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PubMed1991

Estimation of maximum tolerated dose for long-term bioassays from acute lethal dose and structure by QSAR.

A quantitative structure-activity relationship (QSAR) model has been developed to estimate maximum tolerated doses (MTD) from structural features of chemicals and the corresponding oral acute lethal doses (LD50) as determined in male rats. The model is based on a set of 269 diverse chemicals which have been tested under the National Cancer Institute/National Toxicology Program (NCI/NTP) protocols. The rat oral LD50 value was the strongest predictor. Additionally, 22 structural descriptors comprising nine substructural MOLSTAC(c) keys, three molecular connectivity indices, and sigma charges on 10 molecular fragments were identified as endpoint predictors. The model explains 76% of the variance and is significant (F = 35.7) at p less than 0.0001 with a standard error of the estimate of 0.40 in the log (1/mol) units used in Hansch-type equations. Cross-validation showed that the difference between the average deleted residual square (0.179) and the model residual square (0.160) was not significant (t = 0.98).

Animals↗

PubMed1971

Regulation of tryptophan biosynthetic enzymes in Neurospora crassa.

The formation of enzymatic activities involved in the biosynthesis of tryptophan in Neurospora crassa was examined under various conditions in several strains. With growth-limiting tryptophan, the formation of four enzymatic activities, anthranilic acid synthetase (AAS), anthranilate-5-phosphoribosylpyrophosphate phosphoribosyl transferase (PRAT), indoleglycerol phosphate synthetase (InGPS), and tryptophan synthetase (TS) did not occur coordinately. AAS and TS activities began to increase immediately, whereas PRAT and InGPS activities began to increase only after 6 to 12 hr of incubation. In the presence of amitrole (3-amino-1,2,4-triazole), the formation of TS activity in a wild-type strain was more greatly enhanced than were AAS and InGPS activities. With a tr-3 mutant, which ordinarily exhibits an elevated TS activity, amitrole did not produce an increase in TS activity greater than that observed on limiting tryptophan. With tr-3 mutants, the increased levels of TS activity could be correlated with the accumulation of indoleglycerol in the medium; prior genetic blocks which prevented or reduced the synthesis of indoleglycerol also reduced the formation of TS activity. The addition of indoleglycerol to cultures of a double mutant (tr-1, tr-3) which could not synthesize indoleglycerol markedly stimulated the production of TS activity but not PRAT activity; the production of TS activity reached the same level with limiting or with excess tryptophan. A model explaining these and other related observations on enzyme formation in N. crassa is proposed.

Cell-Free System↗

PubMed2000

Smoking and stress: common denominators for periodontal disease, heart disease, and diabetes mellitus.

The scientific evidence supporting the relationship between periodontal disease and two major health problems of the US population, i.e., cardiovascular disease and diabetes mellitus, is discussed. Evidence supporting the behavioral and psychosocial factors mediating the relationship between periodontal infection and these systemic conditions, namely smoking and stress, is presented, as well as models explaining these relationships. Treatment protocols are suggested for the clinical management of patients who smoke, are diabetic, or are at risk for cardiovascular disease.

Cardiovascular Diseases↗

PubMed1989

Drug abuse: a biopsychiatric model.

The effects of drug abuse are caused by the stimulation or inhibition of different neurotransmitters, chiefly gamma-aminobutyric acid, acetylcholine, norepinephrine, dopamine, serotonin and beta-endorphin. The biopsychiatric model focuses on neurotransmitter activity to diagnose and treat overdose and addiction. This model explains how different drugs exert their effects and provides a rationale for specific pharmacologic intervention in the drug-abusing patient.

Amphetamines↗

PubMed1990

Effect of nematode infections and management practices on growth performance of calves on commercial dairy farms.

Liveweight of calves on 86 dairy farms was measured at the end of the grazing season and related per herd to the level of exposure to nematode infection estimated in October and December. There were significant between-herd variations in all the serological infection parameters measured. On average 20.5 larvae per gram faeces (geometric mean) were found in October. Faecal samples of 20.5% of the herds contained lungworm larvae. Liveweight of calves deviated per herd from -59.8 kg to +52.2 kg from an age-adjusted population mean after their first grazing season. Growth performance was significantly related negatively to several serological and parasitological parameters. Data were fitted by means of both linear and segmented curvilinear regression. By combining infection parameters 19% of the variation in growth performance among herds could be explained. Infection parameters involved were antibody titre against Cooperia spp., egg output and lungworm larval count. It was found that antibody titres were significantly correlated positively to herd age, while pepsinogen values and egg output were negatively correlated to age. Combining supplementary feeding and anthelmintic treatment during the grazing season with the infection parameters into one model explained approximately 30% of the observed variation in growth performance among herds. It was shown that these findings were consistent with those of a similar study conducted on the same farms a year earlier, although there were clear differences between the years. Finally, significant positive relations were found between the levels of exposure to nematode parasites within farms between two consecutive years.

Age Factors↗

PubMed1998

Median mononeuropathy among active workers: are there differences between symptomatic and asymptomatic workers?

The objective was to determine whether symptomatic workers with an abnormal sensory nerve conduction study consistent with carpal tunnel syndrome differed, in terms of electrophysiologic measures, psychosocial, demographic, anthropometric, or ergonomic variables, from workers with an asymptomatic median mononeuropathy. This was a cross-sectional study of active workers at six different work sites. Cases were defined as workers with electrodiagnostic findings of a median mononeuropathy in either hand, based on a 0.5-msec prolongation of the median sensory evoked peak latency compared to the ulnar latency. This group was stratified on the basis of symptoms of numbness, tingling, burning or pain in the hand. The two groups were compared in terms of demographic, anthropomorphic, psychosocial, electrophysiologic, and ergonomic risk factors. Active workers from six different sites were tested; five sites involved manufacturing workers, and one site represented clerical workers. One hundred eighty-four active workers with a median mononeuropathy were documented on nerve conduction studies. These workers represented a subset of more than 700 workers screened at six different locations. The main outcome measure was the patient's report of symptoms of pain, numbness, tingling or burning in the hand or fingers that lasted more than 1 week or occurred three or more times at the initial screening. Workers with a median mononeuropathy who complained of hand symptoms were more likely to be female, to have jobs with higher hand repetition levels, to have higher ratings of job security, not to have a history of diabetes, to use more force in their job with more abnormal postures of their wrist and fingers, and to have a trend toward a more prolonged median sensory distal latency. Most logistic regression models explained less than 15% of the variance (pseudo R2). Women with jobs that have higher ergonomic risks and no history of diabetes were more likely to have reported symptoms associated with carpal tunnel syndrome compared to other workers with a documented median mononeuropathy. Psychosocial variables were not particularly discriminatory. None of the models allows enough precision to predict on an individual basis.

Adult↗

PubMedDate not supplied

V1 mechanisms and some figure-ground and border effects.

V1 neurons have been observed to respond more strongly to figure than background regions. Within a figure region, the responses are usually stronger near figure boundaries (the border effect), than further inside the boundaries. Sometimes the medial axes of the figures (e.g., the vertical midline of a vertical figure strip) induce secondary, intermediate, response peaks (the medial axis effect). Related is the physiologically elusive "cross-orientation facilitation", the observation that a cell's response to a grating patch can be facilitated by an orthogonally oriented grating in the surround. Higher center feedbacks have been suggested to cause these figure-ground effects. It has been shown, using a V1 model, that the causes could be intra-cortical interactions within V1 that serve pre-attentive visual segmentation, particularly, object boundary detection. Furthermore, whereas the border effect is robust, the figure-ground effects in the interior of a figure, in particular, the medial axis effect, are by-products of the border effect and are predicted to diminish to zero for larger figures. This model prediction (of the figure size dependence) was subsequently confirmed physiologically, and supported by findings that the response modulations by texture surround do not depend on feedbacks from V2. In addition, the model explains the "cross-orientation facilitation" as caused by a dis-inhibition, to the cell responding to the center of the central grating, by the background grating. Furthermore, the elusiveness of this phenomena was accounted for by the insight that it depends critically on the size of the figure grating. The model is applied to understand some figure-ground effects and segmentation in psychophysics: in particular, that contrast discrimination threshold is lower within and at the center of a closed contour than that in the background, and that a very briefly presented vernier target can perceptually shine through a subsequently presented large grating centered at the same location.

Animals↗

PubMed2006

Tracheid analysis and modeling of the minor veins of the coleus and smilax leaves.

Tracheid analysis was carried out on the veinlets and minor veins of the coleus (Solenostemon scutellarioides [L.] Codd) leaf. Third- to fifth-order, or minor, veins average 3.4 tracheids in tandem and they bipartition islets when these enclosed islets reach a critical size; both these features of vein length and islet size contribute to a self-similar process of vein pattern generation. An areole was calculated to be initially comprised of about ten cells making the patterning event for vein formation requiring only a few cells. An algorithmic model developed here for minor vein formation includes five production rules, and this computer model explains the 3-4 tracheids per minor vein, presence of isolated tracheids, the structure of veinlets, and the elaborate branching patterns of veinlets in coleus and other plants.

Body Patterning↗

PubMed1977

Quantitative structure--activity relationships. 7. The bilinear model, a new model for nonlinear dependence of biological activity on hydrophobic character.

The bilinear model, log 1/C =a log P-b log (betaP+1) +C, a new model for nonlinear dependence of biological activity on hydrophobic character, is applied to 57 data sets of biological activity values in homologous series. From a comparison of the statistical parameters and the residuals obtained with the bilinear model and the parabolic model, the superiority of the bilinear model for a precise quantitative description of both linear and nonlinear parts of sturcture-activity relationships can be derived; the bilinear model explains the particular effect that in homologous series the relationship between biological activity and hydrophobic character is strictly linear for the lower members, while for higher members this relationship is nonlinear.

Animals↗

PubMed2000

Solvent effects on squid sodium channels are attributable to movements of a flexible protein structure in gating currents and to hydration in a pore.

1. Solvent effects on the time course of gating and sodium currents were analysed in squid sodium channels using four non-electrolytes of different size, glycerol, erythritol, glucose and sucrose, to separate effects of viscosity from those of osmolarity and to obtain viscosity and osmolarity parameters that were independent of molecular size. 2. The gating and sodium currents were reversibly slowed in a voltage-independent manner as the non-electrolyte concentration increased. 3. Solvent effects were analysed using a model in which the percentage change in time constant was expressed by an equation involving the viscosity parameter alpha and the osmolarity parameter delta: t/t0 = alpha (eta/eta 0) - 1 + 100 alpha-1)exp(delta delta pi), where eta/eta 0 is solution viscosity and delta pi is increase in osmolarity. Since the solution viscosity was found experimentally to be a function of the solution osmolarity, solvent effects are described by an equation with one independent variable eta/eta 0 or delta pi. 4. Voltage sensor movement, reflected in gating currents, was primarily sensitive to viscosity, as its decay time constant was a function of eta/eta 0, with only a minor sensitivity to osmolarity (delta was 2-3 water molecules). 5. For sodium currents, alpha was equal to that of gating currents but delta was 2-3 times greater, suggesting that the final channel opening was primarily sensitive to osmolarity (delta delta was 5 water molecules). The relative ineffectiveness of the largest non-electrolyte, sucrose, suggested that this osmolarity-sensitive step in channel opening occurred in the narrow pore region. 6. Sodium channel inactivation was primarily sensitive to osmolarity (delta delta was 8-12 water molecules). 7. The observed viscosity dependence of the sodium current activation and inactivation processes was attributable to the viscosity-dependent process accompanying the gating current. 8. This model explains why non-electrolytes slow sodium currents while electrolytes do not. 9. Viscosity effects on gating currents can be explained by a process in which non-electrolytes interact with the flexible hydrophilic parts of sodium channel proteins, but osmolarity effects on the final step need to be explained by a local interaction of several water molecules with fluctuating protein segments in the pore.

Animals↗

PubMed1975

Actions and interactions of dipropylacetate and penicillin on evoked potentials of excised prepiriform cortex of guinea pig.

Slices from guinea pig brain containing the lateral olfactory tract (LOT) and the prepiriform cortex were studied in vitro. Field potentials, evoked by stimulation of the LOT, were recorded extracellularly. This field potential comprises a compound action potential, a surface negative wave (identified as EPSP), and superimposed positive peaks ("population spikes" or PSs) reflecting postsynaptic activity. In a previous article the penicillin-induced increase of EPSP and of both amplitude and number of PSs was described. Now we are reporting the slight depression of EPSP and PSs and the prevention of the appearance of penicillin-induced PSs by an antiepileptic drug sodium dipropylacetate (Depakine). The effect was dose-dependent. Models explaining the effects of penicillin and dipropylacetate are discussed.

Animals↗

PubMedDate not supplied

[Mechanism of the effect of neuronal response suppression in the auditory nerve during exposure to bitonal stimuli].

It is supposed that interreceptor currents existing due to microphonic and summating potentials are the exiting factors for the neuron endings of the cochlear nerve. A model is proposed of the formation of the cochlear neuron responses under the stimulation of the hearing system by a tone signal with a changing frequency and by a signal consisting of two tones. It is shown that the proposed model explains the effect of inhibition of the neuron response to a given tone signal when another tone signal of proper intensity arises in a definite frequency region.

Hearing↗

PubMed2005

Prediction of back strength using anthropometric and strength measurements in healthy females.

OBJECTIVES: The purpose of this study was to develop a regression equation to predict back extensor maximal voluntary contraction (back strength) for females based on several anthropometric and strength measurements using a multiple regression technique. BACKGROUND: Back strength is an important parameter in low back pain studies. However, the measurement of back strength is problematic in certain populations such as low back pain patients and pregnant women. METHODS: Back strength was measured as both moment at L4/L5 and force. Ten anthropometric or strength measurements were chosen to develop the prediction equation. The data used for developing the models were from eighty non-pregnant female subjects, age 18-42 and with no history of back pain in the past year. Backwards stepwise analysis was performed in order to choose the best fit predictors. The predictive ability of each of the models was checked using the cross-validation technique on 20 other subjects. FINDINGS: Two prediction models were developed for moment and force, respectively. The models explained 46.9% and 48.2% of the variance in back strength. No multicollinearity problem was found. The validation study showed that the observed back strength was highly correlated with the predicted back strength. INTERPRETATION: Mass, height, trunk length, grip strength and quadriceps strength are the best predictors of back strength in this study. The models developed in this study can be used for both general female low back pain patients and the pregnancy population.

Adolescent↗

PubMed1997

Transitions in infant feeding during the first year of life.

OBJECTIVE: To document ages at which transitions in infant feeding occur, to compare these transitions to literature reports from the 1970s and 80s, and to identify maternal characteristics related to the age of the infant when solid food was first introduced. METHODS: Ninety-eight mother/infant pairs (middle and upper socioeconomic status) participated in the longitudinal study. Using a randomized, incomplete block design, in-home interviews were conducted by trained personnel when infants were 2, 3, 4, 6, 8, 10, and 12 months of age; each mother/infant pair was seen four or five times. Information on food intake, including breast milk/formula, was collected at each interview. Means +/- SD and frequencies were calculated, and least squares analysis of variance was used to develop a predictive model related to the introduction of cereal. RESULTS: Most mothers decided on the initial feeding mode (breastfeeding or formula) prior to pregnancy; 83% breastfed initially although most (76%) totally discontinued breastfeeding by 6 months. Infants' ages varied greatly when each of the seven categories of food was introduced, cereal was added to the infants' diets at a mean age of 3.8 +/- 1.4 (SD) months, juice 4.7 +/- 2.2, fruit 4.9 +/- 1.6, vegetables 5.2 +/- 1.3, mixed foods 7.8 +/- 2.1, table foods 8.2 +/- 2.1, and meat 8.2 +/- 2.1. The multivariate model explained 59% of the variability in ages of infants when cereal (generally the first solid food) was added. Significant variables (p < or = 0.05) were feeding mode, recommendation by the physician, and the interaction between feeding mode and education of the mother. Mother's employment and sibling rank of the infant contributed to the model (p = 0.06 and p = 0.09, respectively). Infants' age when cereal was added was not related to the variables of gender or birth weight. CONCLUSIONS: The finding that the mothers' decision whether or not to breastfeed was made prior to conception supports the importance of population-based education aimed at women in the child-bearing years as well as patient instruction early in the pregnancy. However, the duration of breastfeeding was shorter than was reported in the 1980s. Infants varied greatly in ages when the seven categories of complementary foods were added to their diets. Although recommendations for delaying introduction of solid foods until the infant is 4 to 6 months of age have been in place for more than a decade, about half the mothers in this study did so earlier. Characteristics of mothers who introduced cereal earliest (i.e., mean age of infants < 4 months) were more likely to be formula feeding when cereal was added, to feed cereal via the bottle, to be primiparous, to be employed outside the home, and/or not to cite the physician as a source for guiding the infant's transition to supplemental food.

Adult↗

PubMed2003

Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence.

Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, represents a new and potentially important target in cardio-renal disease. A model of the active site of ACE2, based on the crystal structure of testicular ACE, has been developed and indicates that the catalytic mechanism of ACE2 resembles that of ACE. Structural differences exist between the active site of ACE (dipeptidyl carboxypeptidase) and ACE2 (carboxypeptidase) that are responsible for the differences in specificity. The main differences occur in the ligand-binding pockets, particularly at the S2' subsite and in the binding of the peptide carboxy-terminus. The model explains why the classical ACE inhibitor lisinopril is unable to bind to ACE2. On the basis of the ability of ACE2 to cleave a variety of biologically active peptides, a consensus sequence of Pro-X-Pro-hydrophobic/basic for the protease specificity of ACE2 has been defined that is supported by the ACE2 model. The dipeptide, Pro-Phe, completely inhibits ACE2 activity at 180 microM with angiotensin II as the substrate. As with ACE, the chloride dependence of ACE2 is substrate-specific such that the hydrolysis of angiotensin I and the synthetic peptide substrate, Mca-APK(Dnp), are activated in the presence of chloride ions, whereas the cleavage of angiotensin II is inhibited. The ACE2 model is also suggestive of a possible mechanism for chloride activation. The structural insights provided by these analyses for the differences in inhibition pattern and substrate specificity among ACE and its homologue ACE2 and for the chloride dependence of ACE/ACE2 activity are valuable in understanding the function and regulation of ACE2.

Amino Acid Sequence↗

PubMed1997

Comparative molecular field analysis of a series of paclitaxel analogues.

A series of 94 paclitaxel analogues exhibiting antitumor activity by promoting the assembly of microtubules and inhibiting the disassembly process of microtubules to tubulin were investigated using the comparative molecular field analysis (CoMFA) method. These compounds belonging to 10 structural classes were randomly divided into a training set of 80 compounds and a test set of 14 compounds. Since the three-dimension structure of ligand--receptor complex is unknown, from X-ray and NMR data we rationally selected the three-dimension structure of paclitaxel in a polar solution as the active conformation and starting structure for molecule modeling, the other molecules were aligned using this molecule model as the template. The most optimal CoMFA yielded a two-components model, with significant cross-validation r2cv of 0.640 and conventional r2 of 0.868. The predictive ability of training set model was tested on the test set of 14 compounds. The tests not only revealed the robustness of the CoMFA model but demonstrated that for our model r2pred based on the mean activity of test set compounds can accurately estimate external predictivity but r2pred based on the mean activity of training set compounds overestimated the model. The CoMFA model explained why the activity of taxoid is sensitive to the stereochemistry of the atoms at C-2' and C-3' positions and the presence of hydroxyl group at C-2' position. The other factors affecting activity were also elucidated according to standard coefficient contour maps of steric and electrostatic fields derived from the CoMFA model.

Antineoplastic Agents↗

PubMed2000

The formation of a flexible DNA-binding protein chain is required for efficient DNA unwinding and adenovirus DNA chain elongation.

The adenovirus DNA-binding protein (DBP) binds cooperatively to single-stranded DNA (ssDNA) and stimulates both initiation and elongation of DNA replication. DBP consists of a globular core domain and a C-terminal arm that hooks onto a neighboring DBP molecule to form a stable protein chain with the DNA bound to the internal surface of the chain. This multimerization is the driving force for ATP-independent DNA unwinding by DBP during elongation. As shown by x-ray diffraction of different crystal forms of the C-terminal domain, the C-terminal arm can adopt different conformations, leading to flexibility in the protein chain. This flexibility is a function of the hinge region, the part of the protein joining the C-terminal arm to the protein core. To investigate the function of the flexibility, proline residues were introduced in the hinge region, and the proteins were purified to homogeneity after baculovirus expression. The mutant proteins were still able to bind ss- and double-stranded DNA with approximately the same affinity as wild type, and the binding to ssDNA was found to be cooperative. All mutant proteins were able to stimulate the initiation of DNA replication to near wild type levels. However, the proline mutants could not support elongation of DNA replication efficiently. Even the elongation up to 26 nucleotides was severely impaired. This defect was also seen when DNA unwinding was studied. Binding studies of DBP to homo-oligonucleotides showed an inability of the proline mutants to bind to poly(dA)(40), indicating an inability to adapt to specific DNA conformations. Our data suggest that the flexibility of the protein chain formed by DBP is important in binding and unwinding of DNA during adenovirus DNA replication. A model explaining the need for flexibility of the C-terminal arm is proposed.

Adenoviridae↗

PubMed2006

Deciphering the effects of climate on animal populations: diagnostic analysis provides new interpretation of Soay sheep dynamics.

Soay sheep on the island of Hirta exhibit periodic population collapses that have been proposed to result from nonlinear interactions between weather, population density, and age structure. Here we employ a diagnostic approach to reanalyze the data from 1985 to 2004 and find that climate mainly affects the equilibrium population size, thus acting as a lateral perturbation. From this, we derive a simple energetic model for a population interacting with its food supply in the presence of variable winter weather. This model explains the strong nonlinearity in the Soay sheep population regulation function and provides a framework for evaluating climatic perturbations. We examined two integrative climatic indexes, one representing effects on forage production and the other representing the severity of winter weather. Results suggest that the latter has the main effect on Soay sheep population dynamics. Models incorporating this variable provided fairly accurate predictions of Soay sheep population fluctuations. The diagnostic approach offers an objective way to develop simple, nonstructured population models that are useful for understanding the causes of population fluctuations and predicting population changes, provided they are based on a careful consideration of the underlying biological and/or ecological mechanisms.

Animals↗