PubMed Health⌕ Search

Biomedical subjects

K P Davies

Publications and source records attributed to K P Davies.

At least 19 recordsLinked to original sources
PubMed2003

The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo.

PURPOSE: We have previously reported that 1 intracorporeal injection of 100 microg hSlo/pcDNA reversed the effect of aging on erectile function in a rat model in vivo for at least 2 months. We report our further investigations of the amplitude, duration and physiological relevance of this novel gene transfer approach. MATERIALS AND METHODS: A total of 191 retired breeder Sprague-Dawley rats were given a single intracavernous injection of phosphate buffered saline, 1,000 microg pcDNA, or 10, 100 or 1,000 microg pcDNA/hSlo. The animals were studied 1 to 6 months after injection. The intracorporeal pressure (ICP) response to cavernous nerve stimulation and immunostaining as well as hematoxylin and eosin staining were done to evaluate effector nerve integrity and tissue histology, respectively. RESULTS: Gene transfer prevented an age related decrease in resting ICP and a physiologically relevant, significant effect on normalizing erection in vivo, as determined by submaximal (0.5 mA) and maximal (4.0 mA) cavernous nerve stimulation. The effects were observed 1 month after transfection and sustained for 6 months at the 100 and 1,000 microg doses of pcDNA/hSlo (p <0.026). CONCLUSIONS: The physiological manifestations of gene transfer were detected as an amelioration of the age related decrease in resting ICP, and parallel increase in the magnitude of the cavernous nerve stimulated an ICP response to a level at which visible erections were again observed in this rat model of aging in vivo.

Animals↗
PubMed2002

The physiology, pathophysiology and therapeutic potential of gap junctions in smooth muscle.

Phenotypic variability in smooth muscle cells accounts, in large part, for the incredible functional diversity required of the involuntary hollow organs of the body (i.e., respiratory passages, blood vessels, gastrointestinal tract, urogenital tract, etc.). In all instances coordination of smooth muscle cell responses, that is, contraction and relaxation, is critical to normal organ function. While numerous biological mechanisms exist for coordinating smooth muscle cell responses, intercellular communication through gap junctions represents a common denominator present in all organ systems. In this report, we review the evidence documenting the presence and functional significance of myocyte gap junctions to physiologically distinct organ systems, and furthermore, provide some examples of their putative roles in organ pathology. Finally, we advance the thesis that despite their ubiquity and heterogeneous expression, gap junctions are nonetheless potentially attractive therapeutic targets for the treatment of certain smooth muscle disorders. Their therapeutic efficacy will necessarily hinge on the existence of connexin isoform-selective junctional effects. The overall rationale for targeting the intercellular pathway is therefore analogous to strategies that target other ubiquitously expressed ion channels, such as calcium or potassium channels. Such strategies have proved efficacious for the treatment of a wide range of human smooth muscle disorders including hypertension, urinary incontinence and sexual function.

Animals↗
PubMed2001

An enhanced linkage map of the sheep genome comprising more than 1000 loci.

A medium-density linkage map of the ovine genome has been developed. Marker data for 550 new loci were generated and merged with the previous sheep linkage map. The new map comprises 1093 markers representing 1062 unique loci (941 anonymous loci, 121 genes) and spans 3500 cM (sex-averaged) for the autosomes and 132 cM (female) on the X chromosome. There is an average spacing of 3.4 cM between autosomal loci and 8.3 cM between highly polymorphic [polymorphic information content (PIC) > or = 0.7] autosomal loci. The largest gap between markers is 32.5 cM, and the number of gaps of > 20 cM between loci, or regions where loci are missing from chromosome ends, has been reduced from 40 in the previous map to 6. Five hundred and seventy-three of the loci can be ordered on a framework map with odds of > 1000 : 1. The sheep linkage map contains strong links to both the cattle and goat maps. Five hundred and seventy-two of the loci positioned on the sheep linkage map have also been mapped by linkage analysis in cattle, and 209 of the loci mapped on the sheep linkage map have also been placed on the goat linkage map. Inspection of ruminant linkage maps indicates that the genomic coverage by the current sheep linkage map is comparable to that of the available cattle maps. The sheep map provides a valuable resource to the international sheep, cattle, and goat gene mapping community.

Animals↗
PubMed1999

c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function.

Chromatin organization plays a key role in the regulation of gene expression. The evolutionarily conserved SWI/SNF complex is one of several multiprotein complexes that activate transcription by remodelling chromatin in an ATP-dependent manner. SWI2/SNF2 is an ATPase whose homologues, BRG1 and hBRM, mediate cell-cycle arrest; the SNF5 homologue, INI1/hSNF5, appears to be a tumour suppressor. A search for INI1-interacting proteins using the two-hybrid system led to the isolation of c-MYC, a transactivator. The c-MYC-INI1 interaction was observed both in vitro and in vivo. The c-MYC basic helix-loop-helix (bHLH) and leucine zipper (Zip) domains and the INI1 repeat 1 (Rpt1) region were required for this interaction. c-MYC-mediated transactivation was inhibited by a deletion fragment of INI1 and the ATPase mutant of BRG1/hSNF2 in a dominant-negative manner contingent upon the presence of the c-MYC bHLH-Zip domain. Our results suggest that the SWI/SNF complex is necessary for c-MYC-mediated transactivation and that the c-MYC-INI1 interaction helps recruit the complex.

Binding Sites↗
PubMed1997

Manipulation of the vsg co-transposed region increases expression-site switching in Trypanosoma brucei.

Disruption of a region of DNA in Trypanosoma brucei immediately upstream of the expressed telomere-proximal variant surface glycoprotein gene (vsg), known as the co-transposed region (CTR), can cause a dramatic increase in the rate at which the active expression site (ES) is switched off and a new ES is switched on. Deletion of most of the CTR in two ESs caused a greater than 100-fold increase in the rate of ES switching, to about 1.3 x 10(-4) per generation. A more dramatic effect was observed when the entire CTR and the 5' coding region of the expressed vsg221 were deleted. In this case a new ES was activated within a few cell divisions. This switch also occurred in cell lines where a second vsg had been inserted into the ES, prior to CTR deletion. These cell lines, which stably co-expressed the inserted and endogenous Vsgs, in equal amounts, did not differ from the wild-type in growth rate or switching frequency, suggesting that simultaneous expression of two Vsgs has no intrinsic effect. CTR deletion did not disturb the inserted vsg117. We tentatively conclude that it was not the disruption of the vsg221 in itself that destabilized the ES. All of the observed switches occurred without additional detectable DNA rearrangements in the switched ES. Deletion of the 70-bp repeats and/or a vsg pseudogene upstream of the CTR did not affect ES stability. Several speculative interpretations of these observation are offered, the most intriguing of which is that the CTR plays some role in modulating chromatin conformation at an ES.

Animals↗
PubMed1996

Stable expression of mosaic coats of variant surface glycoproteins in Trypanosoma brucei.

The paradigm of antigenic variation in parasites is the variant surface glycoprotein (VSG) of African trypanosomes. Only one VSG is expressed at any time, except for short periods during switching. The reasons for this pattern of expression and the consequences of expressing more than one VSG are unknown. Trypanosoma brucei was genetically manipulated to generate cell lines that expressed two VSGs simultaneously. These VSGs were produced in equal amounts and were homogeneously distributed on the trypanosome surface. The double-expressor cells had similar population doubling times and were as infective as wild-type cells. Thus, the simultaneous expression of two VSGs is not intrinsically harmful.

Animals↗