Loss of m6A demethylase ALKBH5 alleviates hypoxia-induced pulmonary arterial hypertension via inhibiting Cyp1a1 mRNA decay.

BACKGROUND: Hypoxia-induced pulmonary artery hypertension (HPH) is a complication of chronic hypoxic lung disease and the third most common type of pulmonary artery hypertension (PAH). Epigenetic mechanisms play essential roles in the pathogenesis of HPH. N6-methyladenosine (m6A) is an important modified RNA nucleotide involved in a variety of biological processes and an important regulator of epigenetic processes. To date, the precise role of m6A and regulatory molecules in HPH remains unclear. METHODS: HPH model and pulmonary artery smooth muscle cells (PASMCs) were constructed from which m6A changes were observed and screened for AlkB homolog 5 (Alkbh5). Alkbh5 knock-in (KI) and knock-out (KO) mice were constructed to observe the effects on m6A and evaluate right ventricular systolic pressure (RVSP), left ventricular and septal weight [RV/(LV + S)], and pulmonary vascular remodeling in the context of HPH. Additionally, the effects of Alkbh5 knockdown using adenovirus were examined in vitro on m6A, specifically in PASMCs with regard to proliferation, migration and cytochrome P450 1A1 (Cyp1a1) mRNA stability. RESULTS: In both HPH mice lung tissues and hypoxic PASMCs, a decrease in m6A was observed, accompanied by a significant up-regulation of Alkbh5 expression. Loss of Alkbh5 attenuated the proliferation and migration of hypoxic PASMCs in vitro, with an associated increase in m6A modification. Furthermore, Alkbh5 KO mice exhibited reduced RVSP, RV/(LV + S), and attenuated vascular remodeling in HPH mice. Mechanistically, loss of Alkbh5 inhibited Cyp1a1 mRNA decay and increased its expression through an m6A-dependent post-transcriptional mechanism, which hindered the proliferation and migration of hypoxic PASMCs. CONCLUSION: The current study highlights the loss of Alkbh5 impedes the proliferation and migration of PASMCs by inhibiting post-transcriptional Cyp1a1 mRNA decay in an m6A-dependent manner.

Identification of ferroptosis-related key genes associated with immune infiltration in sepsis by bioinformatics analysis and in vivo validation.

OBJECTIVES: Sepsis is a life-threatening infectious disease in which an immune inflammatory response is triggered. The potential effect of ferroptosis-related genes (FRGs) in inflammation of sepsis remained unclear. We focused on identifying and validating core FRGs and their association with immune infiltration in blood from currently all patients with sepsis. METHODS: All current raw data of septic blood were obtained from Gene Expression Omnibus. After removing the batch effect merging into a complete dataset and obtaining Diferentially expressed genes (DEGs). Common cross-talk genes were identified from DEGs and FRGs. WGCNA, GO, KEGG, PPI, GESA, ROC curves, and LASSO regression analysis were performed to indentify and validate key genes based on external septic datasets. Infiltrated immune cells in 2 hub genes (MAPK14 and ACSL4) were conducted using CIBERSORT algorithm and Spearman correlation analysis. Further, the expressions of 2 core FRGs were verified in the LPS-induced ALI and cardiac injury sepsis mice. RESULTS: MAPK14 and ACSL4 were identified, mostly enriched in T cell infiltration through NOD-like receptor signaling pathway according to the high or low 2 hub genes expression. The upregulated 2 ferroptosis-related genes were validated in LPS-induced ALI and cardiac injury mice, accompanied by upregulation of the NLRP3 pathway. CONCLUSION: MAPK14 and ACSL4 could become robustly reliable and promising biomarkers for sepsis by regulating ferroptosis through the NLRP3 pathway, which is mainly associated with T-cell infiltration.

Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD.

Chronic inflammatory and immune responses play key roles in the development and progression of chronic obstructive pulmonary disease (COPD). PANoptosis, as a unique inflammatory cell death modality, is involved in the pathogenesis of many inflammatory diseases. We aim to identify critical PANoptosis-related biomarkers and explore their potential effects on respiratory tract diseases and immune infiltration landscapes in COPD. Total microarray data consisting of peripheral blood and lung tissue datasets associated with COPD were obtained from the GEO database. PANoptosis-associated genes in COPD were identified by intersecting differentially expressed genes (DEGs) with genes involved in pyroptosis, apoptosis, and necroptosis after normalizing and removing the batch effect. Furthermore, GO, KEGG, PPI network, WGCNA, LASSO-COX, and ROC curves analysis were conducted to screen and verify hub genes, and the correlation between PYCARD and infiltrated immune cells was analyzed. The effect of PYCARD on respiratory tract diseases and the potential small-molecule agents for the treatment of COPD were identified. PYCARD expression was verified in the lung tissue of CS/LPS-induced COPD mice. PYCARD was a critical PANoptosis-related gene in all COPD patients. PYCARD was positively related to NOD-like receptor signaling pathway and promoted immune cell infiltration. Moreover, PYCARD was significantly activated in COPD mice mainly by targeting PANoptosis. PANoptosis-related gene PYCARD is a potential biomarker for COPD diagnosis and treatment.

Photoinduced Remote C(sp3)-H Phosphonylation of Amides.

The present study reports an unprecedented protocol for the phosphonylation of unactivated C(sp3)-H bonds. By utilizing 1 mol % 4DPAIPN (1,2,3,5-tetrakis(diphenylamino)-4,6-dicyanobenzene) as the catalyst, satisfactory yields of γ-phosphonylated amides are obtained through a visible-light-induced reaction between N-((4-cyanobenzoyl)oxy)alkanamides and 9-fluorenyl o-phenylene phosphite at room temperature. This protocol demonstrates broad substrate scope and wide functional group compatibility.

Thin-cap fibroatheroma in acute coronary syndrome: Implication for intravascular imaging assessment.

Acute coronary syndrome (ACS), a significant cardiovascular disease threat, has garnered increased focus concerning its etiological mechanisms. Thin-cap fibroatheroma (TCFA) are central to ACS pathogenesis, characterized by lipid-rich plaques, profuse foam cells, cholesterol crystals, and fragile fibrous caps predisposed to rupture. While TCFAs may be latent and asymptomatic, their pivotal role in ACS risk is undeniable. High-resolution imaging techniques like Optical coherence tomography (OCT) and Intravascular ultrasound (IVUS) are instrumental for effective TCFA detection. Therapeutic strategies encompass pharmacological and interventional measures, including antiplatelet agents, statins, and Percutaneous Coronary Intervention (PCI), aiding in plaque stabilization, inflammation reduction, and rupture risk mitigation. Despite the strong correlation between TCFAs and adverse prognoses in ACS patients, early detection and rigorous treatment significantly enhance patient prognosis and diminish cardiovascular events. This review aims to encapsulate recent advancements in TCFA research within ACS, covering formation mechanisms, clinical manifestations, and prognostic implications.

Ultrastrong to nearly deep-strong magnon-magnon coupling with a high degree of freedom in synthetic antiferromagnets.

Ultrastrong and deep-strong coupling are two coupling regimes rich in intriguing physical phenomena. Recently, hybrid magnonic systems have emerged as promising candidates for exploring these regimes, owing to their unique advantages in quantum engineering. However, because of the relatively weak coupling between magnons and other quasiparticles, ultrastrong coupling is predominantly realized at cryogenic temperatures, while deep-strong coupling remains to be explored. In our work, we achieve both theoretical and experimental realization of room-temperature ultrastrong magnon-magnon coupling in synthetic antiferromagnets with intrinsic asymmetry of magnetic anisotropy. Unlike most ultrastrong coupling systems, where the counter-rotating coupling strength g2 is strictly equal to the co-rotating coupling strength g1, our systems allow for highly tunable g1 and g2. This high degree of freedom also enables the realization of normalized g1 or g2 larger than 0.5. Particularly, our experimental findings reveal that the maximum observed g1 is nearly identical to the bare frequency, with g1/ω0 = 0.963, indicating a close realization of deep-strong coupling within our hybrid magnonic systems. Our results highlight synthetic antiferromagnets as platforms for exploring unconventional ultrastrong and even deep-strong coupling regimes, facilitating the further exploration of quantum phenomena.

Construction of a g-C3N4/Bi(OH)3 Heterojunction for the Enhancement of Visible Light Photocatalytic Antibacterial Activity.

Photocatalytic technology has been recently conducted to remove microbial contamination due to its unique features of nontoxic by-products, low cost, negligible microbial resistance and broad-spectrum elimination capacity. Herein, a novel two dimensional (2D) g-C3N4/Bi(OH)3 (CNB) heterojunction was fabricated byincorporating Bi(OH)3 (BOH) nanoparticles with g-C3N4 (CN) nanosheets. This CNB heterojunction exhibited high photocatalytic antibacterial efficiency (99.3%) against Escherichia coli (E. coli) under visible light irradiation, which was 4.3 and 3.4 times that of BOH (23.0%) and CN (28.0%), respectively. The increase in specific surface area, ultra-thin layered structure, construction of a heterojunction and enhancement of visible light absorption were conducive to facilitating the separation and transfer of photoinduced charge carriers. Live/dead cell staining, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) assays and scanning electron microscopy (SEM) have been implemented to investigate the damage to the cell membrane and the leakage of the intracellular protein in the photocatalytic antibacterial process. The e-, h+ and O2•- were the active species involved in this process. This study proposed an appropriate photocatalyst for efficient treatment of bacterial contamination.

Antiplatelet effects of the CEACAM1-derived peptide QDTT.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) restricts platelet activation via platelet collagen receptor GPVI/FcRγ-chain. In this study, screening against collagen-induced platelet aggregation was performed to identify functional CEACAM1 extracellular domain fragments. CEACAM1 fragments, including Ala-substituted peptides, were synthesized. Platelet assays were conducted on healthy donor samples for aggregation, cytotoxicity, adhesion, spreading, and secretion. Mice were used for tail bleeding and FeCl3-induced thrombosis experiments. Clot retraction was assessed using platelet-rich plasma. Extracellular segments of CEACAM1 and A1 domain-derived peptide QDTT were identified, while N, A2, and B domains showed no involvement. QDTT inhibited platelet aggregation. Ala substitution for essential amino acids (Asp139, Thr141, Tyr142, Trp144, and Trp145) in the QDTT sequence abrogated collagen-induced aggregation inhibition. QDTT also suppressed platelet secretion and "inside-out" GP IIb/IIIa activation by convulxin, along with inhibiting PI3K/Akt pathways. QDTT curtailed FeCl3-induced mesenteric thrombosis without significantly prolonging bleeding time, implying the potential of CEACAM1 A1 domain against platelet activation without raising bleeding risk, thus paving the way for novel antiplatelet drugs.

What is the context? The study focuses on Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its role in platelet activation, particularly through the GPVI/FcRγ-chain pathway.The research aims to identify specific fragments of CEACAM1's extracellular domain that could restrict platelet activation, without increasing bleeding risk.What is new? The researchers identified a peptide called QDTT derived from the A1 domain of CEACAM1's extracellular segment. This peptide demonstrated the ability to inhibit platelet aggregation, secretion, and GP IIb/IIIa activation.The study also revealed that specific amino acids within the QDTT sequence were essential for its inhibitory effects on collagen-induced aggregation.What is the impact? The findings suggest that the A1 domain-derived peptide QDTT from CEACAM1 could serve as a potential basis for developing novel antiplatelet drugs. This peptide effectively limits platelet activation and aggregation without significantly prolonging bleeding time, indicating a promising approach to managing thrombosis and related disorders while minimizing bleeding risks.

Photoinduced Decarboxylative Radical Phosphinylation.

Reported herein is an unprecedented protocol for C(sp3 )-phosphinylation. With 1 mol % 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.

Ultrathin Co-N-C Layer Modified Pt-Co Intermetallic Nanoparticles Leading to a High-Performance Electrocatalyst toward Oxygen Reduction and Methanol Oxidation.

The development of low platinum-based alloy electrocatalysts is crucial to accelerate the commercialization of fuel cells, yet remains a synthetic challenge and an incompatibility between activity and stability. Herein, a facile procedure to fabricate a high-performance composite that comprises Pt-Co intermetallic nanoparticles (IMNs) and Co, N co-doped carbon (Co-N-C) electrocatalyst is proposed. It is prepared by direct annealing of homemade carbon black-supported Pt nanoparticles (Pt/KB) covered with a Co-phenanthroline complex. During this process, most of Co atoms in the complex are alloyed with Pt to form ordered Pt-Co IMNs, while some Co atoms are atomically dispersed and doped in the framework of superthin carbon layer derived from phenanthroline, which is coordinated with N to form Co-Nx moieties. Moreover, the Co-N-C film obtained from complex is observed to cover the surface of Pt-Co IMNs, which prevent the dissolution and agglomeration of nanoparticles. The composite catalyst exhibits high activity and stability toward oxygen reduction reactions (ORR) and methanol oxidation reactions (MOR), delivering outstanding mass activities of 1.96 and 2.92 A mgPt -1 for ORR and MOR respectively, owing to the synergistic effect of Pt-Co IMNs and Co-N-C film. This study may provide a promising strategy to improve the electrocatalytic performance of Pt-based catalysts.

GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux.

Glutathione S-transferase P1(GSTP1) is known for its transferase and detoxification activity. Based on disease-phenotype genetic associations, we found that GSTP1 might be associated with bone mineral density through Mendelian randomization analysis. Therefore, this study was performed both in vitro cellular and in vivo mouse model to determine how GSTP1 affects bone homeostasis. In our research, GSTP1 was revealed to upregulate the S-glutathionylation level of Pik3r1 through Cys498 and Cys670, thereby decreasing its phosphorylation, further controlling the alteration of autophagic flux via the Pik3r1-AKT-mTOR axis, and lastly altering osteoclast formation in vitro. In addition, knockdown and overexpression of GSTP1 in vivo also altered bone loss outcomes in the OVX mice model. In general, this study identified a new mechanism by which GSTP1 regulates osteoclastogenesis, and it is evident that the cell fate of osteoclasts is controlled by GSTP1-mediated S-glutathionylation via a redox-autophagy cascade.

Preparation and characterization of permeability and mechanical properties of three-dimensional porous stainless steel.

Porous materials are indispensable in biomedical and chemical catalysis fields, but it is still a challenging task to fabricate them with excellent permeability and mechanical properties at the same time. Herein, a new type of three-dimensional porous stainless steel (3DPSS) was fabricated by compression moulding and vacuum sintering. The pore size distribution, air permeability, and mechanical properties of 3DPSS were studied. The results indicated that the radial air permeability reached 3.1 × 10-11 m2, which was approximately 19.7 times greater than the axial air permeability. Interestingly, the axial compressive strength was 91.3% higher than the radial compressive strength and reached 1249 MPa, which was significantly better than that of conventional porous stainless steel and porous titanium as well as porous high entropy alloys. The main characteristics of 3DPSS fracture were metallurgical bonding surface fracture, necking fracture and shear fracture of the wire mesh. This study provides an effective method for the preparation of three-dimensional porous materials, which is convenient for industrial production. It is of great significance to expand the potential application range of porous materials, in particular in fields requiring comprehensive permeability and mechanical properties.

Identification of immune-related hub genes and miRNA-mRNA pairs involved in immune infiltration in human septic cardiomyopathy by bioinformatics analysis.

Abstract: Septic cardiomyopathy (SCM) is a serious complication caused by sepsis that will further exacerbate the patient's prognosis. However, immune-related genes (IRGs) and their molecular mechanism during septic cardiomyopathy are largely unknown. Therefore, our study aims to explore the immune-related hub genes (IRHGs) and immune-related miRNA-mRNA pairs with potential biological regulation in SCM by means of bioinformatics analysis and experimental validation. Method: Firstly, screen differentially expressed mRNAs (DE-mRNAs) from the dataset GSE79962, and construct a PPI network of DE-mRNAs. Secondly, the hub genes of SCM were identified from the PPI network and the hub genes were overlapped with immune cell marker genes (ICMGs) to further obtain IRHGs in SCM. In addition, receiver operating characteristic (ROC) curve analysis was also performed in this process to determine the disease diagnostic capability of IRHGs. Finally, the crucial miRNA-IRHG regulatory network of IRHGs was predicted and constructed by bioinformatic methods. Real-time quantitative reverse transcription-PCR (qRT-PCR) and dataset GSE72380 were used to validate the expression of the key miRNA-IRHG axis. Result: The results of immune infiltration showed that neutrophils, Th17 cells, Tfh cells, and central memory cells in SCM had more infiltration than the control group; A total of 2 IRHGs were obtained by crossing the hub gene with the ICMGs, and the IRHGs were validated by dataset and qRT-PCR. Ultimately, we obtained the IRHG in SCM: THBS1. The ROC curve results of THBS1 showed that the area under the curve (AUC) was 0.909. Finally, the miR-222-3p/THBS1 axis regulatory network was constructed. Conclusion: In summary, we propose that THBS1 may be a key IRHG, and can serve as a biomarker for the diagnosis of SCM; in addition, the immune-related regulatory network miR-222-3p/THBS1 may be involved in the regulation of the pathogenesis of SCM and may serve as a promising candidate for SCM therapy.

Integrated bioinformatics analysis for novel miRNAs markers and ceRNA network in diabetic retinopathy.

In order to seek a more outstanding diagnosis and treatment of diabetic retinopathy (DR), we predicted the miRNA biomarkers of DR and explored the pathological mechanism of DR through bioinformatics analysis. Method: Based on public omics data and databases, we investigated ncRNA (non-coding RNA) functions based on the ceRNA hypothesis. Result: Among differentially expressed miRNAs (DE-miRNAs), hsa-miR-1179, -4797-3p and -665 may be diagnosis biomarkers of DR. Functional enrichment analysis revealed differentially expressed mRNAs (DE-mRNAs) enriched in mitochondrial transport, cellular respiration and energy derivation. 18 tissue/organ-specific expressed genes, 10 hub genes and gene cluster modules were identified. The ceRNA networks lncRNA FBXL19-AS1/miR-378f/MRPL39 and lncRNA UBL7-AS1/miR-378f/MRPL39 might be potential RNA regulatory pathways in DR. Conclusion: Differentially expressed hsa-miR-1179, -4797-3p and -665 can be used as powerful markers for DR diagnosis, and the ceRNA network: lncRNA FBXL19-AS1/UBL7-AS1-miR-378f-MRPL39 may represent an important regulatory role in DR progression.

Identification and Validation of Immune-Related Biomarker Gene and Construction of ceRNA Networks in Septic Cardiomyopathy.

Septic cardiomyopathy (SCM) is a cardiac dysfunction caused by severe sepsis, which greatly increases the risk of heart failure and death, and its molecular mechanism is unclear. The immune response has been reported to be an important process in septic cardiomyopathy and is present in the cardiac tissue of patients with sepsis, suggesting that the immune response may be an underlying mechanism of myocardial injury in SCM. Therefore, we explored the role of immune-related genes (IRGs) in SCM and aimed to identify pivotal immune-related targets with the aim of identifying key immune-related targets in SCM and potential therapeutic mechanisms involved in the pathological process of SCM. To explore the regulatory mechanisms of immune responses in SCM, we identified differentially expressed genes (DEGs) shared in the SCM datasets GSE179554 and GSE40180 by bioinformatics analysis and then obtained hub genes from the DEGs. Then, we obtained the immune-related hub genes (IRHGs) by intersecting the hub genes with IRGs and performed quantitative reverse transcription polymerase chain reaction to confirm the abnormal expression of IRHGs. Finally, we further constructed an immune-related lncRNA-miRNA-IRHG ceRNA regulatory network. In this study, we identified an IRHG that may be involved in the pathogenesis of SCM, which helps us to further elucidate the role of immune response in SCM and gain insights into the molecular mechanisms and potential therapeutic targets of SCM.

Charpy Impact Behavior of a Novel Stainless Steel Powder Wire Mesh Composite Porous Plate.

A novel powder wire mesh composite porous plate (PWMCPP) was fabricated with 304 stainless steel powders and wire mesh as raw materials by vacuum solid-state sintering process using self-developed composite rolling mill of powder and wire mesh. The effects of different mesh volume fractions, mesh diameters, and sintering temperatures on the pore structure and Charpy impact properties of PWMCPPs were studied. The results show that PWMCPPs have different shapes and sizes of micropores. Impact toughness of PWMCPPs decreases with increasing wire mesh volume fraction, and increases first and then decreases with increasing wire mesh diameter, and increases with increasing sintering temperature. Among them, the sintering temperature has the most obvious effect on the impact toughness of PWMCPPs, when the sintering temperature increased from 1160 °C to 1360 °C, the impact toughness increased from 39.54 J/cm2 to 72.95 J/cm2, with an increased ratio of 84.5%. The tearing between layers, the fracture of the metallurgical junction, and the fracture of wire mesh are the main mechanisms of impact fractures of the novel PWMCPPs.

Radical trifluoromethylation.

The trifluoromethyl group plays an increasingly important role in pharmaceuticals, agrochemicals and materials. This tutorial describes recent advances in trifluoromethylation of carbon-centered radical intermediates.

Cobalt-Catalyzed Markovnikov-Selective Radical Hydroacylation of Unactivated Alkenes with Acylphosphonates.

Acylphosphonates having the 5,5-dimethyl-1,3,2-dioxophosphinanyl skeleton are developed as efficient intermolecular radical acylation reagents, which enable the cobalt-catalyzed Markovnikov hydroacylation of unactivated alkenes at room temperature under mild conditions. The protocol exhibits broad substrate scope and wide functional group compatibility, providing branched ketones in satisfactory yields. A mechanism involving the Co-H mediated hydrogen atom transfer and subsequent trapping of alkyl radicals by acylphosphonates is proposed.

Copper-Catalyzed Ring-Opening 1,3-Aminotrifluoromethylation of Arylcyclopropanes.

The copper-catalyzed reaction of arylcyclopropanes, N-fluorobis(arenesulfonyl)imides, and (bpy)Zn(CF3)2 (bpy = 2,2'-bipyridine) at room temperature affords the corresponding ring-opening 1,3-aminotrifluoromethylation products in satisfactory yields. The protocol is highly regioselective, providing a convenient entry to γ-trifluoromethylated amines. A mechanism involving the trifluoromethylation of benzyl radicals is proposed.

Enantioselective Total Synthesis of (+)-Corymine and (-)-Deformylcorymine.

We report herein the first enantioselective total synthesis of akuammiline alkaloids (+)-corymine and (-)-deformylcorymine. Starting from commercially available N-nosyltryptamine, the target molecules are both achieved in 11 steps. Key elements of the design include (a) a copper-catalyzed enantioselective addition of dimethyl malonate to a 3-bromooxindole to secure the C7 all-carbon quaternary stereocenter, (b) a one-step construction of cyclohexyl and pyrrolidinyl rings via intramolecular nucleophilic C- and N-addition, and (c) a nickel-promoted 7-endo cyclization of alkenyl bromide to furnish the azepanyl ring. The strategy is further extended to the synthesis of another three members of the akuammiline family, namely, (-)-10-demethoxyvincorine, (-)-2(S)-cathafoline, and (-)-3-epi-dihydrocorymine 17-acetate.