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.     

Effect of laterality discrimination on joint position sense and cervical range of motion in patients with chronic neck pain: a randomized single-blind clinical trial

Purpose: The main objective of the present study was to evaluate the effects of laterality discrimination training on neck joint position sense and cervical range of motion (ROM) in patients with chronic non-specific neck pain (NSCNP).

Materials and methods: Forty-eight patients with NSCNP were randomly assigned to the neck group (NG) that observed neck images or the foot group (FG) that observed foot images. Response time, response accuracy, cervical ROM, and joint position error (JPE) were the main variables. The secondary outcome measures included psychosocial variables.

Results: Differences between groups in the cervical ROM for flexion (p?=?.043) were obtained, being NG group the one which obtained greater values. NG showed an improvement in right rotation (p?=?.018) and a decrease in flexion was found in the FG (p?=?.039). In JPE, differences between groups were obtained in the left rotation (p?=?.021) and significant changes were found in the NG for flexion, extension, and left rotation movements (p?<?.05). Moderate associations were found between left and right accuracy regarding to post-intervention flexion and right rotation (r?=?0.46, r?=?0.41; p?<?.05) in NG.

Conclusion: Improvements in cervical range of motion and joint position sense are obtained after the performance of the laterality discrimination task of images of the neck but not the feet. Visualization of images of the painful region presents moderate correlations with the accuracy and response time in the movements of flexion and right rotation.     

Impact of apolipoprotein A1- or lecithin:cholesterol acyltransferase-deficiency on white adipose tissue metabolic activity and glucose homeostasis in mice

High density lipoprotein (HDL) has attracted the attention of biomedical community due to its well-documented role in atheroprotection. HDL has also been recently implicated in the regulation of islets of Langerhans secretory function and in the etiology of peripheral insulin sensitivity. Indeed, data from numerous studies strongly indicate that the functions of pancreatic β-cells, skeletal muscles and adipose tissue could benefit from improved HDL functionality. To better understand how changes in HDL structure may affect diet-induced obesity and type 2 diabetes we aimed at investigating the impact of Apoa1 or Lcat deficiency, two key proteins of peripheral HDL metabolic pathway, on these pathological conditions in mouse models. We report that universal deletion of apoa1 or lcat expression in mice fed western-type diet results in increased sensitivity to body-weight gain compared to control C57BL/6 group. These changes in mouse genome correlate with discrete effects on white adipose tissue (WAT) metabolic activation and plasma glucose homeostasis. Apoa1-deficiency results in reduced WAT mitochondrial non-shivering thermogenesis. Lcat-deficiency causes a concerted reduction in both WAT oxidative phosphorylation and non-shivering thermogenesis, rendering lcat^?/? mice the most sensitive to weight gain out of the three strains tested, followed by apoa1^?/? mice. Nevertheless, only apoa1^?/? mice show disturbed plasma glucose homeostasis due to dysfunctional glucose-stimulated insulin secretion in pancreatic β-islets and insulin resistant skeletal muscles. Our analyses show that both apoa1^?/? and lcat^?/? mice fed high-fat diet have no measurable Apoa1 levels in their plasma, suggesting no direct involvement of Apoa1 in the observed phenotypic differences among groups.     

The Circadian Clock Gene Circuit Controls Protein and Phosphoprotein Rhythms in Arabidopsis thaliana

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