CEBPG regulates ERCC5/XPG expression in human bronchial epithelial cells and this regulation is modified by E2F1/YY1 interactions.

Marked inter-individual variation in lung cancer risk cannot be accounted for solely by cigarette smoke and other environmental exposures. Evidence suggests that variation in bronchial epithelial cell expression of key DNA repair genes plays a role. Variation in these genes correlates with variation in expression of CEBPG and E2F1 transcription factors. Here, we investigated the mechanistic basis for correlation of the DNA repair gene ERCC5 (previously known as XPG) with CEBPG and E2F1. CEBPG expression vector transfected into H23 or H460 cell lines up-regulated endogenous ERCC5 and also luciferase from a reporter construct containing 589 bp of ERCC5 5' regulatory region. A recognition site for CEBPG and a region containing sites for YY1 on the sense strand and E2F1 on the anti-sense strand participated in CEBPG up-regulation of ERCC5. CEBPG, E2F1 and YY1 binding to their respective sites were confirmed by electrophoretic mobility shift assay. Thus, we conclude that CEBPG regulates ERCC5 expression and this regulation is modified by E2F1/YY1 interactions. Several polymorphisms have been identified in these regions and, based on the data presented here, it is reasonable to hypothesize that they may contribute to risk for bronchogenic carcinoma.

Geometry-dependent scattering through quantum billiards: experiment and theory.

We present experimental studies of geometry-specific quantum scattering in microwave billiards of a given shape. We perform full quantum-mechanical scattering calculations and find excellent agreement with experimental results. We also carry out semiclassical calculations where the conductance is given as a sum over all classical trajectories between the leads, each of the trajectories carrying a quantum-mechanical phase. We unambiguously demonstrate that the characteristic frequencies of the oscillations in the transmission and reflection amplitudes t and r are related to the length distribution of the classical trajectories between the leads, whereas the frequencies of the probabilities T=/t/(2) and R=/r/(2) can be understood in terms of the length difference distribution in the pairs of classical trajectories. We also discuss the effect of nonclassical "ghost" trajectories, i.e., trajectories that include classically forbidden reflection off the lead mouths.

Alterations in cardiac myosin isozymes associated with aging and chronic hypertension: their modulation with nifedipine.

OBJECTIVE: Pressure induced left ventricular hypertrophy is associated with alterations in distribution of cardiac myosin isozymes. This study evaluated the influence of aging, superimposed chronic hypertension on aging, and treatment with nifedipine on cardiac myosin isozyme proportions. METHODS: Myosin isozyme (V1, V2, and V3) proportions were investigated by pyrophosphate gel electrophoresis, and left ventricular to body weight ratio was studied in two subgroups each of hypertensive and normotensive rats, with and without nifedipine treatment. Nifedipine treatment was started at 48 weeks and concluded at 60 weeks. RESULTS: For all four groups, the V1 level was the lowest (range 15%-24%), V3 was the highest (47%-60%), and V2 was intermediate (25%-29%). The left ventricular weight to body weight ratio was 25% higher (p < 0.001) in the untreated old hypertensive v old rats, but V1 level was of the same magnitude in both these groups. The left ventricular weight to body weight ratio was 18% lower (p < 0.001) in the old hypertensive treated v untreated rats. The V1 level was higher in both treated groups; old normotensive as well as old hypertensive rats. The changes in V1 were not statistically correlated with arterial pressure and left ventricular to body weight ratio. CONCLUSIONS: The profound decrease in V1 myosin isozyme proportion acquired with aging is not accentuated by superimposed chronic hypertension. The aging process, and not the left ventricular hypertrophy by itself, seems to be the principal determinant of the myosin isozyme shift. The myosin isozyme shift that occurs with aging is not fixed, and can be partially reversed or prevented by nifedipine.

Substance P modulates autonomic nerve activity in canine hearts.

We examined the hypothesis that substance P (SP) acts as an "afferent neuromodulator" in the heart regulating the response of the cardiac autonomic nerves to reflexes originating in the heart. We employed the acute, isovolumic canine heart preparation in which the amplitude of the chamber pressure accurately reflects changes in contractility. The heart was decentralized except for one-half of the right vagus, which was left intact to permit afferent communication with the central nervous system, while the remaining one-half was tightly ligated so that the distal part could be used for efferent stimulation. SP was injected in doses of 2-10 micrograms ic. There were no significant inotropic responses to 2 and 5 micrograms SP, whereas 10 micrograms produced positive inotropy of 5-15%. When vagal tone was elevated with sustained vagal stimulation, the same doses of SP increased contractility by 12-28%. Similarly, during right stellate ganglion stimulation (SS), SP decreased contractility 8-22%. After the intact half of the right vagus was sectioned, SP modulation of vagal responses was unaffected, while modulation of atrial, but not ventricular, responses to SS was significantly attenuated. When tested on a series of cardiac-denervated dogs, SP had no effect on cardiac inotropy at any dose. However, when contractility was increased with isoproterenol infusion, SP caused a small decrease in ventricular contractility. These results suggest that SP acts as a modulator of cardiac autonomic neural tone. It is possible that the neuropeptide is released from intramyocardial afferent collateral fibers and inhibits the elevation in vagal or sympathetic nerve activity initiated by activation of cardiac primary afferent nerves.

Tachyphylaxis of the intrinsic cardiac nerves to nicotine: effects on A-V nodal conduction.

1. The possibility that responses of the intrinsic cardiac nerves (ICN) of the dog to nicotinic stimulation are influenced by tachyphylaxis to repeated administration of nicotine (NIC) was evaluated in an anaesthetized preparation. Prolongation of A-V conduction was used as an index of ICN responsiveness. 2. Twenty dogs were placed on cardiopulmonary bypass and an electrode was sutured over the His bundle. Both vagi were sectioned, beta-adrenoceptor blockade instituted, and the hearts were paced. Nicotine (2-100 micrograms) was administered directly into the coronary circulation via an aortic catheter. Tachyphylaxis was estimated from the rate of deterioration of negative dromotropic effect of NIC in response to various protocols of repeated doses. 3. Tachyphylaxis was not observed in response to repeated doses of acetylcholine. 4. Tachyphylaxis to nicotine was found to be both time- and dose-dependent; i.e. increasing the dose or decreasing the time between doses to less than 3 min augmented its development. 5. Tachyphylaxis was pronounced after 5 x 100 micrograms doses of NIC, even if the test doses were greater than 3 min apart and 20 min was allowed to elapse between the two series of test doses. 6. These data are descriptive in nature and no mechanism for the tachyphylaxis could be deduced. Pharmacokinetic data of this nature have not been previously reported for nicotinic stimulation of the intrinsic parasympathetic ganglia of the canine heart. Tachyphylaxis can be avoided when testing the intrinsic innervation of the canine heart if the doses used are less than 100 micrograms and are administered at least 3 min apart.

Atrioventricular responses of canine heart following chronic unilateral vagotomy.

The intrinsic cardiac nerves (ICN) have been shown to develop supersensitivity to nicotine (NIC) following complete extrinsic cardiac denervation. The present experiments were performed to delineate the pattern of ICN distribution in the heart by examining the pattern of NIC supersensitivity after unilateral vagotomy (VGX). Thirty-eight dogs were placed on cardiopulmonary bypass and inotropy evaluated by means of isovolumic pressures from fluid-filled balloons placed in the atria and ventricles. The animals were divided into three groups: group I, sham-operated controls; group II, animals studied 1-2 wk after VGX; and group III, animals studied 8-12 wk after VGX. Chronotropic and inotropic responses were evaluated in terms of NIC and acetylcholine (ACh) dose-response curves as well as frequency-response curves to stimulation of the intact vagus nerve (0.5-30 Hz). No change in NIC sensitivity was observed in group II, and vagal frequency-response curves were identical to group I. In group III dogs, both the right atrium and right ventricle showed significant increases in NIC sensitivity after left vagotomy. All group III animals showed right-shifted frequency-response curves. We conclude that nicotinic supersensitivity of the ICN and inotropic unresponsiveness to vagal stimulation occur but are slow in developing (70-130 days); and preganglionic sprouting does not appear to play a functional role in the adjustment of cardiac control mechanisms to unilateral vagotomy.

Source of intrinsic innervation of canine ventricles: a functional study.

Recently it has been suggested that the parasympathetic innervation of the ventricles is by way of postganglionic axones that emanate from ganglion cells in the atria, reaching the ventricles by traversing the atrioventricular (AV) groove. We designed a series of experiments to test this hypothesis. Phenol (89%) was applied to the AV groove and surrounding 5 mm of epicardium in 21 dogs on cardiopulmonary bypass. The effects of intracoronary acetylcholine (ACh; 1-5 micrograms) and intracoronary nicotine (NIC; 25-100 micrograms) on cardiac isovolumic pressures were evaluated after beta-blockade. In another series of experiments, eight dogs were exposed to phenol in the same way and allowed to recover for 7-10 days. Atrial and ventricular responses to NIC were unaffected by phenol application to the AV groove in the acute animals when compared with application of saline alone. However, in the chronic animals, pretreatment with phenol 7-10 days previously reduced the ventricular responses to NIC by 70% while leaving the atrial responses intact. These data indicate that the intrinsic cardiac nerves (ICN) of the canine ventricles consist primarily of postganglionic parasympathetic axones which arise from supraventricular ganglia and cross the AV groove.

Measurement of parallelism of the surfaces of a transparent sample using two-beam nonlocalized fringes produced by a laser.

A detailed analysis of an interference technique for measuring the parallelism of the two surfaces of a transparent sample is presented. The technique utilizes the displacement of the center of a set of two-beam, high-visibility, nonlocalized circular fringes, which are produced when divergent laser light is incident on the sample, to give a direct measure of the wedge angle between the two surfaces of the sample. A simple equation is given relating the displacement of the center of the circular fringe system to the wedge angle. The technique is simple and lends itself to use under shop conditions.