Mechanistic Studies of Small Molecule Ligands Selective to RNA Single G Bulges.

Small-molecule RNA binders have emerged as an important pharmacological modality. A profound understanding of the ligand selectivity, binding mode, and influential factors governing ligand engagement with RNA targets is the foundation for rational ligand design. Here, we report a novel class of coumarin derivatives exhibiting selective binding affinity towards single G RNA bulges.

A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death.

Background: HOIP is the catalytic subunit of the E3 ligase complex (linear ubiquitin chain assembly complex), which is able to generate linear ubiquitin chains. However, the role of rare HOIP functionally deficient variants remains unclear. The pathogenic mechanism and the relationship with immune deficiency phenotypes remain to be clarified.

Crosstalk between KIF1C and PRKAR1A in left atrial myxoma.

Cardiac myxoma (CM) is the most common benign cardiac tumor, and most CMs are left atrial myxomas (LAMs). Six variations of KIF1C, c.899 A > T, c.

Case Report: A Novel Homozygous Mutation in Due to Paternal Uniparental Isodisomy of Chromosome 12 in a Case of External Ophthalmoplegia With Rib and Vertebral Anomalies.

External ophthalmoplegia with rib and vertebral anomalies (EORVA) is characterized by congenital nonprogressive external ophthalmoplegia, ptosis, scoliosis, torticollis, vertebral, and rib anomalies, caused by homozygous mutations in the myogenic factor 5 gene () located on chromosome 12q21.31. Uniparental disomy (UPD) is a rare inheritance of a pair of chromosomes originating from only one parent.

Partially Represses the Abnormal Electrical Activity of SCN3B in Cardiac Arrhythmias by Downregulation of IL-2.

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that to be downregulated.

Kidney stone disease and cardiovascular events: a study on bidirectional causality based on mendelian randomization.

Background: Kidney stone disease (KSD) has been reported to be associated with several cardiovascular diseases. However, the causality between the conditions remains unknown. In the study, we performed a study on bidirectional causality by two-sample Mendelian randomization (MR) to investigate the causality between KSD and cardiovascular diseases including coronary atherosclerosis, hypertension, and cardiomyopathy.

Novel Partial Exon 51 Deletion in the Duchenne Muscular Dystrophy Gene Identified Whole Exome Sequencing and Long-Read Whole-Genome Sequencing.

Duchenne muscular dystrophy (DMD), one of the most common progressive and severely disabling neuromuscular diseases in children, can be largely attributed to the loss of function of the gene on chromosome Xp21.2-p21.1.

Construction of Enantioenriched γ,γ-Disubstituted Butenolides Enabled by Chiral Amine and Lewis Acid Cascade Cocatalysis.

Herein we report a cascade cocatalysis strategy for the facile construction of chiral γ,γ-disubstituted butenolides. The synthetic manifold employs simple alkynoic acids instead of the preformed silyloxy furans or 5-substituted furan-2(3)-ones. In situ formed 5-substituted furan-2(3)-ones by AgNO or PhPAuCl/AgOTf catalyzed cyclization of alkynoic acids can smoothly engage in the subsequent chiral diphenylprolinol TMS-ether catalyzed Michael and Michael-aldol reactions.

Site-Specific Incorporation of a Dithiolane Containing Amino Acid into Proteins.

We have genetically encoded a dithiolane containing amino acid (dtF) in () using a polyspecific aminoacyl-tRNA synthetase (aaRS)/amber suppressor tRNA pair. To demonstrate the utility of dtF for bioapplications, we synthesized gold nanoparticle (AuNP) constructs with a mutant superfolder green fluorescent protein (sfGFP) [sfGFP-AuNP] as a model for the protein-metal conjugation. The resulting sfGFP-AuNP constructs show directional homogeneity and enhanced chemical durability compared to their cysteine analogues toward excess environmental 1,4-dithiothreitol (DTT).

Rational design of a function-based selection method for genetically encoding acylated lysine derivatives.

A foundation of genetic code expansion is the evolution of orthogonal aminoacyl-tRNA synthetase to recognize a non-canonical amino acid, which typically involves read-through of amber stop codon in the genes used in selection. The process is time-consuming, labor-intensive, and susceptible to certain bias. As a complementation, herein, we rationally designed a function-based method to directed evolution of aminoacyl-tRNA synthetase for acylated lysine derivatives.

Progress toward a reduced phage genetic code.

All known living organisms use at least 20 amino acids as the basic building blocks of life. Efforts to reduce the number of building blocks in a replicating system to below the 20 canonical amino acids have not been successful to date. In this work, we use filamentous phage as a model system to investigate the feasibility of removing methionine (Met) from the proteome.

Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity.

The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high-throughput screen.

Numerical investigation of cavity self-oscillation and noise radiation induced by turbulent flow at non-zero inclination angle.

A hybrid numerical approach was used on a three-dimensional cavity at a non-zero inclination angle of the upstream section to reveal the mechanism of self-oscillation and the characteristics of far-field sound field. In this hybrid approach, the unsteady flow physics was captured by a compressible large eddy simulation, and the far-field sound field was calculated by the FW-H integral equation, with the noise source provided by near-field calculation. The mechanism of self-oscillation was revealed based on the instantaneous flow field structure and the pressure inside the cavity.

Chemo- and Regioselective Organo-Photoredox Catalyzed Hydroformylation of Styrenes via a Radical Pathway.

An unprecedented, chemo- and regioselective, organo-photoredox catalyzed hydroformylation reaction of aryl olefins with diethoxyacetic acid as the formylation reagent is described. In contrast to traditional transition metal promoted ionic hydroformylation reactions, the new process follows a unique photoredox promoted, free radical pathway. In this process, a formyl radical equivalent, produced from diethoxacetic acid through a dye (4CzIPN) photocatalyzed, sequential oxidation-decarboxylation route, regio- and chemoselectively adds to a styrene substrate.

Synthesis of Aldehydes by Organocatalytic Formylation Reactions of Boronic Acids with Glyoxylic Acid.

Reported herein is a conceptually novel organocatalytic strategy for the formylation of boronic acids. New reactivity is engineered into the α-amino-acid-forming Petasis reaction occurring between aryl boronic acids, amines, and glyoxylic acids to prepare aldehydes. The operational simplicity of the process and its ability to generate structurally diverse and valued aryl, heteroaryl, and α,β-unsaturated aldehydes containing a wide array of functional groups, demonstrates the practical utility of the new synthetic strategy.

Visible-Light-Promoted Nickel- and Organic-Dye-Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent.

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel- and organic-dye-mediated photoredox catalysis is reported. Distinct from widely used palladium-catalyzed formylation processes, this reaction proceeds by a two-step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN-mediated photoredox reaction. The formyl-radical equivalent then undergoes nickel-catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products.

Synthesis of Tryptanthrins by Organocatalytic and Substrate Co-catalyzed Photochemical Condensation of Indoles and Anthranilic Acids with Visible Light and O.

A metal-free catalytic approach to tryptanthrins has been achieved for the first time. The unique process is realized by an organocatalytic and indole and anthranilic acid substrate co-catalyzed photochemical oxidative condensation with visible light and O. The truly environmentally friendly reaction conditions enable various reactants to participate in the process to deliver structurally diverse tryptanthrins.

Aniline-Promoted Cyclization-Replacement Cascade Reactions of 2-Hydroxycinnamaldehydes with Various Carbonic Nucleophiles through In Situ Formed N,O-Acetals.

In this study, we report the harnessing of new reactivity of N,O-acetals in an aminocatalytic fashion for organic synthesis. Unlike widely used strategies requiring the use of acids and/or elevated temperatures, direct replacement of the amine component of the N,O-acetals by carbon-centered nucleophiles for C-C bond formation is realized under mild reaction conditions. Furthermore, without necessary preformation of the N,O-acetals, an amine-catalyzed in situ formation of N,O-acetals is developed.

Dynamic Kinetic Resolution of Biaryl Lactones via a Chiral Bifunctional Amine Thiourea-Catalyzed Highly Atropo-enantioselective Transesterification.

A solution to the unmet synthetic challenge of achieving highly atropo-enantioselective transesterification of Bringmann's lactones has been realized, employing a chiral bifunctional amine thiourea as promoter. The synergistic activation of the lactones and alcohols/phenols by the respective thiourea and amine groups is crucial for achieving the highly enantioselective, high-yielding dynamic kinetic resolution process. This protocol gives highly optically pure, axially chiral biaryl compounds with a broad substrate scope under mild reaction conditions.

Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses.

Purpose: We characterize calpain-5 (CAPN5) expression in retinal and neuronal subcellular compartments.

Methods: CAPN5 gene variants were classified using the exome variant server, and RNA-sequencing was used to compare expression of CAPN5 mRNA in the mouse and human retina and in retinoblastoma cells. Expression of CAPN5 protein was ascertained in humans and mice in silico, in mouse retina by immunohistochemistry, and in neuronal cancer cell lines and fractionated central nervous system tissue extracts by Western analysis with eight antibodies targeting different CAPN5 regions.

Dietary Supplementation with Organoselenium Accelerates Recovery of Bladder Expression, but Does Not Improve Locomotor Function, following Spinal Cord Injury.

Selenium is an essential element required for activity of several antioxidant enzymes, including glutathione peroxidase. Because of the critical role of the antioxidant system in responding to traumatic events, we hypothesized that dietary selenium supplementation would enhance neuroprotection in a rodent model of spinal cord injury. Rats were maintained on either a control or selenium-enriched diet prior to, and following, injury.

Facile Installation of 2-Reverse Prenyl Functionality into Indoles by a Tandem N-Alkylation-Aza-Cope Rearrangement Reaction and Its Application in Synthesis.

An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency.