressure using sodium nitroprusside. In the clinical environment, a controller must be aggressive to achieve specific step response characteristics (less than 10 min settling time, less than 10 mm Hg overshoot), yet conservative enough to prevent overreactions to large disturbances, which are common in both the operating room and the intensive care unit. These mutually exclusive requirements make it difficult to design a closed-loop controller for this environment. To prevent possible overreactions, while maintaining proper step response, an aggressive adaptive controller has been designed to achieve the desired step response, and a SUPERVISOR has been designed around the adaptive controller to limit potential overreactions in the presence of disturbances. Simulations and dog experiments demonstrate the potential for increased safety and efficacy using this dual approach to the control of a complex physiological system.

Animals↗
PubMed1992

Supervisory adaptive control of arterial pressure during cardiac surgery.

A supervisory adaptive controller has been designed for the closed-loop control of mean arterial pressure during cardiac surgery, using sodium nitroprusside. This controller consists of a pole-placement and proportional-plus-integral feedback regulator, multiple-model adaptation, and a supervisor. The pole-placement and proportional-plus-integral regulator was designed to meet aggressive step response characteristics. Multiple-model adaptation was chosen to ensure rapid and stable adjustments for changes in key patients parameters. The supervisor was designed to provide safety and efficacy of control during disturbances that are common during cardiac surgery. We studied the ability of this supervisory adaptive controller to regulate arterial pressure during cardiac surgery on nineteen patients. The controller, through the action of the supervisor, detected and responded appropriately to the great majority of disturbances. This study demonstrated that supervisory adaptive control has the potential to provide clinically acceptable regulation of arterial pressure.

Cardiac Surgical Procedures↗
PubMed1992

The relationship between increased platelet count and megakaryocyte size in bronchial carcinoma.

This study investigates megakaryocyte size in bronchial carcinoma and its relationship to platelet count, mean platelet volume and platelet function, the latter determined in vivo by measurement of the cutaneous bleeding time. Measurements were performed in 19 patients with bronchial carcinoma and 11 patients with a hiatus hernia (controls). Platelet count (335 +/- 123 v. 241 +/- 72 x 10(9)/l) and megakaryocyte total area (772 +/- 135 v. 666 +/- 105 microns 2) (mean +/- standard deviation) were both significantly increased in patients with bronchial carcinoma when compared to controls whilst the bleeding time was shorter in the patient group (253 +/- 116 v. 321 +/- 80 s). Patients with bronchial carcinoma were older (60.2 +/- 8.4 v. 48.8 +/- 13.2 years) and smoked more heavily (760 +/- 511 v. 92 +/- 175 cigarette years) than controls. Megakaryocyte size, platelet count and bleeding time all correlated with smoking habit (r = 0.395, P = 0.031; r = 0.622, P less than 0.001; r = 0.515, P = 0.004 respectively). There were no statistically significant differences between the groups with respect to gender or mean platelet volume. When considering all patients, significant correlations existed between platelet count and megakaryocyte area (r = 0.400, P = 0.029), and bleeding time and megakaryocyte area (r = -0.365, P = 0.047). The megakaryocyte nuclear and cytoplasmic areas were positively correlated (r = 0.855, P less than 0.001). This study suggests that the elevated platelet count in patients with bronchial carcinoma is mediated by an increase in the size of bone marrow megakaryocytes although the results are compounded by the association between smoking and megakaryocyte/platelet parameters.

Bleeding Time↗
PubMed1992

Characterization of the Streptomyces clavuligerus argC gene encoding N-acetylglutamyl-phosphate reductase: expression in Streptomyces lividans and effect on clavulanic acid production.

The argC gene of Streptomyces clavuligerus encoding N-acetylglutamyl-phosphate reductase (AGPR) has been cloned by complementation of argC mutants Streptomyces lividans 1674 and Escherichia coli XC33. The gene is contained in an open reading frame of 1,023 nucleotides which encodes a protein of 340 amino acids with a deduced molecular mass of 35,224 Da. The argC gene is linked to argE, as shown by complementation of argE mutants of E. coli. Expression of argC from cloned DNA fragments carrying the gene leads to high levels of AGPR in wild-type S. lividans and in the argC mutant S. lividans 1674. Formation of AGPR is repressed by addition of arginine to the culture medium. The protein encoded by the argC gene is very similar to the AGPRs of Streptomyces coelicolor, Bacillus subtilis, and E. coli and, to a lesser degree, to the homologous enzymes of Saccharomyces cerevisiae and Anabaena spp. A conserved PGCYPT domain present in all the AGPR sequences suggests that this may be the active center of the protein. Transformation of S. clavuligerus 328, an argC auxotroph deficient in clavulanic acid biosynthesis, with plasmid pULML30, carrying the cloned argC gene, restored both prototrophy and antibiotic production.

Aldehyde Oxidoreductases↗
PubMed1992

Sequential expression of multiple POU proteins during amphibian early development.

The octamer motif is a common cis-acting regulatory element that functions in the transcriptional control regions of diverse genes and in viral origins of replication. The ability of a consensus octamer motif to stimulate transcription of a histone H2B promoter in frog oocytes suggests that oocytes contain a transcriptionally active octamer-binding protein(s). We show here that frog oocytes and developing embryos contain multiple octamer-binding proteins that are expressed in a sequential manner during early development. Sequences encoding three novel octamer binding-proteins were isolated from Xenopus cDNA libraries by virtue of their homology with the DNA binding (POU) domain of Oct-1. The predicted POU domains of these proteins were most highly related to mammalian Oct-3 (also termed Oct-4), a germ line-specific gene required for mouse early development. Transcripts from these amphibian POU-domain genes were most abundant during early embryogenesis and absent from most adult somatic tissues. One of the genes, termed Oct-60, was primarily expressed as a maternal transcript localized in the animal hemisphere in mature oocytes. The protein encoded by this gene was present in oocytes and early embryos until the gastrula stage of development. Transcripts from a second POU-domain gene, Oct-25, were present at low levels in oocytes and early embryos and were dramatically upregulated during early gastrulation. In contrast to the Oct-60 mRNA, translation of Oct-25 mRNA appeared to be developmentally regulated, since the corresponding protein was detected in embryos during gastrulation but not in oocytes or rapidly cleaving embryos. Transcripts from the third POU protein gene, Oct-91, were induced after the midblastula transition and reached their highest levels of accumulation during late gastrulation. The expression of all three genes decreased during late gastrulation and early neurulation. By analogy with other members of the POU-domain gene family, the products of these genes may play critical roles in the determination of cell fate and the regulation of cell proliferation.

Amino Acid Sequence↗
PubMed1992

Penicillin and cephalosporin biosynthetic genes: structure, organization, regulation, and evolution.

Penicillins and cephalosporins are produced by a wide variety of microorganisms, including some filamentous fungi, many gram-positive streptomycetes, and a few gram-negative unicellular bacteria. All produce these beta-lactam antibiotics by essentially the same biosynthetic pathway. Recently, most of the penicillin and cephalosporin biosynthetic genes have been cloned, sequenced, and expressed. The biosynthetic genes code for enzymes that possess multifunctional peptide synthetase, cyclase, epimerase, expandase, hydroxylase, lysine aminotransferase, and acetyltransferase activities and are organized in chromosomal gene clusters and coordinately expressed. DNA hybridization screens of streptomycetes demonstrate that beta-lactam biosynthetic genes may be more widespread in nature than is indicated by conventional antibiotic screens. They offer the possibility of expanding the search for organisms with potential to make new beta-lactam antibiotics. Attempts to improve current yields of beta-lactams in production strains by introducing into them additional copies of biosynthetic genes have been partially successful. Comparative sequence analysis of bacterial and fungal beta-lactam biosynthetic genes show they share very high sequence identity. A model that explains the similarity of biosynthetic genes from an evolutionary standpoint assumes horizontal gene-transfer between the two groups of organisms. Indirect evidence suggests the transfer occurred from the bacteria to the fungi.

Amino Acid Sequence↗
PubMed1992

Constitutive and inducible nitric oxide synthases in human megakaryoblastic cells.

Human megakaryoblastic cells (Meg-01) were found to possess constitutive and express inducible nitric oxide (NO) synthase activities. The constitutive NO synthase was Ca+(+)- and NADPH-dependent, as is the NO synthase found previously in human platelets. Stimulation of Meg-01 cells by the cytokines interleukin-1 beta (0.15-32.5 ng/ml) and tumor necrosis factor-alpha (0.15-10 ng/ml) resulted in expression of the inducible, Ca+(+)-independent, NO synthase. This activity was increased by the addition of NADPH, tetrahydrobiopterin and sepiapterin as cofactors. Induction of this enzyme was accompanied by a decrease in the constitutive NO synthase activity, a phenomenon which was prevented or reversed by dexamethasone (1 microM). Thus, human early differentiated megakaryocytic cells can synthesize NO from L-arginine by both the constitutive and the inducible NO synthases. These findings indicate that these enzymes may play an important biological role in megakaryocyte and platelet functions.

Amino Acid Oxidoreductases↗
PubMed1992

Perivascular innervation is lost in experimental atherosclerosis.

Nerve fibers, immunohistochemically positive for neuropeptide Y, tyrosine hydroxylase, calcitonin gene-related peptide and substance P, form a perivascular network surrounding the carotid arteries of New Zealand White rabbits. Transmission electron microscopy demonstrates that the nerve fibers are primarily located at the adventitial-medial border. Placing a silastic collar around a carotid artery for 14 days, in rabbits fed a diet high in cholesterol, resulted in a focal, intimal thickening in 10 out of 12 rabbits. Contralateral sham-operated arteries showed no intimal thickening. At sites where intimal thickening occurred, there was a disappearance of the perivascular nerve network. The carotid arteries from rabbits that did not respond to the collar and the sham-operated carotid arteries showed an intact and normal perivascular nerve network. In the group of animals which responded to the collar with intimal thickening, there was evidence of a proliferative response proximal to the collar and in this same tissue there was evidence of degeneration of nerve fibers. In conclusion, it has been demonstrated for the first time that, in regions of the carotid artery where intimal thickening occurred, there was an associated degeneration of the perivascular nerve network. The cause of this degeneration and its functional consequences require further investigation.

Animals↗
PubMed1992

The vasa vasorum of the rabbit carotid artery.

The anatomy of the vasa vasorum of the carotid arteries was assessed by light and electron microscopy in a series of 25 New Zealand White male rabbits. The low viscosity acrylic resin, LR White, was used to cast the microvasculature. The carotid artery was found to have an endothelial monolayer placed directly upon a broad fenestrated internal elastic lamina. The media consisted of 12-18 laminae comprised of smooth muscle cells, elastin, collagen and ground substance. Vasa vasorum were confined to the adventitial layer, with no penetration into the media. They arose directly from the lumen of the carotid artery in addition to the arterial branching points. The potential role of the vasa vasorum in the aetiology of atherosclerotic plaques is discussed.

Animals↗
PubMed1991

Influence of platelet size on outcome after myocardial infarction.

Although platelet characteristics have an important influence on ischaemic heart disease, the nature of the association of platelet size and platelet count with death and reinfarction after an index heart attack is unknown. Mean platelet volume (MPV), a determinant of platelet reactivity, was measured in 1716 men six months after myocardial infarction (MI). Deaths and recurrent ischaemic heart disease events were then assessed at two years. MPV was greater in 126 men who had a further ischaemic event (fatal or non-fatal) than in the 1590 men who had no further MI (p less than 0.001). In addition, the MPV was larger in men who died than in those who did not (p less than 0.001). There was no difference in platelet count between these groups. When analysed by quartiles, consistent trends of increasing age-adjusted relative odds of death and recurrent ischaemic events were noted for MPV. MPV did not correlate with known ischaemic heart disease risk factors such as blood pressure, blood lipids, fibrinogen, white cell count, or plasma viscosity. We believe that MPV is a further independent risk factor for recurrent MI.

Aged↗
PubMed1991

Finger clubbing.

Explore the source record for details and available documents.

Blood Platelets↗
PubMed1991

Human monocyte characteristics are altered in hypercholesterolaemia.

Peripheral blood monocytes are involved during atherogenesis in adhering to endothelium, migrating into the subendothelial space and taking-up lipoproteins to become macrophage/foam cells. We have assessed whether peripheral blood monocyte characteristics are altered in human hyperlipidaemia in age/sex/smoking status matched pairs of patients and controls. Monocytes from the hypercholesterolaemic patients, as opposed to the controls, were more sensitive to stimulation by the agonist, N-formyl-methionyl-leucyl-phenylalanine, with respect to chemokinesis (stimulation index 1.48 +/- 0.17 vs. 1.10 +/- 0.14), chemotaxis (4.05 +/- 0.55 vs. 2.72 +/- 0.24) and adhesion to porcine aortic endothelial monolayers (1.26 +/- 0.05 vs. 1.17 +/- 0.06). The patients' monocyte total surface expression of the adhesion glycoprotein CD11b/CD18 (37.5 +/- 7.1 vs. 36.0 +/- 7.1), but not CD11c/CD18 (31.6 +/- 7.2 vs. 31.4 +/- 6.8), was increased; however, the monocytes in hyperlipidaemia were larger (9.15 +/- 0.11 microns vs. 8.98 +/- 0.11 microns) such that the surface density of CD11b/CD18 was not altered (0.144 +/- 0.029 vs. 0.142 +/- 0.029). The data suggest that circulating monocytes are functionally different in hypercholesterolaemia. This may explain the increased involvement by monocytes in hypercholesterolaemia-related atherogenesis.

Animals↗