Molecular analysis of four males with mental retardation and deletions of Xq21 places the putative MR region in Xq21.1 between DXS233 and CHM.
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Biomedical subjects
Publications and source records attributed to M May.
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In the yeast Saccharomyces cerevisiae, the sugar-induced expression of various genes coding for glycolytic enzymes is triggered by increases in the concentrations of different internal metabolites. Here, we show that the induction of the glycolytic isoenzyme enolase 2 is strictly dependent on the abilities of different mutant strains to increase the level of glucose-6-phosphate after the addition of sugars. In contrast, the induction of alcohol dehydrogenase I is dependent on increasing concentrations of metabolites in the late stages of glycolysis.
X linked recessive deafness accounts for only 1.7% of all childhood deafness. Only a few of the at least 28 different X linked syndromes associated with hearing impairment have been characterised at the molecular level. In 1960, a large Norwegian family was reported with early onset progressive sensorineural deafness, which was indexed in McKusick as DFN-1, McKusick 304700. No associated symptoms were described at that time. This family has been restudied clinically. Extensive neurological, neurophysiological, neuroradiological, and biochemical, as well as molecular techniques, have been applied to characterise the X linked recessive syndrome. The family history and extensive characterisation of 16 affected males in five generations confirmed the X linked recessive inheritance and the postlingual progressive nature of the sensorineural deafness. Some obligate carrier females showed signs of minor neuropathy and mild hearing impairment. Restudy of the original DFN-1 family showed that the deafness is part of a progressive X linked recessive syndrome, which includes visual disability leading to cortical blindness, dystonia, fractures, and mental deficiency. Linkage analysis indicated that the gene was linked to locus DXS101 in Xq22 with a lod score of 5.37 (zero recombination). Based on lod-1 support interval of the multipoint analysis, the gene is located in a region spanning from 5 cM proximal to 3 cM distal to this locus. As the proteolipid protein gene (PLP) is within this region and mutations have been shown to be associated with non-classical PMD (Pelizaeus-Merzbacher disease), such as complex X linked hereditary spastic paraplegia, PLP may represent a candidate gene for this disorder. This family represents a new syndrome (Mohr-Tranebjaerg syndrome, MTS) and provides significant new information about a new X linked recessive sydromic type of deafness which was previously thought to be isolated deafness.
Anax junius is a large dragonfly that regulates thoracic temperature (Tth) during flight. This species, like several other intermittently endothermic insects, achieves control of Tth at least in part by increasing circulation of hemolymph to the abdomen at high air temperature (Ta), thus facilitating heat loss from the thorax. In this paper, I demonstrate that heat transfer to the head is also under active control, very probably owing to temperature-sensitive alteration of hemolymph circulation. As a result, head temperature (Th) is strikingly elevated above Ta during endothermic warm-up and flight. Furthermore, during unrestrained flight in the field, Th is regulated actively by increasing hemolymph circulation from the warm thorax at low Ta. Concurrent measurements of abdominal temperature (Tab) confirm that the abdomen is used as a 'thermal window' at Ta>30 °C but apparently not at lower Ta; thus, some additional mechanism(s) must exist for regulation of Tth at low Ta.
The large, endothermic dragonfly Anax junius regulates the temperatures of its thorax (Tth) and head (Th) during flight. At high ambient temperature (Ta) it is able to dispose of excess heat from the thorax by increasing hemolymph circulation to the abdomen, but recent evidence suggests that heat loss to the abdomen is largely passive at Ta<30 °C. Nevertheless, these insects continue to regulate Tth and Th at least down to 20 °C and probably at much lower values of Ta. As Ta declines, A. junius glide less, probably fly faster when feeding, and increase their wingbeat frequency when patrolling. Presumably as a result of these behavioral changes, heat production, and thus inferred flight metabolic rate, is inversely proportional to Ta. This is the first demonstration based on field data that an insect regulates body temperature while flying by altering heat production.
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Aarskog-Scott syndrome was tentatively mapped to Xq13 on the basis of an X:8 translocation by Bawle et al. [Am J Med Genet 17:595-602, 1984]. A review of the cytogenetics and the use of molecular markers in that family have resulted in revision of the breakpoints of the translocation to Xp 11.2 and 8q11.21 [Glover et al., Hum Mol Genet 2:1717-1718, 1993]. Two families, including one of the two initial families with Aarskog-Scott syndrome [Scott, BD:OAS VII (6): 240-246, 1971], have participated in our study to evaluate the localization of the gene for Aarskog-Scott syndrome to the pericentromeric region of the X chromosome. Using a series of DNA probes, we have been able to confirm linkage to the X chromosome, with multipoint analysis indicating the most likely localization of the gene to be on the proximal short arm.
Human papillomavirus type 16 (HPV16) induces squamous intraepithelial lesions of the cervical mucosa which may develop into invasive cancer. The expression of viral oncogenes in advanced neoplasias appears increased relative to the proliferating cell layers of low grade lesions raising questions about molecular mechanisms of deregulation of transcription. In a lymph node metastasis of a cervical cancer, we observed full-length HPV16 plasmids and molecules with a small deletion, which was mapped to the long control region (LCR). Both wild type and shortened LCR were amplified by PCR, cloned into the promoter test plasmid pBLCAT6 and sequenced to identify a 107 bp deletion from position 7794 to 7901 in the short LCR. CAT expression in cervical cancer-derived HT3, SiHa and CaSki cells appeared 5- to 6-fold increased under the control of the short LCR. This could be traced back to elevated levels of mRNA initiated at the viral oncogene promoter. A slight further increase in CAT expression was noted in the presence of the HPV16 E2 protein which is probably due to the deletion of one E2 binding site and consequent relief from E2 repression. Computer-assisted sequence analysis and band-shift experiments with purified YY1 protein and wild type or mutated oligonucleotides identified four binding sites for this cellular transcriptional repressor within the promoter-proximal segment of the HPV16 LCR, three of which were removed by the deletion. A LCR fragment comprising these YY1 binding sites was cloned in front of the heterologous thymidine kinase gene promoter and suppressed CAT expression 3- to 4-fold.(ABSTRACT TRUNCATED AT 250 WORDS)
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The noncoding region of the highly oncogenic, epidermodysplasia verruciformis-associated human papillomavirus type 8 contains a negative regulatory element (NRE). Quantitative RNase protection analysis confirmed that the NRE sequence acts as a silencer of transcription. A 38-bp sequence upstream of late promoter P7535 down-regulated expression from the homologous P7535 promoter, as well as the heterologous tk gene promoter, independently of its orientation relative to the test promoters. It also reduced gene expression when cloned downstream of the transcription units. Transient expression assays with keratinocytes and fibroblasts of epidermodysplasia verruciformis patients and controls demonstrated that the NRE activity is not cell specific. Gel retardation tests suggested that NRE specifically interacts with only one nuclear factor. Mutational analysis identified three NRE mutants which no longer formed a detectable DNA-protein complex but still repressed transcription, indicating that protein-DNA interaction is not relevant for the silencer function. The NRE contains a binding site of viral trans activator protein E2. It was shown that expression of E2 overrides the inhibitory effect of the NRE sequences. Binding of E2 and that of the cellular factor were mutually exclusive. The bifunctional nature of NRE acting as a silencer and a target site for viral trans activator E2 offers an interesting opportunity to regulate the switch from early to late transcription in the human papillomavirus life cycle.
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The incidence of complications of endoscopic sinus surgery (ESS) in a combined experience with 2108 total patients is compared to complications in 11 other series of patients (2583 total) who underwent ESS and 6 series of patients (2110 total) who underwent traditional endonasal sinus surgery. The incidence of major perioperative complications was 0.85%, with cerebrospinal fluid (CSF) leak being the most common. The most common minor complications of ESS were those related to orbital penetration and middle turbinate adhesions; minor complications occurred in 6.9% of the 2108 patients. There were no statistically significant differences in the overall incidences of major complications between this series and the other two groups. Recommendations are made for the prevention of complications during ESS.
In nonsurgical management of benign prostatic hyperplasia, drugs which interfere with prostate contraction mediated through the alpha-1 adrenergic receptor are used. Clonidine acts at alpha adrenergic and I1-imidazoline receptors. In the present study, we found the Kd for [3H]clonidine binding to I1 sites in canine prostate to be 4 +/- 1 nM; the Bmax was 18 +/- 2 fmol/mg of protein. Inhibition of binding by imidazolines and by brain extracts containing putative endogenous ligand confirmed the identity of these sites as I1-imidazoline. Autoradiographic studies showed localization of both I1 and alpha-2 sites to the glandular epithelium. We sought to determine whether in vivo activation of the I1-imidazoline sites by clonidine mediates its contractile action in canine prostate. Dose-response curves were generated for para-aminoclonidine in the presence of vehicle alone, yohimbine (alpha-2 antagonist), idazoxan (alpha-2/I1/I2 antagonist) and prazosin (alpha-1 antagonist). Prazosin was the most effective antagonist. Yohimbine was less effective and did not effectively discriminate between para-aminoclonidine and phenylephrine, an alpha-1-selective agonist. Idazoxan antagonized para-aminoclonidine, but by not more than 50% at any dose. These results suggest that clonidine is active primarily at alpha-1 receptors on prostate smooth muscle in vivo. Thus the function of the I1 and alpha-2 receptors in the prostate remains to be determined; however, they may be involved in epithelial cell function.
An unusual case is reported in which a preauricular cyst associated with a congenital cholesteatoma caused facial nerve paralysis in a 40-year-old woman. The patient underwent three exploratory temporal bone operations to locate a source of facial nerve compression, but the cause of the palsy was not found until resection of a preauricular cyst revealed an epithelial tract that was traced through the external auditory canal and across the tegmen tympani to the site of the cholesteatoma.
Platelet-derived growth factor (PDGF) is a disulfide-linked dimer comprised of two related polypeptide chains. To investigate the effects of an inactivating lesion introduced into one chain of the nascent PDGF dimer, approaches were developed to optimize synthesis, assembly, secretion, and purification of heterodimers between normal PDGF A and wild-type or mutant PDGF B. PDGF AB heterodimers were released into culture fluids less efficiently than PDGF AA, but to a greater degree than the cell-associated PDGF BB. These results suggest that interactions between two chains influence PDGF secretion. Analysis of heterodimers between PDGF A and disabled PDGF B mutants on cells that express either alpha or beta PDGFRs demonstrated that the impaired biologic activity of the mutant PDGF B chain was ameliorated with respect to binding and triggering of alpha PDGFRs. In cells that expressed both receptor types, heterodimers of mutant PDGF B and wild-type PDGF A gained substantially in their ability to recruit and trigger alpha, but not beta, PDGFRs. Partial rescue of impaired PDGF B mutant chain function by dimer formation with a wild-type PDGF A chain implies that interchain interactions markedly affect PDGFR binding and activation.
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