Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation.

BACKGROUND: Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood. METHODS: We generated NR4A3-/- mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification. RNA-seq was performed to determine the transcriptional profile of NR4A3-/- vascular smooth muscle cells under ß-glycerophosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the gene regulatory mechanisms of NR4A3 in arterial calcification and target genes regulated by histone lactylation. RESULTS: NR4A3 expression was upregulated in calcified aortic tissues from chronic kidney disease mice, 1,25(OH)2VitD3 overload-induced mice, and human calcified aorta. NR4A3 deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast differentiation-related gene expression, and reduced calcium deposition in the vasculature. Further, NR4A3 deficiency lowered the glycolytic rate and lactate production during the calcification process and decreased histone lactylation. Mechanistic studies further showed that NR4A3 enhanced glycolysis activity by directly binding to the promoter regions of the 2 glycolysis genes ALDOA and PFKL and driving their transcriptional initiation. Furthermore, histone lactylation promoted medial calcification both in vivo and in vitro. NR4A3 deficiency inhibited the transcription activation and expression of Phospho1 (phosphatase orphan 1). Consistently, pharmacological inhibition of Phospho1 attenuated calcium deposition in NR4A3-overexpressed vascular smooth muscle cells, whereas overexpression of Phospho1 reversed the anticalcific effect of NR4A3 deficiency in vascular smooth muscle cells. CONCLUSIONS: Taken together, our findings reveal that NR4A3-mediated histone lactylation is a novel metabolome-epigenome signaling cascade mechanism that participates in the pathogenesis of medial arterial calcification.

Fine-tuning an aromatic ring-hydroxylating oxygenase to degrade high molecular weight polycyclic aromatic hydrocarbon.

Rieske nonheme iron aromatic ring-hydroxylating oxygenases (RHOs) play pivotal roles in determining the substrate preferences of polycyclic aromatic hydrocarbon (PAH) degraders. However, their potential to degrade high molecular weight PAHs (HMW-PAHs) has been relatively unexplored. NarA2B2 is an RHO derived from a thermophilic Hydrogenibacillus sp. strain N12. In this study, we have identified four "hotspot" residues (V236, Y300, W316, and L375) that may hinder the catalytic capacity of NarA2B2 when it comes to HMW-PAHs. By employing structure-guided rational enzyme engineering, we successfully modified NarA2B2, resulting in NarA2B2 variants capable of catalyzing the degradation of six different types of HMW-PAHs, including pyrene, fluoranthene, chrysene, benzo[a]anthracene, benzo[b]fluoranthene, and benzo[a]pyrene. Three representative variants, NarA2B2W316I, NarA2B2Y300F-W316I, and NarA2B2V236A-W316I-L375F, not only maintain their abilities to degrade low-molecular-weight PAHs (LMW-PAHs) but also exhibited 2 to 4 times higher degradation efficiency for HMW-PAHs in comparison to another isozyme, NarAaAb. Computational analysis of the NarA2B2 variants predicts that these modifications alter the size and hydrophobicity of the active site pocket making it more suitable for HMW-PAHs. These findings provide a comprehensive understanding of the relationship between three-dimensional structure and functionality, thereby opening up possibilities for designing improved RHOs that can be more effectively used in the bioremediation of PAHs.

RNA Helicase DDX5 Maintains Cardiac Function by Regulating CamkIIδ Alternative Splicing.

BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear. METHODS: We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing. RESULTS: We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CamkIIδ), thus preventing the production of CaMKIIδA, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca2+ homeostasis. In line with this, we found increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKIIδA partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice. CONCLUSIONS: These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF.

Origin of iodine preferential attack at sulfur in phosphorothioate and subsequent P-O or P-S bond dissociation.

Iodine-induced cleavage at phosphorothioate DNA (PT-DNA) is characterized by extremely high sensitivity (∼1 phosphorothioate link per 106 nucleotides), which has been used for detecting and sequencing PT-DNA in bacteria. Despite its foreseeable potential for wide applications, the cleavage mechanism at the PT-modified site has not been well established, and it remains unknown as to whether or not cleavage of the bridging P-O occurs at every PT-modified site. In this work, we conducted accurate ωB97X-D calculations and high-performance liquid chromatography-mass spectrometry to investigate the process of PT-DNA cleavage at the atomic and molecular levels. We have found that iodine chemoselectively binds to the sulfur atom of the phosphorothioate link via a strong halogen-chalcogen interaction (a type of halogen bond, with binding affinity as high as 14.9 kcal/mol) and thus triggers P-O bond cleavage via phosphotriester-like hydrolysis. Additionally, aside from cleavage of the bridging P-O bond, the downstream hydrolyses lead to unwanted P-S/P-O conversions and a loss of the phosphorothioate handle. The mechanism we outline helps to explain specific selectivity at the PT-modified site but also predicts the dynamic stoichiometry of P-S and P-O bond breaking. For instance, Tris is involved in the cascade derivation of S-iodo-phosphorothioate to S-amino-phosphorothioate, suppressing the S-iodo-phosphorothioate hydrolysis to a phosphate diester. However, hydrolysis of one-third of the Tris-O-grafting phosphotriester results in unwanted P-S/P-O conversions. Our study suggests that bacterial DNA phosphorothioation may more frequently occur than previous bioinformatic estimations have predicted from iodine-induced deep sequencing data.

Logic Signal Amplification System for Sensitive Electrochemiluminescence Detection and Subtype Identification of Cancer Cells.

Achieving sensitive detection and accurate identification of cancer cells is vital for diagnosing and treating the disease. Here, we developed a logic signal amplification system using DNA tetrahedron-mediated three-dimensional (3D) DNA nanonetworks for sensitive electrochemiluminescence (ECL) detection and subtype identification of cancer cells. Specially designed hairpins were integrated into DNA tetrahedral nanostructures (DTNs) to perform a catalytic hairpin assembly (CHA) reaction in the presence of target microRNA, forming hyperbranched 3D nanonetworks. Benefiting from the "spatial confinement effect," the DNA tetrahedron-mediated catalytic hairpin assembly (DTCHA) reaction displayed significantly faster kinetics and greater cycle conversion efficiency than traditional CHA. The resulting 3D nanonetworks could load a large amount of Ru(phen)32+, significantly enhancing its ECL signal, and exhibit detection limits for both miR-21 and miR-141 at the femtomolar level. The biosensor based on modular logic gates facilitated the distinction and quantification of cancer cells and normal cells based on miR-21 levels, combined with miR-141 levels, to further identify different subtypes of breast cancer cells. Overall, this study provides potential applications in miRNA-related clinical diagnostics.

Enhanced Aggregation-Induced Delayed Electrochemiluminescence Triggered by Spatial Perturbation of Organic Dots.

Development of highly efficient, heavy-metal-free electrochemiluminescence (ECL) materials is attractive but still challenging. Herein, we report an aggregation-induced delayed ECL (AIDECL) active organic dot (OD) composed of a tert-butoxy-group-substituted benzophenone-dimethylacridine compound, which shows high ECL efficiency. The resultant ODs exhibit 2.1-fold higher ECL efficiency compared to control AIDECL-active ODs. Molecular stacking combined with theoretical calculations suggests that tert-butoxy groups effectively participate in the intermolecular interactions, further inhibiting the molecular motions in the aggregated states and thus accelerating radiative decay. On the basis of these ODs exhibiting excellent ECL performance, a proof-of-concept biosensor is constructed for the detection of miR-16 associated with Alzheimer's disease, which demonstrates excellent detection ability with the limit of detection of 1.7 fM. This work provides a new approach to improve the ECL efficiency and enriches the fundamental understanding of the structure-property relationship.

Genome-wide identification, expression analysis of WRKY transcription factors in Citrus ichangensis and functional validation of CiWRKY31 in response to cold stress.

BACKGROUND: Ichang papeda (Citrus ichangensis), a wild perennial plant of the Rutaceae family, is a cold-hardy plant. WRKY transcription factors are crucial regulators of plant growth and development as well as abiotic stress responses. However, the WRKY genes in C. ichangensis (CiWRKY) and their expression patterns under cold stress have not been thoroughly investigated, hindering our understanding of their role in cold tolerance. RESULTS: In this study, a total of 52 CiWRKY genes identified in the genome of C. ichangensis were classified into three main groups and five subgroups based on phylogenetic analysis. Comprehensive analyses of motif features, conserved domains, and gene structures were performed. Segmental duplication plays a significant role in the CiWRKY gene family expansion. Cis-acting element analysis revealed the presence of various stress-responsive elements in the promoters of the majority of CiWRKYs. Gene ontology (GO) analysis and protein-protein interaction predictions indicate that the CiWRKYs exhibit crucial roles in regulation of both development and stress response. Expression profiling analysis demonstrates that 14 CiWRKYs were substantially induced under cold stress. Virus-induced gene silencing (VIGS) assay confirmed that CiWRKY31, one of the cold-induced WRKYs, functions positively in regulation of cold tolerance. CONCLUSION: Sequence and protein properties of CiWRKYs were systematically analyzed. Among the 52 CiWRKY genes 14 members exhibited cold-responsive expression patterns, and CiWRKY31 was verified to be a positive regulator of cold tolerance. These findings pave way for future investigations to understand the molecular functions of CiWRKYs in cold tolerance and contribute to unravelling WRKYs that may be used for engineering cold tolerance in citrus.

Interfacial Hydrogen-Bond Interactions Driven Assembly toward Polychromatic Copper Nanoclusters.

Constructing versatile metal nanoclusters (NCs) assemblies through noncovalent weak interactions between inter-ligands is a long-standing challenge in interfacial chemistry, while compelling interfacial hydrogen-bond-driven metal NCs assemblies remain unexplored so far. Here, the study reports an amination-ligand o-phenylenediamine-coordinated copper NCs (CuNCs), demonstrating the impact of interfacial hydrogen-bonds (IHBs) motifs on the luminescent behaviors of metal NCs as the alteration of protic solvent. Experimental results supported by theoretical calculation unveil that the flexibility of interfacial ligand and the distance of cuprophilic CuI···CuI interaction between intra-/inter-NCs can be tailored by manipulating the cooperation between the diverse IHBs motifs reconstruction, therewith the IHBs-modulated fundamental structure-property relationships are established. Importantly, by utilizing the IHBs-mediated optical polychromatism of aminated CuNCs, portable visualization of humidity sensing test-strips with fast response is successfully manufactured. This work not only provides further insights into exploring the interfacial chemistry of NCs based on inter-ligands hydrogen-bond interactions, but also offers a new opportunity to expand the practical application for optical sensing of metal NCs.

A multifunctional flavoprotein monooxygenase HspB for hydroxylation and C-C cleavage of 6-hydroxy-3-succinoyl-pyridine.

Flavoprotein monooxygenases catalyze reactions, including hydroxylation and epoxidation, involved in the catabolism, detoxification, and biosynthesis of natural substrates and industrial contaminants. Among them, the 6-hydroxy-3-succinoyl-pyridine (HSP) monooxygenase (HspB) from Pseudomonas putida S16 facilitates the hydroxylation and C-C bond cleavage of the pyridine ring in nicotine. However, the mechanism for biodegradation remains elusive. Here, we refined the crystal structure of HspB and elucidated the detailed mechanism behind the oxidative hydroxylation and C-C cleavage processes. Leveraging structural information about domains for binding the cofactor flavin adenine dinucleotide (FAD) and HSP substrate, we used molecular dynamics simulations and quantum/molecular mechanics calculations to demonstrate that the transfer of an oxygen atom from the reactive FAD peroxide species (C4a-hydroperoxyflavin) to the C3 atom in the HSP substrate constitutes a rate-limiting step, with a calculated reaction barrier of about 20 kcal/mol. Subsequently, the hydrogen atom was rebounded to the FAD cofactor, forming C4a-hydroxyflavin. The residue Cys218 then catalyzed the subsequent hydrolytic process of C-C cleavage. Our findings contribute to a deeper understanding of the versatile functions of flavoproteins in the natural transformation of pyridine and HspB in nicotine degradation.IMPORTANCEPseudomonas putida S16 plays a pivotal role in degrading nicotine, a toxic pyridine derivative that poses significant environmental challenges. This study highlights a key enzyme, HspB (6-hydroxy-3-succinoyl-pyridine monooxygenase), in breaking down nicotine through the pyrrolidine pathway. Utilizing dioxygen and a flavin adenine dinucleotide cofactor, HspB hydroxylates and cleaves the substrate's side chain. Structural analysis of the refined HspB crystal structure, combined with state-of-the-art computations, reveals its distinctive mechanism. The crucial function of Cys218 was never discovered in its homologous enzymes. Our findings not only deepen our understanding of bacterial nicotine degradation but also open avenues for applications in both environmental cleanup and pharmaceutical development.

BAP1 loss confers sensitivity to bromodomain and extra-terminal inhibitors in renal cell carcinoma.

The tumor suppressor gene BRCA1 associated protein-1 (BAP1) is frequently mutated in renal cell carcinoma (RCC). BAP1 loss-of-function mutations are associated with poor survival outcomes. However, personalized therapy for BAP1-mutated RCC is currently not available. Previously, we found that BAP1 loss renders RCC cells more sensitive to bromodomain and extra-terminal (BET) inhibitors, as demonstrated in both cell culture and xenografted nude mice models. Here, we demonstrate that BAP1 loss in murine RCC cells enhances sensitivity to BET inhibitors in ectopic and orthotopic allograft models. While BAP1 deletion suppresses RCC cell survival in vitro, it does not impede tumor growth in immunocompetent murine models. Thus, the effect of BAP1 loss on the interactions between tumor cells and host microenvironment plays a predominant role in RCC growth, highlighting the importance of utilizing immunocompetent animal models to assess the efficacy of potential anticancer therapies. Mechanistically, BAP1 deletion compromises DNA repair capacity, rendering RCC cells more vulnerable to DNA damage induced by BET inhibitors. Our results indicate that BET inhibitors show promise as targeted therapy for BAP1-deficient RCC.

Structural confirmation of position isomers 2-(2-methylaminoprolyl)benzofuran and 5-(2-methylaminopropyl)benzofuran: a combined mass spectrometric and computational study.

RATIONALE: Phenylethylamines are one of the most common types of new psychoactive substances, following synthetic cannabinoids and synthetic cathinones. They are regulated in many countries because of their strong hallucinogenic effects, which can cause serious nerve damage. There is a wide variety of phenylethylamines, exhibiting rapid renewal and extremely similar structures, therefore accurate qualitative analysis of isomers is a difficult problem in current drug analysis. METHODS: The dissociation pathways of the position isomers 2-(2-methylaminoprolyl)benzofuran (2-MAPB) and 5-(2-methylaminopropyl)benzofuran (5-MAPB) were investigated by gas chromatography-mass spectrometry and liquid chromatography coupled to high-resolution quadrupole Orbitrap MS. The dissociation patterns of the phenethylamine-based designer drugs 2-MAPB and 5-MAPB were explored and extended in this work based on MS combined with density functional theory studies. RESULTS: For electron ionization mass spectrometry (EI-MS) analysis, the dissociation patterns of 2-MAPB were similar to those of 5-MAPB. For electrospray ionization mass spectrometry (ESI-MSn ) analysis, the hydrogen atom on amino group was facile to form a intramolecular hydrogen bond with the oxygen atom on the parent nucleus of benzofuran in the structure of 2-MAPB, leading to higher abundance of the product ion at m/z 58. However, there was a conjugated system between the positive charge formed by the cleavage of the 5-MAPB side chain and the benzofuran ring, enabling the 5-MAPB to generate a product ion at m/z 131. Computational study showed that energy barrier and spin density difference distribution jointly control the selective dissociation in EI-MS, while different types of orbital interaction induced by intramolecular hydrogen bond led to different dissociation results in ESI-MSn . CONCLUSIONS: These different dissociation patterns could be used to distinguish 2-MAPB from 5-MAPB. This could assist forensic laboratories in the differentiation and characterization of potential isomers in these kinds of compounds, especially in mixtures.

From Pb6(HPO3)(H2PO3)Cl9 to Pb6(HPO3)2Br8(H2O)·H2O: Halogen Regulation to Achieve Inorganic Metal Phosphite Halide Nonlinear Optical Material with Unprecedented Pb-Centered Polyhedral Units.

Nonlinear optical (NLO) crystals are widely used in various fields. The introduction of lone-pair cations is regarded as an effective strategy to explore NLO crystals. In this work, two novel lead phosphite halides, centrosymmetric Pb6(HPO3)(H2PO3)Cl9 and noncentrosymmetric Pb6(HPO3)2Br8(H2O)·H2O, were obtained via a hydrothermal method. Pb6(HPO3)(H2PO3)Cl9 is the first reported lone-pair metal phosphite with two kinds of phosphite groups (HPO32- and H2PO3-) and Pb6(HPO3)2Br8(H2O)·H2O is the first inorganic NLO phosphite halide with a phase-matchable SHG effect of 1.02 × KDP. In addition, the Pb-centered polyhedral units of PbOCl4, PbOCl6, PbO2Cl5, PbO2Br5, PbOBr6, and PbO3(H2O)Br3 in these two structures have never been reported before. An in-depth study on the structure-property relationship of the two compounds with halogen substitution is also performed.

(C5H12N2S)Hg(NO3)2: A Mercury Nitrate Nonlinear Optical Crystal Motivated by Heteroatom Coordination Strategy.

Effective design and synthesis of second-order nonlinear optical (NLO) materials hold immense significance in driving modern science and technology advancements. In this study, we synthesized a new acentric mercury nitrate, (C5H12N2S)Hg(NO3)2, by regulating the coordination of the Hg atom through the introduction of a heteroatom. It exhibits an unprecedented [(C5H12N2S)2Hg2(NO3)4]∞ chain composed of Hg2+, NO3-, and organic molecule C5H12N2S. Notably, (C5H12N2S)Hg(NO3)2 demonstrates an unprecedented HgO3S unit and a second harmonic generation (SHG) intensity of 1.3 × KDP at 1064 nm, presenting the second-order nonlinear mercury nitrate constructed by organic molecule. Theoretical calculations suggest that the HgO3S unit and organic molecule C5H12N2S significantly contribute to the SHG effect. This study demonstrates that the incorporation of heteroatoms is an effective strategy for the development of new NLO materials.

From ZnF2 to ZnF2(H2O)4: Partial Substitution Achieves Structural Transformation and Nonlinear Optical Activity while Keeping Short Ultraviolet Cutoff Edge.

Exploring nonlinear optical (NLO) materials with short ultraviolet cutoff edges are significant for developing an all-solid-state laser. Here, a noncentrosymmetric zinc fluoride hydrate, ZnF2(H2O)4, was synthesized by a hydrothermal method. It crystallizes in the polar space group of Pca21. The compound consists of the central Zn2+ combined with F- and coordination water to form the [ZnF2(H2O)4] octahedra, and each octahedron is isolated from each other to form a 0-dimensional structure. As an acentric compound, ZnF2(H2O)4 shows a phase-matchable second-harmonic-generation (SHG) activity with an intensity about 0.5 times that of KH2PO4. More attractively, it also shows a short ultraviolet cutoff edge below 200 nm, which is rare in reported halide hydrate systems. Interestingly, from ZnF2 to ZnF2(H2O)4, the partial substitution of the coordinated F atoms by H2O molecules leads to the structural transformation from centric to acentric with SHG activity off to on. Structural analyses, NLO activity, and theoretical calculations are presented in this work.

Centric Sc(HPO3)(H2PO3)(H2O) and Acentric Sc(H2PO3)3: Two Ultraviolet Scandium Phosphite Optical Crystals.

Exploring ultraviolet (UV) nonlinear-optical (NLO) materials is significant for the conversion of a high-frequency laser. Two scandium phosphites, Sc(HPO3)(H2PO3)(H2O) and Sc(H2PO3)3, were successfully synthesized. Centric Sc(HPO3)(H2PO3)(H2O) exhibits a short UV cutoff edge (<200 nm) and a unique double-layer structure of [Sc2(HPO3)2(H2PO3)2(H2O)2]∞. The acentric Sc(H2PO3)3 exhibits a three-dimensional [Sc(H2PO3)3]∞ structure with a large band gap of 4.05 eV, and it demonstrates a moderately phase-matchable second-harmonic-generation response [0.60 × KDP (KH2PO4)] at 1064 nm. The crystal structures, optical properties, and theoretical calculations of the two compounds are discussed. This work will promote the exploration of new NLO phosphite materials.

C(NH2)3Cd(C2O4)Cl(H2O)·H2O and BaCd(C2O4)1.5Cl(H2O)2: Two Oxalate Chlorides Obtained by Chemical Scissors Strategy Exhibiting Low-Dimensional Structural Networks and Balanced Overall Optical Properties.

Low-dimensional crystalline materials have attracted much attention due to their special physical and chemical properties. Herein, two new oxalate chlorides, C(NH2)3Cd(C2O4)Cl(H2O)·H2O and BaCd(C2O4)1.5Cl(H2O)2, were synthesized. C(NH2)3Cd(C2O4)Cl(H2O)·H2O presents the unique {[Cd(C2O4)Cl(H2O)]-}∞ zigzag chain, while BaCd(C2O4)1.5Cl(H2O)2 shows a novel {[Cd(C2O4)1.5Cl]2-}∞ layer. They showed large measured band gaps, which were 3.76 and 4.53 eV, respectively, and the latter was the largest band gap in the A-M-C2O4-X (A = Monovalent cationic or alkaline earth metals, X = F, Cl, Br, I) family. They exhibit a large calculated birefringence of 0.075 and 0.096 at 1064 nm, respectively. This study promotes the exploration of synthesizing low-dimensional crystalline materials with balanced overall optical performances by a chemical scissors strategy.

Hg16O12(NO3)6F2(H2O): A Mercury-Rich Nitrate Oxyfluoride with Diverse Triple-Coordinated Mercury-Based Units That Exhibits an Unparalleled [(Hg16O12F2(H2O))6+]∞ Cationic Framework and a Large Birefringence.

Designing new compounds based on anion regulation has been widely favored due to the production of diverse crystal structures and excellent optical properties. Here, a new nitrate oxyfluoride, Hg16O12(NO3)6F2(H2O), has been obtained through a hydrothermal reaction. It crystallizes in the centric Ibca space group and shows a novel three-dimensional [(Hg16O12F2(H2O))6+]∞ cationic framework composed of interconnected HgO2F, HgO3, and HgO2(H2O) units, with isolated NO3- groups as balanced anions to build the whole structure. Notably, the HgO2F and HgO2(H2O) units are first presented here among mercury (Hg)-based compounds. Additionally, Hg16O12(NO3)6F2(H2O) exhibits a large birefringence of 0.17 at 546 nm. This work enriches the multiformity of Hg-based compounds and provides a route for developing promising birefringent materials.

Functional characterization of RIP2 in large yellow croaker (Larimichthys crocea), a protein involved in the host antiviral responses via NF-κΒ, IRF3/7 related signaling.

As an adaptor protein functions essentially in the activation of NF-κΒ and MAPK signaling pathways mediated by NOD1 and NOD2, RIP2 plays important roles in the host innate immune responses. In the present study, the RIP2 ortholog termed Lc-RIP2 was identified and characterized in large yellow croaker (Larimichthys crocea). It was revealed that Lc-RIP2 is consisted of an open reading frame (ORF) of 1695 bp, encoding a protein of 564 aa, with an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD). Subcellular localization assays demonstrated that Lc-RIP2 was a cytosolic protein, which was broadly distributed in the examined tissues/organs, and could be induced in response to poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulations in vivo according to qRT-PCR analysis. Notably, Lc-RIP2 overexpression in vitro was sufficient to abolish SVCV proliferation in EPC cells, and could significantly induce the activation of NF-κB, IRF3, IRF7, and IFN1 promoters. In addition, luciferase assays found that Lc-RIP2 could cooperate with Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7 in NF-κB activation, associate with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-IRF3, and Lc-IRF7 in IRF3 activation, enhance Lc-TRIF, Lc-MAVS, Lc-TRAF3, and Lc-TRAF6 mediated IRF7 activation, and Lc-IRF3 mediated IFN1 activation, whereas suppress NF-κB activation when co-expressed with Lc-TRIF. Co-immunoprecipitation (Co-IP) assays also demonstrated that Lc-RIP2 interacts separately with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7. It is thus collectively indicated that Lc-RIP2 function dominantly in the regulation of the host innate immune signaling.

Comparison of vonoprazan bismuth-containing triple therapy with quadruple therapy in Helicobacter pylori-infected treatment-naive patients: a prospective multicenter randomized controlled trial.

BACKGROUND AND AIM: Helicobacter pylori infection is linked to various gastrointestinal conditions, such as chronic active gastritis, peptic ulcers, and gastric cancer. Traditional treatment options encounter difficulties due to antibiotic resistance and adverse effects. Therefore, the aim of this study was to explore the effectiveness of a new treatment plan that combines vonoprazan (VPZ), amoxicillin, and bismuth for the eradication of H. pylori. METHODS: A total of 600 patients infected with H. pylori were recruited for this multicenter randomized controlled trial. Patients treated for H. pylori elimination were randomly assigned at a 1:1 ratio to receive 14 days of vonoprazan-based triple therapy (vonoprazan + amoxicillin + bismuth, group A) or standard quadruple therapy (esomeprazole + clarithromycin + amoxicillin + bismuth, group B). Compliance and adverse effects were tracked through daily medication and side effect records. All patients underwent a 13C/14C-urea breath test 4 weeks after treatment completion. RESULTS: Intention-to-treat (ITT) and per-protocol (PP) analyses revealed no substantial differences in H. pylori eradication rates between groups A and B (ITT: 83.7% vs 83.2%; PP: 90.9% vs 89.7%). However, significant differences were observed in the assessment of side effects (13.7% vs 28.6%, P < 0.001). Specifically, group A had significantly fewer "bitter mouths" than group B did (3.7% vs 16.2%, P < 0.001). CONCLUSION: Triple therapy comprising vonoprazan (20 mg), amoxicillin (750 mg), and bismuth potassium citrate (220 mg) achieved a PP eradication rate ≥90%, paralleling standard quadruple therapy, and had fewer adverse events and lower costs (¥306.8 vs ¥645.8) for treatment-naive patients.

Serum BAFF level is associated with the presence and severity of coronary artery disease and acute myocardial infarction.

OBJECTIVE: The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear. METHODS: Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI. RESULTS: Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P < 0.0001) and the GRACE score (r = 0.5684, P < 0.0001). Logistic regression analysis demonstrated that increased BAFF levels were an independent risk factor for CAD (adjusted OR 1.305, 95% CI 1.078-1.580) and AMI (adjusted OR 2.874, 95% CI 1.708-4.838) after adjusting for confounding variables. Additionally, elevated BAFF levels were significantly associated with a high GRACE score (GRACE score 155 to 319, adjusted OR 4.297, 95% CI 1.841-10.030). BAFF exhibited a sensitivity of 75.0% and specificity of 71.4% in differentiating CAD patients with a high SYNTAX score, and a sensitivity of 75.5% and specificity of 72.8% in identifying AMI patients with a high GRACE score. CONCLUSION: Circulating BAFF levels serve as a valuable diagnostic marker for CAD and AMI. Elevated BAFF levels are associated with the presence and severity of these conditions, suggesting its potential as a clinically relevant biomarker in cardiovascular disease.