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PubMed1998

The signal model: a possible explanation for the conversion of DNA double-strand breaks into chromatid breaks.

PURPOSE: To present and evaluate the 'signal' model for the formation of radiation-induced chromatid breaks. CONCLUSIONS: Chromatid breaks in human cells represent the apparent interstitial loss of up to about 40 Mbp of DNA, difficult to account for as single lesions under the classical 'breakage-and-reunion' hypothesis. If breakage-first resulted from two interacting DNA double-strand breaks (dsb) with the loss or displacement of the intervening fragment, a dose-squared relationship would be predicted for chromatid breaks. However, the relationship between chromatid break frequency and dose for human cells is linear. The alternative 'exchange' model of Revell is based on the principle of the interaction of two initiating lesions, thus also predicting a dose-squared relationship for chromatid 'breaks'. The signal model explains the conversion of dsb into chromatid breaks on the assumption that a single dsb generates a signal which triggers the cell to initiate a recombinational exchange involving a large loop of chromatin. Incomplete exchanges would be observed as chromatid breaks. Possible candidates for the signalling molecule(s) are DNA protein kinase (DNA PK) and the ATM protein.

Animals↗

PubMedDate not supplied

[A stereochemical model for DNA-Na+ (H20) complex].

By computer calculation with the use of atom-atom potentials a stereochemical model of the DNA-hydrate Na+ complex was obtained according to which the Na+(H2O)6 octahedrons are localized in the narrow groove of DNA with formation of a great number of van der vaals contacts and hydrogen bonds. The model explains why the C-form of DNA is stabilized in the Na-DNA complex which is formed in the presence of 80% methanol (v/v). A possibility of the existence of such complexes in vivo at the DNA regions surrounded with media of diminished water activity (the DNA-membrane complex, chromosomes, phage heads) is discussed.

Binding Sites↗

PubMed2005

Biophysical characterization of anionic lipoplexes.

Transfection efficiency of liposomal gene delivery vectors depends on an optimal balance in the electro-chemical and structural properties of the transfection-capable complexes. We have recently reported a novel anionic lipoplex DNA delivery system composed of a ternary complex of endogenous occurring non-toxic anionic lipids, physiological Ca2+ cations, and plasmid DNA encoding a gene of interest with high transfection efficiency and low toxicity. In this work, we investigate the electro-chemical and structural properties anionic lipoplexes and compare them with those of Ca2+-DNA complexes. Biophysical characterization is used to explain the transfection efficiency of anionic lipoplexes in mammalian CHO-K1 cells. Circular dichroism and fluorescence spectroscopy showed that the plasmid DNA underwent conformational transition from native B-DNA to Z-DNA due to compaction and condensation upon Ca2+-mediated complexation with anionic liposomes. Zeta potential measurements and gel electrophoresis studies demonstrated that Ca2+ interaction with plasmid DNA during the formation of lipoplexes also led to increased association of supercoiled plasmid DNA with the lipoplexes, leading to charge neutralization which is expected to facilitate transfection. However, even 10-fold higher concentrations of Ca2+ alone (in the absence of the anionic liposomes) were unable to induce these changes in plasmid DNA molecules. A model explaining the possible mechanism of anionic lipoplex formation and the correlation of high transfection efficiency to biophysical properties was proposed. These studies confirm the utility of biophysical studies to identify optimal formulation conditions to design efficient liposomal gene delivery vectors.

Anions↗

PubMed2001

The renal Na-HCO3-cotransporter expressed in Xenopus laevis oocytes: change in stoichiometry in response to elevation of cytosolic Ca2+ concentration.

The Na+-HCO3- cotransporter of rat kidney (rkNBC) was expressed in Xenopus laevis oocytes to test whether cytosolic Ca2+ ([Ca2+]i) affects the cotransport stoichiometry. The current/voltage relationship of giant inside-out membrane patches of rkNBC-expressing oocytes was measured at near-physiological Na+ and HCO3- concentrations and the cotransport current, INBC, was defined as the current inhibited by 0.25 mmol/l tenidap. Essentially, we determined the reversal potential (VI=0) of INBC and the slope conductance (gNBC). The coupling ratio of (HCO3-) to Na+ (q) was calculated from VI=0. As reported in the preceding publication [Ducoudret et al., Pflügers Arch (2001) DOI 10.1007/s004240100594], in Ca2+-free solutions q was 2:1. This did not change when [Ca2+]i was increased to 0.1 micromol/l. At 0.5 micromol/l, however, only a few patches showed q=2:1, while most patches exhibited q=3:1. This indicates that [Ca2+]i affected the transport function of membrane-resident rkNBC molecules, and the bimodal distribution of VI=0 points to an indirect effect possibly mediated by differently expressed Ca2+-dependent protein kinases. The shift in q was associated with the predicted near twofold increase in gNBC and was confirmed by measurements of VI=0 at different Na+ and HCO3- concentrations. Because we previously observed that the cotransport in proximal tubule cells is susceptible to carbonic anhydrase (CA) inhibition, but only if it works at q=3:1, we propose that kNBC has three transport sites: when working at q=2:1 it binds 2 (HCO3-)+1 Na+, and while at q=3:1 it binds 1 CO3(2-)+1 HCO3- +1 Na+. The latter is equivalent to the transfer of 3 (HCO3-) +1 Na+, because in the presence of CA the generation of 1 CO3(2-) on one side of the membrane and its disintegration on the other transiently liberates 1 CO2, which follows by diffusion. This model explains the increase in (HCO3-) transport that is associated with the change in q from 2:1 to 3:1 by a selectivity change of a binding site from HCO3- to CO3(2-). This is more likely than the induction of a new transport pouch for a third (HCO3-) ion, which would require exceedingly large conformational changes of the transport protein.

Animals↗

PubMed2004

High-fidelity DNA sensing by protein binding fluctuations.

One of the major functions of RecA protein in the cell is to bind single-stranded DNA exposed upon damage, thereby triggering the SOS repair response. We present fluorescence anisotropy measurements at the binding onset, showing enhanced DNA length discrimination induced by adenosine triphosphate consumption. Our model explains the observed DNA length sensing as an outcome of out-of-equilibrium binding fluctuations, reminiscent of microtubule dynamic instability. The cascade architecture of the binding fluctuations is a generalization of the kinetic proofreading mechanism. Enhancement of precision by an irreversible multistage pathway is a possible design principle in the noisy biological environment.

Adenosine Triphosphate↗

PubMed2003

Conjugation of catechols by recombinant human sulfotransferases, UDP-glucuronosyltransferases, and soluble catechol O-methyltransferase: structure-conjugation relationships and predictive models.

Conjugation of a structurally diverse set of 53 catechol compounds was studied in vitro using six recombinant human sulfotransferases (SULTs), five UDP-glucuronosyltransferases (UGT) and the soluble form of catechol O-methyltransferase (S-COMT) as catalyst. The catechol set comprised endogenous compounds, such as catecholamines and catecholestrogens, drugs, natural plant constituents, and other catechols with diverse substituent properties and substitution patterns. Most of the catechols studied were substrates of S-COMT and four SULT isoforms (1A1, 1A2, 1A3, and 1B1), but the rates of conjugation varied considerably, depending on the substrate structure and the enzyme form. SULT1E1 sulfated fewer catechols. Only low activities were observed for SULT1C2. UGT1A9 glucuronidated catechols representing various structural classes, and almost half of the studied compounds were glucuronidated at a high rate. The other UGT enzymes (1A1, 1A6, 2B7, and 2B15) showed narrower substrate specificity for catechols, but each glucuronidated some catechols at a high rate. Dependence of specificity and rate of conjugation on the molecular structure of the substrate was characterized by structure-activity relationship analysis and quantitative structure-activity relationship modeling. Twelve structural descriptors were used to characterize lipophilicity/polar interaction properties, steric properties, and electronic effects of the substituents modifying the catechol structure. PLS models explaining more than 80% and predicting more than 70% of the variance in conjugation activity were derived for the representative enzyme forms SULT1A3, UGT1A9, and S-COMT. Several structural factors governing the conjugation of catechol hormones, metabolites, and drugs were identified. The results have significant implications for predicting the metabolic fate of catechols.

Catechol O-Methyltransferase↗

PubMed2004

Predicting the efficiency of UAG translational stop signal through studies of physicochemical properties of its composite mono- and dinucleotides.

In this study, we explored the problem of predicting the UAG stop-codon read-through efficiency. The reported nucleotide sequences were first converted into physicochemical property vectors before being presented to a machine learning algorithm. Two sets of physicochemical properties were applied: one for mononucleosides (in terms of steric bulk, hydrophobicity and electronics) and another for dinucleotides. To the best of our knowledge, this is the first report of how dinucleotides are converted into principle components derived from NMR chemical shift data. A few efficiency prediction models were then derived and a comparison between mononucleoside and dinucleotide-based models was shown. In the derived models, the coefficients of these property based predictors lend themselves to bio-physical interpretations, an advantage which is demonstrated in this study via a prediction model based on the steric bulk factor. Although it is quite simple, the steric bulk factor model explained well the effect of sequence variations surrounding the amber stop codon and the tRNA bearing UCCU anticodon. We further proposed new alternatives at position -1 and +4 of a UAG stop codon sequence to enhance the readthrough efficiency. This research may contribute to a better understanding of the readthrough mechanisms and may also help to study the normal translation termination process.

Codon, Terminator↗

PubMed2002

Pharmacoepidemiological analysis of provincial differences between consumption of macrolides and rates of erythromycin resistance among Streptococcus pyogenes isolates in Spain.

The M phenotype is by far the most common mechanism of erythromycin resistance among Streptococcus pyogenes isolates in Spain. A geographic analysis of the relationship between within-country differences in the prevalence of M-type resistance to erythromycin in S. pyogenes and the level of consumption of 14- and 15-membered macrolides within different provinces was carried out. From 1998 to 1999, a nationwide multicenter surveillance study yielded 2,039 consecutive pharyngeal isolates of S. pyogenes. Data on antibiotic consumption for the same period were gathered from IMS Health, and the corresponding daily defined doses per 1,000 inhabitants per day were calculated according to the Anatomic Therapeutic Classification index. Macrolide use was subdivided into dosages given three times a day (TID), twice a day (BID), or once a day (OD). Spearman nonparametric correlation coefficients (R) were calculated, and variables proving to be significantly associated (P < 0.1) were introduced into a linear regression model. The total consumption of macrolides presented a significant correlation with the prevalence of resistance (R = 0.527; P = 0.032). Neither TID nor BID macrolide consumption showed significant correlations. Only OD consumption had a significance below 0.1. These data are consistent with the hypothesis that only the total consumption of macrolides influences the local rates of M-type erythromycin resistance in S. pyogenes, and subgroups of macrolides seem to have an additive rather than a selective effect by contributing to increasing the final amount of macrolides used. Local variations in total consumption were associated only with BID consumption (R = 0.849; P = 0.004). The simple linear regression with total macrolide consumption showed a considerable determination coefficient (R(2) = 0.678; P = 0.006). The model explains up to 68% of the measured variation and is clearly better as a predictor of the prevalence of resistance than the mere mean is. By solving the regression equation, the resultant value of 2.2 defined doses per 1,000 inhabitants per day fits with the existence of a critical threshold of selective pressure.

Anti-Bacterial Agents↗

PubMedDate not supplied

Predicting adolescents' intake of fruits and vegetables.

OBJECTIVE: To explore potential predictors of adolescents' fruit and vegetable intake by expanding on current theory and drawing from other adolescent research. DESIGN: This research reports on baseline and interim data from a school-based intervention study. Data were collected through surveys administered to students at the beginning and end of their 7th grade year. SETTING: The students attended 16 public schools in Minnesota. PARTICIPANTS: Data were collected on 3878 students; approximately half were female and 67% were white. All students in the 7th grade cohort were invited to participate in the surveys and over 94% completed both surveys. VARIABLES MEASURED: Our dependent variable, fruit and vegetable intake, was assessed by a validated fruit and vegetable food frequency scale. Predictive factors assessed included parenting style, spirituality/religiosity, depressive symptoms, and other commonly assessed predictors. ANALYSIS: Generalized linear mixed model regression. Omnibus test of association using P <.05 is reported. RESULTS: Subjective norms, barriers, knowledge, usual food choice, parenting style, spirituality/religiosity, and depressive symptoms were statistically significant predictors of intake. The model explained about 31% of the variance in fruit and vegetable consumption. CONCLUSIONS AND IMPLICATIONS: To better understand adolescents' fruit and vegetable intake, we must explore novel predictors. Our results need to be replicated, and more exploratory research in this field is needed.

Adolescent↗

PubMed2006

The gatekeeper residue controls autoactivation of ERK2 via a pathway of intramolecular connectivity.

Studies of protein kinases have identified a "gatekeeper" residue, which confers selectivity for binding nucleotides and small-molecule inhibitors. We report that, in the MAP kinase ERK2, mutations at the gatekeeper residue unexpectedly lead to autoactivation due to enhanced autophosphorylation of regulatory Tyr and Thr sites within the activation lip that control kinase activity. This occurs through an intramolecular mechanism, indicating that the gatekeeper residue indirectly constrains flexibility at the activation lip, precluding access of the phosphoacceptor residues to the catalytic base. Other residues that interact with the gatekeeper site to form a hydrophobic cluster in the N-terminal domain also cause autoactivation when mutated. Hydrogen-exchange studies of a mutant within this cluster reveal perturbations in the conserved DFG motif, predicting a route for side chain connectivity from the hydrophobic cluster to the activation lip. Mutations of residues along this route support this model, explaining how information about the gatekeeper residue identity can be transmitted to the activation lip. Thus, an N-terminal hydrophobic cluster that includes the gatekeeper forms a novel structural unit, which functions to maintain the "off" state of ERK2 before cell signal activation.

Animals↗

PubMed2004

[Normalization of the Brief Repeatable Battery of Neuropsychological tests (BRB-N) for German-speaking regions. Application in relapsing-remitting and secondary progressive multiple sclerosis patients].

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) is a neuropsychological screening battery, often applied in multiple sclerosis (MS) patients. It is almost exclusively administered in trials and not in the daily practice routine because of the lack of normative values. Using a stepwise linear regression analysis, the dependence of test results on age, gender, and education of 241 healthy control subjects was investigated. Z-values of -1.68 or less were considered pathological. Based on the normative values, the proportions of cognitively impaired patients with relapsing-remitting MS (RRMS, n=43) and secondary progressive MS patients (SPMS, n=60) were calculated. The regression model explained 2.7-25.0% of the variance of test performances. Cognitive impairment occurred in 38% and in 47% of the RRMS and the SPMS groups, respectively. In both groups attention and concentration impairment was prominent, while in the SPMS group memory was also frequently affected. The proportion of cognitively impaired MS patients reflected the figures that could be found in the literature.

Adolescent↗

PubMed1997

A neuropsychological model relating self-awareness to hostility.

Neuropsychological advances may help researchers better understand the relationship between psychological constructs. This paper proposes a neuropsychological model explaining the negative relationship between hostility and "self-awareness," which has been suggested by previous research [H. A. Demaree and D. W. Harrison (1995a) "Behavioral, Physiological, and Neuropsychological Correlates of Hostility," manuscript submitted for publication; L. H. Epstein and P. A. Cluss (1982) "A Behavioral Medicine Perspective on Adherence to Long-Term Medical Regimes," Journal of Consulting and Clinical Psychology, Vol. 50, pp. 950-971; M. F. Scheier et al. (1974) "Self-Awareness and Physical Aggression," Journal of Experimental and Social Psychology, Vol. 10, pp. 254-273]. The authors review the role of the right cerebrum in both hostility and "self-awareness"--including arousal, perceptual, expressive, and integrative processes. Using identifiable tracts in the brain, the model suggests how deficits in "self-awareness"--poor awareness of physiological arousal, natural and emotional environment, etc.--may enhance the probability of hostility expression. This model is supported by previous empirical research and provides direction for future neuropsychological investigation.

Awareness↗

PubMed2000

Does acute bronchitis really exist? A reconceptualization of acute viral respiratory infections.

BACKGROUND: Considerable overlap exists in patient presentations and physical findings in viral upper respiratory tract infections (URIs) and acute bronchitis. Our goal was to determine whether there are any clinical cues that could help physicians differentiate between these 2 conditions. METHODS: We performed a retrospective chart audit on 135 patients who had been given a diagnosis of acute bronchitis and a random sample of 409 patients with URIs over a 2.5-year period. Patient and provider characteristics, patient symptoms, and physical findings were compared with bivariate analyses and then entered into a logistic regression model. RESULTS: In bivariate analyses, a number of demographic variables, symptoms, and signs were associated with acute bronchitis. Multivariate analysis showed that the strongest independent predictors of acute bronchitis were cough (adjusted odds ratio [AOR]=21.12; 95% confidence interval [CI], 6.01-74.26), and wheezing on examination (AOR=12.16; 95% CI, 5.39-27.42). Nausea was the strongest independent predictor that the diagnosis would not be acute bronchitis (AOR=0.01; 95% CI, 0.01-0.85). However, there was considerable overlap between the 2 conditions, and the logistic model explained only 37% of the variation between the diagnoses. CONCLUSIONS: We hypothesize that sinusitis, URI, and acute bronchitis are all variations of the same clinical condition (acute respiratory infection) and should be conceptualized as a single clinical entity, with primary symptoms related to different anatomic areas rather than as different conditions.

Acute Disease↗

PubMed2005

Role of lipid protrusions in the function of interfacial enzymes.

Secretory phospholipase A(2) (sPLA(2)) is a class of interfacially active enzymes that selectively hydrolyze lipid molecules organized at interfaces like membranes. We present a simple theoretical model that relates the sPLA(2) action to the protrusions of the lipid molecules. The model explains (1) the observed enhancement of enzymatic activity by lipids with flexible, neutral, water-soluble polymers linked to their head groups and (2) the lag-burst kinetics of sPLA(2). It yields qualitative predictions of the effect of the initial composition of the membrane, the molecular weight of the polymer, and the composition of the hydrolysis products.

Cell Surface Extensions↗

PubMedDate not supplied

Evaluation of bone mineral density in patients with rheumatoid arthritis. Influence of disease activity and glucocorticoid therapy.

OBJECTIVES: To study bone mass and the factors that influence bone mass in rheumatoid arthritis patients versus controls. PATIENTS AND METHODS: 85 patients (73 women) with a mean age of 57 +/- 11 years and a mean disease duration of 13 +/- 9 years were compared to 85 age- and sex-matched controls. Among the patients, 62 (76%) had positive rheumatoid factor tests and 51 (60%) were receiving steroid therapy, with a mean daily dose of 10 +/- 4 mg and a mean duration of 7 +/- 6 years. The following parameters were determined: morning stiffness duration, painful and swollen joint counts, Lee's and Ritchie's indices, Health Assessment Questionnaire score, erythrocyte sedimentation rate, and C-reactive protein. Bone mineral density was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry (Sophos L-XRA). RESULTS: In the nonsteroid-treated patients, bone mineral density was similar to that in controls at the lumbar spine but was decreased by 8% (95% confidence interval [CI], 1.8-14.2%) at the femoral neck (0.76 +/- 0.14 g/cm2 versus 0.83 +/- 0.15 g/cm2; P = 0.03). Decreases of 11.5% (95% CI, 8.1-14.9%) at the lumbar spine and 10.4% (95% CI, 6.4-14.4%) at the femoral neck were found in the steroid-treated patients versus the nonsteroid-treated patients. In the patient group, femoral neck bone mineral density was significantly negatively correlated with age (r = -0.5), the Heath Assessment Questionnaire score (r = -0.27), and the erythrocyte sedimentation rate (r = -0.25), whereas only the first two variables were significantly correlated with lumbar bone mineral density. A multiple linear regression model including age, glucocorticoid use, rheumatoid factor, the Health Assessment Questionnaire score, and the erythrocyte sedimentation rate was constructed and adjusted for the number of variables. This model explained 44.7% of the variance of femoral neck bone mineral density. CONCLUSION: Rheumatoid arthritis is associated with a decrease in bone mass that is most marked in patients with active and/or severe disease and in those who take glucocorticoids.

Absorptiometry, Photon↗

PubMed1992

Factors affecting the ingestion of fluoride dentifrice by children.

Several factors affecting the amount of fluoride ingested during toothbrushing by 2- to 7-year-old children were investigated. The specific purpose of this study was to determine the contribution of age, the amount of dentifrice used, and rinsing after brushing to the variation in the ingestion of fluoride dentifrice. Four hundred and five children brushed their teeth in front of a portable sink. The tubes of dentifrice in gel (0.24% NaF) were weighed before and after use to determine the amount of toothpaste used. The fluoride content of the collected liquids was determined with a fluoride-ion-specific electrode. The amount of fluoride ingested was derived by determining the difference between the amounts used and recovered. The amount of dentifrice used, the age, and the rinsing habits, entered in a multiple regression model, explained up to 66 percent of the total variation in the amount of fluoride ingested. The amount of dentifrice used accounted by itself for 60 percent of the total variation. Therefore, these results indicate that the quantity of dentifrice used was the most important factor affecting the ingestion of fluoride through toothbrushing by young children.

Age Factors↗

PubMed1993

Determinants of children's health care use: an investigation of psychosocial factors.

Factors related to the amount of health care used by 5- to 11-year-old children in a health maintenance organization (HMO) were investigated using a comprehensive multivariate model that assessed the contribution of child health need, mental health, and social functioning; maternal mental health, social support and health care utilization; and family functioning and life events. Mothers reported on the 450 participating children. Health care visits for a two-year retrospective period were obtained from the computerized encounter system. Child health need and maternal patterns of health care use were powerful predictors of the overall amount of health care used, and these factors discriminated high users from low users of care. Family conflict was associated with a higher volume of care, while children's depressive symptoms and non-white race were related to lower use. Maternal social support, mental health, and life events were not predictive of use in either full multivariate model. Enabling factors were held relatively constant by participation of all families in a prepaid HMO. The multiple regression model explained 33% of the variance in use, slightly more than in previous studies of children's health care use. When included in a comprehensive analysis, child and family psychosocial characteristics help to explain children's health care use beyond what is possible using simple health and illness variables. The implications of these findings in the development of further research and to the practice of routine pediatric care are discussed.

Adult↗

PubMed1986

Pulse-wave model of brachial arterial pressure modulation in aging and hypertension.

We apply a pulse-wave theory to a model of the human arm arterial system that predicts the changes in the arterial pressure waveform as it traverses the vasculature (increased pulse pressure, sharper main wave, disappearance of the aortic incisura, and appearance of a diastolic dicrotic wave) and also predicts the observed modulation of the waveform during phenylephrine-induced vasoconstriction and nitroglycerin-induced vasodilation. The model considers the arm arterial system as a tapered, distensible tube that bifurcates and then ends in a loop, with sidebranch networks represented by distributed Windkessels. The model uses verifiable values for realistic parameters. We found that the vertical modulation of the dicrotic wave, in humans, decreased with advancing age and with high blood pressure. The model explained these findings in terms of increasing vascular rigidity and decreasing small vessel vasodilator responsiveness. We noted a significant negative correlation between the arterial level of plasma norepinephrine and the amount of modulation of the dicrotic wave after nitroglycerin among subjects 40 yr old or younger, suggesting a sympathetic neurogenic contribution to the vascular abnormalities observed in relatively young patients with essential hypertension.

Adult↗