Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation of PKC isozyme-specifc modulators acting via the C1 domain, the binding site for the lipid second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. Synthetic eforts had recently led to the identifcation of AJH-836, a DAG-lactone with preferential afnity for novel isozymes (nPKCs) relative to classical PKCs (cPKCs). Here, we compared the ability of AJH-836 and a prototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to induce changes in gene expression in a lung cancer model. Gene profling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereas AJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9, and MMP10 were among the genes most prominently induced by PMA, an efect impaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive gene signature analysis and bioinformatics eforts, including functional enrichment and transcription factor binding site analyses of dysregulated genes, identifed major diferences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the diferential involvement of individual PKC isozymes in the control of gene expression, our studies emphasize the importance of generating targeted C1 domain ligands capable of diferentially regulating PKC isozyme-specifc function in cellular models.Centro de Investigaciones Inmunológicas Básicas y Aplicada

Modular synthesis of functional polymer nanoparticles from a versatile platform based on poly(pentafluorophenylmethacrylate)

Control of functionalities in polymer nanoparticles (PNPs) is important for their application. Thus, there is an interest for well-defined nanoparticle platforms to which desired functions could readily, and in modular fashion, be imparted. Herein, we report an amine-reactive PNP platform for the modular synthesis of functional PNPs from poly(pentafluorophenylmethacrylate) (poly(PFPMA)) through a simple substitution/nanoprecipitation/photo-crosslinking strategy. Substitution of amine containing coumarin into poly(PFPMA) allows for the achievement of structural stability of nanoprecipitated particles through photo-crosslinking after nanoprecipitation, making it possible to carry out subsequent chemical transformations in organic solvents if needed. We demonstrate that various small molecules and an amine-terminated polymer could be used to modify the crosslinked PNPs to endow them with various functions including fluorescence and responsiveness to temperature changes. The functional PNPs were characterized with variable temperature dynamic light scattering (DLS), UV-vis, and photoluminescence (PL) spectroscopy, and transmission electron microscopy (TEM). (C) 2016 Wiley Periodicals, Inc.N

Inverse Vulcanization Polymers with Enhanced Thermal Properties via Divinylbenzene Homopolymerization-Assisted Cross-Linking

High-refractive-index sulfur-rich polymers with significantly improved thermal properties are prepared using divinylbenzene (DVB) as a comonomer in a modified, low-temperature inverse vulcanization with elemental sulfur. Differential scanning calorimetry and Fourier transform infrared studies reveal that under the modified inverse vulcanization conditions, homopolymerized DVB segments form, leading to high glass-transition temperatures (T-g > 100 degrees C) and thermal stability previously unattainable from the inverse vulcanization of bifunctional olefin comonomers. On the basis of the modified procedures, a three-step molding process of the inverse vulcanization product of DVB, poly(S-r-DVB), involving (1) prepolymer formation, (2) hot-press compression molding of the soft prepolymer, and (3) thermal annealing of the molded product is demonstrated. The molded high-sulfur-content poly(S-r-DVB) exhibits a high refractive index (n > 1.85), along with high midwave infrared transmittance. Combined with a high T-g, these properties render poly(S-r-DVB) with properties highly desirable in applications involving infrared optics.N

Secure and reliable blockchain-based eBook transaction system for self-published eBook trading.

As eBook readers have expanded on the market, various online eBook markets have arisen as well. Currently, the online eBook market consists of at least publishers and online platform providers and authors, and these actors inevitably incur intermediate costs between them. In this paper, we introduce a blockchain-based eBook market system that enables self-published eBook trading and direct payments from readers to authors without any trusted party; because authors publish themselves and readers purchase directly from authors, neither actor incurs any intermediate costs. However, because of this trustless environment, the validity, ownership and intellectual property of digital contents cannot be verified and protected, and the safety of purchase transactions cannot be ensured. To address these shortcomings, we propose a secure and reliable eBook transaction system that satisfies the following security requirements: (1) verification of the ownership of each eBook, (2) confidentiality of eBook contents, (3) authorization of a right to read a book, (4) authentication of a legitimate purchaser, (5) verification of the validity and integrity of eBook contents, (6) safety of direct purchase transactions, and (7) preventing eBook piracy and illegal distribution. We provide practical cryptographic protocols for the proposed system and analyze the security and simulated performance of the proposed schemes

Fine particulate concentrations over East Asia derived from aerosols measured by the advanced Himawari Imager using machine learning

Fine particulate matter with a diameter below 2.5 lim (PM2.5) is deleterious to the cardiovascular and respiratory systems. It is often difficult to assess the effects of PM2.5 on human health over regions with limited ground monitoring sites, especially in East Asia. As an alternative, we estimated near-surface PM2.5 concentrations by analyzing Advanced Himawari Imager (AHI) Yonsei Aerosol Retrieval (YAER) products. This study incorporates daytime data for East Asia covering the Korean Peninsula, China, Japan, Southeast Asia, and southern Mongolia. We collocated AHI YAER product pixels with meteorological, land-cover, and other ancillary data for the period from March 2018 to February 2019. To estimate PM2.5 concentrations over wide areas spanning many countries displaying various relationships between aerosol optical depth and PM2.5, monthly models were developed by considering both the spatial and temporal characteristics of ground-based PM2.5 measurements. Random forest machine learning model estimated ground-level mass concentrations of PM2.5; subsequent 10-fold cross vali-dation (CV) yielded a CV R-2 value of 0.81 and a CV root mean squared error (RMSE) of 12.3 lig m(-3). We investigated the spatial pattern of PM2.5 concentrations over multiple countries and seasonal variation in PM2.5 concentrations. Diurnal variation of a severe PM2.5 event in the Korean Peninsula was investigated as a case study. The model captured the extremely heterogeneous spatial distribution of PM2.5 concentrations peaked around local noon. To measure the capability of the developed model to estimate PM2.5 concentrations in areas with few in-situ data, its predictive performance was evaluated using a dataset independent of the training process with an R-2 of 0.60 and RMSE of 8.18 lig m(-3). This study demonstrates the potential for satellite-based PM2.5 estimation for areas with insufficient measuring stations

Discovery of Novel Dual Adenosine A(2A) and A(1) Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents

New compounds with 1H-pyrazolo [3,4-d]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A(2A) and A(1) receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA(2A) K-i = 13.3 nM; hA(1) K-i = 55 nM) and full antagonism (hA(2A) IC50 = 136 nM; hA(1) IC50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson's disease, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A(2A)/A(1) receptor antagonist, 11o, is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.N

Mechanochemical Ring-Opening Metathesis Polymerization: Development, Scope, and Mechano-Only Copolymer Synthesis

Ruthenium-alkylidene initiated ring-opening metathesis polymerization (Ru-ROMP) was realized under solid-state conditions employing a mechanochemical ball milling method, promoting greenness and broadening scope. High-speed ball milling provided sufficient mixing and energy to the reaction mixture comprised of the catalyst and solid monomers, thus eliminating the need for solvents. Studies on the catalytic species and ball milling parameters (liquid-assisted grinding, vibration frequency, and ball size) revealed that mechanical energy regulated solid-state Ru-ROMP and it follows similar mechanistic features of solution-phase reactions. The solubility and miscibility of monomer and Ru-initiator are not a limitation in solid-state ball milling. Without the use of a solvent, a wide spectrum of solid monomers, including ionomer, fluorous monomer, and macromonomers, were successfully polymerized. Finally, effective direct copolymerization of immiscible monomers such ionic/hydrophobic and ionic/fluorous monomers resulted in a set of copolymers that are difficult to make using traditional solution procedures