Transcriptional repression: lessons from thyroid hormone action and promyelocytic leukaemia

We report seemingly unique craniofacial malformations and deglutition dysfunction in a sib pair. The boy had right maxillomandibular alveolar synechae, ankylosis of right temporomandibular joint, hypoplasia of the zygomatico-maxillary region, nasal deviation to the left, choanal stenosis, and exophthalmos due to shallow orbita. His ears were apparently low-set with prominent lobules. He had severe gastroesophageal reflux and increasing respiratory problems and died at age 11 months. Psychomotor development was normal. His 10-year-old sister had similar craniofacial malformations and a cleft soft palate. She also had a severe deglutition dysfunction and developed a thoracolumbar kyphoscoliosis. Psychomotor development was normal. The parents were healthy and non-consanguineous. The malformations in the sibs do not fit any reported craniofacial malformation syndrome and may represent a previously unrecognized monogenic disorder. This may be an autosomal recessive or dominant trait with gonadal mosaicism in one of the parents.     

Cracking in γ-TiAl due to high speed particle impact

Cracking due to small particle impacts on prospective γ-TiAl blades in jet turbine engines has been studied experimentally and theoretically. Flat rectangular specimens of two γ-TiAl alloys, with edges chamfered to resemble the taper of blades, were subjected to small particle impacts. The forms of damage observed resembled those revealed by earlier studies using specimens that were cast closely to the shape of blade leading edges. Numerical simulations of the impact events were carried out using finite element analysis, using uniaxial stress-strain behavior that was obtained in compression at high strain rates. A criterion for cracking is proposed that requires critical levels of plastic strain and tensile stress. Predictions of crack extent that were based on such a combined criterion were found to be in the range of observations. The predictive methodology, together with information on the fatigue strength of various damage states, potentially offers designers the opportunity to examine the risk associated with small particle damage on contemplated blades.     

Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.     

The immunosuppressive activity of Ascaris suum is due to high molecular weight components

Allylamine (AA, 3-aminopropene) is a specific cardiovascular toxin used experimentally to model myocardial necrosis and atherosclerosis. In these physiologic experiments, 10-day AA exposure (100 mg . kg-1 . day-1 by gavage) produced severe myocardial necrosis and increased heart rate but did not affect systolic blood pressure in rats. Mid-thoracic aortic ring segments were removed, and reactivity to contractile and relaxant agonists was tested. Aortic rings (approximately 3 mm) from AA-treated rats were contracted significantly more by high potassium (100 mM) and slightly more by norepinephrine (NE, 10 microM) than anatomically matched control aortic rings. No difference in aortic ring NE sensitivity or percentage relaxation in response to acetylcholine (1 microM) or sodium nitroprusside (100 microM) was detected between control and AA-treated rat aortic rings. Allylamine (1 microM-1 mM) induced modest, concentration-dependent contractions and tension oscillations in aortic rings from both control and AA-treated rats. Aortic rings from AA-treated rats, however, were more sensitive to AA. Vascular smooth muscle cells derived from control and AA-treated rat aortas had similar toxic sensitivity to AA in vitro using the MTT viability assay. The mechanisms by which AA exposure increased heart rate in vivo and contractility of aortic rings are unknown. These experiments support the previously proposed concept that AA-induced acute myocardial necrosis is due to coronary vasospasm and myocardial ischemia and cell injury.