Simultaneous Fitting Of Data Research Articles

#13 MAGDALENA - A randomized study on neurodevelopment after fetal exposure to SSRIs

Isothermal titration calorimetry data for very low c (≡K[M]0) must normally be analyzed with the stoichiometry parameter n fixed — at its known value or at any reasonable value if the system is not well characterized. In the latter case, ΔH° (and hence n) can be estimated from the T-dependence of the binding constant K, using the van't Hoff (vH) relation. An alternative is global or simultaneous fitting of data at multiple temperatures. In this Note, global analysis of low-c data at two temperatures is shown to estimate ΔH° and n with double the precision of the vH method.

Analysis of multitemperature isothermal titration calorimetry data at very low c: Global beats van't Hoff

Isothermal titration calorimetry data for very low c (≡K[M]0) must normally be analyzed with the stoichiometry parameter n fixed — at its known value or at any reasonable value if the system is not well characterized. In the latter case, ΔH° (and hence n) can be estimated from the T-dependence of the binding constant K, using the van't Hoff (vH) relation. An alternative is global or simultaneous fitting of data at multiple temperatures. In this Note, global analysis of low-c data at two temperatures is shown to estimate ΔH° and n with double the precision of the vH method.

Acentric langanite La3Ga5.5Nb0.5O14 crystal: a new nonlinear crystal for the generation of mid-infrared parametric light.

The mid-infrared spectral range extending from 2 to 6 μm is significant for scientific and technological applications. A promising nonlinear oxide crystal La3Ga5.5Nb0.5O14 (LGN) is proposed and fully characterized for the first time to our knowledge. The transparency range extends between 0.28 and 7.4 μm. The two principal refractive indices were measured and we found that the nonlinear coefficient d11 = 3.0 ± 0.1 pm/V at 0.532 μm. The simultaneous fit of data allowed us to refine the Sellmeier equations of LGN and to calculate the tuning curves for optical parametric generation (OPG) pumped at 1.064 μm. Calculations are consistent with recorded data and also show the generation of a supercontinuum between 1.5 and 3.5 μm when pumped at 0.98 μm by a Ti:Sapphire laser.

Distance-Resolving Voltage Clamp Fluorometry (drVCF) Quantifies Intramolecular Transitions in the Human BK and CI-VSP Voltage Sensors Under Physiologically-Relevant Conditions

The BK channel voltage-sensing domain (VSD) exhibits important differences from the canonical VSD model: an additional helix (S0), a decentralized distribution of voltage-sensing charges throughout S2-S3-S4 and cooperative S2/S4 activation transitions. To understand the voltage-evoked conformational rearrangements of this unique voltage sensor, and address the unmet need of quantifying short-range intramolecular distances in conducting channels under physiological conditions, we have been developing a new theoretical and experimental framework: distance-resolving Voltage Clamp Fluorometry (drVCF).drVCF exploits state-dependent collisional quenching of site-specifically conjugated tetramethylrhodamine fluorophores of different length by tryptophan. Firstly, voltage-evoked, Trp-dependent fluorescence deflections of each label are acquired from the VSD of conducting human BK channels expressed in Xenopus oocytes using VCF-enabled cut-open oocyte voltage clamp. The labeling site/tryptophan distance in the resting and active states is determined by fitting VCF data to quenching probability density over distance, generated by fluorophore molecular dynamics simulations. Simultaneous fitting of data from multiple fluorophores results in well-constrained solutions. Confidence intervals are established using bootstrap resampling.At rest, S0, S1 and S2 are approximately equidistant from S4: S0-S4 mean=12.5A; 95% CI [12.4-12.8A]; S1-S4=11.9A [10.4-12.9A]; S2-S4=11.5A [8.8-12.3A]. Upon VSD activation, S4 diverges from S0 (22.0A [21.4-23.1A]) and S1 (18.4A [17.7-20.0A]), while the S2-S4 distance exceeds 24A. Using this information, we constructed a structural model for the BK voltage sensor in the resting and active states. Applying drVCF in Ci-VSP, we resolved that positions 137 (S1) and 212 (S4) are 19-24A apart in the active state, as in the atomic structure (22A: Li et al., 2014; PDB#4G7V). Thus, the new drVCF approach complements FRET-based techniques for distance measurements of short-range transitions under physiologically-relevant conditions.

Differential emission measure and electron distribution function reconstructed from RHESSI and SDO observations

To solve a number of problems in solar physics related to mechanisms of energy release in solar corona parameters of hot coronal plasma are required, such as energy distribution, emission measure, differential emission measure, and their evolution with time. Of special interest is the distribution of solar plasma by energies, which can evolve from a nearly Maxwellian distribution to a distribution with a more complex structure during a solar flare. The exact form of this distribution for low-energy particles, which receive the bulk of flare energy, is still poorly known; therefore, detailed investigations are required. We present a developed method of simultaneous fitting of data from two spacecrafts Solar Dynamics Observatory/Atmospheric Imaging Assembly (SDO/AIA) and Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI), using a differential emission measure and a thin target model for the August 14, 2010 flare event.

Antiarthritis Effect of a Novel Bruton's Tyrosine Kinase (BTK) Inhibitor in Rat Collagen-Induced Arthritis and Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling: Relationships between Inhibition of BTK Phosphorylation and Efficacy

Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation, and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. The objective of this study was to evaluate the antiarthritis effect of GDC-0834 [R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], a potent and selective BTK inhibitor, and characterize the relationship between inhibition of BTK phosphorylation (pBTK) and efficacy. GDC-0834 inhibited BTK with an in vitro IC(50) of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC(50) of 1.1 and 5.6 μM in mouse and rat, respectively. Administration of GDC-0834 (30-100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle-diameter time-course data. This model incorporated a transit model to characterize nondrug-related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle- and GDC-0834-treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (k(in)) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats.

Characterization of Proexosite I on Prothrombin

Activation of prothrombin by factor Xa is accompanied by expression of regulatory exosites I and II on the blood coagulation proteinase, thrombin. Quantitative affinity chromatography and equilibrium binding studies with a fluorescein-labeled derivative of the exosite I-specific peptide ligand, hirudin(54-65) ([5F]Hir(54-65) (SO(3)(-)), were employed to identify and characterize this site on human and bovine prothrombin and its expression on thrombin. [5F]Hir(54-65)(SO(3)(-)) showed distinctive fluorescence excitation spectral differences in complexes with prothrombin and thrombin and bound to human prothrombin and thrombin with dissociation constants of 3.2 +/- 0.3 micrometer and 25 +/- 2 nm, respectively, demonstrating a 130-fold increase in affinity for the active proteinase. The bovine proteins similarly showed a 150-fold higher affinity of [5F]Hir(54-65)(SO(3)(-)) for thrombin compared with prothrombin, despite a 2-5-fold lower affinity of the peptides for the bovine proteins. Unlabeled, Tyr(63)-sulfated and nonsulfated hirudin peptides bound competitively with [5F]Hir(54-65)(SO(3)(-)) to human and bovine prothrombin and thrombin, exhibiting similar, 40-70-fold higher affinities for the proteinases, although nonsulfated Hir(54-65) bound with 7-17-fold lower affinity than the sulfated analog. These studies characterize proexosite I for the first time as a specific binding site for hirudin peptides on both human and bovine prothrombin that is present in a conformationally distinct, low affinity state and is activated with a approximately 100-fold increase in affinity when thrombin is formed.