3D QSAR Pharmacophore Modeling, in Silico Screening, and Density Functional Theory (DFT) Approaches for Identification of Human Chymase Inhibitors

Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating (r = 0.942) pharmacophore model (Hypo1) with two hydrogen bond acceptors, and three hydrophobic aromatic features is generated. After successfully validating “Hypo1”, it is further applied in database screening. Hit compounds are subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with key active site amino acids are identified as potent chymase hits. Moreover, DFT study is performed which confirms very clear trends between electronic properties and inhibitory activity (IC50) data thus successfully validating “Hypo1” by DFT method. Therefore, this research exertion can be helpful in the development of new potent hits for chymase. In addition, the combinational use of docking, orbital energies and molecular electrostatic potential analysis is also demonstrated as a good endeavor to gain an insight into the interaction between chymase and inhibitors

Benign metastasizing leiomyoma of the lung

Benign leiomyomas of the uterus are uncommonly found in association with benign smooth muscle tumors beyond the confines of the uterus. Benign metastasizing leiomyoma (BML) is a rare disease in which the lung is described to be the most afflicted extrauterine organ. We present a brief review of the literature, along with case reports for four patients who were followed up after resection of a pulmonary lesion or after pathological confirmation by biopsy. The clinical course of BML varies from chronic asymptomatic appearance to rapid progression, leading to respiratory failure and death. Our BML patients did not complain of pulmonary symptoms, such as cough, dyspnea, or chest tightness. Pathology revealed benign leiomyomas with no atypia and mitotic activity <5 per 10 high-power field. Immunohistochemical staining was positive for actin and desmin. A standard treatment for BML has not yet been established. Because of the hormone-sensitive characteristics of BML, treatments are based on hormonal manipulation along with either surgical or medical oophorectomy. Benign metastasizing leiomyoma can be observed in postmenopausal women. We observed four patients who did not receive adjuvant hormonal therapy because they were postmenopausal or perimenopausal. All patients are still healthy and show no evidence of recurrence or progression of the disease

Inelastic scattering in a monolayer graphene sheet; a weak-localization study

Charge carriers in a graphene sheet, a single layer of graphite, exhibit much distinctive characteristics to those in other two-dimensional electronic systems because of their chiral nature. In this report, we focus on the observation of weak localization in a graphene sheet exfoliated from a piece of natural graphite and nano-patterned into a Hall-bar geometry. Much stronger chiral-symmetry-breaking elastic intervalley scattering in our graphene sheet restores the conventional weak localization. The resulting carrier-density and temperature dependence of the phase coherence length reveal that the electron-electron interaction including a direct Coulomb interaction is the main inelastic scattering factor while electron-hole puddles enhance the inelastic scattering near the Dirac point.Comment: 12 pages, 3 figures, submitted to PR

Application of Optical Interferometry for Characterization of Thin-Film Adhesion

In this chapter, application of optical interferometry for the characterization of thin-film adhesion to the substrate is discussed. The thin-film system is configured as one of the end mirrors of a Michelson interferometer and oscillated with an acoustic transducer from the substrate side. The oscillation causes sinusoidal displacement of the film surface around the initial (neutral) position, and the interferometer detects its amplitude as the relative phase difference behind the beam splitter. When the driving frequency of this oscillation is tuned to a range where the film-substrate interface is dominantly oscillated, the elasticity of the interface can be analyzed from the oscillation amplitude. The principle of this method is straightforward but in reality, fluctuation of the initial phase (the relative phase corresponding to the initial film position) compromises the signal. A technique known as the carrier fringe method along with spatial frequency domain analysis is employed to reduce the noise associated with the initial phase fluctuation. The possibility of the present method to analyze the so-called blister effect on thin-film adhesion is discussed

What Questions do People Ask on a Human Papillomavirus Website? A Comparative Analysis of Public and Private Questions

Objective: In 2004, we launched the question and answer (Q&A) section on a human papillomavirus (HPV) website (www.hpvkorea.org) that provides ample and regularly updated information about HPV. The purpose of this study is to collect data pertaining to questions posed on this website about HPV and its related diseases and analyze the type of questions and frequency before and after introduction of HPV vaccine in Korea. Using these results, we intend to determine the clinical and practical implications for doctors treating HPV and for HPV website providers

The Raf/MEK/extracellular signal-regulated kinase 1/2 pathway can mediate growth inhibitory and differentiation signaling via androgen receptor downregulation in prostate cancer cells.

Upregulated ERK1/2 activity is correlated with androgen receptor (AR) downregulation in certain prostate cancer (PCa) that exhibits androgen deprivation-induced neuroendocrine differentiation, but its functional relevance requires elucidation. We found that sustained ERK1/2 activation using active Raf or MEK1/2 mutants is sufficient to induce AR downregulation at mRNA and protein levels in LNCaP. Downregulation of AR protein, but not mRNA, was blocked by proteasome inhibitors, MG132 and bortezomib, indicating that the pathway regulation is mediated at multiple points. Ectopic expression of a constitutively active AR inhibited Raf/MEK/ERK-mediated regulation of the differentiation markers, neuron-specific enolase and neutral endopeptidase, and the cyclin-dependent kinase inhibitors, p16(INK4A) and p21(CIP1), but not Rb phosphorylation and E2F1 expression, indicating that AR has a specific role in the pathway-mediated differentiation and growth inhibitory signaling. However, despite the sufficient role of Raf/MEK/ERK, its inhibition using U0126 or ERK1/2 knockdown could not block androgen deprivation-induced AR downregulation in an LNCaP neuroendocrine differentiation model, suggesting that additional signaling pathways are involved in the regulation. We additionally report that sustained Raf/MEK/ERK activity can downregulate full length as well as hormone binding domain-deficient AR isoforms in androgen-refractory C4-2 and CWR22Rv1, but not in LAPC4 and MDA-PCa-2b. Our study demonstrates a novel role of the Raf/MEK/ERK pathway in regulating AR expression in certain PCa types and provides an insight into PCa responses to its aberrant activation

Ethyl 4-hydr­oxy-2,6-diphenyl-1-(2-thio­morpholinopropano­yl)-1,2,5,6-tetra­hydro­pyridine-3-carboxyl­ate

In the title compound, C27H32N2O4S, the thio­morpholine ring adopts a chair conformation and the tetra­hydro­pyridine ring is in a distorted envelope conformation. The mol­ecular structure is stabilized by an intra­molecular O—H⋯O inter­action and the crystal packing is stabilized by an inter­molecular C—H⋯O inter­action, generating an S(6) motif and a dimer of the type R 2 2(18), respectively