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PubMed2001

Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes.

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process.

Blood Glucose↗

PubMed2003

Correction algorithm for finite sample statistics.

Assume in a sample of size M one finds M(i) representatives of species i with i = 1..N*. The normalized frequency pi* triple bond Mi/M, based on the finite sample, may deviate considerably from the true probabilities p(i). We propose a method to infer rank-ordered true probabilities r(i) from measured frequencies M(i). We show that the rank-ordered probabilities provide important informations on the system, e.g., the true number of species, the Shannon- and the Renyi-entropies.

Algorithms↗

PubMed2006

High flow-resolution for mobility estimation in 2D-ENMR of proteins using maximum entropy method (MEM-ENMR).

Multidimensional electrophoretic NMR (nD-ENMR) is a potentially powerful tool for structural characterization of co-existing proteins and protein conformations. By applying a DC electric field pulse, the electrophoretic migration rates of different proteins were detected experimentally in a new dimension of electrophoretic flow. The electrophoretic mobilities were employed to differentiate protein signals. In U-shaped ENMR sample chambers, individual protein components in a solution mixture followed a cosinusoidal electrophoretic interferogram as a function of its unique electrophoretic migration rate. After Fourier transformation in the electrophoretic flow dimension, the protein signals were resolved at different resonant frequencies proportional to their electrophoretic mobilities. Currently, the mobility resolution of the proteins in the electrophoretic flow dimension is limited by severe truncations of the electrophoretic interferograms due to the finite electric field strength available before the onset of heat-induced convection. In this article, we present a successful signal processing method, the Burg's maximum entropy method (MEM), to analyze the truncated ENMR signals (MEM-ENMR). Significant enhancement in flow resolution was demonstrated using two-dimensional ENMR of two protein samples: a lysozyme solution and a solution mixture of bovine serum albumin (BSA) and ubiquitin. The electrophoretic mobilities of lysozyme, BSA and ubiquitin were measured from the MEM analysis as 7.5x10(-5), 1.9x10(-4) and 8.7x10(-5) cm2 V-1 s-1, respectively. Results from computer simulations confirmed a complete removal of truncation artifacts in the MEM-ENMR spectra with 3- to 6-fold resolution enhancement.

Computer Simulation↗

PubMed2002

Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids.

PURPOSE: To characterize the surface thermodynamic properties of two polymorphic forms (I and II) of salmeterol xinafoate (SX) prepared from supercritical fluids and a commercial micronized SX (form 1) sample (MSX). METHODS: Inverse gas chromatographic analysis was conducted on the SX samples at 30, 40, 50, and 60 degrees C using the following probes at infinite dilution: nonpolar probes (NPs; alkane C5-C9 series); and polar probes (PPs; i.e., dichloromethane, chloroform, acetone, ethyl acetate, diethyl ether, and tetrahydrofuran). Surface thermodynamic parameters of adsorption and Hansen solubility parameters were calculated from the retention times of the probes. RESULTS: The free energies of adsorption (- deltaG(A)) of the three samples obtained at various temperatures follow this order: SX-II > MSX approximately/= SX-I for the NPs; and SX-II > MSX > SX-I for the PPs. For both NPs and PPs, SX-II exhibits a less negative enthalpy of adsorption (deltaH(A)) and a much less negative entropy of adsorption (ASA) than MSX and SX-I, suggesting that the high -AGA of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (gammas(D)) is the highest for MSX but the lowest for SX-II at all temperatures studied, whereas the specific component of surface free energy of adsorption (-deltaG(A)SP) is higher for SX-II than for SX-I. That SX-II displays the highest -deltaG(A) for the NP but the lowest gammasD of all the SX samples may be explained by the additional -AGA change associated with an increased mobility of the probe molecules on the less stable and more disordered SX-II surface. The acid and base parameters, K(A) and K(D) that were derived from deltaH(A)SP reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (deltaD, deltap, and deltaH) indicate that the surface of SX-II is the most polar and most energetic of all the three samples in terms of specific interactions (mostly hydrogen bonding). CONCLUSIONS: The metastable SX-II polymorph possesses a higher surface free energy, higher surface entropy, and a more polar surface than the stable SX-I polymorph.

Albuterol↗

PubMed2004

Simulation method for calculating the entropy and free energy of peptides and proteins.

A method called complete hypothetical scanning Monte Carlo has been introduced for calculating the absolute entropy, S, and free energy, F, of fluids. Here, the method is extended to peptide chains in vacuum. Thus, S is calculated from a given sample by reconstructing each conformation step-by-step by using transition probabilities (TPs); at each step, part of the chain coordinates have already been determined (the "frozen past"), and the TP is obtained from a Monte Carlo simulation of the (future) part of the chain whose TPs as yet have not been calculated. Very accurate results for S and F are obtained for the helix, extended, and hairpin microstates of a simplified model of decaglycine (Gly)(10) and (Gly)(16). These results agree well with results obtained by the quasiharmonic approximation and the local states method. The complete HSMC method can be applied to a macromolecule with any degree of flexibility, ranging from local fluctuations to a random coil. Also, the difference in stability, Delta F(mn) = F(m) - F(n) between significantly different microstates m and n can be obtained from two simulations only without the need to resort to thermodynamic integration. Our long-term goal is to extend this method to any peptide and apply it to a peptide immersed in a box with explicit water.

Biophysics↗

PubMed2006

Active acromegaly enhances spontaneous parathyroid hormone pulsatility.

In healthy subjects, parathyroid hormone (PTH) is secreted in a dual fashion, with low-amplitude and high-frequency pulses superimposed on tonic secretion. These 2 components of PTH secretion seem to have different effects on target organs. The aim of our study was to evaluate whether growth hormone excess in acromegaly may modify the spontaneous pulsatility of PTH. Five male patients with newly diagnosed active acromegaly and 8 healthy subjects were evaluated by 3-minute blood sampling for 6 hours. Plasma PTH concentrations were evaluated by multiparameter deconvolution analysis. Plasma PTH release profiles were also subjected to an approximate entropy (ApEn) estimate, which provides an ensemble measure of the serial regularity or orderliness of the release process. In acromegalic patients, baseline serum PTH values were not significantly different from those measured in the healthy subjects, as well as tonic PTH secretion rate, number of bursts, fractional pulsatile PTH secretion, and ApEn ratio. Conversely, PTH pulse half-duration was significantly longer in acromegalic patients vs healthy subjects (11.8+/-0.95 vs 6.9+/-1.6 minutes; P=.05), whereas PTH pulse mass showed a tendency (P=.06) to be significantly greater in acromegalic patients. These preliminary data suggest that growth hormone excess may affect PTH secretory dynamics in patients with acromegaly. Potentially negative bone effects of the modifications of PTH secretory pattern in acromegaly should be investigated.

Acromegaly↗

PubMed2000

Longitudinal changes in growth hormone secretory process irregularity assessed transpubertally in healthy boys.

Clarifying the time evolution, and underlying neuroendocrine regulation, of hormone secretion during puberty is of pivotal importance both physiologically and clinically. We sought to determine whether clinical growth and elevated growth hormone (GH) release in pubertal boys are associated with shifts in the irregularity of GH secretory patterns. We studied GH release in 23 healthy boys longitudinally at approximately 4-mo intervals over a 6-yr period throughout puberty, by repetitive blood sampling at 20-min intervals for 24 h on each study date. To quantify serial irregularity in the GH profiles, we utilized approximate entropy (ApEn), a scale- and model-independent quantification of the extent of sequential "randomness." Complementary statistical analyses establish that on a per-subject basis, serum GH concentration-time series show greatest secretory disorderliness (maximal ApEn) in prepuberty and mid-to-late puberty, followed by a steep decline in ApEn to maximal orderliness in postpubertal adolescence (P < 0.0001, ANOVA). Pooling all subject comparisons, we observed a persistent positive correlation between ApEn and growth velocity (GrVel), Pearson r = 0.467 (P < < 10(-10)). Moreover, in general, ApEn(GH) preceded GrVel evolution, with a time frame lead of 4-8 mo providing the most pronounced correlations between ApEn and GrVel. In the setting of low postpubertal growth, per-subject ApEn values fell to approximately one-half of maximal ApEn values and, on average, were in the 13th percentile from minimal (P < < 10(-10)) for fully mature boys. Thus, in a longitudinal transpubertal analysis, greater irregularity in GH secretion corresponds to greater linear growth in boys, which culminates in highly regular GH secretory dynamics after sexual maturity. In addition to clinical utility, there may be added experimental merit in knowing that GH dynamics typically predict accelerated linear growth in 4-8 mo.

Adolescent↗

PubMed2003

The formation of rhythmic categories and metric priming.

Two experiments on categorical rhythm perception are reported, the object of which was to investigate how listeners perceive discrete rhythmic categories while listening to rhythms performed on a continuous time scale. This is studied by considering the space of all temporal patterns (all possible rhythms made up of three intervals) and how they, in perception, are partitioned into categories, ie where the boundaries of these categories are located. This process of categorisation is formalised as the mapping from the continuous space of a series of time intervals to a discrete, symbolic domain of integer-ratio sequences. The methodological framework uses concepts from mathematics and psychology (eg convexity and entropy) that allow precise characterisations of the empirical results. In the first experiment, twenty-nine participants performed an identification task with 66 rhythmic stimuli (a systematic sampling of the performance space). The results show that listeners do not just perceive the time intervals between onsets of sounds as placed in a homogeneous continuum. Instead, they can reliably identify rhythmic categories, as a chronotopic time clumping map reveals. In a second experiment, the effect of metric priming was studied by presenting the same stimuli but preceded with a duple or triple metre subdivision. It is shown that presenting patterns in the context of a metre has a large effect on rhythmic categorisation: the presence of a specific musical metre primes the perception of specific rhythmic patterns.

Auditory Perception↗

PubMed2001

Basal, pulsatile, entropic, and 24-hour rhythmic features of secondary hyperprolactinemia due to functional pituitary stalk disconnection mimic tumoral (primary) hyperprolactinemia.

Under physiological conditions, PRL secretion is regulated precisely by various stimulating and inhibiting factors. Hyperprolactinemia may arise as a primary consequence of a PRL-secreting pituitary adenoma. Secondary hyperprolactinemia (SH) may emerge in patients with hypothalamic disease, hypophyseal stalk compression, or suprasellar extension of a (nonlactotrope) pituitary adenoma. The latter may reflect diminished delivery of dopamine or other inhibitory factors to normal lactotropes. We hypothesized that diurnal and ultradian rhythms of PRL secretion would differ in secondary (e.g. hypothalamic) and primary (e.g. tumoral states) hyperprolactinemia (PH), assuming that the underlying pathophysiologies differ. To test this clinical postulate, we investigated the patterns of 24-h PRL release in eight patients with SH associated with functional hypothalamo-pituitary disconnection and in eight patients with PH attributable to microprolactinoma. Data in each group were compared with values in healthy gender-matched controls. PRL time series were obtained by repetitive 10-min blood sampling, followed by high- precision immunofluorometric assay. PRL concentration profiles were analyzed by the complementary tools of model-free discrete peak detection, waveform-independent deconvolution analysis, cosinor regression, and the approximate entropy metric to quantitate pulsatile, basal, 24-h rhythmic, and pattern-dependent (entropic) PRL secretion. Patients with tumoral hyperprolactinemia (PH) showed a 2-fold higher 24-h mean serum PRL concentration than patients with SH (62 +/- 13 microg /L vs. 30 +/- 6.9 microg/L, respectively, P = 0.029). Estimated PRL pulse frequency (events/24 h) was similar in the two patient groups (18.5 +/- 0.7 vs. 17.6 +/- 0.8; P = 0.395) but elevated over that in euprolactinemic controls (P < 0.0001 for both). Deconvolution analysis disclosed a mean daily PRL secretion rate of 790 +/- 170 microg in PH patients vs. 380 +/- 85 microg in SH patients (P = 0.030). Nonpulsatile PRL secretion comprised nearly 70% of total secretion in both patient groups and 50% in controls (P < 0.0001). Cosinor analysis revealed similar acrophases in all three study cohorts. The mean skewness of the statistical distribution of the individual PRL sample secretory rates was reduced, compared with controls (P < 10 (-5) for each), but equivalent in SH and PH patients (0.83 +/- 0.12 vs. 0.78 +/- 0.08, respectively), denoting a loss of the normal spectrum of low- and higher-amplitude secretion rates. Approximate entropy, a regularity statistic, was markedly elevated in both patient groups over controls (P < 10 (-6) for each) and was slightly higher in PH patients than in SH patients (1.639 +/- 0.029 vs. 1.482 +/- 0.067, P = 0.048). In summary, patterns of PRL secretion in PH and SH states exhibit an equivalently increased frequency of PRL pulses, a comparably marked rise in nonpulsatile (basal) PRL secretion. Despite overlap, the regularity of PRL release patterns is disrupted even more profoundly in PH (tumoral), compared with SH. Assuming that the orderliness of serial PRL output monitors normal integration within a feedback-controlled neurohormone axis, then the more disorderly patterns of tumoral PRL secretion point to greater regulatory disruption in PH. The latter may reflect abnormal secretory behavior associated with lactotrope neoplastic transformation and/or isolation of the tumor cell mass from normal hypothalamic controls.

Adult↗

PubMed2000

Short-term fasting selectively suppresses leptin pulse mass and 24-hour rhythmic leptin release in healthy midluteal phase women without disturbing leptin pulse frequency or its entropy control (pattern orderliness).

Nutritional signals strongly regulate neuroendocrine axes, such as those subserving release of LH, GH, and TSH, presumptively in part via the adipocyte-derived neuroactive peptide leptin. In turn, leptin release is controlled by both acute (fasting) and long-term (adipose store) nutrient status. Here, we investigate the neuroendocrine impact of short-term (2.5-day) fasting on leptin release in healthy young women studied in the steroid-replete midluteal phase of the normal menstrual cycle. Eight women each underwent 24-h blood sampling at 10-min intervals during a randomly ordered 2.5-day fasting vs. fed session in separate menstrual cycles. Pulsatile leptin release was quantified by model-free Cluster analysis, the orderliness of leptin patterns by the approximate entropy statistic, and nyctohemeral leptin rhythmicity by cosinor analysis. Mean (24-h) serum leptin concentrations fell by 4.6-fold during fasting; namely, from 15.2+/-2.3 to 3.4+/-0.6 microg/L (P = 0.0007). Cluster analysis identified 13.9+/-1.1 and 14.3+/-1.1 leptin peaks per 24 h in the fed and fasting states (P = NS), and unchanging leptin interpeak intervals (89+/-5.4 vs. 92+/-5.3 min). Leptin peak area declined by 4.2-fold (155+/-21 vs. 37+/-7 area units, P = 0.004), due to a reduction in incremental leptin pulse amplitude (4.4+/-0.7 vs. 1.0+/-0.13 microg/L, P = 0.0011). The cosine amplitude and mesor (mean) of the 24-h leptin rhythm decreased by 4-fold, whereas the acrophase (timing of the nyctohemeral leptin peak) remained fixed. The approximate entropy of leptin release was stable, thus indicating preserved orderliness of leptin release patterns in fasting. Cross-correlation analysis revealed both positive (fed) and negative (fasting) leptin-GH relationships, but no leptin-LH correlations. In summary, short-term (2.5-day) fasting profoundly suppresses 24-h serum leptin concentrations and pulsatile leptin release in the sex steroid-sufficient midluteal phase of healthy women via mechanisms that selectively attenuate leptin pulse area and incremental amplitude. In contrast, the pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern 24-h leptin release are not altered by acute nutrient restriction at this menstrual phase. Leptin-GH (but not leptin-LH) showed nutrient-dependent positive (fed) and negative (fasting) cross-correlations. Whether similar neuroendocrine mechanisms supervise altered leptin signaling during short-term nutrient restriction in men, children, or postmenopausal women is not known.

Adult↗

PubMed2005

Calculation of the entropy and free energy by the hypothetical scanning Monte Carlo method: application to peptides.

A new approach, the hypothetical scanning Monte Carlo (HSMC), for calculating the absolute entropy, S, and free energy, F, has been introduced recently and applied first to fluids (argon and water) and later to peptides. In this paper the method is further developed for peptide chains in vacuum. S is calculated from a given MC sample by reconstructing each sample conformation i step-by-step, i.e., calculating transition probabilities (TPs) for the dihedral and bond angles and fixing the related atoms at their positions. At step k of the process the chain's coordinates that have already been determined are kept fixed (the "frozen past") and TP(k) is obtained from a MC simulation of the "future" part of the chain whose TPs as yet have not been determined; when the process is completed the contribution of conformation i to the entropy is, S(i) approximately -ln Pi(k) TP(k). In a recent paper we studied polyglycine chains, modeled by the AMBER force field with constant bond lengths and bond angles (the rigid model). Decaglycine [(Gly)(10)] was studied in the helical, extended, and hairpin microstates, while (Gly)(16) was treated only in the first two microstates. In this paper the samples are increased and restudied, (Gly)(16) is also investigated in the hairpin microstate, and for (Gly)(10) approximations are tested where only part of the future is considered for calculating the TPs. We calculate upper and lower bounds for F and demonstrate that like for fluids, F can be obtained from multiple reconstructions of a single conformation. We also test a more realistic model of (Gly)(10) where the bond angles are allowed to move (the flexible model). Very accurate results for S and F are obtained which are compared to results obtained by the quasiharmonic approximation and the local states method. Thus, differences in entropy and free energy between the three microstates are obtained within errors of 0.1-0.3 kcal/mol. The HSMC method can be applied to a macromolecule with any degree of flexibility, ranging from local fluctuations to a random coil. The present results demonstrate that the difference in stability, DeltaF(mn)=F(m)-F(n) between significantly different microstates m and n, can be obtained from two simulations only without the need to resort to thermodynamic integration. Our long-term goal is to extend this method to any peptide and apply it to a peptide immersed in a box with explicit water.

Computer Simulation↗

PubMed2006

Comprehensive two-dimensional gas chromatography in the analysis of volatile samples of natural origin: a multidisciplinary approach to evaluate the influence of second dimension column coated with mixed stationary phases on system orthogonality.

The study evaluates the influence of selectivity tuning of the stationary phase of the second dimension on the orthogonality of a comprehensive two-dimensional gas chromatography (GC x GC) system. Two different sets of columns, providing independent and semi-independent separation mechanisms were used. The first consisted of a first dimension separating analytes on a volatility basis (i.e. a non-polar polydimethylsiloxane (OV1) column) combined with a second dimension separating by polarity, using columns coated with 100% polyethylene glycol (CW20M), CW20M/OV1 mixtures in ratios of 25-75%, and polydimethylsiloxane, 7% phenyl, 7% cyanopropyl (OV1701). The second set consisted of a first dimension separating analytes on a polarity basis (100% CW20M column) combined with a second dimension separating by volatility, consisting of columns coated with 100% OV1, OV1/CW20M mixtures in ratios of 25-75%, and 100% OV1701. Medium-complexity mixtures of natural origin (i.e. peppermint essential oil and a standard mixture of suspected allergens) consisting of components in a relatively limited range of molecular weights (MW) and volatilities, but belonging to different classes of compounds in a wide range of polarity (mono- and sesquiterpenoids, hydrocarbons and oxygenated compounds) were analysed with the above sets of columns. Different approaches were used to evaluate peak spreading on the GC x GC separation plane and degree of orthogonality of the column sets, namely: (1) a Factor Analysis (FA) approach, estimating the correlation coefficients and spreading angles of the sample components in the two-dimensional chromatographic plane; (2) an Informational Theory (IT) approach, based on determining a group of parameters including: informational entropy, % synentropy and similarity (H); and (3) an approach based on estimating the amount of separation space used, i.e. a practical parameter that directly refers to the experimental separation plane of the GC x GC chromatogram. Results showed that peak spreading in the chromatographic plane, when CW20M and OV1 are combined in different ratios, can be predicted from retention mechanisms, and that the degree of orthogonality measured with different approaches, is consistent with the divergent nature, in terms of polarity of the stationary phases combined in the GC x GC system.

Allergens↗

PubMed2000

Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling.

A new method for the size-distribution analysis of polymers by sedimentation velocity analytical ultracentrifugation is described. It exploits the ability of Lamm equation modeling to discriminate between the spreading of the sedimentation boundary arising from sample heterogeneity and from diffusion. Finite element solutions of the Lamm equation for a large number of discrete noninteracting species are combined with maximum entropy regularization to represent a continuous size-distribution. As in the program CONTIN, the parameter governing the regularization constraint is adjusted by variance analysis to a predefined confidence level. Estimates of the partial specific volume and the frictional ratio of the macromolecules are used to calculate the diffusion coefficients, resulting in relatively high-resolution sedimentation coefficient distributions c(s) or molar mass distributions c(M). It can be applied to interference optical data that exhibit systematic noise components, and it does not require solution or solvent plateaus to be established. More details on the size-distribution can be obtained than from van Holde-Weischet analysis. The sensitivity to the values of the regularization parameter and to the shape parameters is explored with the help of simulated sedimentation data of discrete and continuous model size distributions, and by applications to experimental data of continuous and discrete protein mixtures.

Confidence Intervals↗

PubMed1996

Type I collagen CNBr peptides: species and behavior in solution.

The properties of type I collagen CNBr peptides in solution were studied to investigate the molecular species formed, their conformation, and factors influencing equilibria between peptide species. Peptides formed homologous trimers, even though the native parent protein is heterotrimeric, [alpha 1(I)]2 alpha 2-(I). Their triple-helical content was found to be high (> 75% for most peptides). Full helical content was not reached mainly because of the presence of monomer species; chain misalignment, if present, and trimer unraveling at terminal ends appeared to play a minor role in reducing helicity. Circular dichroism spectra and resistance to trypsin digestion at 4 and 20 degrees C demonstrated that the conformation of trimers was very similar to the collagen triple-helical conformation. Rotary shadowing of peptide alpha 1(I) CB7 supported this finding. Analytical gel filtration in nondenaturing conditions showed that the trimers of some peptides have the ability to autoaggregate. In the case of peptides alpha 1(I) CB8 and alpha 2(I) CB4, most of the intermolecular interactions between trimeric molecules were disrupted by 0.5 M NaCl, demonstrating that their ionic character is important. Changes in ionic strength also altered the hydrodynamic size of single- and triple-stranded molecules. The different molecular species are in equilibrium. The kinetics of the conversion of trimer to monomer species was determined in a time course experiment using trypsin digestion and found to be a relatively slow process (trimer half-life is a few days at 4 degrees C, about one order of magnitude lower at 20 degrees C) with an activation energy of roughly 4-9 kcal/mol. The circular dichroism profile at increasing temperatures showed that the melting temperature for triple-helical peptides is about 6-10 degrees C lower than that of the parent native type I collagen. The folding of peptides is a spontaneous process (exothermic but with unfavourable entropy change), and the triple-helical conformation originates solely as the result of the collagen sequence because it forms from heat-denatured samples.

Animals↗

PubMed2006

Free-energy landscape for beta hairpin folding from combined parallel tempering and metadynamics.

We develop a new free-energy method, based on the combination of parallel tempering and metadynamics, and apply this method to the calculation of the free-energy landscape of the folding beta hairpin in explicit water. We show that the combined method greatly improves the performance of both parallel tempering and metadynamics. In particular, we are able to sample the high free-energy regions, which are not accessible with conventional parallel tempering. We use our results to calculate the difference in entropy and enthalpy between the folded and the unfolded state and to characterize the most populated configurations in the relevant free-energy basins.

Algorithms↗

PubMed2005

Perspective on the reactions between F- and CH3CH2F: the free energy landscape of the E2 and SN2 reaction channels.

Recently, we computed the 3D free energy surface of the base-induced elimination reaction between F(-) and CH(3)CH(2)F by using a powerful technique within Car-Parrinello molecular dynamics simulation. Here, the set of three order parameters is expanded to six, which allows the study of the competing elimination and substitution reactions simultaneously. The power of the method is exemplified by the exploration of the six-dimensional free energy landscape, sampling, and mapping out the eight stable states as well as the connecting bottlenecks. The free energy profile and barrier along the E2 and S(N)2 reaction channels are refined by using umbrella sampling. The two mechanisms do not share a common "E2C-like" transition state. Comparison with the zero temperature profiles shows a particularly significant entropy contribution to the S(N)2 channel.

Algorithms↗

PubMed2006

Neuroendocrine responses to psychological stress in eumenorrheic and oligomenorrheic women.

Neuroendocrine adaptive responses to psychological stress include activation of the hypothalamic-pituitary-adrenal (HPA) axis and sometimes suppression of the hypothalamic-pituitary-gonadal (HPG) axis. In women who experience chronic stress, these responses are probably responsible for disturbances in the menstrual cycle. In the present experiment, we investigated the effect of an acutely stressful situation on the physiological and neuroendocrine responses in college age women. We hypothesized that females who are experiencing some degree of abnormal menstrual function or women who have less-robust cycles (oligomenorrheic females) would exhibit differences in gonadotropin secretion from eumenorrheic females when exposed to psychological stressors. Fifteen women completed this study: eumenorrheic (n = 5) and oligomenorrheic women (n = 5) who experienced a series of psychological stressors, and eumenorrheic controls (n = 5). Blood samples were taken at 10 min intervals for 8 h (09:00-17:00) in each woman during the mid-follicular phase of the menstrual cycle. The psychological stressors were administered for 1 h beginning at 13:00 h. Luteinizing hormone (LH), growth hormone (GH) and cortisol were measured in each sample to assess the effect of stress on secretion of these hormones. Deconvolution analysis was used to analyze pulsatile hormone secretion and the approximate entropy (ApEn) statistic analyzed the regularity of release of each hormone. Although, there were significant changes in heart rate (HR), skin resistance (SR) and cortisol levels in the stressed women during the psychological stressor compared to resting baseline values but not in the controls, there was no difference in either LH or GH secretion between women who experienced stress and those who did not. Furthermore, there were no differences in the LH or GH secretion patterns in the oligomenorrheic and eumenorrheic women exposed to the psychological stressor.

Adolescent↗

PubMed2004

Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men.

Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. Injection of hypocretin-1 acutely suppresses TRH and TSH release in rats. In contrast, subchronic administration does not appear to affect the hypothalamo-pituitary-thyroid ensemble in animals. We explored (in 7 patients and 7 controls) whether hypocretin deficiency impacts circulating TSH levels and circadian timing of TSH release in narcoleptic humans. Plasma TSH concentration profiles (blood samples taken at 10-min intervals during 24 h) and TSH levels in response to TRH injection were analyzed by Cluster, robust regression, approximate entropy (ApEn), and deconvolution. Circulating TSH levels were lower in patients, which was primarily attributable to lower pulse amplitude and nadir concentrations. TSH secretion correlated positively with mean 24-h leptin levels (R2 = 0.46, P = 0.02) and negatively with amount of sleep (R2 = 0.29, P = 0.048). Pattern-synchrony between 24-h leptin and TSH concentrations was demonstrated by significant cross-correlation and cross-ApEn analyses with no differences between controls and patients. Sleep onset was closely associated with a fall in circulating TSH. Features of diurnal rhythmicity of circulating TSH fluctuations were similar in patients and controls, with the acrophase occurring shortly after midnight. Thyroxine and triiodothyronine concentrations were similar in patients and controls and did not display a diurnal rhythm. The response of plasma TSH levels to TRH was also similar in both groups. Sleep patterns in narcoleptics were significantly disorderly compared with controls, as measured by ApEn (P = 0.006). In summary, circulating TSH concentrations are low in hypocretin-deficient narcoleptic men, which could be attributable to their low plasma leptin levels and/or their abnormal sleep-wake cycle.

Adaptation, Physiological↗