The INO80E at 16p11.2 locus increases risk of schizophrenia in humans and induces schizophrenia-like phenotypes in mice.

Background: Chromosome 16p11.2 is one of the most significant loci in the genome-wide association studies (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies having been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized.

Human mood disorder risk gene Synaptotagmin-14 contributes to mania-like behaviors in mice.

Bipolar disorder (BD) and major depressive disorder (MDD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two disorders in clinical symptoms, treatment strategies, and genetic etiology. Here we leverage a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls), followed by independent replications, to investigate their shared genetic basis among Han Chinese.

Copper-Catalyzed Propargylation of Terminal Olefins to Skipped Enynes.

A highly efficient and easy to operate method for synthesizing skipped enynes catalyzed by copper has been reported for the first time. A wide variety of skipped enynes were obtained in acceptable to good yields employing nonactivated terminal olefins as nucleophiles under mild conditions. This protocol features broad substrate scope and high functional group tolerance, therefore enabling late-stage functionalization and a scale-up experiment further to highlight the synthetic utility.

Chiral Phosphoric Acid-Catalyzed Asymmetric Synthesis of Axially Chiral Arylpyrazole.

A chiral phosphoric acid-catalyzed efficient, operationally simple, general method for straightforward syntheses of axially chiral arylpyrazole employing -alkyl of 3-aryl-5-aminopyrazoles reacting with azonaphthalenes was achieved. A wide variety of axially chiral heterobiaryl diamines in generally good yields with excellent enantioselectivities were obtained under mild conditions. In addition, a scaled-up experiment and postmodification of the chiral product further highlighted the synthetic utility.

Asymmetric Synthesis of Optically Active Pyrazolidines or Pyrazoline Derivatives via Ni(II)-Bipyridine-,'-dioxide Complexes.

Easily obtainable and efficient chiral -symmetric bipyridine-,'-dioxide ligands with Ni(OTf) were developed for application in catalyzing [3 + 2] cycloaddition reactions to synthesize optically active fused pyrazolidines or pyrazoline derivatives featuring three contiguous stereogenic centers by employing azomethine imines and α,β-unsaturated 2-acyl imidazoles, affording the corresponding adducts with the opposite configuration compared to previous synthetic products in 80-98% yields with 28-99% ee and >20:1 dr. In addition, subsequent amplification experiments and derivative transformations of the product further demonstrated the efficient catalytic performance of the catalyst Ni(II)-bipyridine-,'-dioxide complexes and the practicality of this synthesis methodology.

Asymmetric Synthesis of Polycyclic Heterocyclic Compounds via Friedel-Crafts Reaction/Cyclization Reaction Catalyzed by Nickel Catalyst.

The first highly enantioselective asymmetric Friedel-Crafts reaction/cyclization reaction of 5-aminopyrazoles with 3-alkenyloxindoles to afford polycyclic heterocyclic compounds bearing an all-carbon quaternary stereocenter catalyzed by a complex of Ni with the -symmetric bipyridine-,'-dioxide ligand has been developed. The relevant products with a wide range of substrates and good functional tolerance were obtained in 89-98% yield with 56-99% ee in the presence of 10 mol % Ni(OTf) and 11 mol % in DCM at 25 °C. Moreover, an experiment on scaling up the process along with the transformations of the cycloadducts further emphasized the practical application of the synthesis.

Cu(II)-Catalyzed Reaction of Ethynyl Methylene Cyclic Carbamates and Amines: Synthesis of Polysubstituted Pyrroles.

A copper-catalyzed efficient, operationally simple, general method for straightforward syntheses of polysubstituted pyrroles employing ethynyl methylene cyclic carbamates as precursors reacting with commercially available amines was first reported. A wide variety of polysubstituted pyrroles were obtained in acceptable to good yields under mild conditions. This protocol features broad substrate scope, high functional group tolerance, and easy operation, therefore enabling late-stage functionalization and rapid synthesis of bioactive compounds, including structurally complex marketed drugs and natural products.

Asymmetric Synthesis of Chiral Cyclopropanes from Vinyl Sulfoxonium Ylides Catalyzed by a Chiral-at-Metal Rh(III) Complex.

A chiral-at-metal Rh(III) complex-mediated [2+1] cyclization of vinyl sulfoxonium ylides with α,β-unsaturated 2,2-acylimidazoles has been demonstrated for the first time. This work provides a practical approach for assembling 1,2,3-trisubstituted chiral cyclopropane with alkyl structural units, which had advantages such as a wide range of substrates, good functional group tolerance, and mild reaction conditions. In addition, further amplification experiments and transformation of cycloaddition products were carried out to highlight the practicality of the method.

Intermolecular Formal [2π + 2σ] Cycloaddition of Enol Silyl Ethers with Bicyclo[1.1.0]butanes Promoted by Lewis Acids.

Silyl enol ethers react with bicyclo[1.1.0]butanes (BCBs) through Yb(OTf)-promoted formal [2π + 2σ] cycloaddition reactions to furnish bicyclo[2.

Genomic landscape and functional characterization of structural variations in schizophrenia and bipolar disorder.

Multiple types of variations have been postulated to confer risk of schizophrenia and bipolar disorder, but majority of present GWAS solely focused on SNPs or small indels, and the impacts of structural variations (SVs) remain less understood. Nevertheless, accumulating evidence suggest that SVs may explain the association signals in certain GWAS hits. Here, we conducted pairwise linkage disequilibrium (LD) analyses of SNPs and SVs in populations from 1000 Genomes Project.

Bipyridine-,'-dioxides Catalysts: Design, Synthesis, and Application in Asymmetric Synthesis of 1-Pyrazolo[3,4-]pyridine Analogues.

A novel type of highly efficient chiral 2-symmetric bipyridine-,'-dioxides ligand application in catalyzing Michael addition/Cyclization of 5-aminopyrazoles with α,β-unsaturated 2-acyl imidazoles has been developed, affording the corresponding adducts in 85-97% yield with up to 99% enantioselectivity under mild conditions with a lower catalyst loading and broad scope. Remarkably, this protocol exhibits advantages in terms of reactivity and enantioselectivity, giving the fact that as low as 2.2 mol % of and 2.

Asymmetric Synthesis of Tertiary α-Hydroxylation-Cyclopentanones via Synergetic Catalysis of Chiral-at-Metal Rhodium(III) Complexes/Pyrrolidine.

Catalytic and asymmetric domino Michael/aldol reaction of 1,2-dicarbonyl compounds with α,β-unsaturated ketones under the synergetic catalysis of chiral-at-metal rhodium complexes and pyrrolidine to deliver tertiary α-hydroxylation-cyclopentanones (45-89% yields with 81-99% ee and up to >20:1 dr) bearing three contiguous stereogenic centers had been established. Moreover, the scalability and practical utility of this protocol were well demonstrated by employing a gram-scale reaction and some representative transformations.

Catalytic asymmetric conjugate addition of coumarins to unsaturated ketones catalyzed by a chiral-at-metal Rh(III) complex.

The first catalytic asymmetric vinylogous Michael addition of coumarins to unsaturated ketones catalyzed by chiral rhodium catalysts has been established. This strategy allowed the synthesis of a variety of highly enantioenriched compounds containing coumarin skeletons in 41-99% yields and 84-99% ee. The developed reaction enriches the chemistry of catalytic asymmetric vinylogous Michael additions of 3-cyano-4-methylcoumarins.

Reduced Vrk2 expression is associated with higher risk of depression in humans and mediates depressive-like behaviors in mice.

Background: Genome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs on VRK2 as well as their roles in the illness are yet to be elucidated.

Methods: Based on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulating VRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice with Vrk2 repression.

Results: We identified a SNP rs2678907 located in the 5' upstream of VRK2 gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues.

Expression and secretion of glycosylated barley oxalate oxidase in Pichia pastoris.

Oxalate oxidase is an enzyme that degrades oxalate and is used in commercial urinary assays to measure oxalate levels. The objective of this study was to establish an enhanced expression system for secretion and purification of oxalate oxidase using Pichia pastoris. A codon optimized synthetic oxalate oxidase gene derived from Hordeum vulgare (barley) was generated and cloned into the pPICZα expression vector downstream of the N-terminal alpha factor secretion signal peptide sequence and used for expression in P.

Asymmetric Synthesis of Chiral Cyclopropanes from Sulfoxonium Ylides Catalyzed by a Chiral-at-Metal Rh(III) Complex.

An enantioselective cyclopropanation reaction of sulfoxonium ylides with β,γ-unsaturated ketoesters catalyzed by a chiral rhodium catalyst has been realized. A variety of optically pure 1,2,3-trisubstituted cyclopropanes was synthesized in 48-89% yields, with up to 99% ee, and with dr >20:1. Furthermore, research shows that a weak coordination between the chiral rhodium catalyst and β,γ-unsaturated ketoesters was responsible for the high diastereoselectivity and enantioselectivity of the corresponding products.

Catalytic Asymmetric Conjugate Addition of 2-Methyl-3,5-dinitrobenzoates to Unsaturated Ketones.

Asymmetric catalytic vinylogous Michael addition of 2-methyl-3,5-dinitrobenzoates to unsaturated ketones catalyzed by chiral rhodium catalysts has been established. This strategy allowed the synthesis of a variety of optically pure compounds containing imidazole and 3,5-dinitrobenzene skeletons in 64-98% yields with 88-98% ee. The developed reaction not only represents highly asymmetric catalytic enantioselective vinylogous Michael addition employing 2-methyl-3,5-dinitrobenzoates as a building block but also enriches the chemistry of catalytic asymmetric vinylogous Michael addition of 2-methyl-3,5-dinitrobenzoates.

Catalytic asymmetric synthesis of diphenylbutazone analogues.

The asymmetric Michael addition of diphenylbutazone and its analogues to α,β-unsaturated 2-acyl imidazoles has been developed with a chiral-at-metal Rh(iii) complex as a catalyst. The corresponding adducts were obtained in good yields (89-98%) with excellent enantioselectivities (up to >99%). The reaction can be conducted on a gram-scale with a low catalyst loading (0.

Chiral-at-Metal Rh(III) Complex-Catalyzed Michael Addition of Pyrazolones with α,β-Unsaturated 2-Acyl Imidazoles.

An efficient enantioselective conjugate addition of pyrazolones with α,β-unsaturated 2-acyl imidazoles catalyzed by chiral-at-metal rhodium complex is reported. The corresponding adducts were obtained in good yields (85%-96%) with excellent enantioselectivities (up to >99%). This protocol exhibits extraordinary reactivity, because of the fact that a complex with as little as 0.

Chiral-at-Metal Rh(III) Complex-Catalyzed Decarboxylative Michael Addition of β-Keto Acids with α,β-Unsaturated 2-Acyl Imidazoles or Pyridine.

A newly prepared chiral-at-metal Rh(III) complex-catalyzed, highly efficient enantioselective decarboxylative Michael addition of β-keto acids with α,β-unsaturated 2-acyl imidazoles or pyridine has been developed, affording the corresponding adducts in 94-98% yield with up to 96% enantioselectivity. This protocol exhibits remarkable reactivity, as the complex with a Rh(III) loading as low as 0.05 mol % can catalyze the decarboxylative Michael addition on a gram scale without loss of enantioselectivity.

Novel detection of pancreatic and duodenal homeobox 1 autoantibodies (PAA) in human sera using luciferase immunoprecipitation systems (LIPS) assay.

We have previously identified pancreatic and duodenal homeobox 1 (Pdx1) autoantibodies (PAA) in sera from both non-obese diabetic (NOD) mice and human type 1 diabetic (T1D) patients. A suitable non-radioactive, sensitive and specific assay is needed for large-scale testing to determine the clinical utility of PAA. Here we reported a liquid-phase luciferase immunoprecipitation system (LIPS) assay by generating a renilla luciferase (Rluc)-Pdx1 fusion protein as a sensitive non-radioactive antigen from mammalian cells combined with immunoprecipitation to detect PAA in human sera.