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At least 793 records · Page 44Linked to original sources
PubMed2005

Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer's disease.

Neurofibrillary tangles (NFTs) are the neuropathological hallmarks in Alzheimer's disease (AD). Densities of NFTs correlate with the dementia status. NFTs reflect the intracellular accumulation of abnormal paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Hyperphosphorylation and truncation have been proposed as key events leading to the genesis of PHFs. A recent hypothesis involving conformational changes has been emerging. These structural modifications of the tau protein were detected by monoclonal antibodies (mAbs) recognizing discontinuous epitopes along the tau molecule such as Alz-50, Tau-66 and MC1. A new mAb, TG-3, detects an early pathology in AD. The epitope of mAb TG-3 maps to phosphorylated Thr231 when the tau molecule is conformationally altered. In the present study, we used confocal microscopy to analyze the state of tau molecule adopting the TG-3 conformation during tangle formation. We also compared mAb TG-3 immunoreactivity with that of mAb Alz-50. Immunoelectronmicroscopy was also performed. N- and C- termini markers evidenced that the tau molecule is intact when it adopts the TG-3 conformation. In addition to NFT, mAb TG-3 also recognized NFT-not bearing-neurons suggesting an early processing of tau prior to NFT formation. Ultrastructural analysis evidenced the presence of TG-3 and Alz-50 immunoreactive products on organelles including mitochondria and endoplasmic reticulum. Nuclear heterochromatin was densely immunolabelled. These results together with the fact that TG-3 immunoreactivity is related to intact tau suggest that the conformation recognized by TG-3 is early staged in the neuronal pathology of AD. In addition, we document that the earliest changes in tau occur closely associated with organelles and heterochromatin.

Aged↗
PubMedDate not supplied

[The structural changes in chromatin at different levels of its organization during aging].

The data about changes in the molecular organization of the cell nucleus during aging are reviewed. Changes in DNA primary and secondary structure include deletions of some sequences, changes in base methylation pattern and the increasing number of DNA breaks. Conditions underlying poor reproducibility of the results obtained in corresponding experiments are discussed. Changes observed in the nucleosomal and supranucleosomal chromatin structure reflect either its increasing compactization or the loss the nucleosomal structure during aging. The data about the increased DNA superhelicity and topoisomerase activity in aging organisms contradict the accepted views about age-related decrease in chromatin activity. It is suggested that the gene activity in aging organisms is specifically altered rather than generally decreased. The data are presented about the ways of preventing or reverting the age-related changes in chromatin structure.

Aging↗
PubMed1992

Structural changes in rat Leydig cells posthypophysectomy: a morphometric and endocrine study.

Short and long term responses of the rat Leydig cell were studied posthypophysectomy, at times when germ cell degeneration was first prominent (6 days) and after long term regression of the testis (28 days). In the short term, virtually all structural parameters relating to the volume and surface area of the Leydig cell and its subcellular organelles were significantly lowered compared with those in control animals. Exceptions were the volumes of the nucleolus, heterochromatin, and lysosomes and the surface areas of the nucleus. Structural decreases were generally on the order of 2- to 5-fold in the 6-day period. A statistical analysis of the percent decreases in the short term was performed to determine whether any particular structural features were more sensitive to hypophysectomy than any others. In most instances, no particular organelles were decreased compared to others. However, lipid, although not commonly seen in rat Leydig cells, showed significantly greater percent decreases compared with several other organelles, indicating that the small amount of lipid present is rapidly lost (used) in the short term. After long term hypophysectomy, all structural parameters of the Leydig cell were significantly lowered compared with those in pituitary-intact animals. Only a few parameters (mitochondrial volume, cell surface area, and the surface areas of inner and outer mitochondrial membranes and smooth endoplasmic reticulum) showed more significant decreases in the long term compared with the short term hypophysectomized animals. Most organelle volumes and surface areas correlated positively and significantly with serum and tissue testosterone levels; the exceptions were the volumes of the nucleolus, heterochromatin, lipid, and lysosomes. Compared with the pituitary-intact animal, the content of LH receptors expressed per testis and per Leydig cell was significantly lower in both hypophysectomized groups; however, the number of receptors per given area of individual Leydig cell plasma membrane remained unchanged. Overall, data show that the Leydig cell manifests marked structural changes during early spermatogenic dysfunction.

Animals↗
PubMed2007

Cancer-related mutations in BRCA1-BRCT cause long-range structural changes in protein-protein binding sites: a molecular dynamics study.

Cancer-associated mutations in the BRCT domain of BRCA1 (BRCA1-BRCT) abolish its tumor suppressor function by disrupting interactions with other proteins such as BACH1. Many cancer-related mutations do not cause sufficient destabilization to lead to global unfolding under physiological conditions, and thus abrogation of function probably is due to localized structural changes. To explore the reasons for mutation-induced loss of function, the authors performed molecular dynamics simulations on three cancer-associated mutants, A1708E, M1775R, and Y1853ter, and on the wild type and benign M1652I mutant, and compared the structures and fluctuations. Only the cancer-associated mutants exhibited significant backbone structure differences from the wild-type crystal structure in BACH1-binding regions, some of which are far from the mutation sites. Backbone differences of the A1708E mutant from the liganded wild type structure in these regions are much larger than those of the unliganded wild type X-ray or molecular dynamics structures. These BACH1-binding regions of the cancer-associated mutants also exhibited increases in their fluctuation magnitudes compared with the same regions in the wild type and M1562I mutant, as quantified by quasiharmonic analysis. Several of the regions of increased fluctuation magnitude correspond to correlated motions of residues in contact that provide a continuous path of fluctuating amino acids in contact from the A1708E and Y1853ter mutation sites to the BACH1-binding sites with altered structure and dynamics. The increased fluctuations in the disease-related mutants suggest an increase in vibrational entropy in the unliganded state that could result in a larger entropy loss in the disease-related mutants upon binding BACH1 than in the wild type. To investigate this possibility, vibrational entropies of the A1708E and wild type in the free state and bound to a BACH1-derived phosphopeptide were calculated using quasiharmonic analysis, to determine the binding entropy difference DeltaDeltaS between the A1708E mutant and the wild type. DeltaDeltaS was determined to be -4.0 cal mol(-1) K(-1), with an uncertainty of 2 cal mol(-1) K(-1); that is, the entropy loss upon binding the peptide is 4.0 cal mol(-1) K(-1) greater for the A1708E mutant, corresponding to an entropic contribution to the DeltaDeltaG of binding (-TDeltaDeltaS) 1.1 kcal mol(-1) more positive for the mutant. The observed differences in structure, flexibility, and entropy of binding likely are responsible for abolition of BACH1 binding, and illustrate that many disease- related mutations could have very long-range effects. The methods described here have potential for identifying correlated motions responsible for other long-range effects of deleterious mutations.

Algorithms↗
PubMed2004

SDS induced structural changes in alpha-crystallin and it's effect on refolding.

Alpha-crystallin, a major eye lens protein and a key member of the small heat shock protein family, acts like a chaperone by preventing aggregation of substrate proteins. One of the hallmarks of most small heat shock proteins is their existence as a large oligomer, the role of which in its function is not understood at present. We have studied the role of the oligomer in the stability of its structure against SDS induced destabilization by CD measurements. Alpha-crystallin from bovine source as well as recombinant preparation was used for this purpose. As SDS concentration was gradually increased, the beta-sheet structure was diminished followed by concomitant increase in the alpha-helical structure. The quaternary structural changes in presence of SDS were also monitored by light scattering, polarization and anisotropy measurements. It was found that the breakdown of the oligomeric structure was nearly complete above 1 mM SDS concentration. The results were compared with that of a monomeric gamma-crystallin, which is also a major beta-sheet protein like alpha-crystallin. When alpha-crystallin was first converted into monomeric random coil structure in presence of 6 M urea and allowed to refold in SDS solution, amount of alpha-helix was more than that incubated directly in the same concentration of SDS. The results show that alpha-crystallin attains extra structural stability against external stress due to its oligomeric structure. The implication for the extra stability is discussed in reference to its function as molecular chaperone.

Animals↗
PubMed1988

Studies of acetylcholine receptor subunit gene expression: chromatin structural changes during myogenesis.

Myogenesis proceeds stepwise from pluripotential stem cell to differentiated myotube. The precise number of transitions that occur along the developmental pathway remains to be determined. We examined the myogenic pathway as modelled by mouse mesodermal stem cell and muscle cell lines for stage-specific alterations in the chromatin structure of the acetylcholine receptor delta and gamma subunit genes. We reasoned that such an analysis would allow us to observe either the primary events in the activation of these muscle-specific genes or processes secondary to the binding of muscle-specific regulatory proteins. We probed chromatin structure with DNase I (deoxyribonuclease I) and precisely mapped to the 5' ends of the delta and gamma genes DNase I hypersensitive (DH) sites whose induction is unique to each myogenic stage. Putative mesodermal stem cells have the simplest pattern of DH sites with no sites near the 5' ends of the delta and gamma genes, whereas differentiated myotubes express the most complex pattern; the myoblast pattern is intermediate and of two types. In muscle cell lines where differentiation must be induced the myoblasts have a simple pattern (one more site than stem cells); in muscle lines where differentiation is spontaneous the myoblasts express a complex pattern of DH sites (one less site than myotubes). Inducible myoblasts seem to be arrested in an earlier step in the myogenic pathway than spontaneously differentiating myoblasts. Thus, myogenic activation of acetylcholine receptor subunit genes appears to be a stepwise process that can be detected by chromatin structural changes specific to four distinct stages of muscle development: stem cell, early myoblast, late myoblast, and differentiated myotube.

Animals↗
PubMedDate not supplied

Structural changes induced by sulphur mustard in rabbit skin.

Sulphur mustard (SM) is a bifunctional alkylating agent which can react with a wide variety of molecules of biological interest. The interaction of SM with animal skin elicits a varied histopathological response in cellular components on a temporal scale. The extracellular matrix (ECM) undergoes tremendous structural changes as a result of SM exposure. Sulphur mustard induces oedema, infiltration of polymorphonuclear cells and destruction of cells. Injury appeared to be most severe on the third day after exposure, when the thickness of the skin registered the maximum change from the control. The initiation of recovery could be noticed on the 6th day, when the intercellular gap in the ECM began to reduce significantly, indicating reformation of damaged skin. Simultaneous reformation was also noticed in the epidermis and other cellular components. However, recovery was far from complete and continued beyond the 6th day.

Animals↗
PubMed1984

Congenital pulmonary vein stenosis: structural changes in a patient with normal pulmonary artery wedge pressure.

A male infant is described who died at 13 months of age with stenosis of all extrapulmonary veins except the left upper vein. The pulmonary artery wedge pressure was normal, the first time this is reported in this condition. At autopsy, there were structural changes of the pulmonary arteries and veins in all lobes with or without pulmonary vein stenosis. Arterial changes-muscle extension, medial hypertrophy and decreased arterial size--analyzed quantitatively were found to be similar in all lobes. Venous medial hypertrophy was more marked in obstructed lobes. These anatomic changes are presumably due to fixed venous obstruction in the pulmonary lobes drained by stenotic veins and to high flow in the left upper lobe.

Cardiac Catheterization↗
PubMed2001

Structural change of mesoporous silica with sonochemically prepared gold nanoparticles in its pores.

Ultrasonic irradiation of mesoporous silica soaked in a mixture of chloroauric acid and isopropanol for 120 min in Ar atmosphere at room temperature yielded Au/SiO2 mesoporous composite, which was characterized by high resolution transmission electron microscopy and optical absorption measurement. The structure of mesoporous silica after sonochemical preparation of gold (Au) nanoparticles within its pores was studied by nitrogen adsorption technique. It has been shown that the structural parameters, such as specific surface area (SSA), porosity (P), the mean pore diameter (lp) were increased significantly after ultrasonic irradiation. It is suggested that the collision of Au nanoparticles with pore walls and localized erosion induced by the asymmetric implosive collapse of cavities on the extensive liquid-solid interface that are responsible for the structural change in the mesoporous solid.

Journal Article↗
PubMed1997

The lumbar extradural structure changes with increasing age.

We have examined the extradural space using a flexible extraduroscope in 74 patients undergoing extradural anaesthesia at the L2-3 interspace. Extraduroscopy showed that the extradural space becomes widely patent and the fatty tissue in the extradural space diminishes with increasing age. We postulate that these age-related structural changes may affect the spread of local anaesthetic in the extradural space.

Adipose Tissue↗
PubMed1993

Structural changes in cytochrome c upon hydrogen-deuterium exchange.

The resonance Raman spectra of yeast ferri- and ferro-iso-1-cytochrome c dissolved in H2O and D2O are reported. Hydrogen exchange in the protein leads to distinct spectral changes of heme vibrational bands, particularly in the region between 670 and 710 cm-1 and at approximately 443 and approximately 450 cm-1. The latter two bands, which have previously been assigned to porphyrin modes including bending vibrations of the propionate side chains [Hildebrandt, P. (1991) J. Mol. Struct. 242, 379-395], reveal frequency shifts by up to 4 cm-1. These shifts are attributed to structural changes of the propionate groups caused by the energetic differences of the hydrogen and deuterium bonds between these substituents and the adjacent amino acid residues. The frequency shifts of the bands between 670 and 710 cm-1 most likely reflect structural differences of the tetrapyrrole macrocycle itself. Time-dependent experiments revealed that the hydrogen exchange processes associated with the changes in the resonance Raman spectra are complete in less than 15 min. The protons which are involved are those in the interior of the heme pocket as concluded by comparison with the exchange rate constants previously determined by NMR spectroscopy [Mayne, L., Paterson, Y., Cerasoli, D., & Englander, S. W. (1992) Biochemistry 31, 10678-10685]. These protons are part of a hydrogen bonding network including the amide protons of Asn-52, Met-80, and Lys-79, the side chain protons of Asn-52, Tyr-67, Thr-78, Trp-59, and Thr-49, and the water molecules 121 and 166.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytochrome c Group↗
PubMed2000

Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors.

Several metabolic abnormalities may be triggered secondary to hyperglycemia in diabetes. Some of these abnormalities may alter expression of vasoactive factors in the target organs of diabetic complications. We investigated alterations of endothelin-1 (ET-1) and its receptors, ET(A) and ET(B), and associated structural changes in the myocardium of streptozotocin-induced diabetic rats after 6 months of hyperglycemia. We further assessed the preventive effects of an ET-receptor antagonist bosentan on these changes. Compared to the non-diabetic, age- and sex-matched control animals, diabetic rats showed hyperglycemia, glucosuria, reduced body weight gain and elevated glycated Hb levels. Measurement of ET-1, ET(A) and ET(B) mRNAs by semiquantitative RT-PCR showed significantly increased mRNA levels in the hearts of diabetic rats. Treatment with bosentan failed to reduce ET-1 or ET(B) mRNA expression in diabetes, however ET(A) mRNA expression was reduced. Immunocytochemically, ET-1 was detected in the cardiomyocytes, endothelium and smooth muscle cells of the larger blood vessels and was increased in diabetes. Autoradiographic localization of ET-1 receptors, using (125)I-ET-1, showed increased binding in the endothelium and myocardium of diabetic animals. Histologically, focal fibrous scarring with apoptotic cardiomyocytes, consistent with changes secondary to microvascular occlusion, was only present in the diabetic rats. In keeping with focal fibrosis, myocardium from diabetic rats further showed significantly increased mRNA expression of two extracellular matrix protein transcripts, fibronectin and collagen alpha 1(IV) which were completely prevented by treatment with bosentan. These data suggest that hyperglycemia-induced upregulation of the ET-system in the heart may be important in the pathogenesis of cardiac involvement in diabetes.

Animals↗
PubMed1989

Time course of structural changes at identified sensory neuron synapses during long-term sensitization in Aplysia.

We have used the gill- and siphon-withdrawal reflex of Aplysia californica to explore the morphological basis of the synaptic plasticity that underlies long-term sensitization. In earlier studies (Bailey and Chen, 1983, 1988a), we described 2 classes of structural changes at identified sensory neuron synapses that occur following long-term sensitization: (1) increases in the number, size, and vesicle complement of active zones and (2) an overall increase in the total number of synaptic varicosities per sensory neuron. In the present study, we have begun to examine which of these anatomical changes might be necessary for the maintenance of long-term sensitization by exploring the time course over which they occur and, in particular, their duration relative to the persistence of the memory assessed behaviorally. Toward this end we have quantitated changes in both the total number of varicosities and their active zone morphology in single HRP-labeled sensory neurons taken from long-term sensitized and control animals at different intervals (1-2 d, 1 week, and 3 weeks) following training. We have found that long-term sensitized animals examined within 48 hr after the completion of training demonstrate an increase in the total number of varicosities per sensory neuron as well as an increase in the incidence, size, and vesicle complement of their synaptic active zones compared with control animals. The increase in the number of varicosities and active zones persists unchanged for at least 1 week, and the increase in active zone number is only partially reversed at the end of 3 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[Structural changes in the plasma membranes during thymocyte irradiation].

Thymocytes were irradiated with doses of 4 to 10(3) Gy. The binding of 1-anilino-naphthalene-8-sulphonate and Ca2+ to plasma membranes; viscosity and lipid peroxidation; Stern-Folmer constant; and the number of SH-groups of membrane proteins were determined. The structural changes in plasma membranes after irradiation of thymocytes were found to be cooperative.

Anilino Naphthalenesulfonates↗
PubMedDate not supplied

[The necessity for structural changes and their medico-economic trends in public health].

Discusses the new socioeconomic conditions in public health, which imply higher requirements to the use of resources and to their quality. Emphasizes that a physician of a general profile promotes the development of such tendencies, the realization of which, in turn, is conductive to other structural changes reflecting the changes in the population health and in changing need in medical care.

Economics, Medical↗
PubMed2004

Defined structural changes occur in a nucleosome upon Amt1 transcription factor binding.

Here, we study the binding of the transcription factor Amt1 to its recognition site near the dyad of a highly positioned nucleosome. We find that the DNA binding domain of Amt1 binds to nucleosomes with only threefold reduced affinity compared to free DNA. We show by fluorescence resonance energy transfer that factor binding at the nucleosomal dyad is accompanied by the partial dissociation of the DNA ends from the histone octamer surface; however, no dissociation or subtle rearrangements of histone subunits is observed. A poly(dA.dT) DNA sequence element adjacent to the transcription factor binding site appears to facilitate factor binding, but is not essential. The methods that we describe here characterize for the first time the subtle structural changes that occur upon transcription factor binding to nucleosomes, and demonstrate the ability of the nucleosome to structurally adapt in response to outside influences.

Animals↗
PubMed2001

Ligand affinity, homodimerization, and ligand-induced secondary structural change of the human vitamin d receptor.

The intrinsic tryptophan fluorescence signal of the full-length nuclear receptor hVDR was used to directly determine the dissociation constants, K(d), of two ligands yielding K(d) = 32 nM for 1alpha,25(OH)(2)D(3) and K(d) = 322 nM for 25(OH)D(3). Ligand binding was accompanied by a conformational change in the alpha-helical part of hVDR as revealed by CD spectroscopy. In addition, the presence of calcitriol was found to be a necessary prerequisite for the homodimerisation of hVDR which was monitored using fluorescence anisotropy. We conclude that the observed ligand-induced structural change of hVDR is conditional for dimerisation of the protein.

Calcifediol↗