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PubMed2006

Nanocluster formation and stabilization fundamental studies: investigating "solvent-only" stabilization en route to discovering stabilization by the traditionally weakly coordinating anion BF4- plus high dielectric constant solvents.

The nanocluster literature contains a wide variety of nanocluster stabilizing agents. In addition to the plethora of putative stabilizing additives, 12 claims appear of "solvent-only" stabilization of transition-metal nanoclusters-a hypothesis that is tested for the first time as part of the present studies. When the two main modes of nanocluster stabilization, electrostatic and steric are considered, "solvent-only" stabilization can only be steric (i.e., is not electrostatic). Solvent-only stabilization would, therefore, require that a strongly coordinated, perhaps even kinetically nonlabile, solvent be present on the nanocluster surface. Hence, an investigation has been conducted into potential sources for the stabilization of prototype Ir(0)n transition-metal nanoclusters prepared from [(1,5-COD)Ir(CH3CN)2][BF4] in five different solvents, with a special focus on the formulation and testing of alternative hypotheses regarding the true source of the nanocluster stabilization in putative solvent-only stabilization conditions. Seven total hypotheses are tested with five being initially ruled out; they are, namely, stabilization by (i) trace chloride (ii), surface hydrides, (iii) scavenged charge, (iv) solvent oxidative addition reactions with the nanocluster surface, or (v) polymerized solvent. This led in turn to two additional main alternative hypotheses: (vi) nanocluster surface ligation by high-donor number solvents (i.e., in the absence of anions) and (vii) nanocluster stabilization by surface-coordination of the traditionally weakly coordinating anion BF(4-). Our results reveal a significant contribution to nanocluster stability from the traditionally weakly coordinating BF(4-) in high dielectric constant solvents, such as propylene carbonate. Literature claims of solvent-only nanocluster stabilization are not supported by our findings. Overall, DLVO (Derjaugin-Landau-Verwey-Overbeek) theory of colloidal stability is supported and found to apply to even traditionally weakly coordinating anions.

Journal Article↗

PubMed1990

Preparation and evaluation of sterically stabilized liposomes: colloidal stability, serum stability, macrophage uptake, and toxicity.

Sterically stabilized liposomes were produced by incorporating a nonionic surfactant, polysorbate 80 (Tween 80), into the lipid bilayer. The sterically stabilized liposomes exhibited a superior entrapment stability compared with surfactant-free liposomes (i.e., liposomes prepared with lipids and cholesterol). The sterically stabilized liposomes were stable at high calcium ion concentrations, and liposome-entrapped carboxyfluorescein was retained within the stabilized liposomes in the presence of serum for at least 5 h. The macrophage uptake of the sterically stabilized liposomes was comparable to that of liposomes containing lipids and cholesterol. The sterically stabilized liposomes were non-toxic, in concentrations up to 3.0 mM, to macrophages. These results indicate that polysorbate 80 can be used to produce stable liposomes without changing the unique macrophage distribution of this drug delivery system.

Cells, Cultured↗

PubMed2004

Enhanced photo-stability, thermal-stability and aqueous-stability of indocyanine green in polymeric nanoparticulate systems.

Photo-degradation, thermal-degradation and aqueous-instability of indocyanine green (ICG) limits its application as a fluorescence contrast agent for imaging purposes. Thus, the objective of this study is to develop polymeric nanoparticles entrapping ICG and to establish its effectiveness in providing photo-stability, thermal stability and aqueous stability to ICG. Nanoparticles entrapping ICG were engineered, characterized and the degradation kinetics of ICG in the nanoparticles was investigated in aqueous media. The entrapment of ICG in the nanoparticles causes a shift in its wavelength of peak fluorescence and a decrease in its peak fluorescence intensity. The degradation of ICG in aqueous nanoparticle suspension followed first-order kinetics for the time period studied. ICG entrapment in the nanoparticles enhanced aqueous-stability of ICG (half-life, t(1/2) was 72.2+/-6.1 h for ICG in the nanoparticles as compared to 16.8+/-1.5 h for free ICG solution), photo-stability of ICG (t(1/2) was 73.7+/-7.5 h for ICG in the nanoparticles as compared to 14.4+/-2.4 h for free ICG solution when exposed to room light from two 32 W normal fluorescent tubes) and thermal-stability of ICG (t(1/2) of ICG at 42 degrees C was 62.4+/-1.7 h for ICG in the nanoparticles as compared to 10.1+/-0.6 h for free ICG solution).

Chemical Phenomena↗

PubMed1992

Enzyme stability in downstream processing. Part 1: enzyme inactivation, stability and stabilization.

In biotechnological recovery processes the instability of the product can lead to large losses in the sequence of recovery processes needed to purify the product. As the cost of the final active product is strongly dependent on the recovery yield, this will lead to an increase in product cost. Therefore knowledge of factors that influence stability is important. This Part 1 contains a review on the factors that influence stability. As stability is very important in enzyme purification this review deals about enzymes and their ability to retain catalytic activity. Inactivation mechanisms and agents are discussed. A short review is given of enzyme structure and stability. This is followed by stabilization strategies and methods.

Journal Article↗

PubMed1976

Continuous Proteolysis with a stabilized stabilized protease. I. Chemical stabilization of an alkaline protease.

Due to the loss of enzymatic activity as a function of time, an alkaline protease, selected for the continuous preparation of protein hydrolysates (J. Boudrant and C. Cheftel, Biotechnol. Bioeng., 18,1735, 1976), was chemically stabilized by a simple treatment with glutaraldehyde. Two fractions, soluble and insoluble, were obtained. The activities of these two fractions were measured with casein and N-benzoyl-L-arginine ethyl ester (BAEE) as a function of glutaraldehyde concentration used. It was noted that the insoluble fraction was practically inactive with the first substrate and that the heat stability of the soluble form was likewise enhanced. Molecular weights of these two forms were unchanged, but the uv-spectrum of the soluble form was modified. From amino acid analysis, it appears that this treatment mainly provokes a decrease in lysine content.

Aldehydes↗

PubMed2006

A test of the transition-metal nanocluster formation and stabilization ability of the most common polymeric stabilizer, poly(vinylpyrrolidone), as well as four other polymeric protectants.

Following an introduction to the nanocluster stabilization literature and DLVO (Derjaugin-Landau-Verwey-Overbeek) theory of colloidal stability, the most common steric stabilizer of transition-metal nanoclusters, poly(vinylpyrrolidone) (PVP), has been examined for its efficacy in the formation, stabilization, and subsequent catalytic activity of prototype, test case Ir(0)n nanoclusters. First, the five criteria established previously for ranking nanocluster protectants for their nanocluster formation and stabilization ability were evaluated for 1 monomer equiv of 10000 average molecular weight (MWav) PVP in the absence, and then presence, of the traditionally weakly coordinating anion BF4- as well as the absence and presence of the strongly coordinating, superior anionic stabilizer P2W15Nb3O62(9-), all in propylene carbonate solvent. It is found that neither 1 equiv of BF4- in propylene carbonate nor 1 monomer equiv of (undried) PVP alone allows for isolable and redissolvable nanoclusters without bulk Ir(0)n metal formation. Careful predrying of the PVP, and by implication other polymers, is shown to be necessary for the formation and stabilization of the nanoclusters. Next, 40 monomer equiv of 10000 MWav PVP and 1 equiv of BF4- in propylene carbonate are shown to allow isolable, redissolvable nanoclusters. Control experiments reveal little difference on nanocluster stabilization by 3500 or 55000 (i.e., vs 10,000) MWav PVP, but yield interesting effects on nanocluster nucleation by the 3500 MWav PVP, as well as by the polymer poly(bis(ethoxy)phosphazene) (PBEP). Four other key polymers reported in the literature to be nanocluster stabilizers are tested by the five criteria method for their efficacy in the formation and stabilization of Ir0n nanoclusters (now in acetone due to the polymers' solubility) and in comparison to each other, specifically, poly(methyl methacrylate) (PMMA), poly(styrene) (PS), poly(methylhydrosilane) (PMHS), and PBEP. Only 40 monomer equiv dried PMMA allows isolable and redissolvable nanoclusters in acetone. Control/reference point experiments show that the electrostatic stabilizer P2W15Nb3O62(9-) is superior to each of the five polymeric stabilizers studied herein in both acetone and propylene carbonate, at least for the test case of Ir(0)n nanoclusters. Further controls show that 40 monomer equiv of PVP added to P2W15Nb3O(62)9--stabilized nanoclusters has no discernible effect on the five criteria other than to reduce by approximately 50% the nanocluster catalytic activity and total catalytic lifetime for cyclohexene hydrogenation. The main finding of this work is that DLVO theory as applied to nanocluster stabilization is fully supported; that is, surface-bound anions in high dielectric constant solvents provide superior stabilization. The importance of even traditionally weakly coordinating anions such as BF4- in nanocluster stabilization is a second, important finding of this work. The fact that HPO4(2-) has been shown to be a simple, cheap, commercially available, thermally robust, and 31P-NMR-handle-containing analogue of the more esoteric P2W15Nb3O62(9-) stabilizer is also discussed in the 14 total Conclusions from this first study ranking polymeric stabilizers of modern transition-metal nanoclusters.

Journal Article↗

PubMed2001

Global stability, local stability and permanence in model food webs.

The dynamical theory of food webs has been based typically on local stability analysis. The relevance of local stability to food web properties has been questioned because local stability holds only in the immediate vicinity of the equilibrium and provides no information about the size of the basin of attraction. Local stability does not guarantee persistence of food webs in stochastic environments. Moreover, local stability excludes more complex dynamics such as periodic and chaotic behaviors, which may allow persistence. Global stability and permanence could be better criteria of community persistence. Our simulation analysis suggests that these three stability measures are qualitatively consistent in that all three predict decreasing stability with increasing complexity. Some new predictions on how stability depends on food web configurations are generated here: a consumer-victim link has a smaller effect on the probabilities of stability, as measured by all three stability criteria, than a pair of recipient-controlled and donor-controlled links; a recipient-controlled link has a larger effect on the probabilities of local stability and permanence than a donor-controlled link, while they have the same effect on the probability of global stability; food webs with equal proportions of donor-controlled and recipient-controlled links are less stable than those with different proportions.

Animals↗

PubMed1993

Step-wise mutation of barnase to binase. A procedure for engineering increased stability of proteins and an experimental analysis of the evolution of protein stability.

We have chosen two members of the microbial RNase family, barnase and binase, which have 85% identity (17 substitutions and 1 deletion) and almost identical three-dimensional structure, to study the evolution of protein stability. The 17 residues that differ are scattered throughout the molecule. Each of the 17 differing residues has been mutated independently and the effect on protein stability analysed. Each point mutation has an effect on protein stability that ranges from +1.1 to -1.1 kcal mol-1. These changes in energy are additive. There is no clear correlation between the type of mutation and the effect on protein stability. A multiple mutant having six of the single mutations that increase the stability of barnase is 3.3 kcal mol-1 more stable than wild type and has the same activity. There could be selective pressure to maintain proteins at a certain stability and, consequently, mutations that decrease stability tend to be counterbalanced by stabilizing mutations. Alternatively, there could simply be pressure to maintain stability above a certain level, and any further increases in stability need not be maintained during evolution. These results suggest a simple way to improve the stability of proteins: choose two homologous proteins that have high similarity, mutate individually all of the residues that differ between the two, and combine the mutations that increase the stability in a multiple mutant.

Amino Acid Sequence↗

PubMed2001

Stabilizing mutations and calcium-dependent stability of subtilisin.

Stability is a property of subtilisin which has proven particularly amenable to enhancement via random mutagenesis and screening, yet the effects of most stabilizing mutations are not understood in structural and energetic detail. This paper seeks to explain the longstanding observation that stabilizing mutations are usually calcium-dependent in their stabilizing effect, irrespective of their proximity to the calcium binding sites. Stabilizing mutations in subtilisin fall into one of three classes. The largest class of mutations stabilize only in the presence of excess calcium. A smaller number of mutations stabilize independently of [calcium], and a few mutations stabilize only in the presence of chelating agents, such as EDTA. This study compares the effects of mutations from each class when introduced into subtilisin BPN' and two calcium-free versions of subtilisin. The calcium-dependent effects of mutations can be explained by considering subtilisin to be in conformational equilibrium between two structurally similar but energetically distinct states: N and N*. The equilibrium from the N* to the N state can be altered either by calcium binding to site A or by mutation. Mutations which stabilize only in the presence of calcium stabilize the N state relative to N*. Mutations which stabilize only in the presence of chelants stabilize the N* state relative to N. As a byproduct of this analysis, we have developed a hyperstable variant of subtilisin whose inactivation at high temperature in the presence of EDTA is 10(5) times slower than wild-type subtilisin.

Bacillus↗

PubMed2005

Effect of sorbitol and residual moisture on the stability of lyophilized antibodies: Implications for the mechanism of protein stabilization in the solid state.

PURPOSE: To investigate the effect of plasticizers on the stability of protein formulations in the solid state and to apply these results to a study of mechanisms of protein stabilization by sugars in the solid sate. METHODS: The IgG1 antibody was formulated with either sucrose or trehalose alone or a mixture of sorbitol with sucrose or trehalose. After lyophilization, the pure protein and sucrose formulations were equilibrated at different relative humidities giving residual moistures from less than 1% to 5% for sucrose systems and up to 17% for pure protein systems. All the samples were stored at 50 degrees C for up to1 month and at 40 and 25 degrees C for up to 6 months. Aggregation and chemical degradation were monitored by size exclusion chromatography (SEC) and ion exchange chromatography (IEX), respectively. The secondary structure was characterized by FTIR using second derivative analysis of Amide I region. Structural relaxation times, tau, an indication of molecular mobility in the glassy matrix, were characterized using the thermal activity monitor (TAM). The tau values of the recombinant human monoclonal antibody (rhuMab) formulation with various water contents were also measured in this study and compared with stability data taken from the literature (Breen ED, Curley JG, Overcashier DE, Hsu CC, Shire SJ, 2001, Pharm Res 18:1345-1353). RESULTS: The structural relaxation time, tau, decreased sharply with increasing water content. However, the stability data suggest a minimum in degradation rate at 2%-3% water content. Addition of a small amount of sorbitol to a sucrose-based formulation resulted in greater retention of native structure, smaller relaxation time, but improved stability. However, with the trehalose-based formulations, addition of sorbitol had no effect on protein structure (FTIR), but the decrease in relaxation time and the improvement in stability were qualitatively similar to the corresponding data obtained with the sucrose-based formulation. CONCLUSION: Glass dynamics as measured by tau could not explain the stability results. Stability correlated best with the preservation of native structure for sucrose-based formulations, but with the trehalose-based formulation, neither structural relaxation time nor extent of native structure was predictive of stability. However, it is possible that the beta-relaxations rather than the alpha-relaxation (i.e., the tau we measured) is critical to the stability. Plasticizers like glycerol may decrease tau for "alpha-motion" but increase tau for "beta-motion" and stabilize proteins (Cicerone MT, Tellington A, Trost L, Sokolov A, 2003, BioProcess Inter 1:1-9).

Absorption↗

PubMed2004

Acute renal failure and intravenous immune globulin: occurs with sucrose-stabilized, but not with D-sorbitol-stabilized, formulation.

OBJECTIVE: To report 2 cases of acute renal failure (ARF) following administration of sucrose-stabilized intravenous immune globulin (IVIG), one of which did not recur following subsequent doses of d-sorbitol-stabilized formulation, and review the relevant literature. CASE SUMMARIES: A 44-year-old white man awaiting heart transplantation developed ARF requiring hemodialysis following administration of sucrose-stabilized IVIG for high alloreactivity to population human leukocyte antigens. Following a return of renal function to baseline, subsequent doses of d-sorbitol-stabilized IVIG were administered without incident. A 90-year-old white man developed ARF after administration of sucrose-stabilized IVIG for monoclonal gammopathy. Renal function returned to baseline, and no subsequent IVIG doses were administered. An objective causality assessment revealed that sucrose-stabilized IVIG was the probable cause of the adverse drug event for both cases. DISCUSSION: Several case reports of ARF secondary to IVIG have been published. Recent publications note that sucrose-stabilized IVIG products have a disproportionately high rate of ARF occurrence (approximately 88%) versus non-sucrose-stabilized formulations. Recent market data for IVIG products indicate that sucrose-stabilized products account for approximately 40% of the total IVIG market. When administered intravenously, sucrose is excreted unchanged in the urine. ARF has been reported in patients receiving large doses of intravenous sucrose. CONCLUSIONS: ARF secondary to IVIG may be more likely to occur with sucrose-stabilized formulations. Before prescribing IVIG, clinicians should consider other nephrotoxic medications, preexisting renal function, age, diabetes mellitus, and rate of infusion. In patients at risk, it may be best to avoid sucrose-stabilized formulations.

Acute Kidney Injury↗

PubMed2002

Nanocluster formation and stabilization fundamental studies: ranking commonly employed anionic stabilizers via the development, then application, of five comparative criteria.

To start, a brief introduction is provided on the importance of transition-metal nanoclusters, on the need to develop and then apply methods to rank the nanocluster formation and then stabilizing abilities of commonly employed anions, solvents, cations, and polymers, and on the somewhat confused literature of nanocluster stabilization. The fundamental importance of surface-adsorbed anions in transition-metal nanocluster stabilization is noted, the reason the present studies begin with a study of nanocluster-stabilizing anions. Next, five criteria, as well as the associated experimental methods, are developed to evaluate the efficacy of nanocluster stabilizing agents. The criteria are of fundamental significance in that they allow the separation of stabilizing agent effects on nanocluster formation from those on nanocluster stabilization. The results from applying the five criteria to four commonly employed anions lead to the first "anion series" of relative nanocluster-formation and stabilizing abilities, at least for the Ir(0) nanoclusters examined and by the following five criteria: [(P(2)W(15)Nb(3)O(61))(2)O](16-) (a Brphinsted-basic polyoxoanion) > C(6)H(5)O(7)(3-) (citrate trianion) > [-CH(2)-CH(CO(2))-](n)(n-) (polyacrylate) approximately Cl(-). In addition to the needed methods and the first anion series, six other (8 total) conclusions are reached, important insights in an area previously lacking hard information about which anions are the better choices for nanocluster formation and stabilization. The results are also of significance in establishing polyoxoanions, notably highly charged and basic polyoxoanions such as [(P(2)W(15)Nb(3)O(61))(2)O](16)(-), as the present "Gold Standards" among currently known nanocluster stabilizing anions, and according to the above five criteria. Such standards provide a reference point for future work aspiring to develop even better nanocluster stabilizing anions, solvents, cations, and polymers or their combinations.

Journal Article↗

PubMed1993

Study on the stability of 17D-204 yellow fever vaccine before and after stabilization.

To monitor the parameters controlling yellow fever vaccine production, eight different lots produced without stabilizers were studied. It was found that the freeze-thaw cycle did not have any adverse effect on virus infectivity and the mean loss in virus titre during lyophilization was 0.51 log10 ml-1. A thermodegradation study after storage of vaccine at different temperatures showed that the vaccine did not pass the accelerated stability test. To stabilize the 17D-204 substrain vaccine, four stabilizers with different sugars and amino acids were examined. The optimum time for addition of the stabilizers was found to be during homogenization of infected embryos. An accelerated stability test at 37 degrees C indicated that stabilizers S1, S2 and S3 kept the vaccine stable for up to 4 weeks, whereas the vaccine was only stable for up to 3 weeks in stabilizer S4. Stabilizer S3 was found statistically to be the best. Reproducibility in production methodology was established by preparing and testing more batches of the vaccine using stabilizer S3.

Animals↗

PubMed2003

Evolutionary stabilization of the gene-3-protein of phage fd reveals the principles that govern the thermodynamic stability of two-domain proteins.

The gene-3-protein (G3P) of filamentous phage is essential for their propagation. It consists of three domains. The CT domain anchors G3P in the phage coat, the N2 domain binds to the F pilus of Escherichia coli and thus initiates infection, and the N1 domain continues by interacting with the TolA receptor. Phage are thus only infective when the three domains of G3P are tightly linked, and this requirement is exploited by Proside, an in vitro selection method for proteins with increased stability. In Proside, a repertoire of variants of the protein to be stabilized is inserted between the N2 and the CT domains of G3P. Stabilized variants can be selected because they resist cleavage by a protease and thus maintain the essential linkage between the domains. The method is limited by the proteolytic stability of G3P itself. We improved the stability of G3P by subjecting the phage without a guest protein to rounds of random in vivo mutagenesis and proteolytic Proside selections. Variants of G3P with one to four mutations were selected, and the temperature at which the corresponding phage became accessible for a protease increased in a stepwise manner from 40 degrees C to almost 60 degrees C. The N1-N2 fragments of wild-type gene-3-protein and of the four selected variants were purified and their stabilities towards thermal and denaturant-induced unfolding were determined. In the biphasic transitions of these proteins domain dissociation and unfolding of N2 occur in a concerted reaction in the first step, followed by the independent unfolding of domain N1 in the second step. N2 is thus less stable than N1, and it unfolds when the interactions with N1 are broken. The strongest stabilizations were caused by mutations in domain N2, in particular in its hinge subdomain, which provides many stabilizing interactions between the N1 and N2 domains. These results reveal how the individual domains and their assembly contribute to the overall stability of two-domain proteins and how mutations are optimally placed to improve the stability of such proteins.

Calorimetry↗

PubMed2001

Synthesis, characterization, solution stability, and X-ray crystal structure of the thiolatocobalamin gamma-glutamylcysteinylcobalamin, a dipeptide analogue of glutathionylcobalamin: insights into the enhanced Co-S bond stability of the natural product glutathionylcobalamin.

Glutathionylcobalamin (gamma-glutamylcysteinylglycinylcobalamin; gamma-GluCysGly-Cbl) is a natural product which functions as an intermediate in the biosynthesis of the active B(12) coenzymes adenosylcobalamin and methylcobalamin. Of interest to the present studies is glutathionylcobalamin's unique stability in comparison to other thiolatocobalamins, notably the > or =6 x 10(4) fold less stable cysteinylcobalamin, Cys-Cbl. In order to determine which parts of the glutathione tripeptide contribute to the overall stability of glutathionylcobalamin, two cysteine-containing dipeptides, which are truncated versions of glutathione, were used to synthesize their corresponding cobalamins, specifically gamma-glutamylcysteinylCbl (gamma-GluCys-Cbl) and cysteinylglycinylcobalamin (CysGly-Cbl). As with glutathionylCbl, the dipeptide gamma-GluCys-Cbl forms a stable thiolatocobalamin. However and most interestingly, CysGly-Cbl is observed to be unstable much like Cys-Cbl. The results require that the extra stability of glutathionylcobalamin and its congeners, compared to cysteinylcobalamin and its analogues, must be derived from destabilization by the gamma-NH(3)(+) group in cysteinylcobalamin, or stabilization by the gamma-NHC(=O)- amide linkage in glutathionylcobalamin, or both. To probe any ground-state structural basis for the possible stabilization in gamma-GluCys-containing cobalamins, gamma-GluCys-Cbl was crystallized and yielded the first X-ray structural determination of a true thiolatocobalamin, and only the second structure of a cobalamin containing a Co-S bond, the first example being Randaccio and co-workers' 1999 structure of the thioketone complex, thioureacobalamin, (NH(2))(2)CSCbl. Key features of the structure of gamma-glutamylcysteinylcobalamin include (i) a normal Co-S bond length of 2.267(2) A, (ii) a Co-N(axial) bond length of 2.049(6) A, (iii) two alternate conformations of the gamma-glutamylcysteinyl moiety, and (iv) folding of the corrin ring upward by 24.2 degrees, the highest degree of folding yet observed for a cobalamin. These results do not show any strong stabilization (e.g., no shortened Co-S bond), although it is not clear for certain what the effect is (stabilizing or destabilizing) of the elongated Co-N(axial) bond; instead, the crystallographic results suggest that the metastable Cys-Cbl probably has a Co-S cleavage transition state that is stabilized (along with, possibly, any ground-state destabilization of the Co-S bond). Overall, the results strongly suggest that placing a positive charge on the gamma-NH(3)(+) stabilizes the Co-S bond cleavage transition state, thereby setting the stage for the needed full thermolysis product and kinetic studies-as a function of the axial-base on-off equilibrium-that will be required to understand in even greater detail the unique stability of glutathionyl- (gamma-glutamylcysteinylglycinyl-) and gamma-glutamylcysteinylcobalamins.

Cobalt↗

PubMed2004

Quantifying tissue loads and spine stability while performing commonly prescribed low back stabilization exercises.

STUDY DESIGN: A quantitative biomechanical comparison of seven different lumbar spine "stabilization exercises." OBJECTIVES: The purpose of this research was to quantify lumbar spine stability resulting from the muscle activation patterns measured when performing selected stabilization exercises. SUMMARY OF BACKGROUND DATA: Many exercises are termed "stabilization exercises" for the low back; however, limited attempts have been made to quantify spine stability and the resultant tissue loading. Ranking resultant stability together with spinal load is very helpful for guiding clinical decision-making and therapeutic exercise design. METHODS: Eight stabilization exercises were quantified in this study. Spine kinematics, external forces, and 14 channels of torso EMG were recorded for each exercise. These data were input into a modified version of a lumbar spine model described by Cholewicki and McGill (1996) to quantify stability and L4-L5 compression. RESULTS: A rank order of the various exercises was produced based on stability, muscle activation levels, and lumbar compression. CONCLUSIONS: Quantification of the calibrated muscle activation levels together with low back compression and resultant stability assists clinical decisions regarding the most appropriate exercise for specific patients and specific objectives.

Adult↗

PubMed1995

VEGF mRNA is reversibly stabilized by hypoxia and persistently stabilized in VEGF-overexpressing human tumor cell lines.

Solid tumor growth is dependent upon angiogenesis, a process by which soluble factors released from a tumor induce the sprouting and growth of new blood vessels from nearby venules into the tumor. This process of tumor vascularization provides tumor cells with nutrients, oxygen, and an enhanced ability to establish metastasis at peripheral sites by migration through the circulatory system. Vascular endothelial growth factor is a potent angiogenic factor that is expressed at low levels by most normal cells, can be upregulated in normal cells by exposure to hypoxia or phorbol esters, and exhibits high levels of constitutive expression in some human tumors and tumor cell lines. The mechanism underlying the stable change that results in VEGF overexpression in tumors is unknown. Here, we demonstrate that both hypoxia and TPA induce stabilization of VEGF mRNA, that stabilization by hypoxia is rapidly reversible upon reexposure to normoxia, and that tumor cell lines exhibiting constitutive overexpression of VEGF also exhibit constitutive stabilization of VEGF transcripts. Stabilized VEGF transcripts in tumor cells are refractile or nearly refractile toward further stabilization by TPA or hypoxia, respectively. Furthermore, cycloheximide induces stabilization of VEGF mRNA in normal cells but has no effect on VEGF transcript stability in tumor cells that contain stabilized transcripts. These results suggest that normal signal transduction mechanisms mediate stabilization of the VEGF mRNA, and that mutations in this regulatory pathway in tumor cells may lead to chronic message stabilization, overexpression of VEGF proteins, and ensuing tumor vascularization.

Animals↗

PubMed1996

Stabilization of human triosephosphate isomerase by improvement of the stability of individual alpha-helices in dimeric as well as monomeric forms of the protein.

Human triosephosphate isomerase (hTIM) is a dimeric enzyme of identical subunits, adopting the alpha/beta-barrel fold. In a previous work, a monomeric mutant of hTIM was engineered in which Met14 and Arg98, two interface residues, were changed to glutamine. Analysis of equilibrium denaturation of this monomeric mutant, named M14Q/R98Q, revealed that its conformational stability, 2.5kcal/mol, is low as compared to the stability of dimeric hTIM (19.3 kcal/mol). The fact that this value is also lower than the conformational stabilities usually found for monomeric proteins suggests that the hTIM monomers are thermodynamically unstable. In the present work, we attempted to stabilize the M14Q/R98Q mutant by introducing stabilizing mutations in alpha-helices of the protein. Five mutations were proposed, designed to increase alpha-helix propensity by introducing alanines at solvent-exposed sites (Q179A, K193A), to introduce favorable interactions with helix dipoles (Q179D, S105D), or to reduce the conformational entropy of unfolding by introducing proline residues at the "N-cap" position of alpha-helices (A215P). Three replacements (Q179D, K193A, and A215P) were found to increase the stability of the native dimeric hTIM and the monomeric M14Q/R98Q. These results suggest that the monomeric hTIM mutant can be stabilized to a considerable extent by following well-established rules for protein stabilization. A comparison of the stabilizing effect performed by the mutations on the dimeric hTIM and the monomeric M14Q/R98Q allowed us to reinforce a model of equilibrium denaturation proposed for both proteins.

Amino Acid Sequence↗