Development of an Automated and Sensitive Microfluidic Device for Capturing and Characterizing Circulating Tumor Cells (CTCs) from Clinical Blood Samples

Current analysis of circulating tumor cells (CTCs) is hindered by sub-optimal sensitivity and specificity of devices or assays as well as lack of capability of characterization of CTCs with clinical biomarkers. Here, we validate a novel technology to enrich and characterize CTCs from blood samples of patients with metastatic breast, prostate and colorectal cancers using a microfluidic chip which is processed by using an automated staining and scanning system from sample preparation to image processing. The Celsee system allowed for the detection of CTCs with apparent high sensitivity and specificity (94% sensitivity and 100% specificity). Moreover, the system facilitated rapid capture of CTCs from blood samples and also allowed for downstream characterization of the captured cells by immunohistochemistry, DNA and mRNA fluorescence in-situ hybridization (FISH). In a subset of patients with prostate cancer we compared the technology with a FDA-approved CTC device, CellSearch and found a higher degree of sensitivity with the Celsee instrument. In conclusion, the integrated Celsee system represents a promising CTC technology for enumeration and molecular characterization.     

Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors

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Molecular docking and CoMFA studies of thiazoloquin(az)olin(on)es as CD38 inhibitors: determination of inhibitory mechanism,pharmacophore interactions,and design of new inhibitors

In this research, molecular docking and 3D-QSAR studies were carried out on a series of 79 thiazoloquin(az)olin(on)es as CD38 inhibitors. Based on docking results, four interactions including hydrogen bonding with main chain of GLU-226 (H-M-GLU-226), Van der Waals interactions with side chain of TRP-125 (V-S-TRP-125), TRP-189 (V-S-TRP-189), and THR-221 (V-S-THR-221) were considered as pharmacological interactions. Active conformation of each ligand was extracted from docking studies and was used for carrying out 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) was performed on CD38 inhibitory activities of these compounds on human and mouse. We developed CoMFA models with five components as optimum models for both data-sets. For human data-set, a model with high predictive power was developed. R², RMSE, and F-test values for training set of this model were .94, .24, and 179.58, respectively, and R² and RMSE for its test set were .92 and .32, respectively. The q² and RMSE values for leave-one-out cross validation test on training set were .78 and .46, respectively, that demonstrate created model is robust. Based on extracted steric and electrostatic contour maps for this model, three inhibitors with pIC₅₀ larger than 8.85 were designed.     

Stability and Control of Human Trunk Movement During Walking

A mathematical model has been developed to study the control mechanisms of human trunk movement during walking. The trunk is modeled as a base-excited inverted pendulum with two-degrees of rotational freedom. The base point, corresponding to the bony landmark of the sacrum, can move in three-dimensional space in a general way. Since the stability of upright posture is essential for human walking, a controller has been designed such that the stability of the pendulum about the upright position is guaranteed. The control laws are developed based on Lyapunov's stability theory and include feedforward and linear feedback components. It is found that the feedforward component plays a critical role in keeping postural stability, and the linear feedback component, (resulting from viscoelastic function of the musculoskeletal system) can effectively duplicate the pattern of trunk movement. The mathematical model is validated by comparing the simulation results with those based on gait measurements performed in the Biomechanics Laboratory at the University of Manitoba.     

ATP regulation of a large conductance voltage-gated cation channel in rough endoplasmic reticulum of rat hepatocytes

ATP-sensitive K⁺ channels play an important role in regulating membrane potential during metabolic stress. In this work we report the effect of ATP and ADP-Mg on a K⁺ channel present in the membrane of rough endoplasmic reticulum (RER) from rat hepatocytes incorporated into lipid bilayers. Channel activity was found to decrease in presence of ATP 100 μM on the cytoplasmic side and was totaly inhibited at ATP concentrations greater than 0.25 mM. The effect appeared voltage dependent, suggesting that the ATP binding site was becoming available upon channel opening. Channel activity was suppressed by the nonhydrolyzable ATP analog (ATPγS), ruling out a phosphorylation-based mechanism. Notably addition of 2.5 mM ADP-Mg to the cytosolic side increased the channel open probability at negative potentials. We conclude that the large conductance voltage-gated cation channel in RER of rat hepatocytes is an ATP and ADP sensitive channel likely to be involved in cellular processes such as Ca²⁺ signaling or control of membrane potential across the endoplasmic reticulum membrane.     

Analytical Approach to the Surface Plasmon Resonance Characteristic of Metal Nanoparticle Dimer in Dipole-Dipole Approximation

This theoretical study deals with the effect of bi-particle interaction on the surface plasmon resonance (SPR) in a dimer which includes two identical metal nanoparticles (NPs). Considering the dipole-dipole interaction in a Drude-like model, an appropriate equation is derived for the permittivity of each NP. The restoration force related to the classical confinement originating from the finite size of NPs is considered, and an appropriate adjustment coefficient is considered for this term through analyzing experimental data. Two different polarizations are considered for the laser beam electric field, and it is shown that the orientation of the electric field has an essential role in the linear optical properties of a dimer. Numerical investigation is accomplished for a dimer of gold NPs with two different diameters of 4 nm and 20 nm. For the parallel polarization, dipole-dipole interaction leads to the redshift of SPR wavelength and increase in its peak value, while for the perpendicular polarization, the absolute opposite results are derived. For all cases, it is shown that SPR wavelength functionality with respect to the geometric factor a/d (NP radius to the separation) can be presented by a cubic equation that fits better than an exponential one suggested by the earlier studies which demonstrates the dipole-dipole characteristic of the interaction. Qualitatively, our results are in good agreement with the other experimental studies.

     

Magnetic Field Effect on Fresnel Coefficients of the Thin Slab of Graphite Nanocomposite

In this theoretical study, optical properties of a thin slab including graphite nanoparticles doped in a host medium such as silica and silicon have been investigated. A constant magnetic field is used for controlling Fresnel coefficients of the slab. Depending on the direction of the normal vector of the basal plane of the graphite structure with respect to the electric field of the incident electromagnetic wave (perpendicular or parallel), optical behavior of graphite is different. Electric permittivity of an individual magnetized graphite nanoparticle is calculated by a semi-empirical Drude-like model for both kinds of the normal vector of the basal plane orientation. By means of well-known Maxwell-Garnett theory, effective permittivity of the magnetized nanocomposite slab is obtained. It is shown that at the mid-IR frequency range, exerting a magnetic field of few hundred Tesla can lead to the substantial variations of Fresnel coefficients. Effect of the magnetic field on the optical properties of the slab is more evident when the population of the graphite nanoparticles with the parallel orientation of the basal plane is increased.

     

Design,Synthesis, Molecular Docking,and Cholinesterase Inhibitory Potential of Phthalimide‐Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease

A novel series of phthalimide‐dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti‐cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti‐AChE and anti‐BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h , respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug‐like properties and were able to cross the BBB.