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PubMed2003

Synthesized variable structure control and gray prediction for a class of perturbed systems.

Based on the Lyapunov stability theorem, we apply a gray prediction scheme to eliminate the "chattering" disadvantage of the traditional variable structure control. By using a moving window of recent past data, we can directly identify the system dynamics and unknown perturbations via the gray prediction scheme. Therefore there is no need for the information of the upper bound of the perturbations in advance. In addition, the presented control scheme ensures the property of the globally uniformly ultimate boundness for the overall controlled system. Finally, a numerical example is given to illustrate the feasibility of the proposed control scheme.

Journal Article↗
PubMed1994

Outgrowth morphology and intracellular calcium of crustacean neurons displaying distinct morphologies in primary culture.

Peptide-secreting neurons from crustacean X-organ regenerating in defined culture possess different ionic current profiles correlated with two distinct morphological types, veiling and branching; voltage-dependent Ca2+ current is prominent in neurons consistently extending large veils, but is small in neurons that repetitively branch. Intracellular free calcium levels ([Ca2+]i) have been implicated in the regulation of neurite outgrowth underlying the establishment of distinct morphologies. Here, basal [Ca2+]i was measured by fura-2 fluorescence ratio imaging from these morphologically distinct neurons and compared. Both morphological types can extend out processes over a [Ca2+]i range (approximately 50 to 300 nM) that is much greater than that reported for neurons of other phyla. Application of high K+ saline led to increases in [Ca2+]i in soma, neurite, and lamellipodium of veiling neurons. Increases were greater for veiling than branching neurons. These observations were consistent with the previous voltage clamp data for calcium currents. Media altered to perturb [Ca2+]i were used to assess the role of [Ca2+]i in veiling or branching outgrowth programs. Outgrowth of veiling cells was arrested by addition of 100 microM Cd2+, a calcium channel blocker. Outgrowth resumed following brief exposures to Cd2+. Branching neurons were unaffected by Cd2+. Cd2+ at lower levels (10 microM) had no effect on outgrowth of either neuronal type, whereas at higher levels (1 mM), outgrowth of both types was arrested. Reduction of extracellular sodium to 0.001 of normal concentration stopped veiling outgrowth, but branching outgrowth continued, although it was less robust. Addition of tetrodotoxin (1 microM) did not alter outgrowth of either neuronal type relative to controls. Thus, peptidergic neurons of differing intrinsic morphologies maintain similar basal [Ca2+]i levels under identical culture conditions, yet show differing sensitivities to manipulations influencing [Ca2+]i with respect to regenerative outgrowth, but not its form.

Animals↗
PubMed2000

Functionality of a membrane protein in bicelles.

Bicelles are bilayered discoidal lipid-detergent assemblies which are useful as model membranes. To date, there has been no direct demonstration of functional viability for an integral membrane protein reconstituted into bicelles. In this contribution, the catalytic activity of diacylglycerol kinase (DAGK) was measured following reconstitution into several different bicelle systems and compared to activities measured in traditional mixed micelles and vesicles. For the most optimal bicelle systems tested, DAGK activities approached those observed in mixed micelles or vesicles. For some other bicellar mixtures tested, activities were much lower, with steady-state kinetic data indicating reduced V(max) rather than perturbations in substrate K(m). Catalytically, DAGK showed a strong preference for bicelles containing 3-(cholamidopropyl)dimethylammonio-2-hydroxy-1-propanesulfonate (CHAPSO) as the detergentcomponent relative to short-chained phosphatidylcholine.DAGK also exhibited a preference for dimyristoylphosphatidylcholine or dipalmitoylphosphatidylcholine bicelles relative to those of dilauroylphosphatidylcholine.

Catalysis↗
PubMed2000

High-Resolution Infrared Study of the nu(7), nu(8), and nu(15) Bands and Millimeter-Wave Investigation of the v(8) = 1 State of CF(2)Cl-CH(3).

High-resolution (Deltavarsigma = 2.3 and 2.9 x 10(-3) cm(-1)) FTIR spectra of natural and (35)Cl monoisotopic CH(3)CF(2)Cl have been recorded at -70 degrees C in the 600-1400 cm(-1) range. The bands nu(7), nu(8), and nu(15) have been rotationally analyzed for both isotopic varieties. With the help of predictions based on nu(8) parameters, the millimeter-wave spectrum of the (35)Cl species in the v(8) = 1 state has been observed and jointly fitted with the IR data. Only a small number of local perturbations have been detected in the spectra. Altogether more than 8000 IR transitions have been fitted with an experimental precision of ca. 3 x 10(-4) cm(-1). Copyright 2000 Academic Press.

Journal Article↗
PubMed1987

The effect of the two epipodophyllotoxin derivatives etoposide (VP-16) and teniposide (VM-26) on cell lines established from patients with small cell carcinoma of the lung.

To determine whether there is any difference between the two epipodophyllotoxin derivatives etoposide and teniposide in their therapeutic effect in small cell carcinoma of the lung (SCCL), they were compared against five human SCCL cell lines in vitro. When the two were compared at equimolar concentrations teniposide was found to be 8-10 times more potent than etoposide, both with 1-h incubation and with continuous incubation in a clonogenic assay and in inducing cell cycle perturbations monitored by flow cytometry. Published pharmacokinetic data suggest that this potency difference is not accompanied by an equivalent increase in toxicity. The concentrations used for the 1-h incubation were about 100-fold the concentrations used in the experiments with continuous incubation to obtain the same degree of cell kill for both drugs. This suggests that they should be given according to a continuous rather than an intermittent schedule.

Animals↗
PubMed1986

Renal effects of angiotensin converting enzyme inhibitors in hypertension.

This review focuses on the renal effects of the angiotensin converting enzyme inhibitors, captopril and enalapril. Emphasis is placed on the renal response to these drugs in patients with primary essential hypertension, and in hypertension accompanying renal parenchymal disease. Specifically reviewed are the renal function and hemodynamic, salt and water, body fluid composition, and urinary protein excretion responses. The interruption of the renin-angiotensin-aldosterone axis has the potential to produce a variety of favorable renal responses, including reduction of renal vascular resistance, enhancement of renal blood flow, enhancement of glomerular filtration rate, acute natriuresis, sustained diuresis, and a decrease in urinary protein excretion. Data in support of these potential renal perturbations are presented and discussed. The results suggest that the angiotensin converting enzyme inhibitors are important therapeutic agents in the treatment of hypertensive disease, in that they may modify pathophysiologic renal abnormalities encountered in this disease state.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Endothelial dysfunction in venous pulmonary hypertension in the neonatal piglet.

In a group of neonatal piglets an increase in pulmonary arterial pressure was obtained within 2 weeks after a partial mechanical obstruction of the left atrium by a balloon catheter. Mean pulmonary artery pressure in the hypertensive animals (n = 6) was 24 +/- 2 mm Hg as compared (p < 0.01) with 15 +/- 1 mm Hg in controls (n = 6) or 9 +/- 2 mm Hg in sham-operated piglets (n = 6). Cardiac index was reduced in hypertensive versus control and sham groups: 0.15 +/- 0.01 versus 0.32 +/- 0.05 and 0.29 +/- 0.04 L.min-1.kg-1 (p < 0.05), respectively. There was no detectable difference on histologic examination in the pulmonary arteries between the three groups. Right ventricular hypertrophy was observed in the group with pulmonary hypertension. In hypertensive piglets, isolated conduit pulmonary arteries did not relax when stimulated with acetylcholine; they always relaxed to sodium nitroprusside. These data suggest that the first stages of perturbations reported during pulmonary venous hypertension occur at the level of the pulmonary vascular endothelium. This neonatal model of pulmonary hypertension is simple to perform and might be useful for further investigations.

Acetylcholine↗
PubMed1986

The effect of clofibrate on the phospholipid composition of the peroxisomal membranes in mouse liver.

Membranes were prepared from peroxisomes which had been isolated from the livers of normal mice and from mice treated with clofibrate (a hypolipidemic drug and peroxisome proliferator). Phospholipid analysis of these membranes revealed that clofibrate treatment resulted in a decrease in the membrane content of phosphatidylcholine, the most abundant phospholipid, and a concomitant increase in the amount of lysophosphatidylcholine, this latter component reaching a level of almost 6% of the total membrane phospholipid. The concentrations of other phospholipids in these membranes were not significantly altered. The parallel analysis of microsomal membranes demonstrated an analogous increase in the level of lysophosphatidylcholine following clofibrate treatment. In control experiments with microsomal membranes employing quinacrine, an inhibitor of phospholipase A2, the increased lysophosphatidylcholine concentration was still observed in clofibrate-treated animals. As well, a decrease in the proportion of microsomal phosphatidylcholine with clofibrate treatment was seen when quinacrine was used. Fatty acid analysis of the phosphatidylcholines from peroxisomal membranes showed some minor changes, including an increase in one component tentatively identified as docosahexaenoic acid, in clofibrate-treated animals. Overall, these data demonstrate that clofibrate causes a marked perturbation of the phospholipid composition of peroxisomal membranes, and are interpreted as indicating that the main site of action of the drug is the deacylation-reacylation cycle between phosphatidylcholine and lysophosphatidylcholine.

Animals↗
PubMed1989

Inositol lipid metabolism in vasopressin stimulated hepatocytes from rats infused with tumor necrosis factor.

We studied the effect of i.v. infusion of human recombinant tumor necrosis factor alpha (rHuTNF alpha, Cetus, 15 micrograms/100 g bw over 3 h) on vasopressin (VP)-stimulated 32P-inositol lipid turnover and the release of 3H-inositol phosphates in isolated rat hepatocytes. The early VP-induced decrease (within 30 s) in 32P-phosphatidylinositol 4-phosphate and 32P-phosphatidylinositol 4,5-bisphosphate labeling was significantly reduced (-40%) and at the same time the uptake of 32P into phosphatidic acid was 50% lower than in saline-infused (matched control) rats. Within 5 min of VP-stimulation, lower 32P phosphatidylinositol (-40%) and higher 32P-phosphatidic acid (+30%) labeling were observed in rHuTNF alpha-infused rats. Infusion of rHuTNF alpha also affected the VP-induced release of 3H-inositol phosphates. The accumulation of 3H-inositol-labeled water soluble products was decreased by 25% and 17% at 30 s and 10 min, respectively. These data show that rHuTNF alpha mimics early perturbations induced by Escherichia coli endotoxin infusion in VP-stimulated inositol lipid metabolism in rat hepatocytes.

Animals↗
PubMed1995

Diets enriched in unsaturated fatty acids enhance apolipoprotein A-I catabolism but do not affect either its production or hepatic mRNA abundance in cynomolgus monkeys.

To determine the mechanisms whereby dietary fatty acids influence high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I concentrations, ten cynomolgus monkeys were fed each of three experimental diets enriched in saturated (SAT), monounsaturated (MONO), or polyunsaturated (POLY) fatty acids in a crossover design consisting of three 13-week periods, with each animal serving as its own control. Each diet contained 30% of energy as fat with 0.22 mg cholesterol/kcal and differed solely by the isocaloric substitution of fatty acids as 18% of total energy calories. The replacement of dietary saturated fatty acids with either monounsaturated or polyunsaturated fatty acids, respectively, resulted in significant reductions of plasma total cholesterol (-17%; -30%), HDL cholesterol (-32%; -41%), and apo A-I (-37%; -44%) concentrations, while no significant differences were noted in plasma lipid or apo A-I concentrations when the MONO and POLY phases were compared. Although the MONO and POLY diets were similar in their effects on plasma lipids and apolipoproteins, the HDL of monkeys fed the POLY diet, as compared with either the SAT or the MONO diets, contained more cholesteryl ester and phospholipid but less total protein, resulting in a significantly lower total lipid to protein constituent ratio. Metabolic experiments revealed that the significantly lower plasma apo A-I concentrations observed during both the MONO and POLY phases relative to SAT were directly attributable to enhanced HDL apo A-I catabolism. Conversely, neither HDL apo A-I production rates nor hepatic apo A-I mRNA concentrations were significantly affected by dietary fatty acid perturbation in this study. Taken together, these data indicate that fractional catabolic rate is the predominant mechanism by which dietary fatty acids differentially modulate circulating concentrations of HDL apo A-I in this species when all other dietary variables are held constant.

Animals↗
PubMed1992

Probing protein structure by solvent perturbation of nuclear magnetic resonance spectra. Nuclear magnetic resonance spectral editing and topological mapping in proteins by paramagnetic relaxation filtering.

Soluble spin labels, which "bleach" the surface proton resonances of a protein to n.m.r. measurements, can provide useful information about protein conformation and dynamics. The use of the soluble nitroxide, TEMPOL, has been explored to show the correlation of the paramagnetic perturbations of protein two-dimensional n.m.r. data with proton exposure to the free radical in hen egg-white lysozyme. The results demonstrate that the nitroxide approaches the protein randomly, and that the extent of the observed paramagnetic effects reflects the native folding pattern of the protein. A correlation of spectral simplification with the known tertiary structure establishes the feasibility of new strategies for topological mapping of surface and buried protons of the protein. Application to the elucidation of protein structure and to the study of dynamical processes is discussed.

Amino Acid Sequence↗
PubMed1984

Design and thermometry of an intracavitary microwave applicator suitable for treatment of some vaginal and rectal cancers.

The construction of a modified coaxial cable as an intracavitary microwave applicator suitable for use in some vaginal and rectal cancers is presented. Thermometry was performed for microwave frequencies of 300, 400, 650, and 915 MHz. Temperature profiles in tissue phantoms were obtained with non-perturbing temperature probes and thermography, and the data were compared with those obtained in dogs. The temperature profiles were dependent on the frequency of the microwaves and the insertion depth of the applicator. In addition, an acrylic cylindrical spacer external to the applicator also altered the heating pattern. Therefore, with proper combinations of frequency, insertion depth and spacer, the applicator can be used for heating tumors in some clinical situations.

Animals↗
PubMed2005

Musculoskeletal support of lumbar spine stability.

Using a biomechanical model and experimental data the self-stabilising behaviour of antagonistic trunk muscles was analyzed. The biomechanical model is constituted of a pair of antagonistic Hill-type muscles, their geometric arrangement with respect to the spine, and the instantaneous centre of rotation in frontal plane. Using Ljapunov's theory, the stability of certain motion and loading situations was analyzed. Applying a sensitivity analysis, the influence of different muscle properties and the geometric arrangement on stability was investigated. The simulations revealed that the stability of spinal movements depended primarily on the geometrical arrangement of muscles and the position of the centre of rotation of the spine, the latter was affected in turn by the activities of the profound muscles. To stabilize the situations simulated oblique muscle arrangements were necessary. In order to define an instantaneous centre of rotation in the lower region of the spine negative attachment angles (medio-lateral decline) of muscles were necessary, corresponding to the real anatomy of obliquus externus muscles. More cranially located instantaneous centres of rotation required positive attachment angles for stability, corresponding to obliquus internus or multifidus muscles. Furthermore, the fibre-type distribution of muscles influenced the stability of the system, i.e. a high percentage of fast-twitch-fibres supported the stabilisation. Conclusions drawn from the simulations were supported by experimental data. Sudden loads and quick-release perturbations with two different amplitudes were applied to the upper body of ten male subjects. In comparison to sudden load situations preactivation of muscles due to an external load, i.e. quick-release perturbation, led to significantly less dependency of the amplitude of deflection on the amplitude of the perturbation. This observation relates to the self-stabilising properties of the musculoskeletal system. In conclusion, training seems to be advantageous if directed towards not only enhancing the endurance capacity of the muscles, but also increasing the cross-sectional area of oblique fast-twitch-fibres. Training should also improve the co-ordination of deep and superficial trunk muscles. These findings may influence physiotherapy and training programs for low back pain patients.

Journal Article↗
PubMed2001

Peroxynitrite induced nitration and inactivation of myofibrillar creatine kinase in experimental heart failure.

OBJECTIVE: Oxidative stress is implicated in the initiation and progression of congestive heart failure, but the putative reactive species and cellular targets involved remain undefined. We have previously shown that peroxynitrite (ONOO(-), an aggressive biological oxidant and nitrating agent) potently inhibits myofibrillar creatine kinase (MM-CK), a critical controller of contractility known to be impaired during heart failure. Here we hypothesized that nitration and inhibition of MM-CK participate in cardiac failure in vivo. METHODS: Heart failure was induced in rats by myocardial infarction (left coronary artery ligation) and confirmed by histological analysis at 8 weeks postinfarct (1.3+/-1.4 vs. 37.7+/-3.2% left ventricular circumference; sham control vs. CHF, n=10 each). RESULTS: Immunohistochemistry demonstrated significantly increased protein nitration in failing myocardium compared to control (optical density: 0.58+/-0.06 vs. 0.93+/-0.09, sham vs. CHF, P<0.05). Significant decreases in MM-CK activity and content were observed in failing hearts (MM-CK k(cat): 6.0+/-0.4 vs. 3.0+/-0.3 micromol/nM M-CK/min, P<0.05; 6.8+/-1.3 vs. 4.7+/-1.2% myofibrillar protein, P<0.05), with no change in myosin ATPase activity. In separate experiments, isolated rat cardiac myofibrils were exposed to ONOO(-) (2-250 microM) and enzyme studies were conducted. Identical to in vivo studies, selective reductions in MM-CK were observed at ONOO(-) concentrations as low as 2 microM (IC(50)=92.5+/-6.0 microM); myosin ATPase was unaffected with ONOO(-) concentrations as high as 250 microM. Concentration dependent nitration of MM-CK occurred and extent of nitration was statistically correlated to extent of CK inhibition (P<0.001). Immunoprecipitation of MM-CK from failing left ventricle yielded significant evidence of tyrosine nitration. CONCLUSION: These data demonstrate that cardiac ONOO(-) formation and perturbation of myofibrillar energetic controllers occur during experimental heart failure; MM-CK may be a critical cellular target in this setting.

Animals↗
PubMed2003

Role of the N and C-terminal strands of beta 2-microglobulin in amyloid formation at neutral pH.

Beta 2-microglobulin (beta(2)m) is known to form amyloid fibrils de novo in vitro under acidic conditions (below pH 4.8). Fibril formation at neutral pH, however, has only been observed by deletion of the N-terminal six residues; by the addition of pre-assembled seeds; or in the presence of Cu(2+). Based on these observations, and other structural data, models for fibril formation of beta(2)m have been proposed that involve the fraying of the N and C-terminal beta-strands and the consequent loss of edge strand protective features. Here, we examine the role of the N and C-terminal strands in the initiation of fibrillogenesis of beta(2)m by creating point mutations in strands A and G and comparing the properties of the resulting proteins with variants containing similar mutations elsewhere in the protein. We show that truncation of buried hydrophobic side-chains in strands A and G promotes rapid fibril formation at neutral pH, even in unseeded reactions, and increases the rate of fibril formation under acidic conditions. By contrast, similar mutations created in the remaining seven beta-strands of the native protein have little effect on the rate or pH dependence of fibril formation. The data are consistent with the view that perturbation of the N and C-terminal edge strands is an important feature in the generation of assembly-competent states of beta(2)m.

Amyloid↗
PubMed1987

Modification of myosin subfragment 1 tryptophans by dimethyl(2-hydroxy-5-nitrobenzyl)sulfonium bromide.

Modification of tryptophanyl residues (Trps) of myosin subfragments 1 (S-1) was performed with dimethyl(2-hydroxy-5-nitrobenzyl)sulfonium bromide (DHNBS). Under controlled conditions, pH 6 at 0 degrees C and 10-min reaction with 10-100-fold molar excess, K+(EDTA) activity was reduced down to less than half, whereas Ca2+-ATPase activity increased and acto-S-1-ATPase was not affected. The number of modified Trps (up to 2.5) agreed well with the number of 2-hydroxy-5-nitrobenzyl moieties incorporated in S-1. The thiol groups of S-1 were not affected up to 50-fold molar excess of DHNBS, thus indicating that the modification was selective for Trps. The modification of as few as one Trp caused a blue shift of the emission spectrum, accompanied by a reduction in the fluorescence quantum yield. The accessibility of Trps to the fluorescence quencher acrylamide is drastically reduced upon modification, indicating that DHNBS-reactive Trps are more "exposed" than the DHNBS-refractive ones. DHNBS modification did not seem to affect the ATP-induced tryptophan fluorescence enhancement of S-1. The effect of DHNBS modification of the intrinsic fluorescence of S-1 indicates that the modified Trps are located in a polar environment and that they may be identical with the long-lifetime Trps of Torgerson [Torgerson, P. (1984) Biochemistry 23, 3002-3007]. The most reactive Trp is located in the N-terminal 27-kDa fragment of the S-1 heavy chain. It might also be inferred from the above data that the nonexposed and ATP-perturbed Trp(s) is (are) located in the 50-kDa fragment.

Actins↗
PubMed1998

Incorporation of tryptophan analogues into staphylococcal nuclease: stability toward thermal and guanidine-HCl induced unfolding.

The tryptophan analogues, 5-hydroxytryptophan, 7-azatryptophan, 4-fluorotryptophan, 5-fluorotryptophan, and 6-fluorotryptophan, have been biosynthetically incorporated into Staphylococcal nuclease, its V66W mutant, and the Delta 137-149 fragment of the latter mutant. The guanidine-HCl induced unfolding and thermal unfolding of these proteins were studied to characterize the effect of incorporation of these tryptophan analogues on the thermodynamic stability of the proteins. The three proteins have tryptophan residues at positions 140 (in wild type) and 66 (in the Delta 137-149 fragment of V66W) and at both positions (in V66W). The unfolding data show that 5-hydroxytryptophan does not perturb the stability of wild-type nuclease, but it destabilizes the fragment and causes the V66W mutant to unfold in a more cooperative manner. 7-Azatryptophan is found to destabilize all three proteins. 4-Fluorotryptophan is slightly stabilizing of the three proteins, but the other two fluorotryptophans do not alter the stability of the proteins.

Amino Acid Substitution↗
PubMed2002

The elusive vanadate (V(3)O(9))(3-): isolation, crystal structure, and nonaqueous solution behavior.

The isolation, crystal structure, and nonaqueous solution characteristics of the first trinuclear vanadate are presented. The crystal structure reveals a six-membered cyclic arrangement of alternating vanadium and oxygen atoms for the anion of [(C(4)H(9))(4)N](3)(V(3)O(9)). The (51)V NMR spectrum of this compound in CD(3)CN exhibits multiple peaks. The relative intensities of each resonance can be altered by concentration and temperature changes, the later of which are reversible. Addition of [(C(4)H(9))(4)N]Br and NaClO(4) also perturbs the equilibria between species observed. Conductivity data for [(C(4)H(9))(4)N](3)(V(3)O(9)) in CH(3)CN as a function of concentration display pronounced curvature and indicate formation of a neutral species in solution at the highest concentrations studied. Stoichiometric mixtures of [(C(4)H(9))(4)N](3)(V(3)O(9)) with the known vanadates [(C(4)H(9))(4)N](3)(HV(4)O(12)), [(C(4)H(9))(4)N](3)(V(5)O(14)), and [(C(4)H(9))(4)N](3)(H(3)V(10)O(28)) are prepared and examined by (51)V NMR. Equilibration between the various vanadates is observed and characterized. Resonances for these known vanadates, however, cannot be used to identify the peaks found for [(C(4)H(9))(4)N](3)(V(3)O(9)), alone, in solution. The existence of ion pairs in acetonitrile is the only interpretation for the solution behavior of [(C(4)H(9))(4)N](3)(V(3)O(9)) consistent with all data. As such, we can directly observe each possible ion pairing state by (51)V NMR: (V(3)O(9))(3-) at -555 ppm, [[(C(4)H(9))(4)N](V(3)O(9))] (2-) at -569 ppm, [[(C(4)H(9))(4)N](2)(V(3)O(9))](-) at -576 ppm, and [(C(4)H(9))(4)N](3)(V(3)O(9)) at -628 ppm. To the best of our knowledge, [(C(4)H(9))(4)N](3)(V(3)O(9)) presents the first case in which every possible ion paired state can be observed directly from a parent polyion. Isolation and characterization of this simple metal oxo moiety may now facilitate efforts to design functional polyoxometalates.

Journal Article↗