Superhydrophobic Electrospun PI/PTFE Membranes with Ultralow Dielectric Constants for High-Frequency Telecommunication.

High-frequency, high-power, and high-speed telecommunication in a complex environment promotes the development of dielectric materials toward a low dielectric constant, low dielectric loss, good thermal properties, and long-term reliability. Here, polyimide/polytetrafluoroethylene (PI/PTFE) nanofiber membranes with an inherent super hydrophobicity, excellent dielectric properties, good thermal stability, and enhanced tensile strength were prepared via a simple electrospinning strategy and an imidization reaction. The obtained PI/PTFE membranes demonstrate a superlow average dielectric constant of 1.22-1.27 and a dielectric loss of 0.032-0.048 in high frequency, together with an enhanced tensile strength, benefiting from the special nanofiber-bead structure formed in the composite membrane. The mixing of polyamic acid (PAA) and PTFE in the electrospinning solution endows the obtained PI/PTFE nanofiber membrane with a uniform distribution of PTFE and thus an inherent superhydrophobicity with a water contact angle of 156.1 and 159.2° for PI/PTFE-30% and PI/PTFE-40%, respectively. Besides, the hydrophobicity could be kept even after standing more than 10,000 water drops, and the thermal properties exhibited promising results with Tmax = 587 °C and Td5% = 423 °C, rendering these PI/PTFE membranes favorable alternatives for prospective telecommunication.

Review of advances in molecular structure and biological function of alpha toxin of Clostridium perfringens.

Alpha toxin has become the subject of research in recent years. The objective of this article was to review and summarize recent research on the molecular structure and biological function of the alpha toxin of Clostridium perfringens. This includes the work of our research team, as well as that of other researchers. Clostridium perfringens is an anaerobic, spore-forming, Gram-positive bacillus. It can cause various intestinal diseases, such as gas gangrene, food poisoning, non-foodborne diarrhea, and enteritis. Clostridium perfringens can be classified into 5 toxinotypes A, B, C, D, and E, based on the production of major toxins. Each type of C. perfringens produces alpha toxin, which is one of the most important lethal and dermonecrotic toxins and is considered a primary virulence factor. Alpha toxin is a multifunctional metalloenzyme with phospholipase C and sphingomyelinase activities that simultaneously hydrolyze phosphatidylcholine and sphingomyelin. It can therefore destroy the integrity of cell membranes and eventually cause cell lysis. The clinical effects of alpha toxins are characterized by cytotoxicity, hemolytic activity, lethality, skin necrosis, platelet aggregation, and increased vascular permeability. Future research will concentrate on the pathogenesis of a lpha toxin exposure, clarifying the interaction between alpha toxin and the cell membrane and investigating the mechanism of activating platelet function. This research will have substantial theoretical and practical value in controlling disease progression, identifying targeted therapeutic sites, and reducing the toxic effects of vaccines.

La toxine alpha est devenue l'objet de recherches ces dernières années. L'objectif de cet article était de passer en revue et de résumer les recherches récentes sur la structure moléculaire et la fonction biologique de la toxine alpha de Clostridium perfringens. Cela inclut les travaux de notre équipe de recherche, ainsi que ceux d'autres chercheurs. Clostridium perfringens est un bacille anaérobie, sporulé et à Gram positif. Il peut provoquer diverses maladies intestinales, telles que la gangrène gazeuse, une intoxication alimentaire, de la diarrhée non alimentaire et une entérite. Clostridium perfringens peut être classé en 5 toxinotypes A, B, C, D et E, en fonction de la production des principales toxines. Chaque type de C. perfringens produit de la toxine alpha, qui est l'une des toxines létales et dermonécrotiques les plus importantes et est considérée comme un facteur de virulence primaire. La toxine alpha est une métalloenzyme multifonctionnelle possédant des activités de phospholipase C et de sphingomyélinase qui hydrolysent simultanément la phosphatidylcholine et la sphingomyéline. Elle peut donc détruire l'intégrité des membranes cellulaires et éventuellement provoquer une lyse cellulaire. Les effets cliniques des toxines alpha sont caractérisés par une cytotoxicité, une activité hémolytique, une létalité, une nécrose cutanée, une agrégation plaquettaire et une augmentation de la perméabilité vasculaire. Les recherches futures se concentreront sur la pathogénèse de l'exposition à la toxine alpha, en clarifiant l'interaction entre la toxine alpha et la membrane cellulaire et en étudiant le mécanisme d'activation de la fonction plaquettaire. Ces recherches auront une valeur théorique et pratique substantielle pour contrôler la progression de la maladie, identifier les sites thérapeutiques ciblés et réduire les effets toxiques des vaccins.(Traduit par Docteur Serge Messier).

A Novel Step-Up Dosage Regimen for Enhancing the Benefit-to-Risk Ratio of Mosunetuzumab in Relapsed or Refractory Follicular Lymphoma.

Mosunetuzumab, a T-cell engaging bispecific antibody targeting CD20xCD3, is approved for treating relapsed/refractory follicular lymphoma. This research supports the approved intravenous clinical dose regimen, summarizing the exposure-response relationships for clinical safety and efficacy. A population pharmacokinetic model and Emax logistic regression exposure-response models for safety and efficacy were developed using data from 439 patients with relapsed/refractory non-Hodgkin lymphoma and 159 patients with relapsed/refractory follicular lymphoma, respectively, from a Phase I/II study (NCT02500407). Data from 0.2 to 60 mg across fixed dosing (Cohort A) and Cycle 1 step-up dosing (Cohort B) were used. Exposure-response models, using two-cycle area-under-the-concentration curve (AUC0-42) as the primary exposure endpoint, accurately depicted the complete response and objective response rate data across a 600-fold AUC0-42 range. The approved clinical dose regimen of 1/2/60/30 mg achieved near-maximal efficacy, with model-estimated CR and ORR (90% confidence interval) of 63.1% (49.7-75.0) and 79.1% (69.1-87.7), respectively. The exposure-response analysis for Grade ≥ 2 cytokine release syndrome identified receptor occupancy (%) within the first two cycles as a driver, with CRS dissipating beyond the first dosing cycle. No exposure-dependent increases were observed for other serious adverse events, including neutropenia and infections. The approved intravenous step-up dose regimen (i.e., step doses of 1 and 2 mg on Day 1 and 8, respectively) mitigated severe CRS risk, allowing safe administration of loading (60 mg) and target doses (30 mg every 3 weeks) to achieve a favorable benefit-risk profile.

Short-term respiratory cadmium exposure partially activates pulmonary NLRP3 inflammasome by inducing ferroptosis in mice.

Cadmium (Cd) is a common environmental metal. Previous studies indicated that long-term respiratory Cd exposure caused lung injury and airway inflammation. The purpose of this study was to evaluate whether short-term respiratory Cd exposure induces pulmonary ferroptosis and NLRP3 inflammasome activation. Adult C57BL/6J mice were exposed to Cd by inhaling CdCl2 aerosol (0, 10, or 100 ppm) for 5 days. Serum and lung Fe2+ contents were elevated in Cd-exposed mice. Oxidized AA metabolites, the major oxidized lipids during ferroptosis, were upregulated in Cd-exposed mouse lungs. Pulmonary MDA content and 4-HNE-positive cells were increased in Cd-exposed mice. ACSL4 and COX-2, two lipoxygenases, were upregulated in Cd-exposed mouse lungs. Further analyses found that phosphorylated NF-kB p65 was elevated in Cd-exposed mouse lungs. Innate immune receptor protein NLRP3 and adapter protein ASC were upregulated in Cd-exposed mouse lungs. Caspase-1 was activated and IL-1ß and IL-18 were upregulated in Cd-exposed mouse lungs. Fer-1, a specific inhibitor of ferroptosis, attenuated Cd-induced elevation of pulmonary NLRP3 and ASC, caspase-1 activation, and IL-1ß and IL-18 upregulation. Finally, mitoquinone (MitoQ), a mitochondria-target antioxidant, suppressed Cd-caused ferroptosis and NLRP3 inflammasome activation. Our results demonstrate that ferroptosis might partially mediate Cd-evoked activation of NLRP3 inflammasome in the lungs.

GNN-DDAS: Drug discovery for identifying anti-schistosome small molecules based on graph neural network.

Schistosomiasis is a tropical disease that poses a significant risk to hundreds of millions of people, yet often goes unnoticed. While praziquantel, a widely used anti-schistosome drug, has a low cost and a high cure rate, it has several drawbacks. These include ineffectiveness against schistosome larvae, reduced efficacy in young children, and emerging drug resistance. Discovering new and active anti-schistosome small molecules is therefore critical, but this process presents the challenge of low accuracy in computer-aided methods. To address this issue, we proposed GNN-DDAS, a novel deep learning framework based on graph neural networks (GNN), designed for drug discovery to identify active anti-schistosome (DDAS) small molecules. Initially, a multi-layer perceptron was used to derive sequence features from various representations of small molecule SMILES. Next, GNN was employed to extract structural features from molecular graphs. Finally, the extracted sequence and structural features were then concatenated and fed into a fully connected network to predict active anti-schistosome small molecules. Experimental results showed that GNN-DDAS exhibited superior performance compared to the benchmark methods on both benchmark and real-world application datasets. Additionally, the use of GNNExplainer model allowed us to analyze the key substructure features of small molecules, providing insight into the effectiveness of GNN-DDAS. Overall, GNN-DDAS provided a promising solution for discovering new and active anti-schistosome small molecules.

Combination of Pirfenidone and Andrographolide Ameliorates Hepatic Stellate Cell Activation and Liver Fibrosis by Mediating TGF-ß/Smad Signaling Pathway.

Background: Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays a central role in the pathogenesis of hepatic fibrosis. Our study aimed to investigate the pharmacological effect and potential mechanism of pirfenidone (PFD) and andrographolide (AGP) separately and together on liver fibrosis of BA. Materials and Methods: The bile ducts of male C57BL/6J mice were ligated or had the sham operation. The in vivo effects of PFD and/or AGP on liver fibrosis of BA were evaluated. Human hepatic stellate cells (LX-2) were also treated with PFD and/or AGP in vitro. Results: PFD and/or AGP ameliorates liver fibrosis and inflammation in the mice model of BA, as evidenced by significant downregulated in the accumulation of collagen fibers, hepatic fibrosis markers (α-SMA, collagen I, and collagen IV), and inflammatory markers (IL-1ß, IL-6, and TNF-α). Moreover, compared with monotherapy, these changes are more obvious in the combined treatment of PFD and AGP. Consistent with animal experiments, hepatic fibrosis markers (α-SMA, collagen I, and CTGF) and inflammatory markers (IL-1ß, IL-6, and TNF-α) were significantly decreased in activated LX-2 cells after PFD and/or AGP treatment. In addition, PFD and/or AGP inhibited the activation of HSCs by blocking the TGF-ß/Smad signaling pathway, and the combined treatment of PFD and AGP synergistically inhibited the phosphorylation of Smad2 and Smad3. Conclusion: The combined application of PFD and AGP exerted superior inhibitive effects on HSC activation and liver fibrosis by mediating the TGF-ß/Smad signaling pathway as compared to monotherapy. Therefore, the combination of PFD and AGP may be a promising treatment strategy for liver fibrosis in BA.

Integrated design and application of stimuli-responsive metal-organic frameworks in biomedicine: current status and future perspectives.

In recent years, metal-organic frameworks (MOFs) have garnered widespread attention due to their distinctive attributes, such as high surface area, tunable properties, biodegradability, extremely low density, high loading capacity, diverse chemical functionalities, thermal stability, well-defined pore sizes, and molecular dimensions. Increasingly, biomedical researchers have turned their focus towards their multifaceted development. Among these, stimuli-responsive MOFs, with their unique advantages, have captured greater interest from researchers. This review will delve into the merits and drawbacks of both endogenous and exogenous stimuli-responsive MOFs, along with their application directions. Furthermore, it will outline the characteristics of different synthesis routes of MOFs, exploring various design schemes and modification strategies and their impacts on the properties of MOF products, as well as how to control them. Additionally, we will survey different types of stimuli-responsive MOFs, discussing the significance of various MOF products reported in biomedical applications. We will categorically summarize different strategies such as anticancer therapy, antibacterial treatment, tissue repair, and biomedical imaging, as well as insights into the development of novel MOFs nanomaterials in the future. Finally, this review will conclude by summarizing the challenges in the development of stimuli-responsive MOFs in the field of biomedicine and providing prospects for future research endeavors.

Mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury.

An earlier study found that respiratory cadmium chloride (CdCl2) exposure caused COPD-like lung injury. This study aimed to explore whether mitochondrial dysfunction-mediated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury. Adult C57BL/6 mice were exposed to CdCl2 (10 mg/L) aerosol for six months. Beta-galactosidase-positive cells, p21 and p16 were increased in CdCl2-exposed mouse lungs. The in vitro experiments showed that γ-H2AX was elevated in CdCl2-exposed alveolar epithelial cells. The cGAS-STING pathway was activated in CdCl2-exposed alveolar epithelial cells and mouse lungs. Cxcl1, Cxcl9, Il-10, Il-1ß and Mmp2, several senescence-associated secretory phenotypes (SASP), were upregulated in CdCl2-exposed alveolar epithelial cells. Mechanistically, CdCl2 exposure caused SIRT3 reduction and mitochondrial dysfunction in mouse lungs and alveolar epithelial cells. The in vitro experiment found that Sirt3 overexpression attenuated CdCl2-induced alveolar epithelial senescence and SASP. The in vivo experiments showed that Sirt3 gene knockout exacerbated CdCl2-induced alveolar epithelial senescence, alveolar structure damage, airway inflammation and pulmonary function decline. NMN, an NAD+ precursor, attenuated CdCl2-induced alveolar epithelial senescence and SASP in mouse lungs. Moreover, NMN supplementation prevented CdCl2-induced COPD-like alveolar structure damage, epithelial-mesenchymal transition and pulmonary function decline. These results suggest that mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury.

Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies.

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

Microstructural brain abnormalities and associated neurocognitive dysfunction in obstructive sleep apnea: a pilot study with diffusion kurtosis imaging.

STUDY OBJECTIVES: We assessed possible brain abnormalities in adult patients with moderate and severe obstructive sleep apnea using the mean kurtosis (MK) from diffusion kurtosis imaging and analyzed the correlation between MK and cognitive function. METHODS: A total of 30 patients with moderate or severe obstructive sleep apnea and 30 healthy controls evaluated by the Montreal Cognitive Assessment scale were enrolled. All participants underwent diffusion kurtosis imaging and 3-dimensional T1-weighted imaging on a 3.0T magnetic resonance scanner. The MK values of gray and white matter brain regions were compared. Partial correlation analysis was used to analyze the correlation between respiratory sleep parameters/cognitive score and MK values in different brain regions. RESULTS: Compared with the healthy controls, the MK of 20 brain regions (13 after false discovery rate correction) and cognitive scores in the obstructive sleep apnea group were significantly lower. In the obstructive sleep apnea group, apnea-hypopnea index was negatively correlated with the MK in the white matter of the right occipital lobe; lowest oxygen saturation was positively correlated with the MK in the bilateral parietal, precentral, and right postcentral cortex; total score on the Montreal Cognitive Assessment scale was positively correlated with MK in the left hippocampus; language function was positively correlated with MK in the white matter of the left parietal lobe; and delayed recall was positively correlated with the MK in right insula cortex and bilateral cingulate. After false discovery rate correction, only the correlations of lowest oxygen saturation with right precentral gyrus cortex and bilateral parietal cortex were significant. CONCLUSIONS: MK values of diffusion kurtosis imaging may provide valuable information in assessing the neurological impacts of obstructive sleep apnea. CITATION: Zhang N, Peng K, Guo J-X, Liu Q, Xiao A-L, Jing H. Microstructural brain abnormalities and associated neurocognitive dysfunction in obstructive sleep apnea: a pilot study with diffusion kurtosis imaging. J Clin Sleep Med. 2024;20(10):1571-1578.

Atomically Precise Mo2Cu17 Bimetallic Nanocluster: Synergistic Mo2O4-Coupled Copper Alkynyl Cluster for the Improved Hydrogen Evolution Reaction Performance.

Electrolytic hydrogen production via water splitting holds significant promise for the future of the energy revolution. The design of efficient and abundant catalysts, coupled with a comprehensive understanding of the hydrogen evolution reaction (HER) mechanism, is of paramount importance. In this study, we propose a strategy to craft an atomically precise cluster catalyst with superior HER performance by cocoupling a Mo2O4 structural unit and a Cu(I) alkynyl cluster into a structured framework. The resulting bimetallic cluster, Mo2Cu17, encapsulates a distinctive structure [Mo2O4Cu17(TC4A)4(PhC≡C)6], comprising a binuclear Mo2O4 subunit and a {Cu17(TC4A)2(PhC≡C)6} cluster, both shielded by thiacalix[4]arene (TC4A) and phenylacetylene (PhC≡CH). Expanding our exploration, we synthesized two homoleptic CuI alkynyl clusters coprotected by the TC4A and PhC≡C- ligands: Cu13 and Cu22. Remarkably, Mo2Cu17 demonstrates superior HER efficiency compared to its counterparts, achieving a current density of 10 mA cm-2 in alkaline solution with an overpotential as low as 120 mV, significantly outperforming Cu13 (178 mV) and Cu22 (214 mV) nanoclusters. DFT calculations illuminate the catalytic mechanism and indicate that the intrinsically higher activity of Mo2Cu17 may be attributed to the synergistic Mo2O4-Cu(I) coupling.

Quantum spin driven Yu-Shiba-Rusinov multiplets and fermion-parity-preserving phase transition in K3C60.

Magnetic impurities in superconductors are of increasing interest due to emergent Yu-Shiba-Rusinov (YSR) states and Majorana zero modes for fault-tolerant quantum computation. However, a direct relationship between the YSR multiple states and magnetic anisotropy splitting of quantum impurity spins remains poorly characterized. By using scanning tunneling microscopy, we systematically resolve individual transition-metal (Fe, Cr, and Ni) impurities induced YSR multiplets as well as their Zeeman effects in the K3C60 superconductor. The YSR multiplets show identical d orbital-like wave functions that are symmetry-mismatched to the threefold K3C60(1 1 1) host surface, breaking point-group symmetries of the spatial distribution of YSR bound states in real space. Remarkably, we identify an unprecedented fermion-parity-preserving quantum phase transition between ground states with opposite signs of the uniaxial magnetic anisotropy that can be manipulated by an external magnetic field. These findings can be readily understood in terms of anisotropy splitting of quantum impurity spins, and thus elucidate the intricate interplay between the magnetic anisotropy and YSR multiplets.

Corrigendum: Transcriptome reveals the role of the htpG gene in mediating antibiotic resistance through cell envelope modulation in Vibrio mimicus SCCF01.

[This corrects the article DOI: 10.3389/fmicb.2023.1295065.].

Assessment of Reference Genes Stability in Cortical Bone of Obese and Diabetic Mice.

Introduction: Bone, a pivotal structural organ, is susceptible to disorders with profound health implications. The investigation of gene expression in bone tissue is imperative, particularly within the context of metabolic diseases such as obesity and diabetes that augment the susceptibility to bone fractures. The objective of this study is to identify a set of internal control genes for the analysis of gene expression. Methods: This study employs reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) to assess gene expression in bone tissue. We selected fourteen housekeeping genes and assessed their stability in the cortical bone of mouse models for obesity and diabetes using four well-established algorithms (GeNorm, BestKeeper, NormFinder, and the comparative Delta Ct method). Results and Conclusion: We identified Rpl13a as the mostly stably expressed reference gene in cortical bone tissue from mouse models of obesity and diabetes (db/db), while Gapdh was found to be the most stable reference gene in another diabetes model, KKAy mice. Additionally, Ef1a, Ppia, Rplp0, and Rpl22 were identified as alternative genes suitable for normalizing gene expression in cortical bone from obesity and diabetes mouse models. These findings enhance RT-qPCR accuracy and reliability, offering a strategic guide to select reference gene for studying bone tissue gene expression in metabolic disorders.

ZEB2 alleviates Hirschsprung's-associated enterocolitis by promoting the proliferation and differentiation of enteric neural precursor cells via the Notch-1/Jagged-2 pathway.

BACKGROUND: Hirschsprung's-associated enterocolitis (HAEC) is a prevalent complication of Hirschsprung's disease (HSCR). Zinc finger E-box binding homeobox 2 (ZEB2) and Notch-1/Jagged-2 are dysregulated in HSCR, but their role in HAEC progression remains poorly understood. We aimed to explore the role and underlying mechanism of enteric neural precursor cells (ENPCs) and the ZEB2/Notch-1/Jagged-2 pathway in HAEC development. METHODS: Colon tissues were collected from HSCR and HAEC patients. ENPCs were isolated from the HAEC group and stimulated by lipopolysaccharide (LPS). The expressions of ZEB2/Notch-1/Jagged-2 were measured using RT-qPCR and Western blot. Immunofluorescence and cell counting kit-8 assays were performed to assess the differentiation and proliferation of ENPCs. Inflammatory factors were measured by ELISA kits. Co-immunoprecipitation and bioinformatic analysis were used to explore the interaction between ZEB2 and Notch-1. Small interfering RNA and overexpression vectors were used to investigate the role and mechanism of ZEB2 and Notch-1 in regulating ENPCs' proliferation and differentiation during HAEC progression. RESULTS: We observed increased LPS in the colon tissues of HAEC, with downregulated ZEB2 expression and upregulated Notch-1/Jagged-2 expression. ZEB2 interacts with Notch-1. LPS treatment downregulated ZEB2 expression, upregulated Notch-1/Jagged-2 expression, and induced proliferation and differentiation disorders in ENPCs, which were reversed by the knockdown of Notch-1. Furthermore, overexpression of ZEB2 inhibited Notch-1/Jagged-2 signaling and ameliorated inflammation and dysfunction in LPS-induced ENPCs. Notch-1 overexpression enhanced LPS-induced dysfunction, but this effect was antagonized by the overexpression of ZEB2. CONCLUSION: Overexpression of ZEB2 ameliorates LPS-induced ENPCs' dysfunction via the Notch-1/Jagged-2 pathway, thus playing a role in HAEC.

ALKBH5 facilitates the progression of infantile hemangioma by increasing FOXF1 expression in a m6A-YTHDF2 dependent manner to activate HK-2 signaling.

Alkylation repair homolog protein 5 (ALKBH5) is reported to participate in infantile hemangioma (IH) progression. However, the underlying mechanism of ALKBH5 in IH remains unclear. Using qRT-PCR and Western blotting, ALKBH5, forkhead box F1 (FOXF1) and hexokinase 2 (HK-2) expressions in IH tissues and IH-derived endothelial cells XPTS-1 were assessed. The Me-RIP assay was used to analyze FOXF1 m6A level. CCK8, colony formation, flow cytometry and transwell assays were employed to determine IH cell viability, proliferation, apoptosis, migration and invasion. The interactions between YTH (YT521-B homology) domain 2 (YTHDF2), FOXF1 and HK-2 were analyzed by RIP, dual luciferase reporter gene assay and/or ChIP assay. The in vivo IH growth was evaluated in immunocompromised mice. FOXF1 was overexpressed in IH tissues, and its silencing inhibited IH cell proliferation, migration and invasion whereas promoting cell apoptosis in vitro. ALKBH5 upregulation facilitated FOXF1 mRNA stability and expression in IH cells in a m6A-YTHDF2-dependent manner. FOXF1 downregulation reversed the impact of ALKBH5 upregulation on IH cellular phenotypes. It also turned out that FOXF1 positively regulated HK-2 expression in IH cells through interacting with the HK-2 promoter. HK-2 upregulation abolished FOXF1 knockdown's inhibition on IH cell aggressive behaviors. ALKBH5 or FOXF1 silencing suppressed IH tumor development via HK-2 signaling in immunocompromised mice. ALKBH5 promoted FOXF1 expression m6A-YTHDF2 dependently, which in turn elevated HK-2 expression, thereby accelerating IH development.

Association between smoking and alcohol drinking and benign adrenal tumors: a Mendelian randomization study.

BACKGROUND: In recent years, the detection rate of adrenal tumors has increased, but it is unclear whether smoking and alcohol drinking are risk factors for benign adrenal tumors. The objective of this study is to employ Mendelian randomization (MR) analysis to explore the causal relationship between smoking, alcohol drinking and susceptibility to benign adrenal tumors. METHODS: We acquired large-scale data from publicly accessible databases on genome-wide association studies (GWAS) pertaining to smoking, alcohol drinking and benign adrenal tumors. A total of 11 sets of instrumental variables (IVs) and 281 associated single nucleotide polymorphic (SNP) loci were identified. The Mendelian randomization analyses were conducted using inverse variance weighting (IVW), MR-Egger regression and weighted median estimation (WME) methods, in addition to sensitivity analyses. RESULTS: There is no causal relationship between smoking status, alcohol drinking status, alcohol intake frequency, alcohol taken with meals, alcohol consumption and benign adrenal tumors, while pack years of smoking and cigarettes per day are risk factors for benign adrenal tumors. The IVW analysis revealed that both the pack years of smoking and cigarettes per day were positively associated with an increased risk of benign adrenal tumors (OR = 2.853, 95%CI = 1.384-5.878, p = 0.004; OR = 1.543, 95%CI = 1.147-2.076, p = 0.004). Two SNPs (rs8042849 in the analysis of pack years of smoking and rs8034191 in the analysis of cigarettes per day) significantly drove the observed causal effects. CONCLUSION: Two-sample Mendelian randomization analysis showed a causal effect between smoking but not alcohol consumption and benign adrenal tumors.

The cAMP Receptor Protein (CRP) of Vibrio mimicus Regulates Its Bacterial Growth, Type II Secretion System, Flagellum Formation, Adhesion Genes, and Virulence.

Vibrio mimicus is a serious pathogen in aquatic animals, resulting in significant economic losses. The cAMP receptor protein (CRP) often acts as a central regulator in highly pathogenic pathogens. V. mimicus SCCF01 is a highly pathogenic strain isolated from yellow catfish; the crp gene deletion strain (Δcrp) was constructed by natural transformation to determine whether this deletion affects the virulence phenotypes. Their potential molecular connections were revealed by qRT-PCR analysis. Our results showed that the absence of the crp gene resulted in bacterial and colony morphological changes alongside decreases in bacterial growth, hemolytic activity, biofilm formation, enzymatic activity, motility, and cell adhesion. A cell cytotoxicity assay and animal experiments confirmed that crp contributes to V. mimicus pathogenicity, as the LD50 of the Δcrp strain was 73.1-fold lower compared to the WT strain. Moreover, qRT-PCR analysis revealed the inhibition of type II secretion system genes, flagellum genes, adhesion genes, and metalloproteinase genes in the deletion strain. This resulted in the virulence phenotype differences described above. Together, these data demonstrate that the crp gene plays a core regulatory role in V. mimicus virulence and pathogenicity.

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.