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PubMed1991

Metabolic stabilization of endplate acetylcholine receptors regulated by Ca2+ influx associated with muscle activity.

During formation of the neuromuscular junction, acetylcholine receptors in the endplate membrane become metabolically stabilized under neural control, their half-life increasing from about 1 day to about 10 days. The metabolic stability of the receptors is regulated by the electrical activity induced in the muscle by innervation. We report here that metabolic stabilization of endplate receptors but not of extrajunctional receptors can be induced in the absence of muscle activity if muscles are treated with the calcium ionophore A23187. Acetylcholine receptor stabilization was also induced by culturing non-stimulated muscle in elevated K+ with the Ca2+ channel activator (+)-SDZ202-791. Conversely, activity-dependent receptor stabilization is prevented in muscle stimulated in the presence of the Ca2+ channel blockers (+)-PN200-110 or D-600. Treatment of muscles with ryanodine, which induces Ca2+ release from the sarcoplasmic reticulum in the absence of activity, does not cause stabilization of junctional receptors. Evidently, muscle activity induces metabolic acetylcholine receptor stabilization by way of an influx of Ca2+ ions through dihydropyridine-sensitive Ca2+ channels in the endplate membrane, whereas Ca2+ released from the sarcoplasmic reticulum is ineffective in this developmental process.

Animals↗
PubMed1995

Human melanoma integrins contribute to arrest and stabilization potential while flowing over extracellular matrix.

To form distant metastases, tumour cells must stabilize adhesive interactions that prevent detachment at secondary sites. Primary receptor-ligand interactions alone may not maintain prolonged adhesive contacts without secondary events that lead to adhesion stabilization. Computerized imaging methods enable us to examine various substrates for: (i) the wall shear adhesion threshold (WSAT), a measure of the dynamic adhesive potential of tumour cells; (ii) the number of tumour cells that adhered; and (iii) the adhesion stabilization lag time (ASLT) or length of time required for tumour cells to stabilize adhesive contacts capable of withstanding high wall shear force (up to 100 dynes/cm2). The relative WSAT ratios found were: wheat germ agglutinin (WGA) > laminin > fibronectin > vitronectin > collagen I > collagen IV > von Willebrand factor (vWF) (the greater the shear rate the higher the adhesive potential). The relative stabilization ratios found were as follows: laminin < fibronectin < vitronectin < collagen IV < collagen I < vWF < WGA (shorter times correlate with greater stabilization potential). Stabilization data using fibronectin as a substrate correlated the best with metastatic potential. Using three melanoma lines of different metastatic potential semiquantitative reverse transcriptase-polymerase chain reaction (PCR) showed a two- to four-fold increase in alpha1, alpha3, alpha4, alpha5, alpha6, and ICAM-1 in the highly metastatic 70W cells compared to the MeWo and non-metastatic 3S5 melanoma cells. There were no differences in alphav, beta1 and beta3 levels among the three melanoma lines, and PCR products for alphaIIb, alpha2, CD36, or ICAM-2 were not detected. The 70W cells also had higher levels of alphax and beta2 (CD11/CD18 and p150 leukocyte antigen) than either the MeWo or 3S5 cells. The data indicate that melanoma cells exhibit differences in the adhesion properties under fluid shear and differences in the expression of adhesion components that correlate with their metastatic potential.

Base Sequence↗
PubMed2005

Long-term relationships between ecological stability and biodiversity in Phanerozoic reefs.

High biodiversity has been shown to enhance ecological stability on small spatial scales and over intervals of weeks to decades. It remains unclear, however, whether this diversity-stability relationship can be scaled up to regional scales, or to longer timescales. Without empirical validation at larger scales, the implications of the diversity-stability relationship for both ecology and long-term conservation strategies cannot readily be resolved. Here I show that in biogenic reefs, ecological stability is related to taxonomic diversity on million-year timescales. The higher the mean reef diversity in a particular time interval, the smaller the change in skeletal density, style of reef building and biotic reef types in the subsequent time interval. Because the relationships apply to a wide spectrum of disturbance regimes and reef types, these results support the hypothesis that species richness itself promotes ecological stability. Carbonate production by reefs, while closely correlated with reef diversity without temporal lag, is not stabilized by reef diversity over these long timescales. This suggests that ecological stability and productivity may be decoupled in natural ecosystems.

Animals↗
PubMed2006

Biodiversity and ecosystem stability in a decade-long grassland experiment.

Human-driven ecosystem simplification has highlighted questions about how the number of species in an ecosystem influences its functioning. Although biodiversity is now known to affect ecosystem productivity, its effects on stability are debated. Here we present a long-term experimental field test of the diversity-stability hypothesis. During a decade of data collection in an experiment that directly controlled the number of perennial prairie species, growing-season climate varied considerably, causing year-to-year variation in abundances of plant species and in ecosystem productivity. We found that greater numbers of plant species led to greater temporal stability of ecosystem annual aboveground plant production. In particular, the decadal temporal stability of the ecosystem, whether measured with intervals of two, five or ten years, was significantly greater at higher plant diversity and tended to increase as plots matured. Ecosystem stability was also positively dependent on root mass, which is a measure of perenniating biomass. Temporal stability of the ecosystem increased with diversity, despite a lower temporal stability of individual species, because of both portfolio (statistical averaging) and overyielding effects. However, we found no evidence of a covariance effect. Our results indicate that the reliable, efficient and sustainable supply of some foods (for example, livestock fodder), biofuels and ecosystem services can be enhanced by the use of biodiversity.

Biodiversity↗
PubMed2001

Quantitative protein stability measurement in vivo.

The equilibrium between the native and denatured states of a protein can be key to its function and regulation. Traditionally, the folding equilibrium constant has been measured in vitro using purified protein and simple buffers. However, the biological environment of proteins can differ from these in vitro conditions in ways that could significantly perturb stability. Here, we present the first quantitative comparison between the stability of a protein in vitro and in the cytoplasm of Escherichia coli using amide hydrogen exchange detected by MALDI mass spectrometry (SUPREX). The results indicate that the thermodynamic stability of monomeric lambda repressor within the cell is the same as its stability measured in a simple buffer in vitro. However, when the E. coli are placed in a hyperosmotic environment, the in vivo stability is greatly enhanced. The in vivo SUPREX method provides a general and quantitative way to measure protein stabilities in the cell and will be useful for applications where intracellular stability information provides important biological insights.

Escherichia coli↗
PubMed2006

Role of nucleotides and phosphoinositides in the stability of electron and proton currents associated with the phagocytic NADPH oxidase.

The phagocytic NADPH oxidase (phox) moves electrons across cell membranes to kill microbes. The activity of this lethal enzyme is tightly regulated, but the mechanisms that control phox inactivation are poorly understood for lack of appropriate assays. The phox generates measurable electron currents, I(e), that are associated with inward proton currents, I(H). To study the inactivation of the phox and of its associated proton channel, we determined which soluble factors can stabilize I(e) (induced by the addition of NADPH) and I(H) (initiated by small depolarizing voltage steps) in inside-out patches from PMA-activated human eosinophils. I(e) decayed rapidly in the absence of nucleotides (tau approximately 6 min) and was maximally stabilized by the combined addition of 5 mM ATP and 50 microM of the non-hydrolysable GTP analogue GTP[S] (guanosine 5'-[gamma-thio]triphosphate) (tau approximately 57 min), but not by either ATP or GTP[S] alone. I(H) also decayed rapidly and was stabilized by the ATP/GTP[S] mixture, but maximal stabilization of I(H) required further addition of 25 muM PI(3,4)P2 (phosphoinositide 3,4-bisphosphate) to the cytosolic side of the patch. PI(3,4)P2 had no effect on I(e) and its stabilizing effect on I(H) could not be mimicked by other phosphoinositides. Reducing the ATP concentration below millimolar levels decreased I(H) stability, an effect that was not prevented by phosphatase inhibitors but by the non-hydrolysable ATP analogue ATP[S] (adenosine 5'-[gamma-thio]triphosphate). Our data indicate that the assembled phox complex is very stable in eosinophil membranes if both ATP and GTP[S] are present, but inactivates within minutes if one of the nucleotides is removed. Stabilization of the phox-associated proton channel in a highly voltage-sensitive conformation does not appear to involve phosphorylation but ATP binding, and requires not only ATP and GTP[S] but also PI(3,4)P2, a protein known to anchor the cytosolic phox subunit p47(phox) to the plasma membrane.

Adenosine Triphosphate↗
PubMed1990

Alkaline serine proteinase from Thermomonospora fusca YX. Stability to heat and denaturants.

The serine proteinase isolated from Thermomonospora fusca YX shows considerable thermal stability up to 80 degrees C, and progressive inactivation occurs at higher temperatures. Lyotropic salts affected the thermal stability of the enzyme at 85 degrees C, suggesting that disruption of hydrophobic interactions play an important role in the decreased thermal stability of the enzyme above 80 degrees C. Thermal stability is highly pH-dependent; above pH 6.0-6.5 there is a sharp decrease in the stability of the enzyme, reflecting increased autolysis. Although some stabilization occurs upon increasing ionic strength, Ca2+ binding does not appear to play a role in thermal stability. Denaturants, i.e. 8 M-urea, 6 M-guanidinium chloride or 1% SDS, had no significant effect on the activity of the enzyme after 24 h at 25 degrees C.

Acetates↗
PubMed2000

Influences of length and syntactic complexity on the speech motor stability of the fluent speech of adults who stutter.

The purpose of the present study was to investigate the impact of utterance length and syntactic complexity on the speech motor stability of adults who stutter. Lower lip movement was recorded from 8 adults who stutter and 8 normally fluent controls. They produced a target phrase in isolation (baseline condition) and the same phrase embedded in utterances of increased length and/or increased syntactic complexity. The spatiotemporal index (STI) was used to quantify the stability of lower lip movements across multiple repetitions of the target phrase. Results indicated: (a) Adults who stutter demonstrated higher overall STI values than normally fluent adults across all experimental conditions, indicating decreased speech motor stability; (b) the speech motor stability of normally fluent adults was not affected by increasing syntactic complexity, but the speech motor stability of adults who stutter decreased when the stimuli were more complex; (c) increasing the length of the target utterance (without increasing syntactic complexity) did not affect the speech motor stability of either speaker group. These results indicate that language formulation processes may affect speech production processes and that the speech motor systems of adults who stutter may be especially susceptible to the linguistic demands required to produce a more complex utterance. The present findings, therefore, support the hypothesis that linguistic complexity is one factor that contributes to the disruptions of speech motor stability characteristic of stuttering.

Adult↗
PubMed2001

Comparative analyses of the conformational stability of a hyperthermophilic protein and its mesophilic counterpart.

Comparison of the conformational stability of an O(6)-methylguanine-DNA methyltransferase (MGMT) from the hyperthermophilic archaeon Thermococcus kodakaraensis strain KOD1 (Tk-MGMT), and its mesophilic counterpart C-terminal Ada protein from Escherichia coli (Ec-AdaC) was performed in order to obtain information about the relationship between thermal stability and other factors, such as thermodynamic parameters, thermodynamic stability and other unfolding conditions. Tk-MGMT unfolded at Tm = 98.6 degrees C, which was 54.8 degrees C higher than the unfolding temperature of Ec-AdaC. The maximum free energy (DeltaG(max)) of the proteins were different; the value of Tk-MGMT (42.9 kJ.mol-1 at 29.5 degrees C) was 2.6 times higher than that of Ec-AdaC (16.6 kJ.mol-1 at 7.4 degrees C). The high conformational stability of Tk-MGMT was attributed to a 1.6-fold higher enthalpy value than that of Ec-AdaC. In addition, the DeltaG(max) temperature of Tk-MGMT was considerably higher (by 22.1 degrees C). The apparent heat capacity of denaturation (DeltaC(p)) of Tk-MGMT was 0.7-fold lower than that of Ec-AdaC. These three synergistic effects, increasing DeltaGmax, shifted DeltaG vs. temperature curve, and low DeltaC(p), give Tk-MGMT its thermal stability. Unfolding profiles of the two proteins, tested with four alcohols and three denaturants, showed that Tk-MGMT possessed higher stability than Ec-AdaC in all conditions studied. These results indicate that the high stability of Tk-MGMT gives resistance to chemical unfolding, in addition to thermal unfolding.

Bacterial Proteins↗
PubMed2001

Enhanced detection criteria in implantable cardioverter defibrillators: sensitivity and specificity of the stability algorithm at different heart rates.

The lack of specificity in the detection of ventricular tachyarrhythmias remains a major clinical problem in the therapy with ICDs. The stability criterion has been shown to be useful in discriminating ventricular tachyarrhythmias characterized by a small variation in cycle lengths from AF with rapid ventricular response presenting a higher degree of variability of RR intervals. But RR variability decreases with increasing heart rate during AF. Therefore, the aim of the study was to determine if the sensitivity and specificity of the STABILITY algorithm for spontaneous tachyarrhythmias is related to ventricular rate. Forty-two patients who had received an ICD (CPI Ventak Mini I, II, III or Ventak AV) were enrolled in the study. Two hundred ninety-eight episodes of AF with rapid ventricular response and 817 episodes of ventricular tachyarrhythmias were analyzed. Sensitivity and specificity in the detection of ventricular tachyarrhythmias were calculated at different heart rates. When a stability value of 30 ms was programmed the result was a sensitivity of 82.7% and a specificity of 91.4% in the detection of slow ventricular tachyarrhythmias (heart rate < 150 beats/min). When faster ventricular tachyarrhythmias with rates between 150 and 169 beats/min (170-189 beats/min) were analyzed, a stability value of 30 ms provided a sensitivity of 94.5% (94.7%) and a specificity of 76.5% (54.0%). For arrhythmia episodes > or = 190 beats/min, the same stability value resulted in a sensitivity of 78.2% and a specificity of 41.0%. Even when other stability values were taken into consideration, no acceptable sensitivity/specificity values could be obtained in this subgroup. RR variability decreases with increasing heart rate during AF while RR variability remains almost constant at different cycle lengths during ventricular tachyarrhythmias. Thus, acceptable performance of the STABILITY algorithm appears to be limited to ventricular rate zones < 170 beats/min.

Aged↗
PubMedDate not supplied

[Residual stability of different interbody fusion techniques after pedicle screw loosening].

INTRODUCTION: In spinal surgery, postoperative failure of pedicle screw instrumentation due to loosening of the implant at the bone-screw interface is a clinically relevant problem. While there are numerous biomechanical studies dealing with stability after internal fixation, little is known about the remaining segmental stability after pedicle screw loosening. We hypothesize that, in cases of implant loosening, the remaining stability is dependent on whether the segment received an isolated pedicle screw instrumentation or a 360 degrees instrumentation. METHODS: Motion analysis was performed under static, damage-free, sagittal strain (preload 100 N) on intact (controls) and posterior monosegmental L5/6 destabilized lumbar spines of sheep. Spine preparations underwent a flectional torque. Changes of spinal profile were radiographically documented, digitalized and then evaluated. Primary insertion of the conical pedicle screws was performed with a torque of 1.4 Nm. Pedicle screw loosening was simulated by turning the inserted screw back either 180 degrees or 540 degrees . Specimens instrumented with screws of differing diameters (5.5 mm and 6.7 mm) as well as non-instrumented pedicles were also compared. RESULTS: Independent of the type of instrumentation, we found that a loosening of pedicle screws increased remaining segmental motion. In maximal flexion (20 degrees ) and loosening of pedicle screws by 540 degrees, we found a statistically significant increase of remaining segmental motion with sole pedicle instrumentation (- 3.1 degrees ) in contrast to 360 degrees instrumentation (- 1.6 degrees ). For extension, a significant discrepancy between the two stabilization methods could not be shown. In cases where screws were firmly inserted, there was no advantage of using pedicle screws with an increased diameter of 6.7 mm. Independent of the type of fixation method, 5.5 mm screws that were inserted in widened pedicles showed a marked decrease of primary segmental stability. CONCLUSION: This study suggests that, concerning the remaining stability, 360 degrees instrumentation is superior in cases where pedicle screw loosening has occurred. The screw diameter plays an only subordinate role in primary segmental stability when the pedicle screws are inserted firmly.

Animals↗
PubMed2000

A quantitative, high-throughput screen for protein stability.

In proteomic research, it is often necessary to screen a large number of polypeptides for the presence of stable structure. Described here is a technique (referred to as SUPREX, stability of unpurified proteins from rates of H/D exchange) for measuring the stability of proteins in a rapid, high-throughput fashion. The method uses hydrogen exchange to estimate the stability of microgram quantities of unpurified protein extracts by using matrix-assisted laser desorption/ionization MS. The stabilities of maltose binding protein and monomeric lambda repressor variants determined by SUPREX agree well with stability data obtained from conventional CD denaturation of purified protein. The method also can detect the change in stability caused by the binding of maltose to maltose binding protein. The results demonstrate the precision of the method over a wide range of stabilities.

Bacterial Proteins↗
PubMed1997

Stability of empty and peptide-loaded class II major histocompatibility complex molecules at neutral and endosomal pH: comparison to class I proteins.

The structure and thermal stability of empty and peptide-filled forms of the murine class II major histocompatibility complex (MHC) molecule I-E(k) were studied at neutral and mildly acidic pH. The two forms have distinct circular dichroic spectra, suggesting that a conformational change may accompany peptide binding. Thermal stability profiles indicate that binding of peptide significantly increases the thermal stability of the empty heterodimers at both neutral and mildly acidic pH. Free energies calculated from these data provide a direct measure of this stabilization and show that the empty form of I-E(k) is significantly more stable than that of class I MHC proteins. Furthermore, for the two MHC class II proteins that were analyzed (I-E(k) and I-A(d)), thermal stability was not significantly altered by acidification. In contrast, of four class I MHC molecules studied, three have shown a significant loss in complex stability at low pH. The marked stability exhibited by their empty form, as well as their resistance to low pH, as observed in this study, correlate well with the ability of class II MHC molecules to traverse and bind peptides in acidic endosomal vesicles.

Amino Acid Sequence↗
PubMed1998

Translation inhibitors stabilize Escherichia coli mRNAs independently of ribosome protection.

Translation inhibitors such as chloramphenicol in prokaryotes or cycloheximide in eukaryotes stabilize many or most cellular mRNAs. In Escherichia coli, this stabilization is ascribed generally to the shielding of mRNAs by stalled ribosomes. To evaluate this interpretation, we examine here how inhibitors affect the stabilities of two untranslated RNAs, i.e., an engineered lacZ mRNA lacking a ribosome binding site, and a small regulatory RNA, RNAI. Whether they block elongation or initiation, all translation inhibitors tested stabilized these RNAs, indicating that stabilization does not necessarily reflect changes in packing or activity of translating ribosomes. Moreover, both the initial RNase E-dependent cleavage of RNAI and lacZ mRNA and the subsequent attack of RNAI by polynucleotide phosphorylase and poly(A)-polymerase were slowed. Among various possible mechanisms for this stabilization, we discuss in particular a passive model. When translation is blocked, rRNA synthesis is known to increase severalfold and rRNA becomes unstable. Meanwhile, the pools of RNase E and polynucleotide phosphorylase, which, in growing cells, are limited because these RNases autoregulate their own synthesis, cannot expand. The processing/degradation of newly synthesized rRNA would then titrate these RNases, causing bulk mRNA stabilization.

Chloramphenicol↗
PubMed1996

Stabilization of chlorophyll a-binding apoproteins P700, CP47, CP43, D2, and D1 by chlorophyll a or Zn-pheophytin a.

Stabilization of chlorophyll a-binding apoproteins P700, CP47, CP43, D2, and D1 against proteolytic degradation has been investigated through in vitro synthesis of chlorophyll a or Zn-pheophytin a in intact etioplasts from barley. Stabilization of the apoproteins was dependent on the concentration of chlorophyll a or Zn-pheophytin a. Zn-pheophytin a was superior to chlorophyll a with respect to the concentration of pigment required for an equal yield of the stabilized chlorophyll a protein CP47, CP43, and P700 and for the total yield of chlorophyll a proteins. Zn-pheophytin a was most efficient for stabilizing CP47 and, at an increased concentration, efficient for stabilizing CP43, P700, and D1. Stabilization of apoproteins was highest after de novo synthesis of 90-300 pmol of Zn-pheophytin a or of about 400-600 pmol of chlorophyll a/4.2 x 10(7) etioplasts. The yield of stabilized chlorophyll proteins decreased at higher concentrations of Zn-pheophytin a, but was unaffected by higher concentrations of chlorophyll a.

Apoproteins↗
PubMed1998

Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor whose expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. Here we show that HuR binds with high affinity and specificity to the element that regulates VEGF mRNA stability by hypoxia. Inhibition of HuR expression abrogates the hypoxia-mediated increase in VEGF mRNA stability. Overexpression of HuR increases the stability of VEGF mRNA. However, this only occurs efficiently in hypoxic cells. We further show that the stabilization of VEGF mRNA can be recapitulated in vitro. Using an S-100 extract, we show that the addition of recombinant HuR stabilizes VEGF mRNA markedly. These data support the critical role of HuR in mediating the hypoxic stabilization of VEGF mRNA by hypoxia.

Antigens, Surface↗
PubMed2001

Identification of novel bifunctional calmodulin-binding and microtubule-stabilizing motifs in STOP proteins.

Although microtubules are intrinsically labile tubulin assemblies, many cell types contain stable polymers, resisting depolymerizing conditions such as exposure to the cold or the drug nocodazole. This microtubule stabilization is largely due to polymer association with STOP proteins. There are several STOP variants, some with capacity to induce microtubule resistance to both the cold and nocodazole, others with microtubule cold stabilizing activity only. These microtubule-stabilizing effects of STOP proteins are inhibited by calmodulin and we now demonstrate that they are determined by two distinct kinds of repeated modular sequences (Mn and Mc), both containing a calmodulin-binding peptide, but displaying different microtubule stabilizing activities. Mn modules induce microtubule resistance to both the cold and nocodazole when expressed in cells. Mc modules, which correspond to the STOP central repeats, have microtubule cold stabilizing activity only. Mouse neuronal STOPs, which induce both cold and drug resistance in cellular microtubules, contain three Mn modules and four Mc modules. Compared with neuronal STOPs, the non-neuronal F-STOP lacks multiple Mn modules and this corresponds with an inability to induce nocodazole resistance. STOP modules represent novel bifunctional calmodulin-binding and microtubule-stabilizing sequences that may be essential for the generation of the different patterns of microtubule stabilization observed in cells.

Amino Acid Motifs↗
PubMed2002

Structure-based design of p18INK4c proteins with increased thermodynamic stability and cell cycle inhibitory activity.

p18(INK4c) is a member of the INK4 family of proteins that regulate the G(1) to S cell cycle transition by binding to and inhibiting the pRb kinase activity of cyclin-dependent kinases 4 and 6. The p16(INK4a) member of the INK4 protein family is altered in a variety of cancers and structure-function studies of the INK4 proteins reveal that the vast majority of missense tumor-derived p16(INK4a) mutations reduce protein thermodynamic stability. Based on this observation, we used p18(INK4c) as a model to test the proposal that INK4 proteins with increased stability might have enhanced cell cycle inhibitory activity. Structure-based mutagenesis was used to prepare p18(INK4c) mutant proteins with a predicted increase in stability. Using this approach, we report the generation of three mutant p18(INK4C) proteins, F71N, F82Q, and F92N, with increased stability toward thermal denaturation of which the F71N mutant also showed an increased stability to chemical denaturation. The x-ray crystal structures of the F71N, F82Q, and F92N p18INK4C mutant proteins were determined to reveal the structural basis for their increased stability properties. Significantly, the F71N mutant also showed enhanced CDK6 interaction and cell cycle inhibitory activity in vivo, as measured using co-immunoprecipitation and transient transfection assays, respectively. These studies show that a structure-based approach to increase the thermodynamic stability of INK4 proteins can be exploited to prepare more biologically active molecules with potential applications for the development of molecules to treat p16(INK4a)-mediated cancers.

Cell Cycle↗