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Cryptosin, a new cardenolide, was found to preferentially bind to Na,K-ATPase enzyme (7), which is believed to be the ouabain binding site on cardiac sarcolemmal membrane. CD spectral studies revealed that cryptosin, in the presence of Na+ and Mg++ ions, bind to Na,K-ATPase and induce a dose-dependent change in the backbone structure of cardiac Na,K-ATPase.
Using polarized ultraviolet (UV) fluorescence microscopy, it was shown that the local damage of muscle fibres causes in their morphologically unchanged parts the alternation of regions, being in different functional states referred to as "pseudocontraction" and "superrelaxation". The pattern of UV fluorescence anisotropy suggests that conformation of contractile proteins by "pseudocontraction" is similar to that at contraction, though changes in sarcomere length do not occur. The "superrelaxation" is characterized by a desorganization of myofilaments. During the spreading of Zenker's necrosis, the "pseudocontraction" is seen transferred first into "superrelaxation", and then into irreversible contracture and rigor. "The boundary of Zenker's necrosis" overlaps with the boundary of the self-propagating irreversible contracture. There is no proper boundary of Zenker's necrosis, because the destructive changes are observed over all the muscle fibre. Contraction nodules arise in the regions of "superrelaxation" and follow the changes of the contractile system, peculiar of contracture. The study of the influence of medium ionic composition on the development of Zenker's necrosis suggests that the arising and spreading of destruction are inseparably associated with the irreverrsible changes of intracellular membrane structures, and with the possibility of propogation of the damage signal by these structures along muscle fibres.
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"Aqueous" and "electrolytic" solutions of DNA from chicken erythrocytes different concentrations of NH4Cl have been investigated. Solutions of the first type were prepared from concentrated aqueous solutions of DNA and the second type solutions by solving a solid DNA in a supporting electrolyte. Studies of the melting curves showed that even the concentrated aqueous solutions of DNA were not completely native. The changes of the secondary structure of DNA caused by solving in deionized water are irreversible. This is confirmed by the abnormal dependence of melting temperatures of DNA on the ionic strength of aqueous solutions that is not characteristic for electrolytic solutions, that is not characteristic for electrolytic solutions. It has been shown that the type of dependence of the melting temperatures on the ionic strength is a more precise test of the secondary structure of DNA than a molar extinction or hyperchromic koefficient.
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PURPOSE: The anterior chamber structure in the supine position and the prone position was investigated with ultrasound biomicroscopy (UBM) in pseudoexfoliation syndrome (PE). METHODS: We studied 12 eyes of 12 PE subjects. Patients were placed in the supine position for 30 minutes, after which UBM was performed. The UBM was repeated after 30 minutes in the prone position. Anterior chamber depth (ACD), angle opening distance 500 microns (AOD 500), and angle recess area (ARA) in 4 quadrants were measured. RESULTS: Following the postural change from the supine position to the prone position, ACD decreased significantly (p < 0.0001). AOD 500 and ARA decreased significantly in the superior (AOD 500: p < 0.05, ARA: p = 0.03) and temporal quadrants (AOD 500: p < 0.0001, ARA: p < 0.0001). CONCLUSIONS: The anterior chamber structural change was greater in the temporal and superior quadrants in the PE eyes. This corresponds with previous reports that zonular involvement by pseudoexfoliation material is more pronounced temporally and superiorly.
BACKGROUND: After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known. METHODS AND RESULTS: Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There were virtually no signs of cellular degeneration, and the interstitial space remained unaltered. The duration of sustained AF did not significantly affect the degree of myolytic cell changes. CONCLUSIONS: Sustained AF in goats leads to predominantly structural changes in the atrial myocytes similar to those seen in ventricular myocytes from chronic hibernating myocardium. These structural changes may explain the depressed contractile function of atrial myocardium after cardioversion. This goat model of AF offers a new approach to study the cascade of events leading to sustained AF and its maintenance.
A model for the solution structure of horse heart ferricytochrome c has been determined by nuclear magnetic resonance spectroscopy combined with hybrid distance geometry-simulated annealing calculations. Forty-four highly refined structures were obtained using a total of 1671 distance constraints based on the observed magnitude of nuclear Overhauser effects and 58 torsion angle restrains based on the magnitude of determined J-coupling constants. The model incorporates six long-lived water molecules detected by pseudo-two-dimensional NOESY-TOCSY spectra. The all-residue root mean square deviation about the average structure is 0.33 +/- 0.04 A for the backbone N, C alpha, and C' atoms and 0.83 +/- 0.05 A for all heavy atoms. The overall topology of the model for solution structure is very similar to that seen in previously reported models for crystal structures of homologous c-type cytochromes though there are a number of significant differences in detailed aspects of the structure. Two of the three main helices display localized irregularities in helical hydrogen bonding resulting in bifurcation of main chain hydrogen bond acceptor carbonyls. The N- and C-terminal helices are tightly packed and display several interhelical interactions not seen in reported crystal models. To provide an independent measure of the accuracy of the model for the oxidized protein, the expected pseudocontact shifts induced by the spin 1/2 iron were compared to the observed redox-dependent chemical shift changes. These comparisons confirm the general accuracy of the model for the oxidized protein and its observed differences with the structure of the reduced protein. The structures of the reduced and oxidized states of the protein provide a template to explain a range of physical and biological data spanning the redox properties, folding, molecular recognition, and stability of the cytochrome c molecule. For example, a redox-dependent reorganization of surface residues at the heme edge can be directly related to the redox behavior of the protein and thereby provides a previously undocumented linkage between structural change potentially associated with molecular recognition of redox partners and the fundamental parameters governing electron transfer.
The structure of Mengo virus had been determined from crystals grown in the presence of 100 mM phosphate buffer at pH 7.4. It is shown that Mengo virus is poorly infectious at the phosphate concentration similar to that in which it was crystallized. Maximal infectivity is achieved at 10 mM phosphate or less in physiological saline. The phosphate effect is ameliorated when the pH is lowered to 4.6. Although it has not been possible to study the crystal structure of the virus at low phosphate concentrations, it is shown that increasing the Cl- concentration at pH 6.2 or decreasing the pH to 4.6 causes substantial conformational changes confined to the "pit," a deep surface depression. These structural changes involve a movement of the "FMDV loop" (GH loop) in VP1, an ordering of the "VP3 loop" (GH loop in VP3) between 3176 and 3182, the displacement of a bound phosphate near the "FMDV loop" (GH loop in VP1), and movement of the carboxy terminus of VP2. The changes in conformation are correlated with the dissociation of the virion into pentamers at pH 6.2 and 150 mM Cl-. The localization of the conformational changes and the correlated role of the phosphate in controlling infectivity support the hypothesis that the "pit" is the receptor attachment site.
Renal structural abnormalities are known to precede the development of proteinuria, hypertension, and reduced renal function in patients with type 1 diabetes. The determinants of these early structural abnormalities are, however, largely unknown. The International Diabetic Nephropathy Study (IDNS) has recruited 243 children and adults (aged 10-40 years) in Montreal, Minneapolis, and Paris to identify and quantify these determinants. All study subjects were normotensive and had normal-to-high glomerular filtration rates (GFRs) and urinary albumin excretion rates (AERs) <100 microg/min at study entry. Only 8 of 243 had an AER > or =20 microg/min (microalbuminuria). Two renal biopsies are obtained at a 5-year intervals, with baseline and follow-up measures of renal function, blood pressure (BP), HbA(1c), plasma lipids, and AER. Herein, we examine the baseline renal biopsy morphometric findings in these subjects and in 87 kidney donor control subjects and explore the associations between findings and clinical and demographic variables. The principal morphometric abnormalities were increased glomerular basement membrane (GBM) width and fractional volume of mesangium [Vv(Mes/glom)] and mesangial matrix [Vv(MM/glom)]. The frequency of these abnormalities increased with increasing duration of diabetes but was observed as early as 2-8 years after onset. Diastolic BP (DBP), but not HbA(1c), was directly associated with these abnormalities. Elevated GFR was associated with only a small increase in peripheral glomerular capillary basement membrane filtration surface density. Center differences were detected in renal structural, renal functional, and BP parameters, especially between the Paris and North American centers. GBM width, Vv(Mes/glom), and Vv(MM/glom) are significantly increased even within a few years of onset of type 1 diabetes. These changes are detectable in normoalbuminuric patients and are related to duration, BP, and study site. Changes in these and other morphometric measures over 5-year follow-up should help clarify the roles of glycemia and other determinants of the rates of development of diabetic nephropathy lesions, as well as their relationships to early changes in BP, albumin excretion, and renal function.
The structural alterations of endothelium and smooth muscle cells of the hind limb and heart veins and arteries were investigated in Golden Syrian hamsters subjected to streptozotocin induced diabetes. Animals were examined at 5, 10, and 15 weeks after induction of diabetes. At each time point body weight and plasma glucose concentrations were recorded. Anesthetised animals were washed out of blood, fixed in situ, and the femoral vein and artery, saphenous vein and artery, and heart veins and coronaries were dissected out, and processed for electron microscopical examination. Anionic sites of the endothelial plasmalemma were visualized by in situ perfusion of cationized ferritin. The endothelial localization of von Willebrand factor was carried out by immunocytochemistry. The results showed that induction of experimental diabetes generated morphological changes of the endothelium and smooth muscle cells of both hind limb and heart vessels. The common alterations developed in endothelial cells of venous and arterial origin consisted in: 1) the development of a secretory phenotype, enriched in biosynthetic and degradative organelles; 2) the abundance of cytoskeletal elements, especially intermediary filaments; 3) the increase in number of fused plasmalemmal vesicles and transendothelial channels, and 4) the hyperplasia of the basal lamina. In contradistinction to the arterial endothelium, the peculiarities of the venous endothelium in the diabetic hamsters examined were: 1) the uniform distribution of the anionic sites exposed on the luminal plasma-lemma (as in normal animals), and 2) the increased number of copies of Weibel-Palade bodies (up to 13 copies per endothelial cell in the hind limb). Von Willebrand factor was immunodetected in Weibel-Palade bodies, Golgi cisternae and some vesicles of normal and diabetic hamsters. With time, and especially pronounced at 15 weeks of diabetes, the smooth muscle cells of veins and arteries examined exhibited a characteristic secretory phenotype, and were surrounded by a reticulated basal lamina and a hyperplasic extracellular matrix (especially pronounced in arteries). These data indicate that diabetes affects both heart and hind limb veins and arteries, producing structural changes of the endothelium and smooth muscle cells which may account, at least in part, for the specific vascular complications.
Small structural perturbations in the enzyme isocitrate dehydrogenase (IDH) were made in order to evaluate the contribution of precise substrate alignment to the catalytic power of an enzyme. The reaction trajectory of IDH was modified (i) after the adenine moiety of nicotinamide adenine dinucleotide phosphate was changed to hypoxanthine (the 6-amino was changed to 6-hydroxyl), and (ii) by replacing Mg2+, which has six coordinating ligands, with Ca2+, which has eight coordinating ligands. Both changes make large (10(-3) to 10(-5)) changes in the reaction velocity but only small changes in the orientation of the substrates (both distance and angle) as revealed by cryocrystallographic trapping of active IDH complexes. The results provide evidence that orbital overlap produced by optimal orientation of reacting orbitals plays a major quantitative role in the catalytic power of enzymes.
Elevated arterial pressure levels increase the hemodynamic load on heart and vessels, thus leading to functional and structural abnormalities. Because cardiac and vascular changes increase the risk of cardiovascular disease, their reversal is an important target of antihypertensive therapy, even though the prognostic value of this regression has not been fully established. In patients with untreated mild-to-moderate essential hypertension and left ventricular hypertrophy, trandolapril, a new angiotensin-converting enzyme inhibitor, reduces blood pressure by decreasing total peripheral resistance and improves both systolic and diastolic ventricular function. The latter effect is not only functional in nature because, after long-term antihypertensive treatment, the improvement in diastolic ventricular function is detectable also after 1-month withdrawal of trandolapril. The concurrent reversal of left ventricular hypertrophy may contribute to the improved left ventricular diastolic function. However, plethysmographic studies suggest that long-term antihypertensive treatment with trandolapril is also able to reverse structural vascular changes in the forearm vascular bed, because after 1-month washout forearm peripheral resistance also is lower than in control conditions. Finally, in hypertensive patients, trandolapril induces significant increases in brachial artery compliance and diameter that persist after 1 month of withdrawal from treatment. The latter observation suggests that trandolapril also is able to reverse the structural changes of the large artery wall.(ABSTRACT TRUNCATED AT 250 WORDS)
The molecular structures and their stabilities at the outmost-layer of the Langmuir-Blodgett (LB) films of stearic acid on solid substrates have been investigated by a highly surface-sensitive spectroscopic technique, sum frequency generation (SFG), in air and in aqueous solution, using the combination of both normal and deuterated stearic acid. Peaks observed in the SFG spectra are mainly attributed to the terminal methyl group at the outmost layer of the LB films. The SFG spectra in air are virtually identical and are independent of the odd-even property and thickness (1-12) of the LB films, indicating that the even-numbered LB film changes its surface structure after passing through the interface between the water subphase and air, especially when the Cd2+ cation was included in the water subphase. Furthermore, we have demonstrated for the first time using in situ SFG measurement that the interfacial molecular structure at the LB bilayer of stearic acid on the hydrophilic substrates significantly change with immersion in the water subphase containing Cd2+ cation while such a structural change has not been observed in the water subphase without Cd2+. These results clearly indicate that a reorganization process takes place on the surface of the stearic acid bilayer induced by the Cd2+ cation. The electrostatic interaction between the carboxylate headgroup of stearic acid via the Cd2+ cation seems to play an important role in the surface reorganization process both in air and in solution.
The structure of epidermis and appearance of keratinocytes is described in intact skin specimens from human corpses stored after death under refrigeration. Two groups of alterations can be identified depending on the epidermal layer. In the spinous layer, the cells are characterized by crescent-shaped nuclei surrounded by a hollow area. The number of such cells increases significantly each day during the first 8 days post mortem (dpm), and their frequencies follow respective regression equations, so as to enable the post mortem time estimation with one day accuracy. In the basal layer, distorted, balloon-shaped cells with pycnotic nuclei appear, which with the lapse of time are forming groups, and eventually the epidermis in those places separates from the dermis. The presence of both described changes seems to indicate whether the skin sample was obtained from the living organism or after the death.
The Cdc7p protein kinase in the budding yeast Saccharomyces cerevisiae is thought to help trigger DNA replication by modifying one or more of the factors that assemble at replication origins (ARSs). To investigate events catalyzed by Cdc7p, we compared the structure of replication origins in cells containing conditional mutations in Cdc7p and Cdc8p, a thymidylate kinase that is required for DNA synthesis. High resolution genomic footprinting indicated that the presumptive lagging strand template in ARS1 became highly sensitive to KMnO(4) modification after the CDC7 execution point. These results suggested that Cdc7p triggers DNA unwinding. The transition from late G(1) phase to the CDC7 execution point and from the CDC7 to the CDC8 execution points was accompanied by small but ARS-dependent changes in DNA topology. These results suggested that DNA unwinding before the CDC8 execution point either is highly localized or that the torsional stress associated with initial DNA unwinding is minimized by compensatory protein-DNA structural changes. The ARS DNA structural attributes evident in cells blocked at the CDC8 execution point were also evident in alpha-factor-blocked, G(1) phase cells containing the CDC7 bypass mutant mcm5/cdc46-bob1. This result strongly suggests that the structural changes during the transition from the CDC7 to CDC8 execution points depend on the Cdc7p protein kinase and involve alteration of the minichromosome maintenance protein complex.
The aggregate structure of lipopolysaccharide isolated from an Re strain of Escherichia coli was examined at different pH values using small angle neutron scattering. At pH values of 6 and 7.4, angle-averaged scattering of the sodium salt of this isolate was consistent with randomly coiled tubular micelles approximately 100 A in diameter. At pH 9.1, however, Kratky analysis of the scattering data was distinctly different and consistent with pairing of uniform tubular micelle sections of length 1440 and 110 A in diameter. Contrast variation measurements of the micelles yielded an average micellar weight of the sample at pH 9.1 of approximately 1.11 X 10(7) daltons and suggested that the aggregates were tubular micelles of size and length similar to that derived from the scattering intensity data. Anisotropic scattering patterns of samples under shear indicated a rigidification of the micelles as the pH was increased to 9.1 and the temperature decreased from 25 to 10 degrees C. The rotational diffusion constants deduced from the observed shear anisotropy indicate that the structure at pH 9.1 must have smallest and largest dimensions which differ by at least an order of magnitude, ruling out spherical or moderately ellipsoidal structures. Analysis of the shear rate needed to induce anisotropic scattering indicated that the stiffness length of the micelles at pH 9.1 was approximately 1000 A and decreased at higher and lower pH values.
PURPOSE: Our aim was to study the effect of chronic ischemia on bladder contraction and detrusor smooth muscle reactivity. The relationship between structural damage and functional changes in the chronically ischemic bladder was also investigated. MATERIAL AND METHODS: Male New Zealand White rabbits were divided into arterial injury (AI), hypercholesterolemia (Hch) and control groups. The AI group (n = 18) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet. The Hch group (n = 8) received a 0.5% cholesterol diet alone. The control group (n = 8) received a regular diet. After 16 weeks, iliac artery and bladder wall blood flows were recorded. Cystometrograms and arteriography were obtained and bladder tissues were processed for isometric tension measurement in the organ bath and for histological evaluation. RESULTS: At 16 weeks, blood flow through the iliac arteries was significantly reduced in the AI group compared with the Hch and control groups. In the AI group, 8 animals developed severe bladder ischemia (SBI) defined as greater than 60% decrease in bladder blood flow, 7 animals developed moderate bladder ischemia (MBI) defined as 40 to 60% decrease in bladder blood flow, and 3 animals failed to develop significant bladder ischemia (<40% decrease in bladder blood flow). In the control animals, bladder blood flow increased prior to contraction, decreased during contraction and rebounded to baseline levels after contraction. In animals with MBI and SBI, the increase in bladder blood flow prior to contraction and the rebound of blood flow after contraction, both seen in control animals, were diminished. Detrusor overactivity (significant increase in the frequency of spontaneous bladder contractions) was observed in the MBI group and impaired bladder contraction in the SBI group. In the organ bath, bladder strips from the MBI group demonstrated increased contractile response to carbachol and electrical field stimulation (EFS) while bladder strips from the SBI group showed impaired contractility. Hch alone produced only short-lived ischemia during bladder contraction and caused significantly lesser functional changes compared with those seen in MBI. Histological examination showed atherosclerotic occlusion in the iliac arteries and bladder microcirculation and marked disruption of urothelium in the MBI and SBI groups. Severe fibrosis was seen in bladder tissue from the SBI group, moderate fibrosis in tissue from the MBI group and mild fibrosis in tissue from the Hch group. CONCLUSIONS: Our studies show that chronic MBI is associated with detrusor overactivity and increased smooth muscle contractility to carbachol and EFS while chronic SBI is associated with impaired detrusor contraction. The mechanism of chronic ischemia-induced bladder dysfunction is not known and may involve multiple physiologic and structural changes in the bladder nerves, receptors and contractile components. Our studies suggest that ischemia-induced structural damage in the urothelium and possible chronic exposure of the underlying tissue and nerves to the urine may also play a role in MBI-induced detrusor overactivity. SBI-induced impairment of bladder contraction may involve, in part, extensive fibrosis and loss of bladder smooth muscle. Histopathophysiologic changes in bladder tissue from our MBI model are similar to those seen in patients with detrusor instability, suggesting that chronic ischemia may play a role in the development of idiopathic detrusor instability.