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Two cases of McArdle's syndrome are reported. One is a "classical" example; the other is unusual because of the in vitro presence of muscle phosphorylase activity. In the latter case, the electronmicroscopic investigation confirmed the diagnosis. The fine structural changes characteristic of this disease are summarized and it is concluded that histochemical studies alone are insufficient to exclude the diagnosis of McArdl's myopathy.
Bis(picolinato)oxovanadium(IV) [VO(pic)2] is one of the most potent insulin-mimetic vanadium complexes. To probe coordination structural changes of this complex in vivo and provide insights into the origin of its high potency, an electron spin-echo envelope modulation (ESEEM) study was performed on organs (kidney, liver and bone) of VO(pic)2- and VOSO4-treated rats. Kidney and liver samples from both types of rats exhibited a 14N ESEEM signal that could be attributed to equatorially coordinating amine nitrogen. The relative intensity of the amine signal was larger for the organs of the rat treated with the less potent VOSO4, suggesting that this amine coordination inhibits the insulin-mimetic activity. The spectra of kidney and liver from the VO(pic)2-treated rat contained a weak signal due to the picolinate imine nitrogen. This suggests that some picolinato species (including both the bispicolinato and a partially decomposed monopicolinato species) still exist in the organs as a minor species, where the proportions of the picolinato species to the total amount of the EPR-detectable VIVO species are estimated as 8-16% in the kidney and 12-24% in the liver. The picolinate ligand presumably serves to prevent VO2+ from being converted into the inactive amine-coordinated species. Bone samples from both types of rats exhibited an ESEEM signal due to 31P nuclei. The VO2+ in bone is therefore most likely incorporated into the hydroxyapatite Ca10(PO4)6(OH)2 matrix, which is consistent with the hypothesis that the bone-accumulated VO2+ is gradually released and transported to other organs as is Ca2+. No 14N signals were observed, even in the bone samples of the VO(pic)2-treated rats, indicating that vanadium uptake by bone requires complete decomposition of the complex.
A clottable protein (coagulogen) isolated from a hemocyte lysate of the Japanese horseshoe crab (Tachypleus tridentatus) was incubated with an endotoxin-activated clotting enzyme(s) partially purified from the same lysate, and its structural change during gel formation was examined. The results indicated that the enzymatic formation of gel involved limited proteolysis of the Arg-Gly and Arg-Thr linkages located in the N-terminal portion of the coagulogen, liberating peptide C.
OBJECTIVE: To evaluate the respective roles of elevated blood pressure and stimulation of the renin-angiotensin system in the development of structural changes in the aortae of rats with renovascular hypertension. MATERIALS AND METHODS: Renovascular hypertensive rats (two-kidney, one clip) were randomly allocated to three different groups and were treated with equihypotensive doses of an angiotensin converting enzyme (ACE) inhibitor (enalapril, 3 mg/kg per day) or of a new long-acting calcium antagonist (mibefradil, 30 mg/kg per day). A renovascular hypertensive group was left untreated. A sham-operated group of rats was used as a normotensive control group. At the end of the 5-week treatment period the rats were killed and their aortae were removed. Medial hypertrophy, elastin and collagen content and density of nuclei were evaluated using quantitative morphometry. The aortic cyclic GMP (cGMP) content was quantified by radioimmunoassay. RESULTS: Hypertension was associated with medial hypertrophy, a decreased elastin: collagen ratio, hypertrophy of the smooth muscle cells and increased cGMP content of the aorta. Mibefradil and enalapril equally prevented the morphological consequences of hypertension (i.e. medial hypertrophy and the decreased elastin:collagen ratio). The aortic cGMP content was increased by enalapril but not by mibefradil. CONCLUSION: The present results show that, even in a high-renin model (two-kidney, one clip), it is possible to prevent or suppress the vascular consequences of hypertension without interfering with the renin-angiotensin system. This suggests that the changes observed in the aorta are directly related to blood pressure or to other mechanisms independent of the renin-angiotensin system, which could be blocked by a calcium antagonist such as mibefradil.
Fluorescence resonance energy transfer (FRET) spectroscopy has been widely used to "measure" dimensions either within or between molecules over distances of 10-100A, a range that is well suited to probing protein structure. The resolution of FRET spectroscopy is substantially lower than X-ray diffraction (XRD) but the technique makes up for this deficit by being particularly good at measuring structural changes in proteins. However, absolute distances measured by FRET spectroscopy remain problematical because of what appears to be an unjustified assumption, namely that calculations of FRET distances assume that the probes are able to undergo free, isotropic motion. This uncertainty may be ascribed to an unknown value for the orientation factor, but other factors may also be important. Common sense suggests that a large (300-500 Da) hydrophobic FRET probe covalently bound to an amino acid side chain of a protein can not undergo true rotational freedom. If this is so, the calculated distances would at best be flawed and at worst be meaningless. In this paper we argue that the orientation parameter is no longer an important issue in the determination of distances determined by FRET using peptides and proteins. Furthermore, we suggest that FRET may be a good form of spectroscopy for testing models of F-actin.
Using the garfish olfactory nerve, the time-courses of lateral expansion (swelling) and birefringence changes in nerve fibers have been examined at the site of application of electric current pulses. The effects of various chemical agents on these non-electrical signs of rapid structural changes in the nerve fibers have been examined. These studies have shown that a pulse of outwardly-directed current through the superficial layer evokes a fast increase, followed by a slow, gradual increase, in the water-content of the nerve fibers. The full significance of these findings in studies of the process of nerve excitation is discussed.
We produced CA1-specific NMDA receptor 1 subunit-knockout (CA1-KO) mice to determine the NMDA receptor dependence of nonspatial memory formation and of experience-induced structural plasticity in the CA1 region. CA1-KO mice were profoundly impaired in object recognition, olfactory discrimination and contextual fear memories. Surprisingly, these deficits could be rescued by enriching experience. Using stereological electron microscopy, we found that enrichment induced an increase of the synapse density in the CA1 region in knockouts as well as control littermates. Therefore, our data indicate that CA1 NMDA receptor activity is critical in hippocampus-dependent nonspatial memory, but is not essential for experience-induced synaptic structural changes.
Long-term memory for sensitization of the gill-withdrawal reflex in Aplysia is associated with the growth of new synaptic connections between sensory and motor neurons. The duration of this structural change parallels the behavioral retention of the memory. Such changes can be reconstituted in dissociated cell culture by repeated presentations of the modulatory neurotransmitter serotonin (5HT) and are associated with an activity-dependent downregulation of NCAM-related cell adhesion molecules thought to contribute to cell recognition and axonal outgrowth during development. Thus, aspects of the mechanisms utilized for learning-related synaptic growth initiated by experience in the adult may eventually be understood in the context of the molecular logic that shapes synaptic circuitry during the later stages of neuronal development.
Variable-temperature (1)H and (13)C NMR measurements of the D(3)-symmetrical triple-helical complexes [Ln(L1-2H)(3)](3)(-) (L1 = pyridine-2,6-dicarboxylic acid; Ln = La-Lu) show evidence of dynamic intermolecular ligand-exchange processes whose activation energies depend on the size of the metal ion. At 298 K, the use of diastereotopic probes in [Ln(L3-2H)(3)](3)(-) (L3 = 4-ethyl-pyridine-2,6-dicarboxylic acid) shows that fast intramolecular P <==> M interconversion between the helical enantiomers occurs on the NMR time scale. Detailed analyses of the paramagnetic NMR hyperfine shifts according to crystal-field independent techniques demonstrate the existence of two different helical structures, one for large lanthanides (Ln = La-Eu) and one for small lanthanides (Ln = Tb-Lu), in complete contrast with the isostructurality proposed 25 years ago. A careful reconsideration of the original crystal-field-dependent analysis shows that an abrupt variation of the axial crystal-field parameter A(0)2 parallels the structural change leading to some accidental compensation effects that prevent the detection of structural variations according to the classical one-nucleus method. Crystal structures in the solid state and density functional theory calculations in the gas phase provide structural models that rationalize the paramagnetic NMR data. A regular triple-helical structure is found for small lanthanides (Ln = Tb-Lu) in which the terdentate chelating ligands are rigidly tricoordinated to the metals. A flexible and distorted structure is evidenced for Ln = La-Eu in which the central pyridine rings interact poorly with the metal ion. The origin of the simultaneous variation of structural parameters and crystal-field and hyperfine constants near the middle of the lanthanide series is discussed together with the use of crystal-field-independent techniques for the interpretation of paramagnetic NMR spectra in axial lanthanide complexes.
Myoglobin's reversible binding of oxygen is a model for studies of protein control of ligand binding and discrimination. Protein relaxation and geminate ligand rebinding subsequent to ligand photodissociation have been studied extensively by a variety of techniques. The ps to ns time scales for these processes are still much shorter than the ms time resolution of X-ray diffraction experiments, but it may be possible to trap these intermediates at low temperatures. We report here an X-ray diffraction investigation of structural changes induced by photolysis of carbonmonoxy myoglobin crystals at 40 K. Our results provide a structural basis for the interpretation of ambient and low temperature spectroscopic observations and molecular dynamics simulations of the ligand photodissociation and binding processes in haem proteins.
We have investigated the loss of histone H1 from chromatin [D'Anna, J. A., Gurley, L. R., & Tobey, R. A. (1982) Biochemistry 21, 3991-4001] and the structure of chromatin from Chinese hamster (line CHO) cells blocked in early S phase by sequential use of isoleucine deprivation G1 block and 1 mM hydroxyurea (HU) blockade. Measurements of H1 content in the cell and histone turnover indicate that H1 is lost from the cell and that there is negligible replacement synthesis of H1 during the period of the S-phase block. As H1 is lost, chromatin appears to undergo structural change. After 10 h of HU block, the new deoxyribonucleic acid (DNA) and a portion of the old DNA have measured nucleosome repeat lengths (37 degrees C digestion) which are less than those of controls and similar to those observed by Annunziato and Seale [Annunziato, A. T., & Seale, R. L. (1982) Biochemistry 21, 5431-5438] for new immature chromatin in the absence of HU. By 24 h of HU block, nearly all of the chromatin has assumed a pseudoimmature conformation in which the nucleosome cores appear to be more closely packed along the DNA chain, but the new DNA is slightly more resistant than old DNA to attack by micrococcal nuclease. Electrophoretic analysis of nucleoprotein particles produced by micrococcal nuclease digestion of nuclei indicates that (1) the distribution of mononucleosome species changes during HU block and (2) some mononucleosome species appear to be enriched in normally minor proteins which may determine the electrophoretic mobility of the nucleoprotein particles in agarose-acrylamide gels. The results raise the possibility that (1) during the early stages of replication (or prior to the passage of the replication fork), H1 is dissociated from initiated replicons and (2) H1 does not reassociate in a concerted fashion with the H1-depleted chromatin until the replication fork has passed and, perhaps, a substantial portion of the replicon has been replicated.
AIM: Left ventricular concentric remodelling defines a modified left ventricular geometry in the presence of a normal left ventricular mass; it is an early and frequent adaptation in arterial hypertension. The present study was designed to evaluate the extent of carotid structural changes in essential hypertensives with left ventricular remodelling. PATIENTS AND METHODS: Two groups of hypertensive patients, who had never previously received anti-hypertensive treatment, 14 with left ventricular concentric remodelling (group I, relative wall thickness 0.48 +/- 0.02) and 48 with normal left ventricular geometry (group II, relative wall thickness 0.37 +/- 0.04) underwent clinical and laboratory examination, echocardiography, carotid artery ultrasonography and 24 h ambulatory blood pressure monitoring (ABPM). The left ventricular dimensions and mass were obtained according to the Penn convention. The intima-media thickness (IMT) of the posterior wall of both common carotid arteries was measured 5, 10 and 20 mm caudally to the bulb and the average value was used for analysis. RESULTS: In both groups age (group I 44 +/- 9 years; group II 40 +/- 9 years), body surface area (group I 1.85 +/- 0.2 m2; group II 1.80 +/- 0.2 m2), duration of hypertension (group I 4.4 +/- 4; group II 3.8 +/- 3.9 years), metabolic parameters and smoking habits were similar. Both clinic and 24 h ABPM values were higher in group I (clinic 157 +/- 12/102 +/- 5; 24 h ABPM 145 +/- 10/95 +/- 7 mmHg) than they were in group II (clinic 146 +/- 11/97 +/- 5; 24 h ABPM = 134 +/- 10/87 +/- 8 mmHg, P < 0.01). The left ventricular mass index (LVMI) and IMT were found to be slightly but significantly greater in group I than they were in group II (LVMI 106 +/- 7 versus 98 +/- 12 g/m2, P < 0.05; IMT 0.68 +/- 0.13 versus 0.61 +/- 0.10 mm, P < 0.05). A significant correlation was found between LVMI and common carotid IMT in the whole group of hypertensive patients (r = 0.43, P < 0.01). CONCLUSIONS: Our results indicate that left ventricular concentric remodelling does not represent the only early cardiovascular change in arterial hypertension but rather is associated often with carotid intima-media thickening.
"This article addresses three questions: (1) Is the high rate of emigration of labor from the Philippines related to the country's trade policy? (2) Why have migration and accompanying remittances not made much of an impact on the growth and structure of the Philippine economy? (3) Would economic growth and structural change eventually curtail labor emigration? The Philippines' history of labor export and its economic development are contrasted with those of Asian NIEs [newly industrialized economies] which have adopted liberal trade regimes."
Overall seventy patients with chronic hypertensive encephalopathy and acute cerebral circulatory disorders were examined, their age ranging between 35 to 75 years, by ACT, MRT, USG. MRT was found out to be the most objective method for identifying structural changes in the brain in cerebrovascular disorders. The main signs of MR-tomography are vascular changes presenting as lacunar infarctions with or without perifocal area of edema, hydrocephalus, brain swelling, intracranial hypertension, poor differentiation of gray and white substances of the brain, with hygromas being readily identifiable. Lacunar infarctions, periventricular edema, dilatation of the ventricular system are regarded as equivalent of clinical signs of chronic hypertensive encephalopathy.
SNAP-25, syntaxin, and synaptobrevin play a key role in the regulated exocytosis of synaptic vesicles, but their mechanism of action is not understood. In vitro, the proteins spontaneously assemble into a ternary complex that can be dissociated by the ATPase N-ethylmaleimide-sensitive fusion protein and the cofactors alpha-, beta-, and gamma-SNAP. Since the structural changes associated with these reactions probably form the basis of membrane fusion, we have embarked on biophysical studies aimed at elucidating such changes in vitro using recombinant proteins. All proteins were purified in a monomeric form. Syntaxin showed significant alpha-helicity, whereas SNAP-25 and synaptobrevin exhibited characteristics of largely unstructured proteins. Formation of the ternary complex induced dramatic increases in alpha-helicity and in thermal stability. This suggests that structure is induced in SNAP-25 and synaptobrevin upon complex formation. In addition, the stoichiometry changed from 2:1 in the syntaxin-SNAP-25 complex to 1:1:1 in the ternary complex. We propose that the transition from largely unstructured monomers to a tightly packed, energetically favored ternary complex connecting two membranes is a key step in overcoming energy barriers for membrane fusion.
We have established granulosa cell lines which express constitutively the rat FSH receptors by cotransfection of primary granulosa cells obtained from preovulatory follicles with SV40 DNA, Ha-ras oncogene and a plasmid expressing FSH receptors. These cells respond specifically to ovine and human FSH by cell rounding, intracellular cAMP accumulation, and progesterone secretion in a dose-dependent manner. A new method for the demonstration and quantitation of changes in cell shape-Small Angle Laser Light Scattering (SALLS) analysis-has been utilized for measurement of cell rounding in response to FSH stimulation in these cells. When cells were incubated with increasing doses of either ovine or human FSH, partial rounding of cells was observed at FSH concentrations as low as 24 pM, while complete rounding of cells was observed at a range of 0.24-2.4 nM of FSH. Following aldehyde fixation, hormone-treated cells were examined using the method of SALLS analysis. Histograms obtained by applying SALLS analysis on FSH stimulated GFSHR-17 cells were a reflection of the structural changes induced by the hormone. FSH- and forskolin-incubated cells yielded structured distributions with defined mean size and standard deviations. Moreover, the increase in sharpness of dominant peak in the histogram was correlated with elevated concentration of FSH in a dose dependent manner. In conclusion, cellular response to FSH is correlated with a specific pattern of light scattered in immortalized granulosa cells expressing functional FSH receptors. Therefore, SALLS analysis may serve as a useful tool for in vitro bioassay of the gonadotropic hormone. Moreover, this method may lend itself to in vitro bioassay of any hormone that induces specific morphological changes in target cells.
The Nissl method and immunocytochemistry were used to study the effects of severe hypobaric hypoxia and its actions in combination with the preconditioning actions of moderate hypoxia on the expression of the early gene proteins c-Fos and NGFI-A as well as structural changes in hippocampal and neocortical neurons in the rat brain. Severe hypoxia was found to suppress c-Fos and NGFI-A synthesis (3-24 h after exposure) and to induce delayed (days 3-7) structural damage to neurons, of the "light" and predominantly the "dark" types, which appear to reflect the development of necrotic and apoptotic processes respectively. Preconditioning with the regime used here corrected these derangements, resulting in increases in the expression of early gene proteins and significant reductions in structural damage to neurons after severe hypoxia.
The strength and, mainly, the direction of a static electric field can be used to control delocalization effects occurring in a non-polar pi-system. The delocalization energy, the weights, and the probabilities of some local electronic structures, the behavior of electron pairs, and the electronic fluctuations are considered and examined in cis-butadiene, used as model system. The effects of the electric field are detected and evaluated in the basis of natural orbital spaces appropriate to investigate the behavior of one- and poly-electron distributions. The consequences of modifying the delocalization effects on structural changes are also investigated. Full geometry optimizations in both Hartree-Fock and MP2 levels show that the changes in bond lengths, guided by the changes of the behavior of the electronic assembly, can be controlled by means of the electric field.