Polyamide Amine Dendrimer Nanoparticles Conjugated with Cis-Diamminedichloroplatinum (CDDP) and miRNA-200c Inhibitor Suppresses Lung Cancer Cell Proliferation

Our study elucidates the effect of folate polyamide amine dendrimer nanoparticles targeting delivery of miRNA-200c inhibitor and CDDP on lung cancer cells proliferation. We established polyamide amine dendrimer nanoparticles binding with CDDP and miRNA-200c inhibitor (Den-PEI-CDDP-siRNA-FA), TEM was employed to detect the morphology of nanoparticles. Agarose gel assay was selected for stabilization test. Cell proliferation were detected by trypanosoma blue exclusion method. The expression of miRNA-200c targeted APKPA12 and apoptosis-related proteins were detected by Western blot and PCR. Finally, apoptosis was analyzed by flow cytometry. Den-PEI-CDDP-siRNA-FA nanoparticles showed excellent stability and drug encapsulation ability. Nanoparticles targeting for FRA to co-deliver siRNA and CDDP could significantly promote cell apoptosis, increase apoptosis-related protein expression, and inhibit cell proliferation. Besides, nanoparticles exerted less venomous effect than untargeted nanoparticles in MRC9 lung fibroblast. Den nanoparticle targeting FRA might be used as the carrier for joint applications with siRNA and CDDP for treating lung cancer.

An Overview on Contact Dermatitis: Simple Review

Contact dermatitis (CD) is usually the result of cumulative exposure to sensitive irritants and accounts for 80% of all contact dermatitis cases. ICD can coexist with atopic dermatitis (AD) and allergic contact dermatitis (ACD). Patients with Alzheimer's disease and ACD may also have a lower infection threshold for ICD. Therefore, it must stand out from EA and CAD lesions. People with ICD have experienced uncontrolled tingling and burning sensations. Itching is typically manifested in patients with AD and ACD. Compared with AD and ACD, ICD lesions are usually well described. The prognosis of ICD is based on the exclusion method. Monitor patients to rule out type 1 and type 4 hypersensitivity reactions. A negative result indicates the prognosis of ICD. Management includes identifying and avoiding irritants through the normal use of emollients. Although ICD is older, it is not uncommon in some majors, and genetics and environment play a vital role in its development.

Distance-based exclusion method for parentage analysis using microsatellites (SSR) markers

Genotyping mistakes represent a challenge in parental assignment where even small errors can lead to significant amounts of unassigned siblings. Different parental assignment algorithms have been designed to approach this problem. The Exclusion method is the most applied for its reliability and biological meaning. However, the resolving power of this method is the lowest for data containing genotyping errors. We introduce a new distance-based approach which we coin as Distance-Based Exclusion (DBE). The DBE method calculates the distance between the offspring haplotype and haplotype of each of the potential fathers. The father with the lowest distance is then assigned as candidate father according to a distance ratio (α). We have tested the Exclusion and DBE methods using a real dataset of 1230 offsprings subdivided into families of 25 individuals. Each family had six potential fathers and one known mother. Compared with the Exclusion method, the DBE method is able to solve 4.7% more individuals (64.4% Exclusion vs 69.1% DBE) using the most restrictive α tested without errors. DBE method can also be used together with the Exclusion method for error calculation and to further solve unassigned individuals. Using a two-step approach, we were able to assign 98.1% of the offsprings with a total predicted error of 4.7%. Considering the results obtained, we propose the use of the DBE method in combination with the Exclusion method for parental assignment.

Diagnostic accuracy of quantitative flow ratio (QFR) and vessel fractional flow reserve (vFFR) estimated retrospectively by conventional radiation saving X-ray angiography

Background Angiography derived FFR reveals good performance in assessing intermediate coronary stenosis. However, its performance under contemporary low X-ray frame and pulse rate settings is unknown. We aim to validate the feasibility and performance of quantitative flow ratio (QFR) and vessel fractional flow reserve (vFFR) under such angiograms. Methods This was an observational, retrospective, single center cohort study. 134 vessels in 102 patients, with angiograms acquired under 7.5fps and 7pps mode, were enrolled. QFR (fQFR and cQFR) and vFFR were validated with FFR as the gold standard. A conventional manual and a newly developed algorithmic exclusion method (M and A group) were both evaluated for identification of poor-quality angiograms. Results Good agreement between QFR/vFFR and FFR were observed in both M and A group, except for vFFR in the M group. The correlation coefficients between fQFR/cQFR/vFFR and FFR were 0.6242, 0.5888, 0.4089 in the M group, with rvFFR significantly lower than rfQFR (p = 0.0303), and 0.7055, 0.6793, 0.5664 in the A group, respectively. AUCs of detecting lesions with FFR ≤ 0.80 were 0.852 (95% CI 0.722–0.913), 0.858 (95% CI 0.778–0.917), 0.682 (95% CI 0.586–0.768), for fQFR/cQFR/vFFR in the M group, while vFFR performed poorer than fQFR (p = 0.0063) and cQFR (p = 0.0054). AUCs were 0.898 (95% CI 0.811–0.945), 0.892 (95% CI 0.803–0.949), 0.843 (95% CI 0.746–0.914) for fQFR/cQFR/vFFR in the A group. AUCvFFR was significantly higher in the A group than that in the M group (p = 0.0399). Conclusions QFR/vFFR assessment is feasible under 7.5fps and 7pps angiography, where cQFR showed no advantage compared to fQFR. Our newly developed algorithmic exclusion method could be a better method of selecting angiograms with adequate quality for angiography derived FFR assessment.

A Combined approach of Pharmacophore Modeling, QSAR Study, Molecular Docking and in silico ADME/Tox prediction of 4-Arylthio & 4- Aryloxy-3- Iodopyridine-2(1H)-one analogs to identify potential Reverse Transcriptase inhibitor: Anti-HIV agents

Background: Reverse transcriptase is an important therapeutic target to treat AIDS caused by the Human Immunodeficiency Virus (HIV). Despite many effective anti-HIV drugs, reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In the present work, we have expedited the use of different computational modules and presented an easy, cost-effective and high throughput screening method to identify potential reverse transcriptase inhibitors. Methods: A congeneric series of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one analogs having anti-HIV activity were subjected to structure-based 2D, 3D QSAR, Pharmacophore Modeling, and Molecular Docking to elucidate the structural properties required for the design of potent HIV-RT inhibitors. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. Results: The 2D and 3D- QSAR models were developed by correlating two and three-dimensional descriptors with activity (pIC50) by sphere exclusion method and k-nearest neighbor molecular field analysis approach, respectively. The significant 2D- QSAR model developed by Partial Least Square associated with the Sphere Exclusion method (PLS-SE) having r2 and q2 values 0.9509 and 0.8038 respectively. The 3D-QSAR model by Step Wise variable selection method (SW-kNN MFA) is more significant which has a cross-validated squared correlation coefficient q2= 0.8509 and a non-cross-validated correlation coefficient pred_r2= 0.8102. The pharmacophore hypothesis was developed which comprised 5 features includes 3 aliphatic regions (Ala), 1 H-bond donor (HDr) and 1 H-bond acceptor (HAc). Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond and π - π interaction with LYS-101, LYS-103, TYR- 181, TYR-188 and TRP-229 residues present at the active site. All the candidates with good bioavailability and ADMET drug likeliness properties. Conclusion: The results of the present work provide more useful information and important structural insights for the discovery, design of novel and potent reverse transcriptase inhibitors with high therapeutic windows in the future.

Theories and methods of virus isoelectric point estimation (Minireview)

Much of virus fate, both in the environment and physical/chemical treatment, is dependent on electrostatic interactions. Developing an accurate means of predicting virion isoelectric point (pI) would help to understand and anticipate virus fate and transport, especially for viruses that are not readily propagated in the lab. One simple approach to predicting pI estimates the pH at which the sum of charges from ionizable amino acids in capsid proteins approaches zero. However, predicted pIs based on capsid charges frequently deviate by several pH units from empirically measured pIs. Recently, the discrepancy between empirical and predicted pI was attributed to the electrostatic neutralization of predictable polynucleotide-binding regions (PBRs) of the capsid interior. In this paper, we review models presupposing the A) influence of the viral polynucleotide on surface charge, or B) contribution of only exterior residues to surface charge. We then compare these models to the approach of excluding only PBRs and hypothesize a conceptual electrostatic model that aligns with this approach. The PBR exclusion method outperformed methods based on 3D structure and accounted for major discrepancies in predicted pIs without adversely affecting pI prediction for a diverse range of viruses. In addition, the PBR exclusion method was determined to be the best available method for predicting virus pI since: A) PBRs are predicted independently of the impact on pI, B) PBR prediction relies on proteome sequences rather than detailed structural models, and C) PBR exclusion was successfully demonstrated on a diverse set of viruses. These models apply to nonenveloped viruses only. A similar model for enveloped viruses is complicated by lack of data on enveloped virus pI, as well as uncertainties regarding the influence of the phospholipid envelope on charge and ion gradients.

Fault-tolerant relative navigation based on Kullback–Leibler divergence

A fault-detection method for relative navigation based on Kullback–Leibler divergence (KLD) is proposed. Different from the traditional χ 2-based approaches, the KLD for a filter is following a hybrid distribution that combines χ 2 distribution and F-distribution. Using extended Kalman filter (EKF) as the estimator, the distance between the priori and posteriori data of EKF is calculated to detect the abnormal measurements. After fault detection step, a fault exclusion method is applied to remove the error observations from the fusion procedure. The proposed method is suitable for the Kalman filter-based multisensor relative navigation system. Simulation and experimental results show that the proposed method can detect the abnormal measurement successfully, and its positioning accuracy after fault detection and exclusion outperforms the traditional χ 2-based method.