Genome-Wide Identification and Expression Analysis of Calmodulin-Like Gene Family in Paspalums vaginatium Revealed Their Role in Response to Salt and Cold Stress.

The calmodulin-like (CML) family is an important calcium (Ca2+) sensor in plants and plays a pivotal role in the response to abiotic and biotic stresses. As one of the most salt-tolerant grass species, Paspalums vaginatum is resistant to multiple abiotic stresses, such as salt, cold, and drought. However, investigations of PvCML proteins in P. vaginatum have been limited. Based on the recently published P. vaginatum genome, we identified forty-nine PvCMLs and performed a comprehensive bioinformatics analysis of PvCMLs. The main results showed that the PvCMLs were unevenly distributed on all chromosomes and that the expansion of PvCMLs was shaped by tandem and segmental duplications. In addition, cis-acting element analysis, expression profiles, and qRT-PCR analysis revealed that PvCMLs were involved in the response to salt and cold stress. Most interestingly, we found evidence of a tandem gene cluster that independently evolved in P. vaginatum and may participate in cold resistance. In summary, our work provides important insight into how grass species are resistant to abiotic stresses such as salt and cold and could be the basis of further gene function research on CMLs in P. vaginatum.

First-Principles Studies on the Structural and Electronic Properties of α-Na2FePO4F with Strong Antisite Disorder.

Polyanionic Na2FePO4F is one of the most important cathode materials for sodium-ion batteries. The orthorhombic ß-Na2FePO4F material has been studied extensively and intensively since it was proposed. In this article, a novel monoclinic sodium phosphate fluoride α-Na2FePO4F is concerned. Kirsanova's experiment showed that Na and Fe ions in α-Na2FePO4F are prone to antisite, leading to strong antisite disorder. Through first-principle calculations, we show that the steric effect, the magnetic exchange and superexchange interactions between transition-metal cations are shown to be the main driving forces for Na+/Fe2+ antisite disorder. We first calculated the crystal structures, electronic properties, and cohesive energies of all the 10 antisite phases of α-Na2FePO4F and ß-Na2FePO4F. Then, we compared the difference charge densities, magnetism, binding energies, and electrostatic potentials of α-Na2FePO4F and ß-Na2FePO4F materials in the antisite and pristine phases. In α-Na2FePO4F, the binding energy of the antisite phase with the lowest binding energy is almost degenerate with that of the pristine phase. Moreover, only small differences of the electrostatic potential and the charge density distribution are found between the antisite (with lowest energy) and the pristine phases of α-Na2FePO4F, which also helped elaborate the facile formation of Na+/Fe2+ antisite in the α-Na2FePO4F material. Our research contributes to the understanding of the mechanism of Na+/Fe2+ antisite and the development of high-performance polyanionic cathode materials.

The effects of vacancy and heteroatoms-doping on the stability, electronic and magnetic properties of blue phosphorene.

In this work, we have systematically studied the stability, electronic structure and magnetic properties of the pristine, four defect states case of blue phosphorene and the six heteroatoms doping in blue phosphorene by first-principles calculations. In our findings, both defects and heteroatoms doping can regulate the band gap of blue phosphorene and the transition from indirect to direct band gap can be dramatically tuned by DV1BP, DV2BP and Al, Si atoms substitutional doping in blue phosphorene. The presence of defects and heteroatoms doping effectively modulates the electronic properties of blue phosphorene, rendering the defect-containing phosphorene semiconducting with a tunable band gap. Spin-orbit coupling can be induced by introducing SV-, DV- defects in blue phosphorene. The results provide theoretical guidance for future bandgap regulation and magnetism, defective and substitutional doping blue phosphorene may have potential electro-optical and electromagnetic applications.

Synthesis of bis(indole) alkaloids from Arundo donax: the ynindole Diels-Alder reaction, conformational chirality, and absolute stereochemistry.

Bis(indole) alkaloids from Arundo donax were synthesized using the first ynindole Diels-Alder reaction. The alkaloids are chiral, having stable enantiomeric conformations with half-lives of racemization of t1/2 = 4150-25100 seconds at room temperature. Their absolute stereochemistry was determined using the exciton chirality method.

N-substituting perturbation on the interaction affinity and recognition specificity between rheumatic immune-related Abl SH3 domain and its peptoid ligands.

Abl is a nonreceptor tyrosine kinase involved in a variety of disease pathways such as rheumatic immune. Full-length Abl protein consists of a catalytic tyrosine kinase (TK) domain as well as two regulatory Src homology domains 2 and 3 (SH2 and SH3, respectively); the latter recognizes and binds to those natural proline-rich peptide segments containing a PxxP motif on the protein surface of its interacting partners. However, natural peptides cannot bind effectively to the modular domain in high affinity and strong selectivity due to their small size and broad specificity. Here, a synthetic proline-rich peptide p41 was used as template; its structural diversity was extended by combinationally replacing the Pro0 and Pro+3 residues with a number of N-substituted amino acids. Consequently, peptide affinity change upon the replacement was derived to create a systematic N-substituting perturbation profile, from which we identified several N-substitution combinations at the Pro0 and Pro+3 residues of p41 PxxP motif that may moderately or significantly improve the peptide binding potency to Abl; they represent potent peptoid binders of Abl SH3 domain, with affinity improved considerably relative to p41. More significantly, the designed potent peptoids were also found to exhibit a good SH3-selectivity for their cognate Abl over other noncognate nonreceptor tyrosine kinases, with S = 9.7-fold.

Stereoselective synthesis of enynones via base-catalyzed isomerization of 1,5-disubstituted-2,4-pentadiynyl silyl ethers or their alcohol derivatives.

1,5-Disubstituted-2,4-pentadiynyl silyl ethers undergo smooth desilylative isomerization to afford cis-enynones as major products with moderate stereoselectivities in the presence of a catalytic amount of KO(t)Bu or DBU. While the isomerization reactions of their alcohol derivatives catalyzed by KOH, KO(t)Bu or NaH take place efficiently to produce trans-enynones with high stereoselectivities. These reactions provide convenient and practical routes for the synthesis of enynones with a wide range of substitution groups.

VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China.

OBJECTIVE: To investigate the contribution of genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 gene VKORC1-1639G>A, cytochrome P450 2C9 gene (CYP2C9), EPHXI, and clinical factors to warfarin sensitivity in southwest Chinese Han patients with mechanical heart valve prostheses. METHODS: A total of 127 patients with mechanical heart valve prostheses who have been followed up at our department during the past 23 years were enrolled in this study and compared to a control group that consisted of 133 randomly selected healthy blood donors. These Chinese patients met stable warfarin dosage requirements and had reached the target international normalized ratio (INR) of 1.5-2.0. PCR and direct sequencing were carried out to identify the polymorphisms of VKORC1-1639G>A (rs9923231), CYP2C9*3 (rs1057910), CYP2C9 IVS3-65G>C (rs9332127), and EPHX1691A>G (rs4653436). In addition, total and free (non-protein-bound) warfarin concentrations were analyzed. RESULTS AND CONCLUSIONS: There were great interindividual differences in warfarin maintenance dosage (ranging from 0.6 to 8.4 mg/day) among the 127 patients with mechanical heart valve prostheses. VKORC1-1639G>A, CYP2C9, EPHX1691A>G polymorphism, body weight, and age were found to affect the dose demands. Multiple linear regression models incorporating genetic polymorphisms of VKORC1, CYP2C9, EPHX1691A>G, and the nongenetic factors of age and body weight were developed, and explained up to 76.8% of the total variation (adjusted R (2) of 0.743) in warfarin maintenance doses in southwest Chinese patients with mechanical heart valve prostheses.

Stereoselective synthesis of beta-hydroxyallenes with multiple contiguous stereogenic centers via aldehyde addition to alpha-alkenyl-substituted zirconacyclopentenes.

A highly stereoselective methodology for the synthesis of beta-hydroxyallenes with multiple stereogenic centers including allenic axial chirality, as well as center chirality, via addition of alpha-alkenylzirconacyclopentenes to aldehyde is described. Remarkably, the reaction occurs with completely different chemoselectivity in comparison with the usual alkyl- or aryl-substituted zirconacyclopentenes; that means, the C-C bond formation occurred selectively at the alkenylic carbon substituted with phenyl or alkyl group, while in the latter cases, insertion of aldehydes into the alkyl-zirconium bond to afford seven-membered oxazirconacycles has usually been observed.

Generation of allenic/propargylic zirconium complexes and subsequent cross-coupling reactions: a facile synthesis of multisubstituted allenes.

The beta-alkoxide elimination reaction of propargylic ether with Negishi reagent leads to allenes and/or alkynes after hydrolysis. The product distribution is highly dependent on the substitution pattern of starting propargylic ethers; that is, aryl- or alkyl-substituted propargylic ethers favor the allene products, whereas TMS-substituted propargylic ethers afford alkynes. DFT calculations revealed that both the large steric effect and the beta-effect of the TMS group favor the alkyne products, reversing the selectivity. Subsequent coupling reactions of the allenic/propargylic zirconium intermediates with aryl iodides in the presence of Pd(PPh(3))(4)/CuCl provide a straightforward route for the synthesis of multisubstituted allenes.

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton.

Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with 11C or 18F. [11C]8 ([11C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [11C]17 ([11C]PAD) and [18F]37 ([18F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.

A Lamin-Binding Ligand Inhibits Homologous Recombination Repair of DNA Double-Strand Breaks.

Nuclear lamins are type V intermediate filament proteins. Lamins, including LA, LB1, LB2, and LC, are the major protein components forming the nuclear lamina to support the mechanical stability of the mammalian cell nucleus. Increasing evidence has shown that LA participates in homologous recombination (HR) repair of DNA double-strand breaks (DSBs) . However, the mechanisms underlying this process are incompletely understood. We recently identified the first lamin-binding ligand 1 (LBL1) that directly binds LA and inhibited cancer cell growth. We provided here further mechanistic investigations of LBL1 and revealed that LA interacts with the HR recombinase Rad51 to protect Rad51 from degradation. LBL1 inhibits LA-Rad51 interaction leading to accelerated proteasome-mediated degradation of Rad51, culminating in inhibition of HR repair of DSBs. These results uncover a novel post-translational regulation of Rad51 by LA and suggest that targeting the LA-Rad51 axis may represent a promising strategy to develop cancer therapeutics.

Anticancer Pyrroloquinazoline LBL1 Targets Nuclear Lamins.

Target identification of bioactive compounds is critical for understanding their mechanism of action. We previously discovered a novel pyrroloquinazoline compound LBL1 with significant anticancer activity. However, its molecular targets remain to be established. Herein, we developed a clickable photoaffinity probe based on LBL1. Using extensive chemical, biochemical, and cellular studies with this probe and LBL1, we found that LBL1 targets nuclear lamins, which are type V intermediate filament (IF) proteins. Further studies showed that LBL1 binds to the coiled-coil domain of lamin A. These results revealed that IF proteins can also be targeted with appropriate small molecules besides two other cytoskeletal proteins actin filaments and microtubules, providing a novel avenue to investigate lamin biology and a novel strategy to develop distinct anticancer therapies.

Discovery of a Potent Anti-tumor Agent through Regioselective Mono-N-acylation of 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine.

7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (1) is a privileged chemical scaffold with significant biological activities. However, the currently accessible chemical space derived from 1 is rather limited. Here we expanded the chemical space related to 1 by developing efficient methods for regioselective monoacylation at N1 , N3 and N7 , respectively. With this novel methodology, a focused library of mono-N-acylated pyrroloquinazoline-1,3-diamines were prepared and screened for anti-breast cancer activity. The structure-activity relationship (SAR) results showed that N3 -acylated compounds were in general more potent than N1 -acylated compounds while N7 -acylation significantly reduced their solubility. Among the compounds evaluated, 7f possessed 8-fold more potent activity than 1 in MDA-MB-468 cells. More importantly, 7f was not toxic to normal human cells. These results suggest that 7f is a novel compound as a potential anti-breast cancer agent without harming normal cells.

Rhenium- and manganese-catalyzed insertion of alkynes into a carbon-carbon single bond of cyclic and acyclic 1,3-dicarbonyl compounds.

Treatment of alkynes with cyclic and acyclic 1,3-dicarbonyl compounds in the presence of a catalytic amount of a rhenium or manganese complex gives ring-expanded and carbon-chain extension products, respectively. In these reactions, alkynes insert into a non-strained carbon-carbon single bond of 1,3-dicarbonyl compounds. The ring-expansion reaction is also promoted by the addition of 4-A molecular sieves instead of a catalytic amount of an isocyanide.

Highly efficient synthesis of functionalized indolizines and indolizinones by copper-catalyzed cycloisomerizations of propargylic pyridines.

The copper-catalyzed cycloisomerizations of 2-pyridyl-substituted propargylic acetates and its derivatives are described, which offer an efficient route to C-1 oxygenated indolizines with a wide range of substituents under mild reaction conditions. The presented method could be readily applied to the synthesis of indolizinones through a cyclization/1,2-migration of tertiary propargylic alcohols.