SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway.

Pathogenic variants in HFE and non-HFE genes have been identified in hemochromatosis in different patient populations, but there are still a certain number of patients with unexplained primary iron overload. We recently identified in Chinese patients a recurrent p.(Arg639Gln) variant in SURP and G-patch domain containing 2 (SUGP2), a potential mRNA splicing-related factor. However, the target gene of SUGP2 and affected iron-regulating pathway remains unknown. We aimed to investigate the pathogenicity and underlying mechanism of this variant in hemochromatosis. RNA-seq analysis revealed that SUGP2 knockdown caused abnormal alternative splicing of CIRBP pre-mRNA, resulting in an increased normal splicing form of CIRBP V1, which in turn increased the expression of BMPER by enhancing its mRNA stability and translation. Furthermore, RNA-protein pull-down and RNA immunoprecipitation assays revealed that SUGP2 inhibited splicing of CIRBP pre-mRNA by a splice site variant at CIRBP c.492 and was more susceptible to CIRBP c.492 C/C genotype. Cells transfected with SUGP2 p.(Arg639Gln) vector showed up-regulation of CIRBP V1 and BMPER expression and down-regulation of pSMAD1/5 and HAMP expression. CRISPR-Cas9 mediated SUGP2 p.(Arg622Gln) knock-in mice showed increased iron accumulation in the liver, higher total serum iron, and decreased serum hepcidin level. A total of 10 of 54 patients with hemochromatosis (18.5%) harbored the SUGP2 p.(Arg639Gln) variant and carried CIRBP c.492 C/C genotype, and had increased BMPER expression in the liver. Altogether, the SUGP2 p.(Arg639Gln) variant down-regulates hepcidin expression through the SUGP2/CIRBP/BMPER axis, which may represent a novel pathogenic factor for hemochromatosis.

Efficacy of remimazolam tosilate versus propofol for total intravenous anaesthesia in urological surgery: A randomised clinical trial.

BACKGROUND: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that acts on the gamma-aminobutyric acid type A receptor (GABAAR). OBJECTIVE: To compare the efficacies of remimazolam (RMZ), and propofol (PROP) combined with remifentanil and cisatracurium for total intravenous anaesthesia (TIVA) in patients undergoing urological surgery. DESIGN: A prospective, single-blind, randomised, noninferiority clinical trial. SETTING: Single centre from 1 January 2022 to 30 March 2022. PATIENTS: A total of 146 adult patients undergoing elective urological surgery. INTERVENTION: Patients were randomly allocated in a 1 : 1 ratio to the PROP or RMZ groups. In the PROP group, anaesthesia was induced with propofol at 100 mg min -1 to reach a bispectral index score (BIS) of 40 to 60. After loss of consciousness (LOC), intravenous fentanyl 3 µg kg -1 was administered, followed by cisatracurium 0.3 mg kg -1 . Patients were intubated 3 min after cisatracurium administration. Anaesthesia was maintained with the combination of propofol (plasma concentration: 2.5 to 4 µg ml -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). In the RMZ group, anaesthesia was induced with remimazolam tosilate starting at 10 mg kg -1  h -1 to reach a BIS of 40 to 60 and maintained between 0.2 and 2 mg kg -1  h -1 . After LOC, fentanyl and cisatracurium were administered and intubation was performed as in the PROP group. Anaesthesia was maintained with a combination of remimazolam (0.2 to 2 mg kg -1  h -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). MAIN OUTCOME MEASURES: The primary outcome was the TIVA success rate. The predefined noninferiority margin considered an absolute difference of 6% in the primary outcome between the groups. The secondary outcomes were vital signs, anaesthesia and surgery characteristics, and adverse events. RESULTS: All patients completed the trial. The success rates of TIVA with remimazolam and propofol were 100 and 98.6%, respectively. The incidence of hypotension during anaesthesia was lower in the RMZ group (26%) than in the PROP group (46.6%) ( P  = 0.016). The median [IQR] total consumption of ephedrine during anaesthesia was higher in the PROP group 10 [0 to 12.5] mg than in the RMZ group 0 [0 to 10] mg ( P  = 0.0002). The incidence of injection pain was significantly higher in the PROP group (76.7%) than in the RMZ group (0; P  < 0.001). No significant differences in the controllability of the anaesthesia depth, anaesthesia and surgery characteristics, or vital signs were observed between the groups. CONCLUSION: Remimazolam demonstrated noninferior efficacy to propofol combined with remifentanil and cisatracurium for TIVA in patients undergoing urological surgery. TRIAL REGISTRATION: Chictr.org.cn, identifier: ChiCTR2100050923. CLINICAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100050923, Principal investigator: Xuehai Guan, Date of registration: 8 November 2021, https://www.chictr.org.cn/showproj.html?proj=133466 ).

A Systematic Investigation of the Kinetic Models Applied to the Transport Behaviors of Aromatic Solvents in Unfilled Hydrogenated Nitrile Rubber/Ethylene Propylene Diene Monomer Composites.

Kinetic models of solvent transport behaviors are widely used in rubber-solvent systems, and some key points are still worthy of attention. In this work, the Korsmeyer-Peppas and Peppas-Sahlin models were chosen to fit the transport behaviors of three aromatic solvents, benzene, toluene and p-xylene, in the hydrogenated nitrile rubber (HNBR)/ethylene propylene diene monomer (EPDM)-based vulcanizates. The different effects of the various selected transport times (ti) used for fitting on the results of the mathematical models were compared. Moreover, a method to obtain the n parameter for the Korsmeyer-Peppas model and the m parameter for the Peppas-Sahlin model at ti = 0 was discussed. It was found that the differences in values of ti greatly influenced the impact on the fitting results of all the parameters for the two models. In addition, the n parameter for the Korsmeyer-Peppas model along with the m parameter for the Peppas-Sahlin model, which can characterize the transport mechanism, showed differing applicability. But the n and m parameters at ti = 0 obtained by linear fitting showed similar rules with some differences in values. These discussions give important guidance for the application of kinetic transport models in rubber-solvent systems.

Systematic Investigation of the Degradation Properties of Nitrile-Butadiene Rubber/Polyamide Elastomer/Single-Walled Carbon Nanotube Composites in Thermo-Oxidative and Hot Oil Environments.

The physical blending method was used in order to prepare nitrile-butadiene rubber/polyamide elastomer/single-walled carbon nanotube (NBR/PAE/SWCNT) composites with better thermal-oxidative aging resistance. The interactions between SWCNTs and NBR/PAE were characterized using the Moving Die Rheometer 2000 (MDR 2000), rheological behavior tests, the equilibrium swelling method, and mechanical property tests. The 100% constant tensile stress and hardness of NBR/PAE/SWCNT composites increased from 2.59 MPa to 4.14 MPa and from 62 Shore A to 69 Shore A, respectively, and the elongation decreased from 421% to 355% with increasing SWCNT content. NBR/PAE/SWCNT composites had improved thermal-oxidative aging resistance due to better interactions between SWCNTs and NBR/PAE. During the aging process, the tensile strength and elongation at break decreased with the increase in aging time compared to the unaged samples, and the constant tensile stress gradually increased. There was a more significant difference in the degradation of mechanical properties when aged in a variety of oils. The 100% constant tensile stress of NBR/PAE/SWCNT composites aged in IRM 903 gradually increased with aging time while it gradually decreased in biodiesel. The swelling index gradually increased with increasing SWCNT content. Interestingly, the swelling index of the composites in cyclohexanone decreased with the increase in SWCNT content. The reasons leading to different swelling behaviors when immersed in different kinds of liquids were investigated using the Hansen solubility parameter (HSP) method, which provides an excellent guide for the application of some oil-resistant products.

Effect of Hot-Pressing Process on Mechanical Properties of UHMWPE Fiber Non-Woven Fabrics.

In order to investigate the influence of a hot-pressing process on the mechanical properties of ultra-high molecular weight polyethylene (UHMWPE) fiber non-woven fabrics with stretch and in-plane shear, UHMWPE non-woven fabric samples were prepared by adjusting the temperature, time, and pressure of the hot-pressing process, and mechanical property tests were carried out so as to clarify the influence of the hot-pressing process on the mechanical properties of the samples. The results show that the hot-pressing process mainly affects the silk-glue bonding strength of the samples; in the test range, with the increase in hot-pressing temperature and time, the tensile strength and in-plane shear strength of the samples increase and then decrease, and the best mechanical properties are obtained at 130 °C and 7 min of hot pressing, respectively; at 130 °C, the in-plane shear strength is 39.94 MPa and the tensile strength is 595.43 MPa; at 7 min, the in-plane shear strength is 63.0 MPa and the tensile strength is 643.30 MPa; with the increase in the hot-pressing pressure, the in-plane shear strength of the samples increases and then decreases, and the highest is 52.60 MPa, achieved at 8 MPa; in the range of 5-8 MPa, the tensile strength of the specimens did not change significantly, and increased significantly at 9 MPa, reaching a maximum strength of 674.55 MPa.

Folic Acid Functionalized AQ4N/Gd@PDA Nanoplatform with Real-Time Monitoring of Hypoxia Relief and Enhanced Synergistic Chemo/Photothermal Therapy in Glioma.

Purpose: Hypoxia is often associated with glioma chemoresistance, and alleviating hypoxia is also crucial for improving treatment efficacy. However, although there are already some methods that can improve efficacy by alleviating hypoxia, real-time monitoring that can truly achieve hypoxia relief and efficacy feedback still needs to be explored. Methods: AQ4N/Gd@PDA-FA nanoparticles (AGPF NPs) were synthesized using a one-pot method and were characterized. The effects of AGPF NPs on cell viability, cellular uptake, and apoptosis were investigated using the U87 cell line. Moreover, the effectiveness of AGPF NPs in alleviating hypoxia was explored in tumor-bearing mice through photoacoustic imaging. In addition, the diagnosis and treatment effect of AGPF NPs were evaluated by magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) on orthotopic glioma mice respectively. Results: In vitro experiments showed that AGPF NPs had good dispersion, stability, and controlled release. AGPF NPs were internalized by cells through endocytosis, and could significantly reduce the survival rate of U87 cells and increase apoptosis under irradiation. In addition, we monitored blood oxygen saturation at the tumor site in real-time through photoacoustic imaging (PAI), and the results showed that synergistic mild-photothermal therapy/chemotherapy effectively alleviated tumor hypoxia. Finally, in vivo anti-tumor experiments have shown that synergistic therapy can effectively alleviate hypoxia and inhibit the growth of orthotopic gliomas. Conclusion: This work not only provides an effective means for real-time monitoring of the dynamic feedback between tumor hypoxia relief and therapeutic efficacy, but also offers a potential approach for the clinical treatment of gliomas.

Effect of alkali pretreatment time on kitchen waste anaerobic digestion performance enhanced by alkali pretreatment combined with bentonite: performance enhancement, microbial community structure, and functional gene analysis.

Kitchen waste was mainly composed of carbohydrates, lipids, and proteins. Anaerobic digestion (AD) of kitchen waste usually occurred acidification and further deteriorated. In our previous study, alkali pretreatment combined with bentonite (AP/Be) treatment was proved to enhance high solid AD of kitchen waste. However, effects of AP time on AP/Be were not yet studied. This study investigated the effects of AP time on AP/Be treatment on enhancing high solid AD. The results showed that compared with the control group, the cumulative methane production rate could be increased by 3.30 times (149.7 mL CH4/g VS) and the volatile solids (VS) reduction rate increased by 63.36%. Microbial community analysis showed that the relative abundance of Methanosarcina and Methanosaeta were increased from 6.49 and 7.83% to 47.14 and 16.39% respectively. Predictive functional analysis showed that AP/Be treatment increased the abundance of energy production and conversion, coenzyme transport, and metabolism. This study revealed the potential mechanism of AP/Be enhanced kitchen waste AD performance and AP/Be was a potential strategy to strengthen AD.

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis (NASH)-related HCC is multifactorial and multistage. However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model (HRAS-HCC) was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage, jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH- related HCC were demonstrated by pathological staining, biochemical analyses, and typical marker gene detections. Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Disruption of PABPN1 phase separation by SNRPD2 drives colorectal cancer cell proliferation and migration through promoting alternative polyadenylation of CTNNBIP1.

Generally shortened 3' UTR due to alternative polyadenylation (APA) is widely observed in cancer, but its regulation mechanisms for cancer are not well characterized. Here, with profiling of APA in colorectal cancer tissues and poly(A) signal editing, we firstly identified that the shortened 3' UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and migration. We found that liquid-liquid phase separation (LLPS) of PABPN1 is reduced albeit with higher expression in cancer, and the reduction of LLPS leads to the shortened 3' UTR of CTNNBIP1 and promotes cell proliferation and migration. Notably, the splicing factor SNRPD2 upregulated in colorectal cancer, can interact with glutamic-proline (EP) domain of PABPN1, and then disrupt LLPS of PABPN1, which attenuates the repression effect of PABPN1 on the proximal poly(A) sites. Our results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1, suggesting that regulation of APA by interfering LLPS of 3' end processing factor may have the potential as a new way for the treatment of cancer.

Frontiers and hotspots of adipose tissue and NAFLD: a bibliometric analysis from 2002 to 2022.

Background: The annual incidence of non-alcoholic fatty liver disease (NAFLD) continues to rise steadily. In recent years, adipose tissue (AT) has gained recognition as a pivotal contributor to the pathogenesis of NAFLD. Employing bibliometric analysis, we examined literature concerning AT and NAFLD. Methods: Relevant literature on AT in NAFLD from 1980 to 2022 was extracted from the Web of Science Core Collection. These records were visualized using CiteSpace and VOSviewer regarding publications, countries/regions, institutions, authors, journals, references, and keywords. Results: Since 2002, a total of 3,330 papers have been included, exhibiting an annual surge in publications. Notably, the quality of publications is superior in the USA and Europe. Kenneth Cusi stands out as the author with the highest number of publications and H-index. Hepatology is the journal boasting the highest citation and H-index. The University of California System holds the highest centrality among institutions. References specifically delve into physiological processes associated with AT in NAFLD. Currently, lipid metabolism and inflammation constitute the principal research mechanisms in the AT-based regulation of NAFLD, with pertinent keywords including microRNA, T cell, hypoxia, sarcopenia, hepatokine, gut microbiota, and autophagy. The Mediterranean diet is among the most widely recommended dietary approaches for potential NAFLD treatment. Conclusion: This paper represents the inaugural bibliometric study on the effects of AT on NAFLD, offering valuable insights and directions for future research.