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Results for “Feature selection stability”

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PubMed1994

NMR-derived three-dimensional solution structure of protein S complexed with calcium.

BACKGROUND: Protein S is a developmentally-regulated Ca(2+)-binding protein of the soil bacterium Myxococcus xanthus. It functions by forming protective, multilayer spore surface assemblies which may additionally act as a cell-cell adhesive. Protein S is evolutionarily related to vertebrate lens beta gamma-crystallins. RESULTS: The three-dimensional solution structure of Ca(2+)-loaded protein S has been determined using multi-dimensional heteronuclear NMR spectroscopy. (Sixty structures were calculated, from which thirty were selected with a root mean square difference from the mean of 0.38 A for backbone atoms and 1.22 A for all non-hydrogen atoms.) The structure was analyzed and compared in detail with X-ray crystallographic structures of beta gamma-crystallins. The two internally homologous domains of protein S were compared, and hydrophobic cores, domain interfaces, surface ion pairing, amino-aromatic interactions and potential modes of multimerization are discussed. CONCLUSIONS: Structural features of protein S described here help to explain its overall thermostability, as well as the higher stability and Ca2+ affinity of the amino-terminal domain relative to the carboxy-terminal domain. Two potential modes of multimerization are proposed involving cross-linking of protein S molecules through surface Ca(2+)-binding sites and formation of the intramolecular protein S or gamma B-crystallin interdomain interface in an intermolecular content. This structural analysis may also have implications for Ca(2+)-dependent cell-cell interactions mediated by the vertebrate cadherins and Dictyostelium discoideum protein gp24.

Amino Acid Sequence↗

PubMed1999

The disulfide-coupled folding pathway of apamin as derived from diselenide-quenched analogs and intermediates.

The sequence of apamin, an 18 residue bee venom toxin, encloses all the information required for the correct disulfide-coupled folding into the cystine-stabilized alpha-helical motif. Three apamin analogs, each containing a pair of selenocysteine residues replacing the related cysteines, were synthesized to mimic the three possible apamin isomers with two crossed, parallel, or consecutive disulfides, respectively. Refolding experiments clearly revealed that the redox potential of selenocysteine prevails over the sequence encoded structural information for proper folding of apamin. Thus, selenocysteine can be used as a new device to generate productive and nonproductive folding intermediates of peptides and proteins. In fact, disulfides are selectively reduced in presence of the diselenide and the conformational features derived from these intermediates as well as from the three-dimensional (3D) structures of the selenocysteine-containing analogs with their nonnatural networks of diselenide/disulfide bridges allowed to gain further insight into the subtle driving forces for the correct folding of apamin that mainly derive from local conformational preferences.

Amino Acid Sequence↗

PubMedDate not supplied

Dramatic effect of the tridentate ligand on the stability of 99mTC "3 + 1" oxo complexes bearing arylpiperazine derivatives.

Mixed-ligand model complexes of general formula [(99m)Tc(O)(kappa(3)-PNX)(kappa(1)-SPh))] [X = O (1a), S (2a)] were prepared in a one-step procedure from [(99m)TcO(4)(-)] using stannous chloride as reducing agent. Stability studies and challenge experiments with glutathione showed that complex 2a presented promising features for pursuing animal studies. The activity in the brain (% dose injected/organ) at 5 min (0.14% +/- 0.03) and 120 min (0.11% +/- 0.02) pi encouraged the synthesis of several mixed-ligand "3 + 1" oxo complexes of general formula [M(O)(kappa(3)-PNS)(kappa(1)-SL))] (M = (99m)Tc, 3a-6a, Re, 3-6), in which the tridentate ligand is the heterofunctionalized phosphine 2-(diphenylphosphanyl)-N-(2-thioethyl)benzamide (PNS) and the co-ligands are different arylpiperazine derivatives (HSL1-HSL4). The (99m)Tc complexes have been characterized by comparison of their retention times in the HPLC chromatogram (gamma-detection) with the retention times of the analogous Re complexes (UV detection at 254 nm). The (99m)Tc complexes, obtained with radiochemical purity higher than 95%, after HPLC purification, are stable in saline, 0.01 M PBS (pH 7.4), rat plasma (4 h, 37 degrees C), and glutathione (10 mM solutions, 2h, 37 degrees C). Binding affinity and selectivity for 5-HT(1A) receptors (relative to the 5-HT(2A) receptor) were determined, complex 5 demonstrating the best values (IC(50) for the 5-HT(1A) 2.35 +/- 0.02 nM; competitor 5-HT(2A) 372 +/- 11 nM). Biodistribution and stability studies in mice indicated a preferred hepatobiliary excretion, a high in vivo stability, but a poor brain uptake.

Animals↗

PubMed2004

Simulation study on effects of signaling network structure on the developmental increase in complexity.

The developmental increase in structural complexity in multicellular lifeforms depends on local, often non-periodic differences in gene expression. These, in turn, depend on a network of gene-gene interactions coded within the organismal genome. To see what architectural features of a network (size, connectivity, etc.) affect the likelihood of patterns with multiple cell types (i.e. patterns where cells express > or = 3 different combinations of genes), developmental pattern formation was simulated in virtual blastoderm embryos with small artificial genomes. Several basic properties of these genomic signaling networks, such as the number of genes, the distributions of positive (inductive) and negative (repressive) interactions, and the strengths of gene-gene interactions were tested. The results show that the frequencies of complex and/or stable patterns depended not only on the existence of negative interactions, but also on the distribution of regulatory interactions: for example, coregulation of signals and their intracellular effectors increased the likelihood of pattern formation compared to differential regulation of signaling pathway components. Interestingly, neither quantitative differences in strengths of signaling interactions nor multiple response thresholds to different levels of signal concentration (as in morphogen gradients) were essential for formation of multiple, spatially unique "cell types". However, those combinations of architectural features that greatly increased the likelihood for pattern complexity tended to decrease the likelihoods for pattern stability and developmental robustness. Nevertheless, elements of complex patterns (e.g. genes, cell type order within the pattern) could differ in their developmental robustness, which may be important for the evolution of complexity. The results show that depending on the network structure, the same set of genes can produce patterns of different complexity, robustness and stability. Because of this, the evolution of metazoan complexity with a combinatorial code of gene regulation may have depended at least as much on selection for favorable distribution of connections between existing developmental regulatory genes as on the simple increase in numbers of regulatory genes.

Animals↗

PubMed1996

Conserved features in the active site of nonhomologous serine proteases.

BACKGROUND: Serine protease activity is critical for many biological processes and has arisen independently in a few different protein families. It is not clear, though, the degree to which these protease families share common biochemical and biophysical properties. We have used a computer program to study the properties that are shared by four serine protease active sites with no overall structural or sequence homology. The program systematically compares the region around the catalytic histidines from the four proteins with a set of noncatalytic histidines, used as controls. It reports the three-dimensional locations and level of statistical significance for those properties that distinguish the catalytic histidines from the noncatalytic ones. The method of analysis is general and can be applied easily to other active sites of interest. RESULTS: As expected, some of the reported properties correspond to previously known features of the serine protease active site, including the catalytic triad and the oxyanion hole. Novel properties are also found, including the spatial distribution of charged, polar, and hydrophobic groups arranged to stabilize the catalytic residues, and a relative abundance of some residues (Val, Tyr, Leu, and Gly) around the active site. CONCLUSIONS: Our findings show that in addition to some properties common to all the proteases examined, there are a set of preferred, but not required, properties that can be reliably observed only by aligning the sites and comparing them with carefully selected statistical controls.

Animals↗

PubMedDate not supplied

[Post-radiotherapy lesions of the brachial plexus. Classification and results of surgical treatment].

A series of 60 cases with a follow-up of 3 to 13 years among 118 operations for post-radiation lesions of the brachial plexus performed between 1978 and 1990 was investigated as a function of three features: 1) anatomic classification according to 3 stages for per-operatory observations of extrinsic and intrinsic compression, 2) clinical classification according to 4 types of sensoro-motor neurological symptoms and 3) the different operative procedures used for decompression. It was concluded that post-radiation plexuses should be operated as early as possible as soon as paraesthesia appears and before the onset of pain since the aim of the operation is to stabilize the clinical course and not achieve cure. It was also found that the best operative procedure is a selective neurolysis of the plexus completed by a pedicled omentoplasty.

Brachial Plexus↗

PubMed2004

[Genetic-physiologic features of reproduction in prolific animals].

Genetic and physiological functional relationships between major reproductive parameters were studied in domestic prolific mammals with special reference to selection-induced changes in fertility and mothering ability in ten generations of pigs of sino-European Tiameslan composite line, which was first bred in France. Based on our hypothesis, balance equations were derived describing highly adaptive functional coadaptations of reproductive traits. Properties of these equations were examined with regard to natural selection. Selection changes of secretory traits of mammary glands were shown to play a leading role in a correlated increase of biological fertility. Genetically controlled regulatory relationships maintained by natural stabilizing selection were established between fertility, sow milk production, perinatal survival, and survival to weaning. Thus, a system of simple complementary equations characterizing an independent integrative reproductive physiological mother-young(s) system was obtained, which had not been previously published. The self-regulated homeostatic mother-young(s) system, studied for the first time ever, ensured homeostatic development of suckling piglets, compensatory regulation, and stabilization at the optimal level of biological (11.6 +/- 0.17 piglets at birth) and actual (10.0 +/- 0.08 piglets at weaning) fertility in the Tiameslan line.

Animals↗

PubMed1999

Calcium-binding properties and molecular organization of bradykinin A solution 1H-NMR study.

The NMR features of bradykinin were investigated in dimethylsulfoxide containing 1% water. The temperature dependence of chemical shifts and ROESY maps were monitored for the major species where all X-Pro bonds are trans. The occurrence of a head-to-tail ionic interaction and intramolecular hydrogen bonds stabilizing a pseudo cyclic arrangement was inferred, a beta turn at the C-terminus being the main feature of the secondary structure. Calcium was shown to bind to the peptide with a dissociation constant Kd = 2.8 + 0.2 mm. 2Pro and 3Pro carbonyls, as well as the 9Arg carboxyl, were assigned as the metal-binding sites. A molecular model of the 1 : 1 metal-complex was obtained. In light of conformational changes experienced by the peptide upon interaction with calcium, a role for the metal was hypothesized in the process of conformational selection from the free to the receptor-bound state of bradykinin.

Bradykinin↗

PubMed2004

Searching for cochlear implant information on the internet maze: implications for parents and professionals.

The present study has three purposes: (a) to determine who disseminates information on cochlear implants on the Web; (b) to describe a representative sample of Web sites that disseminate information on cochlear implants, with a focus on the content topics and their relevance to parents of deaf children; and (c) to discuss the practical issues of Web-based information and its implications for professionals working with parents of deaf children. Using the terms "cochlear implants" and "children," the first 10 sites generated by the four most popular search engines (Google, Yahoo, Microsoft's MSN, and America Online) at two points in time were selected for analysis, resulting in a sample of 31 Web sites. The majority of Web sites represented medically oriented academic departments and government organizations, although a wide variety of other sources containing information about cochlear implants were also located. Qualitative analysis revealed that the content tended to fall into eight categories; however, the important issues of educational concerns, habilitation following surgery, and communication methods were either addressed minimally or neglected completely. Using analytical tools that had been developed to evaluate "user friendliness" in other domains, each Web site was assessed for its stability, service/design features and ease of use. In general, wide variability was noted across the Web sites for each of these factors. The strong recommendation is made that professionals understand and enhance their knowledge of both the advantages and limitations of incorporating the new technology into their work with parents.

Cochlear Implants↗

PubMed2003

Mutation rates: estimating phase variation rates when fitness differences are present and their impact on population structure.

Phase variation is a mechanism of ON-OFF switching that is widely utilized by bacterial pathogens. There is currently no standardization to how the rate of phase variation is determined experimentally, and traditional methods of mutation rate estimation may not be appropriate to this process. Here, the history of mutation rate estimation is reviewed, describing the existing methods available. A new mathematical model that can be applied to this problem is also presented. This model specifically includes the confounding factors of back-mutation and the influence of fitness differences between the alternate phenotypes. These are central features of phase variation but are rarely addressed, with the result that some previously estimated phase variation rates may have been significantly overestimated. It is shown that, conversely, the model can also be used to investigate fitness differences if mutation rates are approximately known. In addition, stochastic simulations of the model are used to explore the impact of 'jackpot cultures' on the mutation rate estimation. Using the model, the impact of realistic rates and selection on population structure is investigated. In the absence of fitness differences it is predicted that there will be phenotypic stability over many generations. The rate of phenotypic change within a population is likely, therefore, to be principally determined by selection. A greater insight into the population dynamics of mutation rate processes can be gained if populations are monitored over successive time points.

Bacteria↗

PubMed2005

Medicinal chemical properties of successful central nervous system drugs.

Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties.

Animals↗

PubMed2000

Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum.

BACKGROUND: Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. METHOD: Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. RESULTS: At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. CONCLUSION: Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.

Adolescent↗

PubMed1999

Human renal cell carcinoma xenografts in SCID mice: tumorigenicity correlates with a poor clinical prognosis.

To establish human renal cell carcinoma (RCC) xenografts for preclinical studies, 55 renal tumors (33 primary and 22 metastatic lesions) were transplanted subcutaneously into severe combined immunodeficient mice. Twenty of 49 evaluable tumors (40.8%) grew with a median latency period of 89 days (36 to 209 days) from the day of engraftment. Tumor growth was stabilized after the fifth passage with a median time between passages of 38 days (19 to 80 days). Tumorigenicity was correlated with the metastatic phenotype of the tumor (54% success rate, p = 0.007) and with reduced survival of patients. Despite a possible evolution of histological features and tumor grading, established RCC xenografts were comparable to parental tumors, as assessed by karyotype and DNA-ploidy analyses. Molecular cytogenetic analysis also revealed specific genetic alterations characterizing distinct RCC types that were constant in parental and corresponding xenografts. In addition, this xenograft model has permitted the selection of minor tumor subclones with a proliferative advantage and minimal overexpressed chromosomal regions. We conclude that severe combined immunodeficient mice are useful recipients for the establishment of long-term RCC xenografts that can be used as valuable tools to evaluate the activity of new therapeutic approaches and to study biological parameters determining in vivo aggressiveness of human RCC.

Adult↗

PubMed1990

Placing patients in the queue for coronary revascularization: evidence for practice variations from an expert panel process.

A panel of 16 cardiologists and cardiac surgeons rated 438 case scenarios for the maximum acceptable delay prior to revascularization, using a scale with seven interventional time frames and two nodes for designating dubious or inappropriate cases. If consensus was defined as agreement by 12 or more panelists, only 1.4 percent of the case scenarios showed consensus on a single rating. Dividing the scale into three broad clinical categories (revascularize promptly, place on a waiting list, or no intervention), 11.4 percent of scenarios showed all 16 panelists agreeing on a single category, rising to 59.4 percent of scenarios if agreement by 12 panelists was accepted as a consensus. The mean difference between the panelists' highest and lowest urgency ratings yielded waiting time differences of two weeks for scenarios of very unstable angina, and more than three months for those with stable angina. However, in a regression model, individual panelist factors on average had less effect than clinical features such as severity and stability of angina, or stenosis of major coronary arteries. These findings strongly support the need for consensus criteria to ensure that triage practices are consistent and fair, and also suggest that widespread adoption of a standardized approach to revascularization priorities may be feasible.

Coronary Artery Bypass↗

PubMed2000

DNA replication fidelity.

DNA replication fidelity is a key determinant of genome stability and is central to the evolution of species and to the origins of human diseases. Here we review our current understanding of replication fidelity, with emphasis on structural and biochemical studies of DNA polymerases that provide new insights into the importance of hydrogen bonding, base pair geometry, and substrate-induced conformational changes to fidelity. These studies also reveal polymerase interactions with the DNA minor groove at and upstream of the active site that influence nucleotide selectivity, the efficiency of exonucleolytic proofreading, and the rate of forming errors via strand misalignments. We highlight common features that are relevant to the fidelity of any DNA synthesis reaction, and consider why fidelity varies depending on the enzymes, the error, and the local sequence environment.

Base Pair Mismatch↗

PubMed1996

N-peptidyl, O-acyl hydroxamates: comparison of the selective inhibition of serine and cysteine proteinases.

Two series of N-aminoacyl, O-benzoyl hydroxamates were designed to investigate the influence of the substituted benzoyl residue on the hydrolytic stability and the reactivity of these potential inhibitors towards selected cysteine and serine proteinases. The inactivators react more rapidly with cysteine proteinases than with the serine enzymes tested. While Z-Phe-Gly-NHO-Nbz is the most reactive inhibitor of cathepsin L, inhibiting the target protein by a second order rate constant of 932.000 M-1 s-1, the bacterial serine proteinase thermitase is inhibited best by Z-Gly-Phe-NHO-Nbz, exhibiting a second-order rate constant of 1.170 M-1 s-1. Thiolsubtilisin, having the thiol-group as the reactive nucleophile instead of serine, exhibits specificity constants of the inactivation two orders of magnitude smaller than subtilisin. The degree of selectivity of the inhibitors relative to cathepsin B, cathepsin L, cathepsin S and papain varies up to two orders of magnitude with respect to their second order rate constant of inactivation. The inhibitory reactivity of these compounds varies only up to sixfold depending on the benzoyl substituent. Similarly, the rate constants for the hydrolytic decomposition of the compounds vary by a factor of about 6, suggesting that the structural and mechanistic features of the compounds which are responsible for decomposition as well as for the enzyme inhibition are the same. Comparing both reactions, the data allow the calculation of an acceleration factor of 2.4 x 10(10) for the inhibition of cathepsin L by its most effective inhibitor, clearly characterizing this enzyme inhibition reaction as enzyme-activated.

Cathepsins↗

PubMed2002

Altered aquaporin-4 expression in human muscular dystrophies: a common feature?

Duchenne Muscular Dystrophy (DMD) is a progressive lethal muscle disease that affects young boys. Dystrophin, absent in DMD and reduced in the milder form Becker Muscular Dystrophy (BMD), binds to several membrane-associated proteins known as dystrophin-associated proteins (DAPs). Once this critical structural link is disrupted, muscle fibers become more vulnerable to mechanical and osmotic stress. Recently, we have reported that the expression of aquaporin-4 (AQP4), a water-selective channel expressed in the sarcolemma of fast-twitch fibers and astrocyte end-feet, is drastically reduced in the muscle and brain of the mdx mouse, the animal model of DMD. In the present study, we analyzed the expression of AQP4 in several DMD/BMD patients of different ages with different mutations in the dystrophin gene. Immunofluorescence results indicate that, compared with healthy control children, AQP4 is reduced severely in all the DMD muscular biopsies analyzed and in 50% of the analyzed BMD. Western blot analysis revealed that the deficiency in sarcolemma AQP4 staining is due to a reduction in total AQP4 muscle protein content rather than to changes in immunoreactivity. Double-immunostaining experiments indicate that AQP4 reduction is independent of changes in the fiber myosin heavy chain composition. AQP4 and a-syntrophin analysis of BMD muscular biopsies revealed that the expression and stability of AQP4 in the sarcolemma does not always decrease when a-syntrophin is strongly reduced. Finally, limb-girdle muscular dystrophy biopsies and facioscapulohumeral muscular dystrophy revealed that AQP4 expression was not altered in these forms of muscular dystrophy. These experiments provide the first evidence of AQP4 reduction in a human pathology and show that this deficiency is an important feature of DMD/BMD.

Aquaporin 4↗

PubMed1988

Comparative separation of human plasma proteins on polysulphated chromatographic media.

Polysulphated chromatographic media, particularly Heparin Sepharose, are generally used to purify a variety of different plasma proteins. Heparin Sepharose, dextran sulphate Sepharose and sulphated dextran are compared with two recently available sulphated cellulose chromatographic media. The potential influence of structural features of different polysaccharides on the interaction with selected plasma proteins has been evaluated with the particular objective of developing an alternative medium for the preparation of specific therapeutic factor concentrates. The studies indicate that the degree of sulphation of the matrix is an important but not a critical determinant for resolution of factors IX and X. Despite large differences in the carbohydrate structure of the matrices, the new sulphated cellulose gel 5.2 had a total protein capacity and specific binding profile comparable to Heparin Sepharose. The sulphated cellulose which is competitively priced, and has excellent stability, is a potential alternative to Heparin Sepharose especially for larger scale industrial processing of factor IX concentrate.

Blood Proteins↗