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PubMed2002

Dynamics of large proteins through hierarchical levels of coarse-grained structures.

Elastic network models have been successful in elucidating the largest scale collective motions of proteins. These models are based on a set of highly coupled springs, where only the close neighboring amino acids interact, without any residue specificity. Our objective here is to determine whether the equivalent cooperative motions can be obtained upon further coarse-graining of the protein structure along the backbone. The influenza virus hemagglutinin A (HA), composed of N = 1509 residues, is utilized for this analysis. Elastic network model calculations are performed for coarse-grained HA structures containing only N/2, N/10, N/20, and N/40 residues along the backbone. High correlations (>0.95) between residue fluctuations are obtained for the first dominant (slowest) mode of motion between the original model and the coarse-grained models. In the case of coarse-graining by a factor of 1/40, the slowest mode shape for HA is reconstructed for all residues by successively selecting different subsets of residues, shifting one residue at a time. The correlation for this reconstructed first mode shape with the original all-residue case is 0.73, while the computational time is reduced by about three orders of magnitude. The reduction in computational time will be much more significant for larger targeted structures. Thus, the dominant motions of protein structures are robust enough to be captured at extremely high levels of coarse-graining. And more importantly, the dynamics of extremely large complexes are now accessible with this new methodology.

Amino Acids↗
PubMed2002

17beta-estradiol matrixpatch removal and reapplication in postmenopausal women: theoretical predictions with an oscillating diffusion coefficient model.

The pharmacokinetic performance of a matrix system for transdermal beta-estradiol (E(2)) delivery after multiple consecutive dosing in postmenopausal women undergoing hormone replacement therapy was investigated. The E(2) plasma profiles determined during the third application in 16 postmenopausal women were compared with results obtained in a published clinical study using the same patch in 24 postmenopausal women without E(2) pretreatment; they were compared with a theoretical diffusion/pharmacokinetic model. A conventional theoretical model with constant model parameter (CPM) obtained from in vitro mass balance experiments in a Franz cell type set up described successfully the transdermal E(2) bioavailability parameter AUC(0-96h) (4341.9 +/- 1513.1; calculated 4250.8) and C(average) (45.0 +/- 13.2; calculated 41.2). Also, experimentally, there was no significant drop in E(2) plasma values after patch removal and reapplication; this was corroborated by calculations. Accumulation of E(2) did not occur when several patches were applied consecutively over a period of 3 weeks. Steady state was achieved following application of the first patch. However, the differences between recorded E(2) plasma profiles and theoretical results detected at specific measurement points cannot be explained by the CPM model. Experimentally obtained plasma profiles were always lower in the morning and higher in the evening than predicted on the basis of the model. Measurements of in vivo skin temperature in the postmenopausal women showed oscillating temperature profiles in the form of a cosinor function: The temperature mesor of untreated postmenopausal women was 34.8 degrees C with an acrophase at 17.0 o'clock (95% CI: 14.30-19.30) and an amplitude of +/- 0.4 degrees C (p = 0.1). During the application of the patch the average temperature next to a patch rose 0.3 degrees C, which was statistically significant (p = 0.1). In the skin under the application of the matrix patch a mesor temperature was detected as 35.6 degrees C with an amplitude of +/- 0.5 degrees C with an acrophase at 17.51 o'clock (95% CI: 14.30-21.00) (p = 0.05). The temperature period was 24 h for all measurements and the maximum temperature was observed at about 16.30 h, and a minimum at about 5.00 h. A linear dependency was detected in in vitro experiments between the log of E(2) permeability and the temperature for stripped skin, epidermis/dermis layer, as well as for the matrix. Modeling of E(2) plasma profiles with oscillating diffusion coefficients (ODM1) with a sine wave function results in this equation: D(1) = D(0x) + Da(x).sin(k.t). D(0x) is the diffusion coefficient determined at 35.6 degrees C, k is 1/24 h, D(a) is the diffusion coefficient of the temperature amplitude, h is hour, and x stands for the respective diffusion layer. It was shown that the experimental E(2) plasma profile variations are more pronounced than can simply be explained by skin temperature variations alone (ODM1 model). A simplex fit with an oscillating diffusion coefficient in the form of a sine wave function for the stratum corneum (ODM2 model) resulted in a temperature amplitude of 1.1 degrees C, about twice as high as was determined in the in vivo measurements (ODM2 model). Therefore, other circadian parameterlike blood flow might superimpose the temperature profile. The improvement in data analysis by incorporating oscillating diffusion coefficients (ODM1 and 2) over CPM was judged from a comparison of experimental data with the calculated plasma profiles with the AIC, Akaikes model selection criterion, which allows ranking between models because it is independent of the scaling of the data points. ODM1 and ODM2 improved the data analysis over CPM by allowing better calculation of experimental C(max), t(max), the time to reach to C(max), and the fluctuation, f. No difference between CPM, ODM1, or ODM2 was found for the bioavailability parameter C(average) and AUC(0-96h).

Administration, Cutaneous↗
PubMed1991

Physiological and pharmacological properties of 5-HT3 receptors--a patch clamp-study.

Whole cell and patch clamp techniques were used to investigate the properties of 5-HT3 receptors of a murine neuroblastoma cell line (N1E-115) and adult rabbit nodose ganglion neurones. In addition, some preliminary results from guinea-pig nodose ganglion neurones are presented. In such cells, voltage-clamped at -60 mV, 5-HT (10 microM) induced an inward current associated with a conductance increase. The results of ion substitution experiments suggest that the 5-HT activated ion channel is permeable to both Na+ and K+ ions with a permeability ratio (PNa/PK) of 0.94 and 0.92 for rabbit nodose ganglion cells and N1E-115 cells respectively. On outside out membrane patches excised from rabbit nodose ganglion neurones, 5-HT (1 microM) activated clearly discernible single channel currents with a conductance of 16.6 +/- 0.7 pS (n = 4). In contrast, fluctuation analysis of 5-HT induced whole cell currents suggests that the single channel conductance of N1E-115 cells is only 0.3 pS, a value some 50 fold lower. The 5-HT-induced whole cell currents recorded from all three preparations were antagonised by the selective 5-HT3 receptor antagonist ondansetron (GR38032F) and by the less selective agents metoclopramide, cocaine and (+)-tubocurarine. However, these preparations demonstrate a differential sensitivity to some antagonists. In particular, (+)-tubocurarine was a potent antagonist in N1E-115 cells (IC50 = 0.85 nM) but was approximately 200 fold (IC50 = 156 nM) and 1200 fold (IC50 = 10 microM) less potent in rabbit and guinea-pig nodose ganglion neurones respectively. Additionally, a novel effect of ketamine (10 microM) to potentiate the 5-HT-induced current of rabbit nodose ganglion neurones is described.

Action Potentials↗
PubMed2001

The thermal environment of arboreal pools and its effects on the metabolism of the arboreal, oophagous tadpoles of a Taiwanese tree frog, Chirixalus eiffingeri (Anura: Rhacophoridae).

We have studied seasonal and diurnal fluctuations of water temperature in bamboo stumps and the effect of temperature on the energy metabolism of arboreal, oophagous tadpoles of Chirixalus eiffingeri. We collected tadpoles (Gosner stage 28-29) in February and August from Chitou, Taiwan and acclimated them to 12 and 22 degrees C. Using a closed system, we measured tadpole oxygen consumption (V.O(2)) at 12, 17 and 22 degrees C. The water temperature was lowest in February (11-13 degrees C), increased rapidly during March and April and was highest from May to August (20-24 degrees C). Diel fluctuations in the temperature of the pools of water in bamboo stumps mirrored fluctuations in air temperature. Tadpoles collected in February and August exhibited metabolic compensation in that tadpoles acclimated at 12 degrees C had significantly higher V.O(2) than those acclimated at 22 degrees C. There are at least two possible explanations for the presence of metabolic compensation in C. eiffingeri tadpoles. Firstly, the larval period of C. eiffingeri ranges from 40 to 78 days, a tadpole could experience relatively large fluctuations in body temperature (up to 10 degrees C) during the development. As a result, C. eiffingeri tadpoles most likely evolved metabolic compensation to maintain activity levels under different thermal environments. Secondly, because arboreal pools are small, thermally unstratified, aquatic microhabitats, tadpoles are unable to behaviorally select preferred temperatures. As a result, metabolic compensation allows tadpoles to regulate their physiological functions.

Adaptation, Physiological↗
PubMed1997

Success in mating: a coordinated approach to fitness through genotypes incorporating genes for stress resistance and heterozygous advantage under stress.

Natural populations are normally exposed to substantial environmental stress. In these circumstances, an association occurs between success in mating and extremes of sexual ornaments, rapid development, long life span, and low fluctuating morphological asymmetry. This association between important fitness traits depends on high metabolic efficiency underlain by genes for stress resistance and heterozygous advantage. In particular, the high energy demands from the development and maintenance of sexual ornaments imply that the "good genes" favored in the sexual selection process should be stress resistant. However, the generalized heterozygous advantage under stress suggests that many interacting genes are involved in promoting metabolic efficiency, so that the "good genes" approach should be replaced by a "good genotypes" approach. This "good genotype" approach has predictive power for incorporating additional fitness traits, especially where metabolic consequences can be perceived.

Animals↗
PubMed1993

Relationship of protein intake to urinary oxalate and glycolate excretion.

The relationship of protein intake to urinary oxalate and glycolate excretion was examined in a large cohort (N = 101) of normal individuals on self-selected diets and in 11 individuals on controlled protein diets. On self-selected diets no correlation was detected between protein intake and urinary oxalate or glycolate excretion. A moderate but significant correlation (r = 0.45; P < 0.001) of oxalate with urea excretion was observed in males but not females, suggesting that there may be a link between urea and oxalate synthesis in males. On controlled protein diets mean oxalate excretion in females on days 7 to 10 of a high protein diet (1.8 g/kg body wt) was 20% higher than on a low protein diet (0.6 g/kg body wt; P = 0.02), but there was no difference in males. Glycolate excretion was significantly higher (P < 0.001) on the high protein diet than on the low protein diet in both sexes. Only a weak precursor-product relationship was observed between glycolate and oxalate. A gender effect was apparent on both self-selected and control diets with females excreting more oxalate and glycolate relative to creatinine than males. A pronounced inter- and intra-individual variability in the excretion of oxalate was observed, even on controlled diets. This suggests that genetic factors and physiological changes such as hormonal fluctuations may contribute more to the variability in oxalate excretion than the dietary intake of protein.

Adult↗
PubMed1999

Manual handling performance: the effects of menstrual cycle phase.

Physiological and subjective responses to physical performance have been shown to interrelate with fluctuations in the female hormonal environment throughout the menstrual cycle. The aim of this study was to examine whether these fluctuations affect the strenuous performance required in manual handling. Seventeen eumenorrheic females performed lifting tasks in five phases of their menstrual cycle. These tasks were maximal isometric lifting strength (MILS) and an endurance lift at 45% MILS (t), at both knee and waist height; and the selection of a maximal acceptable load (MAL) to lift six times per min, for 10 min, in both the sagittal and asymmetric planes. Heart rate response (HR) and rating of perceived exertion (RPE) were recorded throughout each of the lifting tasks. MILS, t and the chosen MAL were unaffected by menstrual phase over both heights and planes of lift (p > 0.05). HR to the isometric endurance lift was greater following ovulation than prior to ovulation by approximately 7 beats.min-1 (p < 0.05). This was true when the data were analysed at 50, 80 and 100% of the time to volitional fatigue, and by an area under the curve procedure. HR to the dynamic lifting tasks was also elevated by approximately 7 beats.min-1 following ovulation. This difference was non-significant due to the low power of the analysis. Re-analysis of the data by re-sampling 1000 matched comparisons produced significant phase variations (p < 0.05). The RPE for all of the lifting tasks was independent of menstrual phase (p > 0.05). The impact of the eumenorrheic menstrual cycle on lifting capability was negligible in the present study. However, the results of this study indicate that all further investigations utilizing HR data to produce recommendations for health and safety in manual handling tasks must control for menstrual cycle phase in female populations.

Adolescent↗
PubMed2005

High spontaneous fluctuation in arterial blood pressure improves the assessment of cerebral autoregulation.

Cerebral autoregulation maintains a relatively constant blood flow despite changes of blood pressure in the brain. Linear models have been extensively applied to identify this mechanism, using spontaneous arterial blood pressure (ABP) fluctuation as input and cerebral blood flow velocity (CBFV) change as output. Although valuable measurements have been achieved by these models, accuracy and consistency are of great concern due to the large variability of results. We therefore investigated whether more reliable measurements can be achieved by selecting only those recordings (or parts of recordings) with relatively high spontaneous variability of ABP. Twenty-four recordings, 7 from hypercapnia and 17 from normocapnia, of ABP and CBFV from 9 healthy adults were analyzed. Two conventional autoregulatory parameters were used to assess cerebral autoregulation. In the absence of a 'gold' standard for the study of dynamic cerebral autoregulation, lower variability of the parameters and higher correlation with pCO(2) were considered as criteria for identifying improved measures of autoregulation. Both significantly lower variability of the parameters, and higher correlation between the parameters and pCO(2) were achieved from the data with higher variability of blood pressure. We therefore conclude that ABP with high variability may effectively stimulate regulatory response in blood flow resulting in improved assessment of cerebral autoregulation.

Arteries↗
PubMed2000

Zinc homeostasis in humans.

Maintaining a constant state of cellular zinc nutrition, or homeostasis, is essential for normal function. In animals and humans, adjustments in zinc absorption and endogenous intestinal excretion are the primary means of maintaining zinc homeostasis. The adjustments in gastrointestinal zinc absorption and endogenous excretion are synergistic. Shifts in endogenous excretion appear to occur quickly with changes in intake just above or below optimal intake. The absorption of zinc responds more slowly, but it has the capacity to cope with large fluctuations in intake. With extremely low zinc intakes or with prolonged marginal intakes, secondary homeostatic adjustments may augment the gastrointestinal changes. These secondary adjustments include changes in urinary zinc excretion, a shift in plasma zinc turnover rates and, possibly, an avid retention of zinc released from selected tissues, such as bone, in other tissues to maintain function.

Animals↗
PubMed2002

Frequency-dependent numerical dynamics in mosquitofish.

Altering the genetic composition of a population can alter several aspects of its numerical dynamics. Whether natural populations routinely contain the genetic variation capable of affecting the stability of those dynamics is less clear. Here we report a study of experimental populations of mosquitofish (Gambusia holbrooki), designed to examine this issue. The experiment examined the numerical effects of varying the initial relative frequency of a rare male genotype. A higher relative frequency of the rare, melanic genotype produced higher mortality rates in melanic males, higher mortality rates in females, higher juvenile abundance, and fewer fluctuations in the numbers of females across time. This work demonstrates that a natural population can harbour genetic variants in a single gender that are capable of inducing qualitative differences in the numerical dynamics of the opposite gender, through the effects of negative frequency-dependent selection.

Animals↗
PubMed1982

Phytohaemagglutinin reactivity in circulating peripheral blood lymphocytes during a Trypanosoma brucei infection: sequential studies in individual guinea-pigs.

This study has analysed the response to phytohaemagglutinin of peripheral blood lymphocytes from guinea-pigs infected with Trypanosoma brucei brucei. By this means it was possible to follow the response of individual animals throughout an infection. A culture method using whole blood permitted fewer cell manipulations and eliminated the necessity to supplement cultures with heterologous serum. Selection of appropriate strains of T.b. brucei produced a relatively chronic infection in guinea-pigs. Results from this system indicate that, even late in the disease, significant mitogen reactivity still remains in some individuals. More significantly, these mitogen 'responders' controlled successive parasitaemic waves producing a fluctuating parasitaemia whereas the animals showing poor mitogen responsiveness--'non-responders' failed to control successive waves and showed plateau parasitaemias.

Animals↗
PubMed1990

Time trends (1980-1987) of ten selected informative morphogenetic variants in a newborn population.

The annual prevalence rates of ten selected informative morphogenetic variants (IMVs) were studied in 31,194 newborn infants over a period of 8 years (1980-1987). Two of them (preauricular sinus and ocular hypertelorism) revealed a highly significant decrease by logistic regression analysis. The other eight presented a stable pattern or small fluctuations which did not reach statistical significance. These data may serve as valuable baseline rates for monitoring IMVs in a specific newborn population. Their potential informative value as indicators of altered morphogenesis and their power for monitoring programs of environmental teratogenicity should be carefully verified.

Congenital Abnormalities↗
PubMed2004

[Validation of the Spanish version of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)].

OBJECTIVE: Validate the questionnaire Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in conditions of regular clinical practice. METHODS: Two hundred and eighty four adult patients with a diagnosis of rhinoconjunctivitis (RC) cared in 37 centers of specialized health care in allergy or otorhinolaryngology services in Spain were analyzed. Patients with RC were included in two groups: clinically non-stable patients who received treatment with an oral second generation antihistaminic (group A), and clinically stable patients (group B). Sociodemographic and clinical variables were collected and the questionnaires RQLQ and EQ-5D were administered in the initial visit and in the second visit 15 days after. Feasibility, validity, reliability and sensitivity related to the change of the RQLQ were analyzed. RESULTS: The mean period (standard deviation) of administration was 9.67 (6.25) minutes and 85.6% of patients needed assistance in order to fill the RQLQ, especially the selection of the characteristics (62.5%). The dimensions of the RQLQ showed a greater association with the dimensions of the EQ-5D that assessed similar aspects and the symptoms in which a greater relation was expected. The alpha Cronbach coefficient of the scorings of the RQLQ fluctuated between 0.85 and 0.96 and the intraclass correlation coefficient fluctuated between 0.68 and 0.89. The sensitivity to the change of the dimensions of the RQLQ, evaluated through the magnitude of the effect between the two visits, ranged between 0.76 and 1.46. CONCLUSIONS: The Spanish version of the RQLQ proved to be a valid instrument for assessing the Health-Related Quality of Life (HRQL) in adult patients with seasonal or perennial RC.

Activities of Daily Living↗
PubMed1994

Neurotransplantation in Parkinson's disease: from open microsurgery to bilateral stereotactic approach: first clinical trial using microelectrode recording technique.

This paper summarizes the results of three controlled clinical trials related to the transplantation of embryonic ventral mesencephalic tissue into the striatum of 46 idiopathic parkinsonian patients exhibiting motor complications on standard levodopa therapy. From January 1988 to April 1990, 30 subjects with fluctuating Parkinson's disease received fetal dopaminergic tissue implants by the open microsurgical technique. In March 1992 the stereotactic approach was adopted for successive fetal mesencephalic cell suspension transplants (7 unilateral and 9 bilateral) into the caudate and putamen of parkinsonian patients with levodopa-induced complex fluctuations and dyskinesias. The neurological assessment performed 12 months before and 3-18 months after transplantation demonstrated a reduction of both the daily time spent in the 'off' condition and the number of daily 'off' periods, and a significant improvement of the motor scale. The stereotactic selective thalamotomy with microelectrode recording was introduced in January 1993, in order to provide a further potential treatment strategy; i.e., the combination of the two surgical trends in Parkinson's disease, the restorative neurotransplantation technique, and the selective lesional approach. In addition to that, microelectrode recording is also used for implantation site selection and functional characterization.

Adrenal Medulla↗
PubMed1989

Impact of total body water fluctuations on estimation of body fat from body density.

The purpose was to investigate the possibility that variability in body weight in females due to water retention causes differences in body density (Db) values determined by hydrostatic weighing (HW). Determination of total body water (TBW) and Db were concurrently measured in seven females who experienced considerable fluctuations in body weight (1.5-4.5 kg) and seven males, ages 19-24. Females were measured when they felt they were at their lowest (LO) and highest (HI) body weights (BW) during a menstrual cycle. Males were randomly tested approximately 3 wk apart. Mean values of selected variables were compared in the LO vs HI testing sessions by paired t-tests. Significant mean differences were found in the females (P less than 0.01) for the following variables: BW (kg) (LO = 58.9, HI = 61.1), Db (g.cc-1) (LO = 1.0430, HI = 1.037), and percent body fat (%BF) as determined by HW alone (LO = 24.8%, HI = 27.6%). Variables significant at the P less than 0.05 level were TBW(l) (LO = 33.6, HI = 35.1) and %TBW of the fat-free body (LO = 74.5, HI = 75.9). However, changes in TBW could not entirely account for observed changes in Db. Only mean BW (kg) was significant (P less than 0.01) in the males (LO = 74.3, HI = 74.6). It is concluded that changes in TBW can in part result in significantly different Db values obtained from HW in females who did experience perceptible changes in BW during a menstrual cycle. The remaining differences may be due to changes in fat and protein content or methodological errors.

Adipose Tissue↗
PubMedDate not supplied

Guaranteed renewability and the problem of risk variation in individual health insurance markets.

Consumers should be protected against fluctuations in premiums for private individual health insurance associated with the onset of high-cost chronic conditions. The most commonly discussed way to do so is through community rating, which provides protection but can require a heavy regulatory burden and can create incentives for adverse selection and cream skimming. This paper describes an alternative method of providing the same type of protection: insurance contract provisions that guarantee renewability for the next coverage period at class-average rates. Drawing on recent work in insurance theory, the paper shows that such protection is feasible in competitive insurance markets. Guaranteed renewability, which is required of all individual health insurance by the Health Insurance Portability and Accountability Act (HIPAA) of 1996, is incomplete because the law fails to require that premiums be the same for all insured persons in a rating class. However, the paper reports the results of a recent survey of state insurance regulation, which indicates that all but three state insurance departments report having such a requirement. The paper concludes with a discussion of possible threats to the protection guaranteed renewability provides against risk segmentation.

Actuarial Analysis↗
PubMedDate not supplied

Intrathoracic distribution and transport of aerosolized silica in the rat.

Short-term exposure of rats to aerosols of the silicon dioxide, cristobalite, leads to pulmonary inflammation persisting several months. Clearance of particles occurs during the first two weeks after cessation of exposure, after which there is little additional clearance in the whole lung. In the present studies, quantitation of silica in lung compartments at selected times following exposure indicated movement of particles between the alveolar space and the lung tissue per se, with increased alveolar silica content associated with decreased silica content in the tissue compartment. Further, changes in the silica content in the alveolar compartment were generally associated with fluctuations in the alveolar macrophage population. Silica accumulated linearly in the mediastinal lymph nodes and thymus for several months after cessation of exposure, while negligible amounts were found in kidney, spleen, liver, and blood. A compartmental model was used to describe the distribution and translocation kinetics of the inhaled silica in the lung and extrapulmonary tissues.

Aerosols↗
PubMed1992

Antigen F1 from Yersinia pestis forms aqueous channels in lipid bilayer membranes.

Antigen F1 is a protein of 17 kDa produced by Yersinia pestis when it is cultured at 37 degrees C. When incorporated into planar lipid bilayer membranes this protein induces fluctuations on membrane conductance typical of the formation of ionic channels. These fluctuations reveal two distinct unitary conductance sizes, one in the range of 800 to 1400 pS and the other in the range of 140 to 600 pS. Zero current potential measurements in the presence of a salt gradient show that the channel is not significantly ion selective. The reversal potential measured in the presence of 0.5 M KCl on the cis side and 0.1 M KCl on the trans side was 3.58 +/- 3.98 mV (N = 7). The non-selectivity of the channel, in addition to its large conductance, suggests that it forms large aqueous pores. The present results, taken together with other data showing that antigen F1 inhibits the activity of phagocytic cells, suggest that antigen F1 acts by forming aqueous pores in the membrane of these target cells.

Antigens, Bacterial↗