Enhanced stripe rust resistance obtained by combining Yr30 with a widely dispersed, consistent QTL on chromosome arm 4BL.

KEY MESSAGE: YrFDC12 and PbcFDC, co-segregated in chromosome 4BL, and significantly interacted with Yr30/Pbc1 to enhance stripe rust resistance and to promote pseudo-black chaff development. Cultivars with durable resistance are the most popular means to control wheat stripe rust. Durable resistance can be achieved by stacking multiple adult plant resistance (APR) genes that individually have relatively small effect. Chinese wheat cultivars Ruihua 520 (RH520) and Fengdecun 12 (FDC12) confer partial APR to stripe rust across environments. One hundred and seventy recombinant inbred lines from the cross RH520 × FDC12 were used to determine the genetic basis of resistance and identify genomic regions associated with stripe rust resistance. Genotyping was carried out using 55 K SNP array, and eight quantitative trait loci (QTL) were detected on chromosome arms 2AL, 2DS, 3BS, 4BL, 5BL (2), and 7BL (2) by inclusive composite interval mapping. Only QYr.nwafu-3BS from RH520 and QYr.nwafu-4BL.2 (named YrFDC12 for convenience) from FDC12 were consistent across the four testing environments. QYr.nwafu-3BS is likely the pleiotropic resistance gene Sr2/Yr30. YrFDC12 was mapped in a 2.1-cM interval corresponding to 12 Mb and flanked by SNP markers AX-111121224 and AX-89518393. Lines harboring both Yr30 and YrFDC12 displayed higher resistance than the parents and expressed pseudo-black chaff (PBC) controlled by loci Pbc1 and PbcFDC12, which co-segregated with Yr30 and YrFDC12, respectively. Both marker-based and pedigree-based kinship analyses revealed that YrFDC12 was inherited from founder parent Zhou 8425B. Fifty-four other wheat cultivars shared the YrFDC12 haplotype. These results suggest an effective pyramiding strategy to acquire highly effective, durable stripe rust resistance in breeding.

Gold(I)-Catalyzed Tandem Cyclization/Hydroarylation of o-Alkynylphenols with Haloalkynes.

A convenient and mild protocol for the gold-catalyzed intermolecular coupling of o-alkynylphenols with haloalkynes to give vinyl benzofurans is reported. In this work, the gold catalyst SIPrAuCl and the co-catalyst NaBARF would corporately promote the intramolecular cyclization of the o-alkynylphenol to benzofuran, and then a selective hydroarylation of benzofuran to haloalkyne was catalyzed by the same catalysts. Computational studies suggest that the hydroarylation process takes place via a concerted nucleophilic attack pathway of the benzofuran to the C2 carbon of the activated haloalkyne, and reveal the original driving force of this hydroarylation process.

Trade-off Predictivity and Explainability for Machine-Learning Powered Predictive Toxicology: An in-Depth Investigation with Tox21 Data Sets.

Selecting a model in predictive toxicology often involves a trade-off between prediction performance and explainability: should we sacrifice the model performance to gain explainability or vice versa. Here we present a comprehensive study to assess algorithm and feature influences on model performance in chemical toxicity research. We conducted over 5000 models for a Tox21 bioassay data set of 65 assays and ∼7600 compounds. Seven molecular representations as features and 12 modeling approaches varying in complexity and explainability were employed to systematically investigate the impact of various factors on model performance and explainability. We demonstrated that end points dictated a model's performance, regardless of the chosen modeling approach including deep learning and chemical features. Overall, more complex models such as (LS-)SVM and Random Forest performed marginally better than simpler models such as linear regression and KNN in the presented Tox21 data analysis. Since a simpler model with acceptable performance often also is easy to interpret for the Tox21 data set, it clearly was the preferred choice due to its better explainability. Given that each data set had its own error structure both for dependent and independent variables, we strongly recommend that it is important to conduct a systematic study with a broad range of model complexity and feature explainability to identify model balancing its predictivity and explainability.

Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation.

S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development.

Structure-Activity Relationship Modeling and Experimental Validation of the Imidazolium and Pyridinium Based Ionic Liquids as Potential Antibacterials of MDR Acinetobacter Baumannii and Staphylococcus Aureus.

Online Chemical Modeling Environment (OCHEM) was used for QSAR analysis of a set of ionic liquids (ILs) tested against multi-drug resistant (MDR) clinical isolate Acinetobacter baumannii and Staphylococcus aureus strains. The predictive accuracy of regression models has coefficient of determination q2 = 0.66 - 0.79 with cross-validation and independent test sets. The models were used to screen a virtual chemical library of ILs, which was designed with targeted activity against MDR Acinetobacter baumannii and Staphylococcus aureus strains. Seven most promising ILs were selected, synthesized, and tested. Three ILs showed high activity against both these MDR clinical isolates.

Focused Library Generator: case of Mdmx inhibitors.

We present a Focused Library Generator that is able to create from scratch new molecules with desired properties. After training the Generator on the ChEMBL database, transfer learning was used to switch the generator to producing new Mdmx inhibitors that are a promising class of anticancer drugs. Lilly medicinal chemistry filters, molecular docking, and a QSAR IC50 model were used to refine the output of the Generator. Pharmacophore screening and molecular dynamics (MD) simulations were then used to further select putative ligands. Finally, we identified five promising hits with equivalent or even better predicted binding free energies and IC50 values than known Mdmx inhibitors. The source code of the project is available on https://github.com/bigchem/online-chem.

Effects of microRNA-292-5p on myocardial ischemia-reperfusion injury through the peroxisome proliferator-activated receptor-α/-γ signaling pathway.

Ischemia-reperfusion injury (IRI) is a major cause of cardiac damage following various pathological processes, such as free radical damage and cell apoptosis. This study aims to investigate whether microRNA-292-5p (miR-292-5p) protects against myocardial ischemia-reperfusion injury (IRI) via the peroxisome proliferator-activated receptor (PPAR)-α/-γ signaling pathway in myocardial IRI mice models. Mouse models of myocardial IRI were established. Adult male C57BL/6 mice were divided into different groups. The hemodynamic indexes, levels of related inflammatory factors and serum myocardial enzymes, and malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were detected. The 2,3,5-triphenyltetrazolium chloride (TTC) staining was applied to determine infarct size. TUNEL staining was used to detect cardiomyocyte apoptosis. RT-qPCR and western blotting were performed to measure the related gene expressions. Compared with the model group and the T0070907 + miR-292-5p inhibitor, the miR-292-5p inhibitor group exhibited decreased incidence and duration time of ventricular tachycardia and ventricular fibrillation, serum myocardial enzymes, TNF-α, IL-6, IL-1ß, MDA, cardiomyocyte apoptosis, expressions of Bax and p53 in addition to increased SOD and GSH-Px activity, and increased expressions of Bcl-2, PPARα, PPARγ, PLIN5, AQP7, and PCK1. The T0070907 group exhibited opposite results compared to the miR-292-5p inhibitor group. The results indicate that miR-292-5p downregulation protects against myocardial IRI through activation of the PPAR-α/PPAR-γ signaling pathway.

Computational models for the classification of mPGES-1 inhibitors with fingerprint descriptors.

Human microsomal prostaglandin [Formula: see text] synthase (mPGES)-1 is a promising drug target for inflammation and other diseases with inflammatory symptoms. In this work, we built classification models which were able to classify mPGES-1 inhibitors into two groups: highly active inhibitors and weakly active inhibitors. A dataset of 1910 mPGES-1 inhibitors was separated into a training set and a test set by two methods, by a Kohonen's self-organizing map or by random selection. The molecules were represented by different types of fingerprint descriptors including MACCS keys (MACCS), CDK fingerprints, Estate fingerprints, PubChem fingerprints, substructure fingerprints and 2D atom pairs fingerprint. First, we used a support vector machine (SVM) to build twelve models with six types of fingerprints and found that MACCS had some advantage over the other fingerprints in modeling. Next, we used naïve Bayes (NB), random forest (RF) and multilayer perceptron (MLP) methods to build six models with MACCS only and found that models using RF and MLP methods were better than NB. Finally, all the models with MACCS keys were used to make predictions on an external test set of 41 compounds. In summary, the models built with MACCS keys and using SVM, RF and MLP methods show good prediction performance on the test sets and the external test set. Furthermore, we made a structure-activity relationship analysis between mPGES-1 and its inhibitors based on the information gain of fingerprints and could pinpoint some key functional groups for mPGES-1 activity. It was found that highly active inhibitors usually contained an amide group, an aromatic ring or a nitrogen heterocyclic ring, and several heteroatoms substituents such as fluorine and chlorine. The carboxyl group and sulfur atom groups mainly appeared in weakly active inhibitors.

Computer modeling in predicting the bioactivity of human 5-lipoxygenase inhibitors.

5-Lipoxygenase (5-LOX) is a key enzyme in the inflammatory path. Inhibitors of 5-LOX are useful for the treatment of diseases like arthritis, cancer, and asthma. We have collected a dataset including 220 human 5-LOX inhibitors for classification. A self-organizing map (SOM), a support vector machine (SVM), and a multilayer perceptron (MLP) algorithm were used to build models with selected descriptors for classifying 5-LOX inhibitors into active and weakly active ones. MACCS fingerprints were used in this model building process. The accuracy (Q) and Matthews correlation coefficient (MCC) of the best SOM model (Model 1A) were 86.49% and 0.73 on the test set, respectively. The Q and MCC of the best SVM model (Model 2A) were 82.67% and 0.64 on the test set, respectively. The Q and MCC of the best MLP model (Model 3B) were 84.00% and 0.67 on the test set, respectively. In addition, 180 inhibitors with bioactivities measured by fluorescence method were further used for a quantitative prediction. Multiple linear regression (MLR) and SVM algorithms were used to build models to predict the [Formula: see text] values. The correlation coefficients (R) of the MLR model (Model Q1) and the SVM model (Model Q2) were 0.72 and 0.74 on the test set, respectively.

Dual Photoredox/Gold Catalysis Arylative Cyclization of o-Alkynylphenols with Aryldiazonium Salts: A Flexible Synthesis of Benzofurans.

A new method for the arylative cyclization of o-alkynylphenols with aryldiazonium salts via dual photoredox/gold catalysis is described. The reaction proceeds smoothly at room temperature in the absence of base and/or additives and offers an efficient approach to benzofuran derivatives. The scope of the transformation is wide, and the limitations are discussed. The reaction is proposed to proceed through a photoredox-promoted generation of a vinylgold(III) intermediate that undergoes reductive elimination to provide the heterocyclic coupling adduct.

Gold-Catalyzed C(sp3)-C(sp2) Suzuki-Miyaura Coupling Reaction.

A gold-catalyzed C(sp3)-C(sp2) Suzuki-Miyaura coupling reaction facilitated by ligand-enabled Au(I)/Au(III) redox catalysis was developed. The cross-coupling of alkyl organometallics was first realized in the redox catalytic cycle in gold chemistry, without the use of external oxidants. This gold-catalyzed C(sp3)-C(sp2) coupling reaction allows a variety of alkyl chain and useful methyl trifluoroborates to react with aryl and vinyl iodides under very mild conditions, which provides a new reactivity pattern for challenging couplings with alkyl organometallics.

Base-assisted transmetalation enables gold-catalyzed oxidative Sonogashira coupling reaction.

The traditional transition metal catalyzed neutral C(sp)-C(sp2) cross-coupling reaction between a nucleophile and an electrophile is a key technique for the formation of carbon-carbon bonds. Herein, we present a general gold-catalyzed oxidative Sonogashira cross-coupling of arylboronic acids and terminal arylalkynes at room temperature with excellent functional-group tolerance and good chemoselectivity. Moreover, our mechanistic studies suggested a third pathway involving a base-assisted transmetalation between the gold(I) catalyst and aryl boronic acid might predominate in our reaction conditions, rather than the previously assumed oxidation of the gold(I) complex or deprotonation of alkynes.

[Reduced circulating endothelial progenitor cells is a risk factor of coronary slow flow].

OBJECTIVE: To explore if reduced number of circulating endothelial progenitor cells (EPCs) is a risk factor for patients with coronary slow flow (CSF). METHODS: Thirty patients with CSF and 30 age and gender matched control subjects with normal coronary angiography were included in the study. Mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation and plated on fibronectin-coated culture dishes. EPCs were characterized as adherent cells double positive for DiI-AcLDL-uptake and lectin-binding by converted fluorescence microscope (×200). RESULTS: Smoking, diabetes mellitus, hypertension and the levels of plasma lipoprotein profile were similar between the two groups (all P > 0.05). The number of EPCs was significantly lower in patients with CSF compared with control subjects (35.7 ± 5.9 vs.53.2 ± 5.9, P < 0.01). TIMI frame counts was correlated with circulating EPCs number (OR = 0.424, 95%CI 0.358 - 0.621, P < 0.01) and not associated with gender, age, smoking, diabetes mellitus, hypertension and the levels of plasma lipoprotein profile. CONCLUSION: Decreased circulating EPCs is an independent risk factor for CSF.

Hemilabile P,N-Ligand-Assisted Gold-Catalyzed Heck Reaction of Aryl and Styryl Iodides with Styrenes.

A gold-catalyzed Heck reaction of aryl and styryl iodides with styrenes was developed. The hemilabile P,N-ligand-assisted gold-catalyzed C(sp2)-C(sp2) cross-coupling can synthesize stilbenes and bistyryl complexes, with good functional-group tolerance and mild conditions. The elementary organometallic steps of migratory insertion and ß-hydride elimination might be involved in this ligand-enabled Au(I)/Au(III)-catalyzed Heck reaction with styrenes.

Flame Retardancy of Nylon 6 Fibers: A Review.

As synthetic fibers with superior performances, nylon 6 fibers are widely used in many fields. Due to the potential fire hazard caused by flammability, the study of the flame retardancy of nylon 6 fibers has been attracting more and more attention. The review has summarized the present research status of flame-retarded nylon 6 fibers from three aspects: intrinsic flame-retarded nylon 6, nylon 6 composites, and surface strategies of nylon 6 fibers/fabrics. The current main focus is still how to balance the application performances, flame retardancy, and production cost. Moreover, melt dripping during combustion remains a key challenge for nylon 6 fibers, and the further developing trend is to study novel flame retardants and new flame-retardancy technologies for nylon 6 fibers.

Gold(I)-Catalyzed Selective Hydroarylation of Indoles with Haloalkynes.

A highly regio- and stereoselective synthesis of a Z-alkenyl indole via the gold-catalyzed addition of an indole to a haloalkyne was developed. In the presence of gold catalyst SIPrAuCl and cocatalyst NaBARF, a broad range of indoles react with haloalkynes to afford Z-alkenyl indoles with high selectivity at room temperature. Computational studies suggest that the hydroarylation reaction takes place via a concerted C2 addition pathway of the indole to the activated haloalkyne.

Photoinduced inverse Sonogashira coupling reaction.

Alkynes are widely used in chemistry, medicine and materials science. Here we demonstrate a transition-metal and photocatalyst-free inverse Sonogashira coupling reaction between iodoalkynes and (hetero)arenes or alkenes under visible-light irradiation. Mechanistic and computational studies suggest that iodoalkynes can be directly activated by visible light irradiation, and an excited state iodoalkyne acted as an "alkynyl radical synthetic equivalent", reacting with a series of C(sp2)-H bonds for coupling products. This work should open new windows in radical chemistry and alkynylation method.

[Study of association of platelet endothelial cell adhesion molecule-1 gene polymorphism with acute myocardial infarction].

OBJECTIVE: To investigate the association of single nucleotide polymorphism (SNP) and its haplotypes of platelet endothelial cell adhesion molecule-1 (PECAM-1) gene with susceptibility to acute myocardial infarction (AMI), and to analyze association the serum levels and genotypes of PECAM-1 with AMI. METHODS: Three SNPs of PECAM-1 gene Leu125Val, Asn563Ser and Gly670Arg were analyzed in 180 patients with AMI and 200 age and sex matched controls, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy, and the serum level of PECAM-1 was determined by enzyme linked immunosorbent assay (ELISA). Frequency of haplotypes and linkage disequilibrium of PECAM-1 gene in different groups were analyzed by SHEsis programs. RESULTS: The distributions of PECAM-1 gene Asn563Ser and Gly670Arg polymorphisms were not different between AMI and control group (P>0.05), but the PECAM-1 gene Leu125Val polymorphism was significantly different (P<0.05). The relative risk suffered from AMI of Val allele was 1.480 folds of the Leu allele carriers [odds ratio (OR)=1.480, 95% confidence interval (CI): 1.111-1.972, P=0.007]; the serum level of PECAM-1 Val allele carriers was significantly higher than that of noncarriers (P<0.01). With the results of the genotyping analyses, PECAM-1 gene Leu125Val, Asn563Ser and Gly670Arg polymorphisms showed strong linkage disequilibrium, and the Val-Ser-Arg haplotype was associated with a significantly increased risk of AMI as compared with the controls (OR=1.489, 95%CI: 1.118-1.984, P=0.006). CONCLUSION: PECAM-1 gene Leu125Val polymorphism and its Val-Ser-Arg haplotype are associated with AMI, Val allele is an important genetic susceptibility gene for AMI. The PECAM-1 Val allele carriers may have a higher risk by enhancing the PECAM-1 expression in the pathogenesis of AMI.

Photosensitized oxidative addition to gold(I) enables alkynylative cyclization of o-alkylnylphenols with iodoalkynes.

The well-established oxidative addition-reductive elimination pathway is the most followed one in transition metal-catalysed cross-coupling reactions. While readily occurring with a series of transition metals, gold(I) complexes have shown some reluctance to undergo oxidative addition unless special sets of ligands on gold(I), reagents or reaction conditions are used. Here we show that under visible-light irradiation, an iridium photocatalyst triggers-via triplet sensitization-the oxidative addition of an alkynyl iodide onto a vinylgold(I) intermediate to deliver C(sp)2-C(sp) coupling products after reductive elimination. Mechanistic and modelling studies support that an energy-transfer event takes place, rather than a redox pathway. This particular mode of activation in gold homogenous catalysis was applied in several dual catalytic processes. Alkynylbenzofuran derivatives were obtained from o-alkynylphenols and iodoalkynes in the presence of catalytic gold(I) and iridium(III) complexes under blue light-emitting diode irradiation.

DDAH2 alleviates myocardial fibrosis in diabetic cardiomyopathy through activation of the DDAH/ADMA/NOS/NO pathway in rats.

Diabetic cardiomyopathy (DCM) is a form of idiopathic heart disease, with signs including hypertrophy of myocardial cells, hypertension­independent fibrosis and coronary artery disease. Considering the involvement of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in diabetes, it was hypothesized that DDAH2 may be beneficial to cardiac function and myocardial fibrosis during the progression of DCM with involvement of the DDAH/asymmetric NG, NGdimethyl­L­arginine (ADMA)/nitric oxide synthase (NOS)/nitric oxide (NO) signaling pathway. Following establishment of diabetic rat models, diabetes­related blood biochemical indices and cardiac function were measured in diabetic rats treated with lentivirus expressing DDAH2, short hairpin RNA against DDAH2, or L­NNA (inhibitor of NOS) to identify the roles of DDAH2 in DCM. The functional roles of DDAH2 in DCM were further determined through detection of the levels of collagen I, matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 2 (TIMP2). The H9C2 myocardial cell line was selected for in vitro experiments. The effects of DDAH2 on the migration of myocardial cells under high glucose conditions were also examined. To further investigate the underlying regulatory mechanism of DDAH2 in DCM, the contents of ADMA and NO, and the activities of DDAH and NOS were observed. The DCM model rats treated with DDAH2 exhibited reduced left ventricular end­diastolic pressure, and decreased blood glucose, total cholesterol, triglyceride, fasting blood glucose, and fasting insulin levels, but exhibited increased left ventricular systolic pressure and maximum rate of left ventricular pressure rise/fall levels in myocardial tissues. Myocardial cells under high glucose conditions treated with DDAH2 showed reductions in collagen I, MMP2 and TIMP2, indicating that DDAH2 reduced cell migration. Decreased levels of ADMA and NO but increased levels of DDAH and NOS were observed following treatment with DDAH2, indicating that the DDAH/ADMA/NOS/NO pathway was activated. These results reveal that the overexpression of DDAH2 attenuates myocardial fibrosis and protects against DCM through activation of the DDAH/ADMA/NOS/NO pathway in DCM rats. These results indicate that DDAH2 is a potential therapeutic candidate for the treatment of DCM.