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PubMed1996

A novel series of DNA triple helix-binding ligands.

We have examined the effect of a series of substituted imidazothioxanthones on the stability of an intermolecular DNA triple helix by DNase I footprinting. We find that several of these compounds promote the formation of a complex between T5C5 and the target site A6G6.C6T6, suggesting that they bind specifically to triplex DNA. The only inactive derivative lacked a protonatable function in the side chain, suggesting that this is an essential feature for triplex stabilization. These compounds, which are amongst the first triplex-binding ligands which possess an uncharged chromophore, are selective for the T.AT rather than the C+.GC triplet.

DNA↗

PubMed2005

Role of the disulphide bridge in folding, stability and function of porcine odorant binding protein: spectroscopic equilibrium studies on C63A/C155A double mutant.

Porcine odorant binding protein (pOBP) contains a single disulphide bridge linking residues Cys63 and Cys155. In order to get information on the role played by this crosslink in determining the structural and functional properties of the protein, we substituted these two Cys residues with two Ala residues by site directed mutagenesis and investigated the changes in folding, stability and functional features, as detected by fluorescence and circular dichroism measurements. In particular, we studied both chemical and thermal unfolding/refolding processes under equilibrium conditions, the first induced by guanidinium hydrochloride and the second by raising the temperature from 15 to 90 degrees C. Chemical unfolding curves, as obtained from intrinsic fluorescence and far-UV circular dichroism data, can be fitted by a simple two-state cooperative sigmoidal function; however, their partial overlap (C(1/2)=0.57+/-0.05 from fluorescence and 0.66+/-0.03 from CD) suggests the formation of an intermediate, which lacks tertiary structural features. Thermal unfolding was found to be reversible if the protein was heated up to 65 degrees C, but irreversible above that temperature because of aggregation. The thermodynamic unfolding parameters of this double mutant protein, when compared to those of the wild type protein, clearly point out the important role played by the disulphide bridge on the stability and function of this protein family and probably of many other lipocalins.

Animals↗

PubMed1997

Changed systemic and cerebral hemodynamics and oxygen supply due to gradual hemorrhagic hypotension induced by an external PID-controller in newborn swine.

An experimental design including an external closed-loop PID-(proportional-integral-differential-)controller is presented which enables the induction of gradual hemorrhagic hypotension at different stages of blood flow reduction up to stages of critically disturbed systemic and regional hemodynamics and oxygen supply. For this purpose nine newborn piglets (12-26 hours old, body weight 1626+/-160 g) were anesthetized and artificially ventilated. Gradual hemorrhagic hypotension was induced at four different steady state stages (stage 1 = 60 mmHg; stage 2 = 50 mmHg; stage 3 = 40 mmHg; stage 4 = 35 mmHg) every 30 minutes by gradual blood withdrawal using external PID controller equipment. Cardiac output and brain regional blood flows were measured by the colored microsphere technique. Systemic and brain regional hemodynamics and O2 supply, metabolic parameters and blood catecholamine concentrations were obtained under baseline conditions and at every 25th minute of the four different steady state stages. About 35 percent of the calculated total blood volume (cTBV) was withdrawn in order to reach the first stage of hemorrhagic hypotension. Further blood withdrawal of about 10 percent of the cTBV, about 5 percent of the cTBV, and about 3 percent of the cTBV were necessary to reach the other respective hypotensive stages. Gradual hemorrhagic hypotension led to an increasing reduction of the cardiac output at every hypotensive stage up to about 20 percent of the baseline value (p<0.05). This was accompanied by a concomitant increase of the total peripheral resistance to about 2.5 fold (p<0.05) and a huge increase in the blood catecholamine concentrations (epinephrine: about 64 fold; norepinephrine: about 35 fold). The induced redistribution of the circulating blood volume was shunted to the vital organs. Therefore, brain cortical blood flow was slightly increased at stage 1 and stage 2. A significant reduction of rCBF did not occur until stage 4 (p<0.05). Regional cerebrovascular resistance was concomitantly reduced at stage 1 and stage 2 (p<0.05) and thereafter again slightly elevated. Brain cortical oxygen consumption was maintained up to stage 2, reduced by about 20% at the next stage of hemorrhagic hypotension (p<0.05) and reached the lowest level of about 50% from baseline at stage 4 (p<0.05). Excellent accuracy and stability was shown at each stage for the external PID controller equipment, so that each given setpoint of the instantaneous mean arterial blood pressure was reached and stabilized even at the lowest hypotensive stage (stage 1: 59.53+/-0.23; stage 2: 50.03+/-0.56; stage 3: 39.18+/-1.75; stage 4: 35.28+/-0.45 mmHg (mean+/-SD)). We conclude that the experimental design presented, with an external PID controller to induce gradual hemorrhagic hypotension in newborn piglets is sufficient for producing functional states with changed systemic and cerebral features with high stability and accuracy, enabling a systematic study of disturbed regional hemodynamics and energy metabolism under steady state conditions even under critically changed states of the systemic cardiovascular regulation.

Animals↗

PubMed2003

Human haemoglobin: a new paradigm for oxygen binding involving two types of alphabeta contacts.

This review summarizes the most recent state of haemoglobin (Hb) research based on the literature and our own results. In particular, an attempt is made to form a unified picture for haemoglobin function by reconciling the cooperative oxygen binding with the stabilization of the bound dioxygen in aqueous solvent. The HbA molecule contains two types of alphabeta contacts. One type is the alpha1beta2 or alpha2beta1 contacts, called sliding contacts, and these are strongly associated with the cooperative binding of O2 to the alpha2beta2 tetramer. The other type is the alpha1beta1 or alpha2beta2 contacts, called packing contacts, but whose role in Hb function was not clear until quite recently. However, detailed pH-dependence studies of the autoxidation rate of HbO2 have revealed that the alpha1beta1 and alpha2beta2 interfaces are used for controlling the stability of the bound O2. When the alpha1beta1 or alpha2beta2 contact is formed, the beta chain is subjected to a conformational constraint which causes the distal (E7) histidine to be tilted slightly away from the bound dioxygen, preventing the proton-catalysed nucleophilic displacement of O2- from the FeO2 by an entering water molecule. This is one of the most characteristic features of HbO2 stability. Finally we discuss the role of the alpha1beta1 or alpha2beta2 contacts by providing some examples of unstable haemoglobin mutants. These pathological mutations are found mostly on the beta chain, especially in the alpha1beta1 contact regions. In this way, HbA seems to differentiate two types of alphabeta contacts for its functional properties.

Hemoglobins↗

PubMed2003

Treatment of advanced Parkinson's disease by subthalamotomy: one-year results.

We studied effects on parkinsonian features at 6 and 12 months in 12 patients who underwent unilateral ablation of subthalamic nucleus (STN). Microelectrode mapping was used, and a lesion was created in the STN using thermal coagulation and confirmed with magnetic resonance imaging. At 6 months postoperatively, improvements were seen in several areas: 1) Unified Parkinson's Disease Rating Scales II and III (UPDRS II and III) scores, 30% in off period, 38% in on period; 2) Schwab and England Scale (S&E) score, 21%; and 3) on dyskinesia, 85%. Contralateral rigidity, bradykinesia, UPDRS II and III scores, and S&E scores remained improved at 12 months. Daily dosage of levodopa requirement was reduced by 42%. Axial motor features, gait, postural stability, off period tremor, and motor fluctuation improved at 6 and 12 months but showed a decline in benefits at 18 months. Complications include 3 cases of hemiballism, of whom 2 patients recovered spontaneously but 1 died from aspiration pneumonia. One patient had asymptomatic hematoma, and 2 suffered transient postural asymmetries. We conclude that unilateral subthalamotomy results in moderate improvement in all aspects of parkinsonian features, allows reduction in the dose of levodopa required, and ameliorates drug-induced complications throughout 12-month assessments.

Adult↗

PubMed2005

Ultraviolet Rayleigh-Mie lidar by use of a multicavity Fabry-Perot filter for accurate temperature profiling of the troposphere.

A UV Rayleigh-Mie scattering lidar system at 355 nm has been upgraded for more-accurate temperature profiling of the troposphere by use of a new multicavity Fabry-Perot etalon (MCFPE) filter. The MCFPE filter, which was designed to improve the stability and operational characteristics of the lidar system, has three filter bandpass functions and separates one Mie scattering and two Rayleigh scattering signals from the lidar return signal and simultaneously acts as a laser frequency discriminator to lock the laser frequency. Moreover, a high-resolution grating is employed to block signal interference from Raman scattering and the solar background. A practical lidar system, which features strong system stabilization and high measurement accuracy, has been built, and the performance of the lidar system has been verified by comparison of temperature profiling between the lidar and a radiosonde. Good agreement between the two instrument measurements was obtained in terms of lapse rate and inversion layer height. Statistical temperature errors of less than 1 K up to a height of 3 km are obtainable with 5 min observation time for daytime measurements.

Journal Article↗

PubMed2002

Distinct dimer interaction and regulation in nitric-oxide synthase types I, II, and III.

Homodimer formation activates all nitric-oxide synthases (NOSs). It involves the interaction between two oxygenase domains (NOSoxy) that each bind heme and (6R)-tetrahydrobiopterin (H4B) and catalyze NO synthesis from L-Arg. Here we compared three NOSoxy isozymes regarding dimer strength, interface composition, and the ability of L-Arg and H4B to stabilize the dimer, promote its formation, and protect it from proteolysis. Urea dissociation studies indicated that the relative dimer strengths were NOSIIIoxy >> NOSIoxy > NOSIIoxy (endothelial NOSoxy (eNOSoxy) >> neuronal NOSOXY (nNOSoxy) > inducible NOSoxy (iNOSoxy)). Dimer strengths of the full-length NOSs had the same rank order as judged by their urea-induced loss of NO synthesis activity. NOSoxy dimers containing L-Arg plus H4B exhibited the greatest resistance to urea-induced dissociation followed by those containing either molecule and then by those containing neither. Analysis of crystallographic structures of eNOSoxy and iNOSoxy dimers showed more intersubunit contacts and buried surface area in the dimer interface of eNOSoxy than iNOSoxy, thus revealing a potential basis for their different stabilities. L-Arg plus H4B promoted dimerization of urea-generated iNOSoxy and nNOSoxy monomers, which otherwise was minimal in their absence, and also protected both dimers against trypsin proteolysis. In these respects, L-Arg alone was more effective than H4B alone for nNOSoxy, whereas for iNOSoxy the converse was true. The eNOSoxy dimer was insensitive to proteolysis under all conditions. Our results indicate that the three NOS isozymes, despite their general structural similarity, differ markedly in their strengths, interfaces, and in how L-Arg and H4B influence their formation and stability. These distinguishing features may provide a basis for selective control and likely help to regulate each NOS in its particular biologic milieu.

Amino Acid Sequence↗

PubMed1991

The three states of globular proteins: acid denaturation.

We describe statistical mechanical theory that aims to predict protein stabilities as a function of temperature, pH, and salt concentration, from the physical properties of the constituent amino acids: (1) the number of nonpolar groups, (2) the chain length, (3) the temperature-dependent free energy of transfer, (4) the pKa's (including those in the native state) and their temperature dependencies. We calculate here the phase diagrams for apomyoglobin and hypothetical variant proteins. The theory captures essential features of protein stability including myoglobin's Tm vs pH as measured by P. L. Privalov [(1979) Advances in Protein Chemistry, Vol. 33, pp. 167-241] and its ionic strength vs pH phase diagram as measured by Y. Goto and A. L. Fink [(1990) Journal of Molecular Biology, Vol. 214, pp. 803-805]. The main predictions here are the following: (1) There are three stable states, corresponding to native (N), compact denatured (C), and highly unfolded (U), with transitions between them. (2) In agreement with experiments, the compact denatured state is predicted to have enthalpy closer to U than N because even though there is considerable hydrophobic "clustering" in C, this nevertheless represents a major loss of hydrophobic contacts relative to configurations (N) that have a hydrophobic "core." (3) C becomes more prominent in the phase diagram with increasing nonpolar content or decreasing chain length, perhaps thus accounting for (a) why lysozyme and alpha-lactalbumin differ in their denatured states, and (b) why shortened Staph nuclease molecules are compact. (4) Of major importance for protein calorimetry is Privalov's observation that the enthalpy of folding, delta H (T, pH) is independent of pH. The theory accounts for this through the prediction that the main electrostatic contribution to stability is not enthalpic; the main contribution is the entropy, mainly due to the different distributions of protons and small ions in the native and denatured states.

Apoproteins↗

PubMed2004

[Central cable system--fully automatic, continuous distraction osteogenesis for the lengthening treatment of large bone defects].

Distraction osteogenesis involving bone transport enables the reconstruction of large bone defects. The main bone fragments are usually stablilised externally, an intermediate bone segment is separated and moved through the defect at a rate of about 1 mm/day. New high-quality bone is built up in the constantly enlarging osteotomy gap. A major problem associated with the method is the fact that the fixation pins are also moved over the same distance, and cut through the soft tissue, often resulting in painful pin tract infections and ugly scars. An automatic motorized bone transport system employing a single central cable now eliminates this problem. The system can be combined with any external fixateur, since the relevant implanted parts for bone transport are independent of the external stabilizer. The surgical procedure, which is easy on the patient, consists of bone segment separation, central cable fixation, and stabilisation of the main fragments, and requires the use of numerous special tools. The distraction itself results in significantly less soft tissue irritation and pain. Pin tract infections are rare, so that changeover to internal fixation after completion of bone transport carries little risk of infection. This article details the technical features of the stabilizing system and the transport and the control systems, and describes the clinical application in a patient.

Adult↗

PubMed2002

Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.

OBJECTIVE: Some of the statin-induced reduction in cardiac events in patients with atherosclerosis may be derived from mechanisms independent of lipid lowering. This study tested in nonhuman primates whether statins can influence inflammation (indicated by vascular cell adhesion molecule-1, interleukin-1beta, tissue factor, and macrophages) and features of plaque stability (indicated by collagen and smooth muscle cells) independent of their effect on plasma cholesterol level. METHODS AND RESULTS: Adult male cynomolgus monkeys (n=12 per group) consumed an atherogenic diet for 12 months while receiving (1) no treatment (control), (2) pravastatin (Prava, 40 mg/kg per day), or (3) simvastatin (Simva, 20 mg/kg per day). Dietary cholesterol was adjusted to equalize plasma cholesterol levels among groups. Although the intima/media ratio in the abdominal aorta did not differ among groups, drug treatment reduced inflammation and features of plaque vulnerability. Macrophage content in the lesions of statin-treated animals was lowered (2.4-fold with Prava and 1.3-fold with Simva; both P<0.001 versus control). Furthermore, lesions had approximately 2-fold less vascular cell adhesion molecule-1, interleukin-1beta, and tissue factor expression in statin-treated versus control animals (P<0.005). Lesional smooth muscle cell and collagen content was 2.1-fold greater in the Prava-treated group (P<0.001) and 1.5-fold greater in the Simva-treated group (P<0.005) than in the control group. CONCLUSIONS: In primates, these results provide further support for the beneficial effect of statins on plaque inflammation and stability in addition to cholesterol lowering.

Animals↗

PubMed2004

Peptaibol zervamicin IIb structure and dynamics refinement from transhydrogen bond J couplings.

Zervamicin IIB (Zrv-IIB) is a channel-forming peptaibol antibiotic of fungal origin. The measured transhydrogen bond (3h)J(NC') couplings in methanol solution heaving average value of -0.41 Hz indicate that the stability of the Zrv-IIB helix in this milieu is comparable to the stability of helices in globular proteins. The N-terminus of the peptide forms an alpha-helix, whereas 3(10)-helical hydrogen bonds stabilize the C-terminus. However, two weak transhydrogen bond peaks are observed in a long-range HNCO spectrum for HN Aib(12). Energy calculations using the Empirical Conformation Energy Program for Peptides (ECEPP)/2 force field and the implicit solvent model show that the middle of the peptide helix accommodates a bifurcated hydrogen bond that is simultaneously formed between HN Aib(12) and CO Leu(8) and CO Aib(9). Several lowered (3h)J(NC') on a polar face of the helix correlate with the conformational exchange process observed earlier and imply dynamic distortions of a hydrogen bond pattern with the predominant population of a properly folded helical structure. The refined structure of Zrv-IIB on the basis of the observed hydrogen bond pattern has a small ( approximately 20 degrees ) angle of helix bending that is virtually identical to the angle of bending in dodecylphosphocholine (DPC) micelles, indicating the stability of a hinge region in different environments. NMR parameters ((1)HN chemical shifts and transpeptide bond (1)J(NC') couplings) sensitive to hydrogen bonding along with the solvent accessible surface area of carbonyl oxygens indicate a large polar patch on the convex side of the helix formed by three exposed backbone carbonyls of Aib(7), Aib(9), and Hyp(10) and polar side chains of Hyp(10), Gln(11), and Hyp(13). The unique structural features, high helix stability and the enhanced polar patch, set apart Zrv-IIB from other peptaibols (for example, alamethicin) and possibly underlie its biological and physiological properties.

Hydrogen Bonding↗

PubMed2002

Characteristic features of symmetry breaking in two-component Bose-Einstein condensates.

We examine the stability properties of the ground state of two-component Bose-Einstein condensates as a function of the interspecies interactions. A stability criterion is identified from the curvature matrix of the Gross-Pitaevskii energy functional subject to the normalization conditions. By analyzing the stability signature, the characteristic features of the spontaneous spatial symmetry breaking are verified in various types of traps. The details of the differences between the continuous symmetry breaking and discrete symmetry breaking are discussed.

Journal Article↗

PubMed1999

Universally conserved positions in protein folds: reading evolutionary signals about stability, folding kinetics and function.

Here, we provide an analysis of molecular evolution of five of the most populated protein folds: immunoglobulin fold, oligonucleotide-binding fold, Rossman fold, alpha/beta plait, and TIM barrels. In order to distinguish between "historic", functional and structural reasons for amino acid conservations, we consider proteins that acquire the same fold and have no evident sequence homology. For each fold we identify positions that are conserved within each individual family and coincide when non-homologous proteins are structurally superimposed. As a baseline for statistical assessment we use the conservatism expected based on the solvent accessibility. The analysis is based on a new concept of "conservatism-of-conservatism". This approach allows us to identify the structural features that are stabilized in all proteins having a given fold, despite the fact that actual interactions that provide such stabilization may vary from protein to protein. Comparison with experimental data on thermodynamics, folding kinetics and function of the proteins reveals that such universally conserved clusters correspond to either: (i) super-sites (common location of active site in proteins having common tertiary structures but not function) or (ii) folding nuclei whose stability is an important determinant of folding rate, or both (in the case of Rossman fold). The analysis also helps to clarify the relation between folding and function that is apparent for some folds.

Amino Acid Sequence↗

PubMed2001

Anabaena apoflavodoxin hydrogen exchange: on the stable exchange core of the alpha/beta(21345) flavodoxin-like family.

An important issue in modern protein biophysics is whether structurally homologous proteins share common stability and/or folding features. Flavodoxin is an archetypal alpha/beta protein organized in three layers: a central beta-sheet (strand order 21345) flanked by helices 1 and 5 on one side and helices 2, 3, and 4 on the opposite side. The backbone internal dynamics of the apoflavodoxin from Anabaena is analyzed here by the hydrogen exchange method. The hydrogen exchange rates indicate that 46 amide protons, distributed throughout the structure of apoflavodoxin, exchange relatively slowly at pH 7.0 (k(ex) < 10(-1) min(-1)). According to their distribution in the structure, protein stability is highest on the beta-sheet, helix 4, and on the layer formed by helices 1 and 5. The exchange kinetics of Anabaena apoflavodoxin was compared with those of the apoflavodoxin from Azotobacter, with which it shares a 48% sequence identity, and with Che Y and cutinase, two other alpha/beta (21345) proteins with no significant sequence homology with flavodoxins. Both similarities and differences are observed in the cores of these proteins. It is of interest that a cluster of a few structurally equivalent residues in the central beta-strands and in helix 5 is common to the cores.

Amino Acid Sequence↗

PubMed2006

Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability.

Macrophages play a key role in atherosclerotic plaque destabilization and rupture. In this light, selective removal of macrophages may be beneficial for plaque stability. However, macrophages are phagocytic cells and thus have an important additional role in scavenging of modified lipoproteins, unwanted or dead cells and cellular debris via phagocytosis. The concept of phagocytosis as well as the underlying mechanisms is well defined but the effect of phagocytosis in terms of plaque stability remains poorly understood. Recent findings point towards a complex role of macrophage phagocytosis in atherogenesis. Macrophages are necessary for removal of apoptotic cells from plaques, but exert strong proatherogenic properties upon phagocytosis of lipoproteins, erythrocytes and platelets. Apart from heterophagy, autophagocytosis better known as autophagy may occur in advanced atherosclerotic plaques. Several lines of evidence indicate that autophagy is initiated in plaque smooth muscle cells as a result of cellular distress. Since autophagy is well recognized as a survival mechanism, autophagic smooth muscle cells in the fibrous cap may reflect an important feature underlying plaque stability. All together, phagocytosis is a crucial process involved in atherogenesis that may significantly affect the stability of the atherosclerotic plaque.

Animals↗

PubMed2004

Efficient three-dimensional metric object modeling from uncalibrated image sequences.

This paper presents a scheme that addresses the practical issues associated with producing a geometric model of a scene using a passive sensing technique. The proposed image-based scheme comprises a recursive structure recovery method and a recursive surface reconstruction technique. The former method employs a robust corner-tracking algorithm that copes with the appearance and disappearance of features and a corner-based structure and motion estimation algorithm that handles the inclusion and expiration of features. The novel formulation and dual extended Kalman filter computational framework of the estimation algorithm provide an efficient approach to metric structure recovery that does not require any prior knowledge about the camera or scene. The newly developed surface reconstruction technique employs a visibility constraint to iteratively refine and ultimately yield a triangulated surface that envelops the recovered scene structure and can produce views consistent with those of the original image sequence. Results on simulated data and synthetic and real imagery illustrate that the proposed scheme is robust, accurate, and has good numerical stability, even when features are repeatedly absent or their image locations are affected by extreme levels of noise.

Algorithms↗

PubMed2005

Prion and water: tight and dynamical hydration sites have a key role in structural stability.

The propensity to form fibril in disease-related proteins is a widely studied phenomenon, but its correlation, if any, with structural characteristics of the associated proteins is not clearly understood. However, the observation has been made that some proteins that readily form amyloid have a significant number of backbone H bonds that are exposed to solvent molecules, suggesting that these regions have a propensity toward protein interaction and aggregation [Fernandez, A. & Scheraga, H. A. (2003) Proc. Natl. Acad. Sci. USA 100, 113-118]. High-resolution x-ray structures of the sheep and human C-terminal prion protein have provided a useful description of surface and partially buried waters. By molecular dynamics simulations, we investigated the structural role of these water molecules. The solvent dynamical behavior on the protein surface reveals significant features about the stability and the potential interactions of the prion protein. The protein presents regions of tightly bound conserved waters that are necessary to hold in place local elements of the fold, as well as regions where the local water is in fast exchange with bulk water. These results are evidenced by a map of the spatial distribution entropy of the solvent around the protein. The particular behavior of the solvent around these regions may be crucial in the folding stability and in terms of aggregation loci.

Amyloid↗

PubMed2004

A comparison of siRNA efficacy predictors.

Short interfering RNA (siRNA) efficacy prediction algorithms aim to increase the probability of selecting target sites that are applicable for gene silencing by RNA interference. Many algorithms have been published recently, and they base their predictions on such different features as duplex stability, sequence characteristics, mRNA secondary structure, and target site uniqueness. We compare the performance of the algorithms on a collection of publicly available siRNAs. First, we show that our regularized genetic programming algorithm GPboost appears to have a higher and more stable performance than other algorithms on the collected datasets. Second, several algorithms gave close to random classification on unseen data, and only GPboost and three other algorithms have a reasonably high and stable performance on all parts of the dataset. Third, the results indicate that the siRNAs' sequence is sufficient input to siRNA efficacy algorithms, and that other features that have been suggested to be important may be indirectly captured by the sequence.

Algorithms↗