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PubMed1998

Early structural changes in acute MS lesions assessed by serial magnetization transfer studies.

BACKGROUND: Whether acute MS lesions are primarily inflammatory or demyelinative is unresolved. Our study examined acute MS lesions longitudinally by quantitative magnetization transfer (MT), an MRI technique that identifies tissue integrity and destruction. METHODS: Four MS patients were studied by serial MRI including MT, conventional T2-weighted images, and postgadolinium T1-weighted images for 9 to 12 months. In 15 new lesions, the MT ratio (MTR) was calculated retrospectively. RESULTS: In 13 lesions, a marked decrease in the MTR was present early during the first 2 months after the onset of the lesion and was followed by a variable increase. In two other lesions, the MTR progressively declined. CONCLUSIONS: These results suggest that major early structural changes compatible with demyelination and followed by remyelination and gliosis, or by continuous demyelination, occur in new MS lesions. The various MTR profiles provide in vivo confirmation of the current knowledge of the progression in MS lesions. Furthermore, MTR may be used to monitor in vivo drug efficacy in new MS lesions.

Adult↗

PubMed1991

Analysis of the distribution of the INCENPs throughout mitosis reveals the existence of a pathway of structural changes in the chromosomes during metaphase and early events in cleavage furrow formation.

The INCENPs are two polypeptides of 135 x 10(3) and 150 x 10(3) Mr that enter mitosis as tightly bound chromosomal proteins, but subsequently leave the chromosomes altogether and become associated with the central spindle and cell cortex at the contractile ring. In the experiments reported here we have used confocal microscopy and immunoelectron microscopy to provide a detailed picture of the intracellular location of these proteins during mitosis. The experiments have not only revealed a number of new details concerning the properties of the INCENPs in mitosis, but have revealed a number of novel aspects of the mitotic process itself. The first of these is the existence of a sequential pathway of structural changes in the chromosomes that occurs during metaphase. This pathway is revealed by the existence of four distinct INCENP staining patterns in mitotic cells. In 'early' and 'early/mid' metaphase, the INCENPs gradually become concentrated at the centromeres, forming a ring at the center of the metaphase plate. During 'mid/late' metaphase they exit from the chromosomes, so that by late metaphase they are found solely in streaks that traverse the plate parallel to the spindle axis. The streaks probably correspond to INCENPs closely associated with microtubule bundles, perhaps as part of the stem body material. Examination of transverse optical sections of the spindle interzone during early anaphase reveals an unexpectedly high degree of order. The INCENP antigens are localized on fibers that are organized into a hollow ring 8 microns in diameter and approximately 4 microns beneath the cell cortex. Measurement of cellular dimensions in the confocal microscope reveals that the maximum diameter of early anaphase cells lies across the spindle equator, so that when the cleavage furrow forms, it does so around the maximum circumference of the cell. During anaphase, a subpopulation of the INCENP antigen becomes localized to the cortex where the furrow will subsequently form. This occurs prior to any other evidence of furrowing. Thus, binding of the INCENPs to this region may represent an early step in furrow formation. Together, these results suggest that the INCENPs may represent a new class of 'chromosomal passenger' proteins that are carried to the spindle equator by the chromosomes and subsequently perform a cytoskeletal role following their release from the chromosomes at the metaphase:anaphase transition.

Anaphase↗

PubMed1982

Reversible fine structural changes in the supraoptic nucleus of the rat following intraventricular administration of colchicine.

A single low dose (3.5 micrograms or 7.0 micrograms) of colchicine injected intraventricularly into normally hydrated or dehydrated (7 or 4 days) and, subsequently, rehydrated (3 hours) rats caused a number of characteristic changes within the perikarya of the supraoptic nucleus. The temporary slow-down of axonal transport of neurosecretory granulated vesicles (NGVs) and their continued synthesis led to a perikaryal accumulation of NGVs, and changes in their electron-density are considered to be indicative of their continued maturation. In some neurons, the biosynthetic pathway appears to be interrupted or temporarily impaired as evidenced by the accumulation of material of varying electron-density and of granules within the cisternae of the rough ER. An increased number of varying types of lysosomes and phagolysosomes is indicative for the disposal of NGVs within the perikaryon. Most of them are, however, removed through resumption of axonal transport which leads to the reestablishment of pre-experimental fine structural characteristics within approximately 9 days. In the osmotically stressed groups, the fine structural changes are more pronounced but equally reversible.

Animals↗

PubMed1993

Use of human lung tissue for studies of structural changes associated with chronic ozone exposure: opportunities and critical issues.

Definitive information on the chronic effects of exposure to ozone (O3) in humans is not available. There is a strong concern that ozone could produce chronic lung damage in humans on the basis that exposures are ubiquitous at levels that produce transient symptoms, function deficits, and lung inflammation in humans and chronic lung damage in laboratory animals. Both prospective and national population surveys suggest an association between chronic O3 exposure and reduced lung function, and a pilot investigation of autopsied lungs of accident victims in Los Angeles reported an unexpectedly high incidence of disease in the centriacinar region, the lung region known to receive the highest dose of inhaled O3. This paper discusses the advantages and limitations of further studies of structural changes in human lung tissue in relation to chronic O3 exposure. The major advantages of such studies are that a) measurable effects may be related to realistic chronic exposures, b) the effects may be described quantitatively and compared directly to those obtained in chronic animal inhalation exposures, and c) evidence for chronic effects may be obtained much more rapidly than in prospective studies. The major limitations are the difficulties in obtaining sufficient reliable information on residential history, physical activity out-of-doors, and smoking and other confounding exposures to lung irritants from next of kin, and limited availability of adequate air quality data for determining ambient concentrations at places of residence and/or outdoor exercise. The paper also discusses approaches to minimizing these limitations in the design of specific studies.

Adolescent↗

PubMed1983

Monolayer black membranes from bipolar lipids of archaebacteria and their temperature-induced structural changes.

The membrane of Caldariella acidophila, an extreme thermophilic archaebacterium, is characterized by unusual bipolar complex lipids. They consist of two nonequivalent polar heads, linked by a C40 alkylic component. The molecular organization of these lipids in the plasma membrane is still a matter of study. In this paper, we present current-voltage measurements on artificial bipolar lipid membranes, indicating that molecules are indeed organized as a covalently bound bilayer, in which each molecule is completely stretched and spans its entire thickness. Furthermore, conformational transitions of these artificial membranes (which could be formed only above 70 degrees C from a lipid/squalene dispersion) are analyzed in the 80 to 15 degrees C temperature range. Abrupt variations in capacitance and valinomycin-induced conductance seem to indicate the occurrence of at least two structural changes. Measurements are also extended to different solvent systems. Results are consistent with the picture of a monolayer bipolar lipid membrane in which few solvent molecules align themselves parallel to the lipophilic chains. The amount of solvent as well as the temperature at which conformational transitions occur, depend on the solvent system in which the lipid is dispersed.

Archaea↗

PubMed2000

Thermal behavior of proteins: heat-resistant proteins and their heat-induced secondary structural changes.

Most proteins are denatured by heat treatment, and the process is usually irreversible. However, some proteins, such as hyperthermophilic proteins are known to be stable even at the boiling temperature of water. We here describe a systematic investigation of thermal behavior of proteins by purifying and characterizing some heat-resistant proteins (HRPs) that are not aggregated upon heat treatment. Although most proteins were precipitated by boiling in a water bath, about 20 and 70 wt % of total proteins appeared to be heat-resistant in Jurkat T-cell lysates and human serum, respectively. We identified major HRPs from Jurkat T-cells and human serum by N-terminal amino acid sequencing and Western blot analysis. HRPs of 20 and 45 kDa (HRP20 and HRP45) were identified as alpha-synuclein and calreticulin, respectively, and HRPs of 60, 27, and 16 kDa (HRP60, HRP27, and HRP16) were identified as human serum fetuin, apolipoprotein A-I, and transthyretin, respectively. By a systematic investigation of the effect of heat on the secondary structure of the purified HRPs by circular dichroic spectroscopy, we observed four major types of thermal behavior, suggesting that the proteins could protect themselves through these pathways. Although our analysis is restricted to protein secondary structural changes, our data indicate that heat resistance of protein can be achieved in several different ways depending on the thermodynamic stability of native (N), unfolded (U), denatured (D), and intermediate (I) states.

Amino Acid Sequence↗

PubMed1998

Structural changes of surfactant protein A induced by cations reorient the protein on lipid bilayers.

Surfactant protein A (SP-A) is an octadecameric hydrophilic glycoprotein and is the major protein component of pulmonary surfactant. This protein complex plays several roles in the body, such as regulation of surfactant secretion, recycling and adsorption of surfactant lipids, and non-serum-induced immune response. Many of SP-A's activities are dependent upon the presence of cations, especially calcium. Here, we have studied in vitro the effect of cations on the interaction of purified bovine SP-A with phospholipid vesicles made of dipalmitoylphosphatidylcholine and unsaturated phosphatidylcholine. We have found that SP-A octadecamers exist in an "opened-bouquet" conformation in the absence of cations and interact with lipid membranes via one or two globular headgroups. Calcium-induced structural changes in SP-A lead to the formation of a clearly identifiable stem in a "closed-bouquet" conformation. This change, in turn, seemingly results in all of SP-A's globular headgroups interacting with the lipid membrane surface and with the stem pointing away from the membrane surface. These results represent direct evidence that the headgroups of SP-A (comprising carbohydrate recognition domains), and not the stem (comprising the amino-terminus and collagen-like region), interact with lipid bilayers. Our data support models of tubular myelin in which the headgroups, not the tails, interact with the lipid walls of the lattice.

Animals↗

PubMed1988

Is the increased responsiveness to verapamil in the forearm resistance vessels of patients with hypertension a consequence of structural change?

A mathematical model has been developed that relates wall tension in resistance vessels to changes in both distending pressure and flow; the effect of alterations in wall: lumen ratio is taken into account. The model indicates that increased autoregulatory activity in the forearm circulation of patients with primary hypertension could result from an increased response of the vascular smooth muscle to increased intraluminal pressure, but it could be accounted for by an increase in wall:lumen ratio from about 0.2 to 0.3. When the effect of the same increase in wall:lumen ratio on response to dilator agents is examined, it appears that the enhanced response to verapamil could be accounted for by structural change and there is no need to postulate a functional change. If this view is correct, however, it becomes necessary to assume a reduced response of the vascular smooth muscle to sodium nitroprusside in patients with hypertension if the unchanged dilator effect of this drug is to be explained.

Dose-Response Relationship, Drug↗

PubMed1993

Spontaneous immortalization of mouse fibroblasts involves structural changes in senescence inducing protein, mortalin.

Mortalin, a novel member of mouse heat shock protein 70 (hsp70) family, is seen to distinguish the cellular mortal and immortal phenotypes by virtue of its cytosolic and perinuclear distribution, respectively. We report here that the cytosolic and perinuclear forms of mortalin from CD1-ICR mouse embryonic fibroblasts and NIH 3T3 cells, respectively, differ by two amino acids, can be distinguished on two-dimensional SDS-polyacrylamide gel. The perinuclear mortalins from RS-4 and Balb/c 3T3 cells harbor the same two amino acids as that of NIH 3T3 cells. However, these when analyzed with C-MEF mortalin did not exhibit the mobility shift equivalent to C-MEF and NIH 3T3 mortalins. The data indicate that the perinuclear mortalin from different immortal fibroblasts are not identical and implicate the possibility of additional structural changes in mortalin during immortalization. Such differences may also contribute to the differential in vitro growth characteristics of these immortal cells.

3T3 Cells↗

PubMed1999

Structural changes in bacteriorhodopsin during ion transport at 2 angstrom resolution.

Crystal structures of the Asp96 to Asn mutant of the light-driven proton pump bacteriorhodopsin and its M photointermediate produced by illumination at ambient temperature have been determined to 1.8 and 2.0 angstroms resolution, respectively. The trapped photoproduct corresponds to the late M state in the transport cycle-that is, after proton transfer to Asp85 and release of a proton to the extracellular membrane surface, but before reprotonation of the deprotonated retinal Schiff base. Its density map describes displacements of side chains near the retinal induced by its photoisomerization to 13-cis,15-anti and an extensive rearrangement of the three-dimensional network of hydrogen-bonded residues and bound water that accounts for the changed pKa values (where Ka is the acid constant) of the Schiff base and Asp85. The structural changes detected suggest the means for conserving energy at the active site and for ensuring the directionality of proton translocation.

Bacteriorhodopsins↗

PubMed2001

Phosphorylation-induced structural changes in the amyloid precursor protein cytoplasmic tail detected by NMR.

The cytoplasmic tail of the amyloid precursor protein (APPc) interacts with several cellular factors implicated in intracellular signaling or proteolytic production of amyloid beta peptide found in senile plaques of Alzheimer's disease patients. APPc contains two threonine residues (654 and 668 relative to APP695, or 6 and 20 relative to APPc) and a serine residue (655 or 7, respectively) that are known to be phosphorylated in vivo and may play regulatory roles in these events. We show by solution NMR spectroscopy of a 49 residue cytoplasmic tail peptide (APP-C) that in all three cases, phosphorylation induces changes in backbone dihedral angles that can be attributed to formation of local hydrogen bonds between the phosphate group and nearby amide protons. Phosphorylation of S7 also induces chemical shift changes in the hydrophobic cluster (residues I8-V13), indicating additional medium-range effects. The most pronounced changes occur upon phosphorylation of T20, a neuron-specific phosphorylation site, where the N-terminal helix capping box previously characterized for this region is altered. Characterization of torsion angles and transient hydrogen bonds indicates that prolyl isomerization of the pThr-Pro peptide bond results from both destabilization of the N-terminal helix capping box and stabilization of the cis isomer by transient hydrogen bonds. The significant population of the cis isomer (9 %) present after phosphorylation of T20 suggests a potential role of selective recognition of cis versus trans isomers in response to phosphorylation of APP. Together, these structural changes indicate that phosphorylation may act as a conformational switch in the cytoplasmic tail of APP to alter specificity and affinity of binding to cytosolic partners, particularly in response to the abnormal phosphorylation events associated with Alzheimer's disease.

Amino Acid Sequence↗

PubMed1982

Activation of rat B lymphocytes. II. Functional and structural changes in "aged" rat B lymphocytes.

Anti-mu, anti-gamma, and anti-delta antibodies induce proliferation of splenic B lymphocytes from young Lewis rats, measured by 3H-TdR uptake. In contrast, splenic B cells of aged Lewis rats respond poorly or not at all to these reagents. T lymphocytes or interleukin 2 (IL-2) of young or aged rats augment the uptake of 3H-TdR in cultures of "young" B cells responding to anti-Ig reagents or LPS and DxS, but have no significant effect on the responses of "old" B cells. Analysis of spleen cells of young and aged rats in a fluorescence-activated cell sorter indicates the density of mu, gamma, and delta isotypes is reduced in "old" B cells, and that B cells of aged rats are significantly larger than those of young rats. These results delineate anatomic and structural changes in B lymphocytes of aged rats.

Aging↗

PubMed2002

Structural changes and molecular interactions of hydrophobin SC3 in solution and on a hydrophobic surface.

The hydrophobin SC3 belongs to a class of small proteins functioning in the growth and development of fungi. Its unique amphipathic property and remarkable surface activity make it interesting not only for biological studies but also for medical and industrial applications. Biophysical studies have revealed that SC3 possesses at least three distinct conformations, named "soluble-state SC3" for the protein in solution, and "alpha-helical-state SC3" and "beta-sheet-state SC3" for the different states of the protein associated at a hydrophobic-water interface. The present fluorescence study shows that the microenvironment of the dansyl-labeled N terminus of soluble-state SC3 is relatively hydrophobic, whereas it is hydrophilic for alpha-helical-state and beta-sheet-state SC3. Fluorescence collisional quenching indicates that the N terminus of soluble-state SC3 is more solvent-accessible than those of alpha-helical-state and beta-sheet-state SC3, with Stern-Volmer constants for acrylamide of 4.63, 0.02, and 0.2 M(-1) for the different states, respectively. Fluorescence resonance energy transfer measurements show that soluble-state SC3 tends to associate in solution but dissociates in TFA. Fluorescence energy transfer was eliminated by conversion of soluble-state SC3 to alpha-helical-state SC3 on a hydrophobic surface, indicating a spatial separation of the molecules in this state. By inducing the beta-sheet state, structural changes were observed, both by CD and by fluorescence, that could be fit to two exponentials with lifetimes of about 10 min and 4 h. Molecules in the beta-sheet state also underwent a slow change in spatial proximity on the hydrophobic surface, as revealed by the reappearance of fluorescence resonance energy transfer in time.

Circular Dichroism↗

PubMed2005

Sodium carbonate treatment induces scoparone accumulation, structural changes, and alkalinization in the albedo of wounded citrus fruits.

Following sodium carbonate treatment, accumulation of scoparone (6,7-dimethoxycoumarin) but not scopoletin (6-methoxy-7-hydroxycoumarin) was found in the albedo of wounded fruit from different Citrus sp. and cultivars. Treating wounded mandarin fruit cv. Fairchild with 5% Na(2)CO(3) (SC) lead to a scoparone accumulation in the albedo of 310, 361, and 382 microg g(-1) fresh weight after 7, 10, and 15 days, respectively. Scoparone accumulation was associated with a decrease in decay severity. When oranges cv. Biondo comune wounded and treated with 5% SC were inoculated with Penicillium digitatum or Penicillium italicum conidia 3 days posttreatment, the decay percentage as compared to untreated wounds was reduced by 97.2 and 93.9%, respectively. Observations by scanning electron microscopy of wounded Citrus fruits treated at 20 degrees C with 2, 3, 4, or 5% (w/v) solutions of sodium carbonate showed structural modifications to the albedo as well as damage to 24-48 h old mycelia of P. digitatum, the cause of citrus green mold. Modifications were more evident in orange, lemon, and grapefruit as compared to mandarin fruit. The efficacy of the treatment was strictly related to the SC interaction with the albedo tissue that, in addition to structural changes, significantly increased tissue pH, affecting P. digitatum pathogenicity. The SC remaining as a film on unwounded flavedo had no effect in preventing contact infection by the Penicillia.

Carbonates↗

PubMed2006

Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow.

Osteoarthritis (OA), the most common of all arthritic conditions, is a social and financial burden to all nations. The most recent research has significantly advanced our understanding of the cause of OA and risk factors associated with it. These findings have provided useful information that has helped in the daily management of patients with OA. Some preventative measures and a number of therapeutic agents and drugs are available, which may help to reduce the progression of OA in certain patients. Moreover, the most recent progress in research has significantly enhanced our knowledge of the factors involved in the development of the disease and of the mechanisms responsible for its progression. This has allowed identification of several new therapeutic targets in a number of pathophysiological pathways. Consequently, the field is opening up to a new era in which drugs and agents that can specifically block important mechanisms responsible for the structural changes that occur in OA can be brought into development and eventually into clinical trials.

Antirheumatic Agents↗

PubMed1995

Structural changes in the rat tympanic membrane following repeated pressure loads.

Healthy adult laboratory rats were exposed to alternating negative pressure and atmospheric pressure to replicate the clinical situation found in patients with chronic sniffing habits and chronic middle ear disease. The rats were placed in a box in which the pressure changed at intervals of 30 s between atmospheric pressure and a negative pressure of -3 kPa. This was repeated continuously for periods of 3 and 7 days. At completion of the experimental period, all rats had a normal otomicroscopic status. However, histological studies demonstrated that the pars flaccida was wrinkled and the loose connective tissue contained large fibroblasts with their long axes lying in a disorganized manner. The cells of the keratinizing epithelium were thicker than normal and mitoses were seen. Epithelial crypts filled with keratin were numerous along the epithelium. In the pars tensa, all layers were thicker than normal. These findings demonstrate that repeated pressure loading can create structural changes in the tympanic membrane.

Animals↗

PubMed1976

[Ultrastructural changes of human skeletal muscle after tendon and nerve injuries. I. Fine-structural changes of the hand muscles after tendor injuries (author's transl)].

During reconstructive procedures performed 4--16 weeks after the tendon lesion the specimens obtained from the injured muscle have been examined by the authors. It was found that after the tendon injury inactivity atrophy develops and a condition of equilibrum could be observed at this time. The most important changes in the fine structure were seen in the contractile elements: there were atrophied, homogenized, fragmentated and ragged independently from the functional unities. The number of the mitochondria was considerably decreased, the sarcoplasmatic reticulum was increased, and the difference between the originally red and white muscular fibres was indistinct. The glycogen content of the musculature was decreased, or it disappeared completely. No pathological changes have been observed in the sarcolemme, the cell nuclei and the motor nerve end-plates.

Adolescent↗

PubMed1997

Octyl-beta-D-glucopyranoside partitioning into lipid bilayers: thermodynamics of binding and structural changes of the bilayer.

The interaction of the nonionic detergent octyl-beta-D-glucopyranoside (OG) with lipid bilayers was studied with high-sensitivity isothermal titration calorimetry (ITC) and solid-state 2H-NMR spectroscopy. The transfer of OG from the aqueous phase to lipid bilayers composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) can be investigated by employing detergent at concentrations below the critical micellar concentration; it can be defined by a surface partition equilibrium with a partition coefficient of K = 120 +/- 10 M-1, a molar binding enthalpy of delta H degrees D = 1.3 +/- 0.15 kcal/mol, and a free energy of binding of delta G degrees D = -5.2 kcal/mol. The heat of transfer is temperature dependent, with a molar heat capacity of delta CP = -75 cal K-1 mol-1. The large heat capacity and the near-zero delta H are typical for a hydrophobic binding equilibrium. The partition constant K decreased to approximately 100 M-1 for POPC membranes mixed with either negatively charged lipids or cholesterol, but was independent of membrane curvature. In contrast, a much larger variation was observed in the partition enthalpy. delta H degrees D increased by about 50% for large vesicles and by 75% for membranes containing 50 mol% cholesterol. Structural changes in the lipid bilayer were investigated with solid-state 2H-NMR. POPC was selectively deuterated at the headgroup segments and at different positions of the fatty acyl chains, and the measurement of the quadrupolar splittings provided information on the conformation and the order of the bilayer membrane. Addition of OG had almost no influence on the lipid headgroup region, even at concentrations close to bilayer disruption. In contrast, the fluctuations of fatty acyl chain segments located in the inner part of the bilayer increased strongly with increasing OG concentration. The 2H-NMR results demonstrate that the headgroup region is the most stable structural element of the lipid membrane, remaining intact until the disordering of the chains reaches a critical limit. The perturbing effect of OG is thus different from that of another nonionic detergent, octaethyleneglycol mono-n-dodecylether (C12E8), which produces a general disordering at all levels of the lipid bilayer. The OG-POPC interaction was also investigated with POPC monolayers, using a Langmuir trough. In the absence of lipid, the measurement of the Gibbs adsorption isotherm for pure OG solutions yielded an OG surface area of AS = 51 +/- 3 A2. On the other hand, the insertion area AI of OG in a POPC monolayer was determined by a monolayer expansion technique as AI = 58 +/- 10 A2. The similar area requirements with AS approximately AI indicate an almost complete insertion of OG into the lipid monolayer. The OG partition constant for a POPC monolayer at 32 mN/m was Kp approximately 320 M-1 and thus was larger than that for a POPC bilayer.

Calorimetry↗