1914G variant of BCHE gene associated with enzyme activity,obesity and triglyceride levels

Polymorphisms of butyrylcholinesterase (BChE) have been reported to be associated to weight, BMI variance and hypertriglyceridemia in adults and adolescents. The aim of the present study was to investigate the association of −116A (SNP: G/A; rs1126680) and 1914G (SNP: A/G; rs3495) variants of BCHE gene with anthropometric and biochemical variables associated with obesity in population sample of 115 individuals, from Southern Brazil. Participants were grouped in two categories: obese (BMI ≥ 30) and non-obese (BMI < 30). The 1914G allele showed significantly higher frequency in the obese group, and carriers of 1914G allele showed lower mean BChE activity when compared to 1914A carriers (p = 0.006). Higher means of BMI (p = 0.02) and triglyceride (TG; p = 0.01) were found in 1914G carriers (BMI = 27.57kg/m²; TG = 150.8 mg/dL) when compared to 1914A homozygotes (BMI = 25.55 kg/m²; TG = 107.9 mg/dL). Carriers of the −116A allele showed lower mean BChE activity than usual homozygotes, and the −116A variant was found in cis with 1914G (p < 0.0001; D′ = 1). The region of BCHE gene that contains the 1914G mutation site is target of microRNAs (miRs) and the response of BChE to glucocorticoids is especially influenced by these miRs. Therefore, it is possible that the 1914G allele can be interfering in gluconeogenesis, hyperglycemia, lipolysis and body fat distribution. This lower activity may cause an imbalance in lipid metabolism, which may lead to an increased predisposition to obesity and to a lower ability to maintain metabolic homeostasis.     

Inverse Problem in Materials Science

Abstract

The importance of the inverse problem in materials science, that is, the determination of unknown parameters in the physico-chemical models from the experimental values is emphasized. The main attention is given to the problem of how to take into account experimental systematic errors during the inverse problem.     

Molecular Dynamics Simulations of Proteins in Water Without the Truncation of Long-range Coulomb Interactions

A new program package (COSMOS90) for molecular dynamics simulations was developed to simulate large molecular systems consisting of more than tens of thousands of atoms without the truncation of long-range coulomb interactions. This program package was based on a new approximation scheme (PPPC) for calculating efficiently the coulomb interactions without sacrificing accuracy. In this approximation scheme, the group of charges at a long distance from each atom was represented by a total charge and total dipole moment of the group. In order to assess the accuracy of PPPC and the ability of COSMOS90, molecular dynamics simulations were carried out for a large system consisting of 16108 atoms (human lysozyme in water) for 50 ps using this program package. The coulomb energy per solute atom was calculated with only five percent of the error found in the 10 Å cut-off approximation (about 0.9 kcal/mol versus 18 kcal/mol, respectively). The molecular dynamics simulations using COSMOS90 require no more CPU time than the simulations based on the 10 Å cut-off approximation of the conventional programs for macromolecular simulations.     

3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis,molecular modeling and QSAR studies

A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC₅₀ = 0.21, 0.21 and 0.23 nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10 mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R² of 0.81.     

Automated binning of microsatellite alleles: problems and solutions

As genotyping methods move ever closer to full automation, care must be taken to ensure that there is no equivalent rise in allele‐calling error rates. One clear source of error lies with how raw allele lengths are converted into allele classes, a process referred to as binning. Standard automated approaches usually assume collinearity between expected and measured fragment length. Unfortunately, such collinearity is often only approximate, with the consequence that alleles do not conform to a perfect 2‐, 3‐ or 4‐base‐pair periodicity. To account for these problems, we introduce a method that allows repeat units to be fractionally shorter or longer than their theoretical value. Tested on a large human data set, our algorithm performs well over a wide range of dinucleotide repeat loci. The size of the problem caused by sticking to whole numbers of bases is indicated by the fact that the effective repeat length was within 5% of the assumed length only 68.3% of the time.     

Influence of IMU position and orientation placement errors on ground reaction force estimation

Wearable inertial measurement units (IMU) have been proposed to estimate GRF outside of specialized laboratories, however the precise influence of sensor placement error on accuracy is unknown. We investigated the influence of IMU position and orientation placement errors on GRF estimation accuracy. Methods: Kinematic data from twelve healthy subjects based on marker trajectories were used to simulate 1848 combinations of sensor position placement errors (range ± 100 mm) and orientation placement errors (range ± 25°) across eight body segments (trunk, pelvis, left/right thighs, left/right shanks, and left/right feet) during normal walking trials for baseline cases when a single sensor was misplaced and for the extreme cases when all sensors were simultaneously misplaced. Three machine learning algorithms were used to estimate GRF for each placement error condition and compared with the no placement error condition to evaluate performance. Results: Position placement errors for a single misplaced IMU reduced vertical GRF (VGRF), medio-lateral GRF (MLGRF), and anterior-posterior GRF (APGRF) estimation accuracy by up to 1.1%, 2.0%, and 0.9%, respectively and for all eight simultaneously misplaced IMUs by up to 4.9%, 6.0%, and 4.3%, respectively. Orientation placement errors for a single misplaced IMU reduced VGRF, MLGRF, and APGRF estimation accuracy by up to 4.8%, 7.3%, and 1.5%, respectively and for all eight simultaneously misplaced IMUs by up to 20.8%, 23.4%, and 12.3%, respectively. Conclusion: IMU sensor misplacement, particularly orientation placement errors, can significantly reduce GRF estimation accuracy and thus measures should be taken to account for placement errors in implementations of GRF estimation via wearable IMUs.