Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor.

Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC values of 0.025 μM and 0.

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway.

Background/aims: Critical roles of phosphatase receptor type O (PTPRO) and toll-like receptor 4 (TLR4) have been implicated in inflammation. However, little is known about their functional effects on atherosclerosis (AS). We aim to study their potential function in AS.

Adipocyte differentiation is regulated by mitochondrial trifunctional protein α-subunit via sirtuin 1.

Mitochondrial trifunctional protein α-subunit (MTPα) is involved in the fatty acid β-oxidation (FAO) pathway. Two MTPα activities, 3-hydroxyacyl-CoA dehydrogenase and long-chain hydratase, have been linked with the occurrence and development of obesity and obesity-related disorders. These activities catalyze two steps in the FAO pathway (the second and third reactions).

Sensation Seeking and Online Gaming Addiction in Adolescents: A Moderated Mediation Model of Positive Affective Associations and Impulsivity.

Based on the Dual Systems Model (Somerville et al., 2010; Steinberg, 2010a) and the biosocial-affect model (Romer and Hennessy, 2007) of adolescent sensation seeking and problem behaviors, the present study examined how (affective associations with online games as a mediator) and when (impulsivity as a moderator) did sensation seeking influence online gaming addiction in adolescence. A total of 375 Chinese male adolescents (mean age = 16.

3D-QSAR, Molecular Docking and Molecular Dynamics Simulation of Pseudomonas aeruginosa LpxC Inhibitors.

As an important target for the development of novel antibiotics, UDP-3--(-3-hydroxymyristoyl)--acetylglucosamine deacetylase (LpxC) has been widely studied. Pyridone methylsulfone hydroxamate (PMH) compounds can effectively inhibit the catalytic activity of LpxC. In this work, the three-dimensional quantitative structure-activity relationships of PMH inhibitors were explored and models with good predictive ability were established using comparative molecular field analysis and comparative molecular similarity index analysis methods.

Arabidopsis Forkhead-Associated Domain Protein 3 negatively regulates peroxisome division.

Peroxisomes are ubiquitous and dynamic eukaryotic organelles capable of altering their abundance in response to environmental and developmental cues, yet the regulatory mechanism of plant peroxisome division/proliferation is unclear. To identify transcriptional regulators of the peroxisome division factor gene PEX11b, we performed a nuclear pull-down experiment and identified Arabidopsis Forkhead-Associated Domain Protein 3 (FHA3) as a novel protein that binds to the promoter of PEX11b. Our data supported the conclusion that, in contrast to the previously identified HY5 HOMOLOG (HYH) protein that promotes the transcription of PEX11b, FHA3 is a negative regulator of PEX11b expression and peroxisome division.

Density Functional Theory Calculation and Raman Spectroscopy Studies of Carbamate Pesticides.

In order to obtain the molecular structure vibration information of carbamate pesticide, three carbamate pesticides (carbaryl, carbofuran and aldicarb) were optimized and calculated with B3LYP hybrid functional and 6-31G(d,p) basis set, and their experimental spectra were collected with the Raman spectrometer. The theoretically calculated spectra were compared with the experimental spectra carefully. The results indicated that the theoretically calculated spectra have a very good match with the experimental spectra.

Cytological analysis of ginseng carpel development.

Panax ginseng Meyer, commonly known as ginseng, is considered one of the most important herbs with pharmaceutical values due to the presence of ginsenosides and is cultivated for its highly valued root for medicinal purposes. Recently, it has been recognized that ginseng fruit contains high contents of triterpene such as ginsenoside Re as pharmaceutical compounds. However, it is unclear how carpel, the female reproductive tissue of flowers, is formed during the three-year-old growth before fruit is formed in ginseng plants.

Impact of salt stress, cell death, and autophagy on peroxisomes: quantitative and morphological analyses using small fluorescent probe N-BODIPY.

Plant peroxisomes maintain a plethora of key life processes including fatty acid β-oxidation, photorespiration, synthesis of hormones, and homeostasis of reactive oxygen species (ROS). Abundance of peroxisomes in cells is dynamic; however mechanisms controlling peroxisome proliferation remain poorly understood because measuring peroxisome abundance is technically challenging. Counting peroxisomes in individual cells of complex organs by electron or fluorescence microscopy is expensive and time consuming.

[Density Functional Theory Calculation and Raman Spectroscopy Studies of Organophosphorus Pesticides].

Organophosphorus pesticides were often used for prevention and control disease and insect of plant, and are acute toxic to human and livestock by anti-ache activity. The molecular geometry of three organophosphorus pesticides(dimethoate, trichlorfon and phosalone) were constructed on Gauss View3.07, and Density functional theory (DFT) was used to optimize and calculate the vibrational wavenumbers of three organophosphorus pesticides by B3LYP hybrid functional and 6-31G(d, p) basis set.

Novelty Seeking, Harm Avoidance, and Cerebral Responses to Conflict Anticipation: An Exploratory Study.

Proactive control allows us to maneuver a changing environment and individuals are distinct in how they anticipate and approach such changes. Here, we examined how individual differences in personality traits influence cerebral responses to conflict anticipation, a critical process of proactive control. We explored this issue in an fMRI study of the stop signal task, in which the probability of stop signal - p(Stop) - was computed trial by trial with a Bayesian model.

Potential Role of the Last Half Repeat in TAL Effectors Revealed by a Molecular Simulation Study.

TAL effectors (TALEs) contain a modular DNA-binding domain that is composed of tandem repeats. In all naturally occurring TALEs, the end of tandem repeats is invariantly a truncated half repeat. To investigate the potential role of the last half repeat in TALEs, we performed comparative molecular dynamics simulations for the crystal structure of DNA-bound TALE AvrBs3 lacking the last half repeat and its modeled structure having the last half repeat.

E3 ubiquitin ligase SP1 regulates peroxisome biogenesis in Arabidopsis.

Peroxisomes are ubiquitous eukaryotic organelles that play pivotal roles in a suite of metabolic processes and often act coordinately with other organelles, such as chloroplasts and mitochondria. Peroxisomes import proteins to the peroxisome matrix by peroxins (PEX proteins), but how the function of the PEX proteins is regulated is poorly understood. In this study, we identified the Arabidopsis RING (really interesting new gene) type E3 ubiquitin ligase SP1 [suppressor of plastid protein import locus 1 (ppi1) 1] as a peroxisome membrane protein with a regulatory role in peroxisome protein import.

Building a Three-Dimensional Nano-Bio Interface for Aptasensing: An Analytical Methodology Based on Steric Hindrance Initiated Signal Amplification Effect.

The development of novel detection methodologies in electrochemiluminescence (ECL) aptasensor fields with simplicity and ultrasensitivity is essential for constructing biosensing architectures. Herein, a facile, specific, and sensitive methodology was developed unprecedentedly for quantitative detection of microcystin-LR (MC-LR) based on three-dimensional boron and nitrogen codoped graphene hydrogels (BN-GHs) assisted steric hindrance amplifying effect between the aptamer and target analytes. The recognition reaction was monitored by quartz crystal microbalance (QCM) to validate the possible steric hindrance effect.

Metal binding mediated conformational change of XPA protein:a potential cytotoxic mechanism of nickel in the nucleotide excision repair.

Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn(2+)-chelated Zn-finger domain of XPA center core portion (i.

Defective Pollen Wall 2 (DPW2) Encodes an Acyl Transferase Required for Rice Pollen Development.

Aliphatic and aromatic lipids are both essential structural components of the plant cuticle, an important interface between the plant and environment. Although cross links between aromatic and aliphatic or other moieties are known to be associated with the formation of leaf cutin and root and seed suberin, the contribution of aromatic lipids to the biosynthesis of anther cuticles and pollen walls remains elusive. In this study, we characterized the rice (Oryza sativa) male sterile mutant, defective pollen wall 2 (dpw2), which showed an abnormal anther cuticle, a defective pollen wall, and complete male sterility.

[Molecular recognition mechanism and motion of HCV NS3/4A protease with Faldaprevir analogue].

Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.

Peroxisomes Extend Peroxules in a Fast Response to Stress via a Reactive Oxygen Species-Mediated Induction of the Peroxin PEX11a.

Peroxisomes are highly dynamic and metabolically active organelles that play an important role in cellular functions, including reactive oxygen species (ROS) metabolism. Peroxisomal dynamics, such as the proliferation, movement, and production of dynamic extensions called peroxules, have been associated with ROS in plant cells. However, the function and regulation of peroxules are largely unknown.

Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery.

Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse. The lack of an experimental three-dimensional CB2 structure has hindered not only the development of studies of conformational differences between the inactive and active CB2 but also the rational discovery of novel functional compounds targeting CB2. In this work, we constructed models of both inactive and active CB2 by homology modeling.

Design and discovery of new pyrimidine coupled nitrogen aromatic rings as chelating groups of JMJD3 inhibitors.

The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor.

Freeze-thaw Caenorhabditis elegans freeze-thaw stress response is regulated by the insulin/IGF-1 receptor daf-2.

Background: Adaption to cold temperatures, especially those below freezing, is essential for animal survival in cold environments. Freezing is also used for many medical, scientific, and industrial purposes. Natural freezing survival in animals has been extensively studied.

CCAAT/enhancer-binding protein CEBP-2 controls fat consumption and fatty acid desaturation in Caenorhabditis elegans.

Mammalian CCAAT/enhancer-binding proteins (C/EBPs) are generally known as regulators in adipocyte differentiation. However, more understanding of the role of C/EBPs in lipid and glucose metabolism remains to be discovered. In this study, we verified the effect of CEBP-2, the homolog of CEBPs, on fat storage in Caenorhabditis elegans.

Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.

Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities.