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PubMed2004

Optimal-sensitivity analysis of ion channel gating kinetics.

We propose a new approach to analysis of kinetic models for ion channel gating, based on application of fluctuating voltages through a voltage clamp, in addition to conventional techniques. We show that the channel kinetics can be probed in a much more sensitive way, leading to more efficient model selection and more reliable estimates of model parameters. We use wavelet transform as an analytic tool for fluctuating currents and parametric dispersion plots as a measure of model compatibility with experimental data.

Algorithms↗
PubMed2006

Fluctuations in Saffman-Taylor fingers with quenched disorder.

We make an experimental characterization of the effect that static disorder has on the shape of a normal Saffman-Taylor finger. We find that static noise induces a small amplitude and long wavelength instability on the sides of the finger. Fluctuations on the finger sides have a dominant wavelength, indicating that the system acts as a selective amplifier of static noise. The dominant wavelength does not seem to be very sensitive to the intensity of static noise present in the system. On the other hand, at a given flow rate, rms fluctuations of the finger width, decrease with decreasing intensity of static noise. This might explain why the sides of the fingers are flat for typical Saffman-Taylor experiments. Comparison with previous numerical studies of the effect that temporal noise has on the Saffman-Taylor finger, leads to conclude that the effect of temporal noise and static noise are similar. The behavior of fluctuations of the finger width found in our experiments, is qualitatively similar to one recently reported, in the sense that, the magnitude of the width fluctuations decays as a power law of the capillary number, at low flow rates, and increases with capillary number for larger flow rates.

Journal Article↗
PubMed1996

Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus. Why some tests fail.

OBJECTIVE: To evaluate whether changes in laboratory test values are either simultaneous with or precede disease exacerbations in patients with systemic lupus erythematosus (SLE). METHODS: At 9, 6, and 3 months preceding a flare in disease activity (defined as a rise of > or = 6 points in the modified SLE Disease Activity Index), laboratory tests were performed to measure patients' hematocrit levels, white blood cell, lymphocyte, and platelet counts, erythrocyte sedimentation rate, C1q binding, DNA binding, and levels of C3 and C4. Flares were classified as either present or absent, and were divided into renal, vasculitic, central nervous system, skin, serosal, and musculoskeletal subgroups. The predictive patterns were 1) the simultaneous change in the test value from the mean of 9, 6, and 3 months preceding a flare to the time of the flare; 2) the gradual change, following a linear time trend, in test results for the same time points; and 3) the change from the mean of 9 and 6 months to 3 months preceding a flare, as a measure of predictive ability. These analyses used repeated-measures analysis of variance models. Multiple linear regression was used to study the cross-sectional association of average-over-time differences in test results with patients' flare subgroup. RESULTS: Among 202 patients with SLE (median followup 86.5 months), 83 flares occurred in 53 patients. Of 189 statistical contrasts performed, only 14 were significant (versus 10 expected), and the differences were of minor importance. Nonetheless, evaluation of all test results over each patient's observed disease course revealed significant differences between selected test values in association with specific types of flare. CONCLUSION: Fluctuations in laboratory test values are poor predictors of disease exacerbations in SLE. Cross-sectional evaluation of some test results revealed differences at the time of flare for those patients who were destined to have different types of flares, because these values differed over the entire study period. This pattern explains the frequent cross-sectional association of disease activity with laboratory test results, and the inconsistent association of flares with recent changes in test values.

Adolescent↗
PubMed2003

Sequence-selective metalation of double-helical oligodeoxyribonucleotides with PtII, MnII, and ZnII ions.

Reactions of [PtCl(dien)](+) (dien=diethylenetriamine), Mn(2+) and Zn(2+) ions with three different double-helical oligodeoxyribonucleotides, which contain the central sequence GGXY (XY=AT, TA or CC) have been monitored by NMR spectroscopy. 2 D [(1)H, (15)N] HSQC/HMQC NMR spectroscopy using (15)N-labeled Pt(dien) shows that the rate of formation of 3'-G-N 7 and 5'-G-N 7 platinated adducts is highly sequence dependent. The relative rates of platination of 5'-G versus 3'-G are largest for the sequence -GGCC-, for which only a small fraction of the 3'-G adduct is formed; for -GGTA-, the rate of 5'-G platination is about eight times that of 3'-G, and for -GGAT- the ratio is 1.2. These values are in qualitative agreement with those obtained for G-N 7/Mn(2+) selectivity as determined by paramagnetic line broadening of the adjacent G-H 8, and also G-N 7/Zn(2+) selectivity as determined by G-H 8 chemical shift changes. Fluctuation in the nucleophilicity of G-N 7 may be explained by variation of the pi-stacking interaction between base residues along the double helix. The reaction mixtures containing platinated 3'-G and 5'-G fractions were separated by HPLC. Since the duplexes are self-complementary, the platinated single strands were readily annealed to duplexes with twofold symmetry and analyzed by 2 D [(1)H, (1)H] NOESY NMR spectroscopy. Unexpectedly, the 5'-G-H 8 resonance signals of both 5'-G and 3'-G platinated duplexes showed large downfield shifts in the range delta=0.3-0.6 ppm, while the 3'-G-H 8 resonance signals in both cases exhibited no, or only slight, upfield shifts. Resonance signals for several other protons in the central region undergo large chemical shift variations induced by platination, indicating that monofunctional binding to DNA leads to appreciable conformational changes.

Base Sequence↗
PubMed1996

Dynamics of the three methionyl side chains of Streptomyces subtilisin inhibitor. Deuterium NMR studies in solution and in the solid state.

Streptomyces subtilisin inhibitor (SSI) contains three methionine residues in a subunit: two (at positions 73 and 70) in the crucial enzyme-recognition sites P1 and P4, respectively, and one (Met 103) in the hydrophobic core. The motions of the side chains of these three Met residues and the changes in mobility on binding with subtilisin were studied by deuterium NMR spectroscopy in solution and in crystalline and powder solids. For this purpose, the wild-type SSI was deuterium-labeled at the methyl groups of all three Met residues, and three artificial mutant proteins were labeled at only one specific Met methyl group each. In solution, for methionines 73 and 70, the effective correlation times were only 0.8-1.0 x 10(-10)s indicating that the two side chains on the surface fluctuate almost freely. On formation of a complex with subtilisin, however, these high mobilities were quenched, giving a correlation time of 1.1 x 10(-8)s for the side chains of methionines 70 and 73. The correlation time of Met 103, located in the hydrophobic core, was at least 1.0 x 10(-8)s in free SSI, showing that its side chain motion is highly restricted. The nature of the internal motions of the three Met side chains was examined in more detail by deuterium NMR spectroscopy of powder and crystalline samples. The spectral patterns of the powder samples depended critically on hydration: immediately after lyophilization, the side-chain motions of the three Met residues were nearly quenched. With gradual hydration to 0.20 gram of water per gram protein-water, the orientational fluctuation of the methyl axes of methionines 70 and 73 was selectively enhanced in both amplitude and frequency (to about 1 MHz) and, at nearly saturating hydration (0.60 gram of water per gram protein-water), became extremely high in amplitude and frequency (> 10 MHz). In contrast, the polycrystalline wild-type SSI spectrum showed fine structures, reflecting characteristic motions of the Met side chains. The polycrystalline spectrum could be reproduced reasonably well by the same motion models and parameters used to simulate the powder spectrum at the final level of hydration, suggesting that the side-chain motions are similar in the fully hydrated powder and in crystals. Spin-lattice relaxation measurements gave evidence that, even in crystals, the methyl axes of all three Met residues undergo rapid motions with correlation times between 10(-8) and 10(-10)s, comparable to the correlation times in solution. Finally, in the hydrated stoichiometric complex of SSI with subtilisin BPN' in the solid state, large-amplitude motions are absent, but the side chains of methionines 70 and/or 73 are likely to have small-amplitude motions.

Bacterial Proteins↗
PubMed2002

Temporal and spatial dynamics of insecticide resistance in Myzus persicae (Hemiptera: Aphididae).

Advances in understanding insecticide resistance in the peach-potato aphid, Myzus persicae (Sulzer), at the genotypic, biochemical and molecular levels have led to rapid and precise methods for the detection of several resistance mechanisms (elevated carboxylesterase, modified acetylcholinesterase or MACE, and knockdown resistance or kdr) in individual insects, and for monitoring their frequencies over space and time. This paper summarises the results of two long-term surveys of resistance dynamics in M persicae in England, based on samples collected directly from field and glasshouse crops or from four 12.2-m suction traps. The study showed marked fluctuations in resistance frequencies that probably reflect the counteracting forces of selection imposed by insecticides for aphids possessing more copies of esterase resistance genes, and selection against these forms when insecticide use is relaxed. There is growing evidence that several different resistance mechanisms in M persicae have associated fitness costs. In the case of esterase and MACE, these costs are apparently strong enough to effect a decline in resistance frequency over winter, and a more prolonged decline over successive cropping seasons when aphid numbers are insufficient to trigger intensive chemical applications. Changes in the overall frequency of resistance genotypes may also be influenced by the predominance of year-round parthenogenesis in M persicae in the UK, leading to non-random associations between mechanisms and selection operating on clonal lineages rather than individual genotypes.

Acetylcholinesterase↗
PubMed2003

Cécile & Oskar Vogt: the significance of their contributions in modern neuroscience.

A) By introducing and propagating the use of multidisciplinary approaches, Cécile and Okar Vogt played a decisive role in establishing brain research as a distinct branch of science, and thus laid the foundations for modern Neuroscience. B) The Vogts' and Brodmann's monumental work on brain cytoarchitectonics, supplemented with electrical stimulation of the exposed cerebral cortex, demonstrated correlations between evoked functional responses and the topography of brain regions endowed with distinct cytoarchitectonic structure (topistic units). This opened the field of functional brain mapping, a subject hotly pursued at the present time. C) One of the most important aspects of Pathoclisis is that the Vogts based their theory on molecular genetics. They envisaged that in any topistic unit the neurons had a different specific, molecular ("physico-chemical") composition, accounting for differences observed in the dynamics of neuronal development and involution. In sublethal injury, the induced genomic reactivity varies according to the selective vulnerability of various topistic units. Thus, in cerebral ischemia, the fluctuating genomic reactivity may play a significant role in designing therapeutic strategies, which would include enhancing regenerative expressions and suppressing harmful ones. D) The pathoclisis theory may be of assistance in analyzing the nature of various genetic disorders, which could be considered for the application of gene therapy.

Germany↗
PubMed1991

Changes in activity and intra-acinar distribution of glucose-6-phosphate dehydrogenase and malic enzyme during pregnancy in rat liver.

Using techniques of microdissection and microassay as well as qualitative histochemistry the activity and intra-acinar distribution of G6PDH and ME were studied on selected days of pregnancy in the rat. Both enzymes show distinct fluctuations during the course of pregnancy in keeping with changes in hepatic lipogenesis. Marked increases in activity are seen as early as the 4th day, while highest values are attained on day 20, with a predominant perivenous induction. On day 22, just before parturition a sharp decrease of both enzyme activities with a flattening of the periportal/perivenous gradient was detected. G6PDH shows proportionally considerably larger increases and more distinct changes in zonation. The perivenous fluctuations in G6PDH activity of late gestation are supposed to be caused primarily by insulin. Although estrogen is known to induce both enzymes, the temporal changes in enzyme activity in pregnancy cannot be related to the action of estrogen alone. The changes in enzyme activity, however, correspond well to those of progesterone, and although no direct action of progesterone on these enzymes has yet been proposed, further work on its effects on enzyme activity and distribution is indicated.

Animals↗
PubMed2006

Autophagy: role in surviving environmental stress.

This conceptual paper addresses the role of lysosomal autophagy in cellular defence against oxidative stress. A hypothesis is proposed that autophagic removal of oxidatively damaged organelles and proteins provides a second tier of defence against oxidative stress. Age pigment or lipofuscin is a product of oxidative attack on proteins and lipids and can accumulate in lysosomes, where it can generate reactive oxygen species (ROS) and inhibit lysosomal function, resulting in autophagic failure. It is further hypothesised that repeated triggering of augmented autophagy can protectively minimise lipofuscin generation; and that animals living in fluctuating environments, where autophagy is repeatedly stimulated by natural stressors, will be generically more tolerant of pollutant stress. Data for resistance to pollutant stress is presented, together with evidence for a correlation between lysosomal stability and macrobenthic diversity. Finally, we speculate that organisms making up functional ecological assemblages in fluctuating environments, where up-regulation of autophagy should provide a selective advantage, may be pre-selected to be tolerant of pollutant-induced oxidative stress.

Animals↗
PubMed1995

Dynamic and elastic properties of F-actin: a normal-modes analysis.

We examine the dynamic, elastic, and mechanical consequences of the proposed atomic models of F-actin, using a normal mode analysis. This initial analysis is done in vacuo and assumes that all monomers are rigid and equivalent. Our computation proceeds from the atomic level and, relying on a single fitting parameter, reproduces various experimental results, including persistence lengths, elastic moduli, and contact energies. The computations reveal modes of motion characteristic to all polymers, such as longitudinal pressure waves, torsional waves, and bending, as well as motions unique to F-actin. Motions typical to actin include a "groove-swinging" motion of the two long-pitch helices, as well as an axial slipping motion of the two strands. We prepare snapshots of thermally activated filaments and quantify the accumulation of azimuthal angular "disorder," variations in cross-over lengths, and various other fluctuations. We find that the orientation of a small number of select residues has a surprisingly large effect on the filament flexibility and elasticity characteristics.

Actins↗
PubMedDate not supplied

Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus.

Anti-double stranded (dsDNA) antibodies are of considerable diagnostic value and are thought to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Fluctuations in anti-dsDNA antibody levels are also used as markers for disease activity and exacerbations. In this study we sought to evaluate the anti-dsDNA antibody level in serum samples collected before the onset of SLE diagnosis. A total of 130 SLE patients were identified with stored serum samples available prior to diagnosis within the US Department of Defense serum repository. All 633 sera available from these patients were screened for anti-dsDNA antibodies using an enzyme linked immunosorbant assay (ELISA). Within this cohort 55% of cases had detectable anti-dsDNA antibodies prior to SLE diagnosis. The onset of anti-dsDNA antibodies ranged from 9.3 years before to within the same month as diagnosis (with a mean onset 2.7 years before diagnosis). In order to assess for fluctuations in anti-dsDNA levels relative to diagnosis, cases were selected with at least two positive samples, one within 6 months and a second greater than 6 months prior to diagnosis (n = 26). Seven of these cases also had samples available shortly after diagnosis (< or = 6 months) for comparison. Fifty-eight percent of the 26 cases developed a significant rise in anti-dsDNA antibody levels within 6 months of diagnosis. A significant decline in anti-dsDNA levels ensued after diagnosis (and following treatment with corticosteroids) in all seven cases with samples available. Patients with a significant rise in anti-dsDNA antibodies at diagnosis were more likely to have renal disease than those who did not (66.7% compared to 27.3%, chi2 =3.94, P<0.05). These data suggest that anti-dsDNA antibodies are present in SLE patient sera much earlier than previously suspected. In addition, the data are consistent with increases in anti-dsDNA levels contributing to the onset of clinical illness in some patients with SLE.

Antibodies, Antinuclear↗
PubMed1995

Bumblebee preference for symmetrical flowers.

Fluctuating asymmetry, which represents small random deviations from otherwise bilateral symmetry, is a measure of the phenotypic quality of individuals indicating the ability of controlled development under given environmental and genetic conditions. I tested whether floral symmetry reliably reflects phenotypic quality measured in terms of pollinator rewards and whether pollinators respond to floral symmetry in a series of observations and experiments on Epilobium angustifolium (Onagraceae). Lower petal asymmetry was negatively related to mean lower petal length, whereas asymmetry in leaf width was positively related to mean leaf width. Flowers visited by bumblebees were larger and more symmetrical than the nearest neighboring flower. This relationship between pollinator preference for large and symmetrical flowers was demonstrated to be causal in experiments in which the lower petals were manipulated symmetrically or asymmetrically. Nectar production was larger in symmetrical flowers, and this may explain the bumblebee preference for flower symmetry. Floral symmetry therefore reliably reflects nectar production and hence enhances pollen transport. Extensive embryo abortion has been documented in E. angustifolium and other outcrossing plant species. Floral fluctuating asymmetry, which reflects general developmental homeostasis, may explain such developmental selection in these plants.

Journal Article↗
PubMed2006

Circadian rhythms of isoprene biosynthesis in grey poplar leaves.

Isoprene (2-methyl-1,3-butadiene) emission varies diurnally in different species. In poplar (Populus spp.), it has recently been shown that the gene encoding the synthesizing enzyme for isoprene, isoprene synthase (ISPS), displays diurnal variation in expression. Working on shoot cultures of Grey poplar (Populus x canescens) placed under a different light regime in phytochambers, we showed that these variations in PcISPS gene expression, measured by quantitative real-time polymerase chain reaction, are not only due to day-night changes, but also are linked to an internal circadian clock. Measurement of additional selected isoprenoid genes revealed that phytoene synthase (carotenoid pathway) displays similar fluctuations, whereas 1-deoxy-d-xylulose 5-phosphate reductoisomerase, possibly the first committed enzyme of the 1-deoxy-d-xylulose 5-phosphate pathway, only shows light regulation. On the protein level, it appeared that PcISPS activity and protein content became reduced under constant darkness, whereas under constant light, activity and protein content of this enzyme were kept high. In contrast, isoprene emission rates under continuous irradiation displayed circadian changes as is the case for gene expression of PcISPS. Furthermore, binding assays with Arabidopsis (Arabidopsis thaliana) late elongated hypocotyl, a transcription factor of Arabidopsis involved in circadian regulation, clearly revealed the presence of circadian-determining regulatory elements in the promoter region of PcISPS.

Alkyl and Aryl Transferases↗
PubMed2006

Hepatitis C infection in Alaska Natives with persistently normal, persistently elevated or fluctuating alanine aminotransferase levels.

BACKGROUND/AIMS: An estimated one-third of patients with chronic hepatitis C virus (HCV) infection have persistently normal alanine transaminase (PNALT); however, in many previous studies alanine aminotransferase (ALT) levels were followed for < or = 12 months. METHODS: We analyzed data from a population-based cohort of 935 Alaska Natives with HCV, recruited from 1994 to 2005, to determine the proportion of persons with PNALT, persistently elevated ALT (PEALT), and fluctuating ALT (FLUXALT) to determine factors for each ALT state. We selected persons with two positive HCV RNA results > or = 1 year apart and > or = 6 ALT levels measured over the subsequent 3 years with at least 1 month between ALT measurements (n = 265). We defined a person as having PNALT, PEALT, or FLUXALT when all six ALT levels were normal, elevated, or did not fit either of the above two categories, respectively, during the 3-year follow-up period. RESULTS: Among 208 persistently HCV RNA-positive persons, 13 had PNALT, 121 PEALT, 74 FLUXALT. Among 77 persons who underwent liver biopsy, those with PEALT were more likely to have Ishak fibrosis scores > 2 compared with persons with FLUXALT (44% vs. 10%, OR 7.0, 95% CI: 1.5-33.2). No statistically significant differences were found in ALT classification by age, gender, infection duration, median body mass index, alcohol consumption, residence, risk behavior, RNA level, or genotype. CONCLUSIONS: Only 6% of persons with chronic HCV had PNALT. Persons with PEALT were significantly more likely to have higher fibrosis scores on liver biopsy than those with FLUXALT. Previous studies with short follow-up periods may have overestimated the proportion of persons with normal ALT levels.

Adult↗
PubMed1991

Voltage-dependent inactivation of the potassium current of embryonic chick hepatocytes.

The whole-cell patch electrode voltage clamp technique was used to study the inactivation properties of the delayed rectifying potassium current of single cultured embryonic chick hepatocytes at 20 degrees C. The potassium current activates maximally within 250-500 ms of membrane depolarization, after which it decays with a monoexponential time course. Both steady-state activation and inactivation are voltage dependent. Steady-state inactivation declines from 100% at -5 mV to 0 near -70 mV. with half inactivation at -41 mV. At the resting potential (EM) of these cells (-21.5 +/- 6.0 mV, n = 36) 6-18% of the IK channels are not inactivated and less than 5% are open. Development and removal of inactivation follow single exponential time courses. The inactivation time constant attains a maximum of around 30 s at -35 mV and is sharply voltage dependent at the EM of these cells. Measurement of EM under current clamp shows random oscillations of 5-10 mV amplitude. We suggest that the voltage- and time-dependent properties of IK, in tandem with a time- and voltage-independent, non-selective current also seen here, would provide the mechanism for a fluctuating EM.

Animals↗
PubMed1985

Intercuspal distances of maxillary pre-molar teeth in Australian Aboriginals.

Intercuspal distances and mesiodistal and buccolingual crown diameters of maxillary pre-molars were recorded from dental casts of 262 Australian Aboriginals. Although mesiodistal and buccolingual dimensions showed sexual dimorphism, no significant differences were noted between the sexes for intercuspal distances. Intercuspal dimensions showed greater variability and fluctuating asymmetry than did either of the traditional measures. No significant differences in heritability were noted among the three dimensions. Correlations between mesiodistal and buccolingual dimensions were higher than those between buccolingual and intercuspal measures. It appears that the sex differences, which are observed in overall crown dimensions, are established after the cusp tips are localized. Intercuspal distances appear to have a strong genetic component of variability, although they show high phenotypic variability and fluctuating asymmetry. Total tooth size may be subject to more intense selective pressures than the sites of initial calcification.

Australia↗
PubMed2004

Compensatory evolution in the human malaria parasite Plasmodium ovale.

The fixation of neutral compensatory mutations in a population depends on the effective population size of the species, which can fluctuate dramatically within a few generations, the mutation rate, and the selection intensity associated with the individual mutations. We observe compensatory mutations and intermediate states in populations of the malaria parasite Plasmodium ovale. The appearance of compensatory mutations and intermediate states in P. ovale raises interesting questions about population structure that could have considerable impact on the control of the associated disease.

Animals↗
PubMed2003

A survey on health effects in a human population exposed to permanent-waving solution containing thioglycolic acid.

Thioglycolic acid (TGA) is the active ingredient of permanent-waving solution (PWS). TGA has been shown to be a chemical of high toxicity, which can be absorbed through intact skin and cause damage to organs or systems in animals. This study evaluated the effect of TGA-containing PWS on the health of a human population in 3 substudies. Firstly, 57 female hairdressers exposed to TGA-containing PWS (cases) and 64 female schoolteachers (controls) were studied. Their menstruation state was evaluated with information obtained from interviews. The results revealed that the menoxenia rate in the cases was significantly higher than that in the controls (22.81% vs 9.38%, p<0.05). Secondly, 8 female hairdressers selected from those that participated in the above survey underwent a fluctuation test for the mutagenic activity of urine. Eight female medical students were chosen as controls. Difference in the mutagenic activity of urine on TA100 between the two groups was highly significant (110.30 +/- 45.95 vs 28.43 +/- 19.33, p<0.01). Finally, a micronucleus assay was carried out on scalp hair follicle cells in healthy volunteers. Scalp hair with the follicle cell mass was sampled from 8 male and 8 female volunteers before permanent waving and at 24, 48 and 72 h after waving. One thousand hair follicle cells were examined by light microscopy. The number of cells containing a micronucleus and the number of micronuclei in each cell was determined. The permillages of micronuclei in hair follicle cells before and after permanent waving were compared. Micronuclei presence reached its peak value (12.44) 24 h after permanent waving, which was significantly higher than that before waving (3.13, p<0.001). The rate decreased progressively after 24 h. Our results suggest that the reproductive function of hairdressers may be affected by long-term exposure to PWS, probably due to the presence of TGA, and more attention should be paid to its potential carcinogenic effects.

Adult↗