3D Chromatin Alteration by Disrupting ß-Catenin/CBP Interaction Is Enriched with Insulin Signaling in Pancreatic Cancer.

The therapeutic potential of targeting the ß-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a ß-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this ß-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the ß-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of how the functional crosstalk between the antagonist and the ß-catenin/CBP interaction affects changes in 3D chromatin architecture and, thereby, gene expression and downstream effects remains to be elucidated. Here, we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate that the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1-a key insulin signaling gene-significantly impeding pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.

A predictive nomogram for short-term outcomes of myasthenia gravis patients treated with low-dose rituximab.

BACKGROUND: This study aims to establish and validate a predictive nomogram for the short-term clinical outcomes of myasthenia gravis (MG) patients treated with low-dose rituximab. METHODS: We retrospectively reviewed 108 patients who received rituximab of 600 mg every 6 months in Huashan Hospital and Tangdu Hospital. Of them, 76 patients from Huashan Hospital were included in the derivation cohort to develop the predictive nomogram, which was externally validated using 32 patients from Tangdu Hospital. The clinical response is defined as a ≥ 3 points decrease in QMG score within 6 months. Both clinical and genetic characteristics were included to screen predictors via multivariate logistic regression. Discrimination and calibration were measured by the area under the receiver operating characteristic curve (AUC-ROC) and Hosmer-Lemeshow test, respectively. RESULTS: Disease duration (OR = 0.987, p = 0.032), positive anti-muscle-specific tyrosine kinase antibodies (OR = 19.8, p = 0.007), and genotypes in FCGR2A rs1801274 (AG: OR = 0.131, p = 0.024;GG:OR = 0.037, p = 0.010) were independently associated with clinical response of post-rituximab patients. The nomogram identified MG patients with clinical response with an AUC-ROC (95% CI) of 0.875 (0.798-0.952) in the derivation cohort and 0.741(0.501-0.982) in the validation cohort. Hosmer-Lemeshow test showed a good calibration (derivation: Chi-square = 3.181, p = 0.923; validation: Chi-square = 8.098, p = 0.424). CONCLUSIONS: The nomogram achieved an optimal prediction of short-term outcomes in patients treated with low-dose rituximab.

[Hip joint biomechanical analysis of the acetabular anatomical reconstruction and nonanatomical reconstruction in total hip arthroplasty for Crowe type â ¢ developmental dysplasia of the hip by finite element method].

OBJECTIVE: To analyze the hip joint biomechanics of the acetabular anatomical reconstruction and nonanatomical reconstruction in total hip arthroplasty (THA) for Crowe type Ⅲ developmental dysplasia of the hip (DDH) by finite element method, which provided theoretical foundation and experimental basis for the anatomical acetabular reconstruction during THA in clinical practice. METHODS: One patient with left end-stage hip arthritis secondary to Crowe type Ⅲ DDH was selected in this study, who underwent total hip arthroplasty in the orthopedic department of the First Affiliated Hospital of Bengbu Medical College in April 2020. This patient was female, 57 years old. The preoperative and postoperative three dimentional CT scan of the patient's pelvis were performed. Fourteen acetabular cup models with different anteversion, inclination and rotation center height were established in Mimics and 3-Matic software. The boundary and load conditions were set in Abaqus software. The Von Mises and stress distribution of the hip joint were calculated and observed. RESULTS: In the Crowe type Ⅲ DDH THA, if the hip rotation center was restored anatomically and the acetabular cup's inclination was set as 40°, the cup's anteversion varied from 5° to 25°, the lowest Von Mises value of acetabular cup and polyethylene liner occured in 20°anteversioin;if the hip rotation center was restored anatomically and the acetabular cup's anteversion was set as 15°, the cup's inclination varied from 35° to 55°, the lowest Von Mises value of acetabular cup and polyethylene liner occured in 35° inclination;if the acetabular cup's anteversion and inclination were set as 15°and 40°respectively, the up migration of hip rotaion center varied from 0 mm to 20 mm, the lowest Von Mises value of acetabular cup and polyethylene liner occured in 10 mm up migration. In all fourteen models, the Von Mises value of the acetabulum, acetabulum cup and polyethylene liner were lowest when the acetabular cup's anteversion and inlcination were 15°, 35° respectively, as well as the rotation center was restored anatomically. CONCLUSION: In total hip arthroplasty for Crowe type Ⅲ DDH, the anatomical restoration of hip rotation center with 15° anteversion and 35° inclination of the acetabular cup are suggested, bone graft above the acetabular cup and additional screws are recommended simultaneously to further reduce the Von Mises of hip joint.

Noble-Metal-Free High-Entropy Alloy Nanoparticles for Efficient Solar-Driven Photocatalytic CO2 Reduction.

Metal nanoparticle (NP) cocatalysts are widely investigated for their ability to enhance the performance of photocatalytic materials; however, their practical application is often limited by the inherent instability under light irradiation. This challenge has catalyzed interest in exploring high-entropy alloys (HEAs), which, with their increased entropy and lower Gibbs free energy, provide superior stability. In this study, 3.5 nm-sized noble-metal-free NPs composed of a FeCoNiCuMn HEA are successfully synthesized. With theoretic calculation and experiments, the electronic structure of HEA in augmenting the catalytic CO2 reduction has been uncovered, including the individual roles of each element and the collective synergistic effects. Then, their photocatalytic CO2 reduction capabilities are investigated when immobilized on TiO2. HEA NPs significantly enhance the CO2 photoreduction, achieving a 23-fold increase over pristine TiO2, with CO and CH4 production rates of 235.2 and 19.9 µmol g-1 h-1, respectively. Meanwhile, HEA NPs show excellent stability under simulated solar irradiation, as well high-energy X-ray irradiation. This research emphasizes the promising role of HEA NPs, composed of earth-abundant elements, in revolutionizing the field of photocatalysis.

Association between the neutrophil-to-lymphocyte ratio and in-hospital mortality in patients with chronic kidney disease and coronary artery disease in the intensive care unit.

BACKGROUND: The objective of this study was to investigate the correlation between neutrophil-to-lymphocyte ratios (NLR) and the risk of in-hospital death in patients admitted to the intensive care unit (ICU) with both chronic kidney disease (CKD) and coronary artery disease (CAD). METHODS: Data from the MIMIC-IV database, which includes a vast collection of more than 50,000 ICU admissions occurring between 2008 and 2019, was utilized in the study and eICU-CRD was conducted for external verification. The Boruta algorithm was employed for feature selection. Univariable and multivariable logistic regression analyses and multivariate restricted cubic spline regression were employed to scrutinize the association between NLR and in-hospital mortality. The receiver operating characteristic (ROC) curves were conducted to estimate the predictive ability of NLR. RESULTS: After carefully applying criteria to include and exclude participants, a total of 2254 patients with CKD and CAD were included in the research. The findings showed a median NLR of 7.3 (4.4, 12.1). The outcomes of multivariable logistic regression demonstrated that NLR significantly elevated the risk of in-hospital mortality (OR 2.122, 95% confidence interval [CI] 1.542-2.921, P < 0.001) after accounting for all relevant factors. Further insights from subgroup analyses unveiled that age and Sequential Organ Failure Assessment (SOFA) scores displayed an interactive effect in the correlation between NLR and in-hospital deaths. The NLR combined with traditional cardiovascular risk factors showed relatively great predictive value for in-hospital mortality (AUC 0.750). CONCLUSION: The findings of this research indicate that the NLR can be used as an indicator for predicting the likelihood of death during a patient's stay in the intensive care unit, particularly for individuals with both CAD and CKD. The results indicate that NLR may serve as a valuable tool for assessing and managing risks in this group at high risk. Further investigation is required to authenticate these findings and investigate the mechanisms that underlie the correlation between NLR and mortality in individuals with CAD and CKD.

High-Efficiency and Ultra-Stable Cesium-Bismuth-Based Lead-free Perovskite Solar Cells without Modification.

Perovskite solar cells (PSCs) have become a new photovoltaic technology with great commercial potential because of their excellent photovoltaic performance. However, the toxicity and poor environmental stability of Pb in Pb-based perovskites limit its large-scale application. Exploring alternatives to Pb is an available approach to develop environmentally friendly PSCs. As an adjacent element of Pb, Bi shows many similar physical and chemical properties; therefore, it is commonly applied for B site substitution in Pb-based PSCs. CsBiSCl2, a new Pb-free perovskite system, was synthesized for the first time as a light absorber. By preparing DMABiS2 as an intermediate, Cs-Bi-based CsBiSCl2 perovskite films with a band gap over 2.012 eV were prepared by introducing CsCl, and the optimal annealing temperature, time, and stoichiometric ratio of the film were explored in this work. The conventional structure of CsBiSCl2 PSCs achieved a power conversion efficiency (PCE) of 10.38%, and the efficiency declined by only 3% after aging in air for 150 days, showing excellent stability, which is one of the most stable devices in inorganic PSCs. This work opens up a new road for the future development of environmentally friendly and commercially stable lead-free PSCs.

Promoting or Prohibiting? Investigating How Time Pressure Influences Innovative Behavior under Stress-Mindset Conditions.

The existing empirical evidence on the relationship between time pressure and innovative behavior is paradoxical. An intriguing yet unresolved question is "When does time pressure promote or prohibit innovative behavior, and how?" We theorize that the paradoxical effect of time pressure on innovative behavior can be elucidated by the moderating role of stress mindset, and we also explore the mediating role of thriving at work. Our research involved a field study of 390 research and development personnel from eight enterprises and research institutes in China to test our proposed model. Results indicated that the stress-is-debilitating mindset negatively moderated the association between time pressure and thriving at work, while the stress-is-enhancing mindset positively moderated the link between time pressure and thriving at work. Furthermore, the findings demonstrated that the stress-is-debilitating mindset negatively moderated the indirect impact of time pressure on employees' innovative behavior through thriving at work, while the stress-is-enhancing mindset positively moderated the indirect effect of time pressure on employees' innovative behavior through thriving at work. The theoretical and practical implications of these findings are also discussed.

Lipid characteristics of lung tissue in silicosis rat model were studied based on lipid metabolomics.

Silicosis is a common occupational disease caused by the long-term inhalation of large amounts of silica dust. Lipid metabolism plays an important role in the progression of silicosis, but its contributing mechanism remains unclear. The aim of this study was to investigate the differential lipid metabolites and active metabolic pathways in silicosis rat lung tissue. We first constructed a silicosis rat model, and randomly divided 24 male SD rats into control group (C), silicosis group for 1 week (S1W), silicosis group for 2 weeks (S2W) and silicosis group for 4 weeks (S4W) with 6 rats in each group. 1 mL SiO2 suspension (50 mg/mL) or normal saline were injected into the trachea, and the rats were killed at 1 week, 2 weeks and 4 weeks, respectively. The lung tissue pathology of the rats was observed by HE staining and VG staining, and the plasma TC and FC levels were detected by the kit. Western blot was used to detect the expression of lipid-related factors CD36, PGC1α and LXR. In addition, lipidomics analysis of lung tissue samples was performed using UPLC-IMS-QTOF mass spectrometer to screen out potential differential metabolites in silicosis models and analyze lipid enrichment, and verified the expression of differential gene CHPT1 in the metabolic pathway. HE and VG staining showed that the number of nodules and fibrosis increased in a time-dependent manner in the silicosis model group, and the levels of TC, FC and CE in silicosis plasma increased. Western blot results showed that PGC1α and LXR decreased in the silicosis model group, while CD36 expression increased. In addition, metabolomics screened out 28 differential metabolites in the S1W group, 32 in the S2W group, and 22 in the S4W group, and found that the differential metabolites were mainly enriched in metabolic pathways such as glycerophospholipid metabolism and ether lipid metabolism, and the expression of differential gene CHPT1 in the metabolic pathway was decreased in the silicosis model group. These results suggest that there are significant changes in lipid metabolites in lung tissue in silicosis rat models, and glycerophospholipid metabolism was significantly enriched, suggesting that glycerophospholipids play an important role in the progression of silicosis. The differential metabolites and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.

Cytochrome P450 2B6 and UDP-Glucuronosyltransferase Enzyme-Mediated Clearance of Ciprofol (HSK3486) in Humans: The Role of Hepatic and Extrahepatic Metabolism.

Ciprofol (HSK3486) is a novel intravenous agent for general anesthesia. In humans, HSK3486 mainly undergoes glucuronidation to form M4 [fraction of clearance (fCL): 62.6%], followed by the formation of monohydroxylated metabolites that further undergo glucuronidation and sulfation to produce M5-1, M5-2, M5-3, and M3 (summed fCL: 35.2%). However, the complete metabolic pathways of HSK3486 in humans remain unclear. In this study, by comparison with chemically synthesized reference standards, three monohydroxylated metabolites [M7-1, 4-hydroxylation with an unbound intrinsic clearance (CLint,u) of 2211 µl/min/mg; M7-2, ω-hydroxylation with a CLint,u of 600 µl/min/mg; and M7-3, (ω-1)-hydroxylation with a CLint,u of 78.4 µl/min/mg] were identified in human liver microsomes, and CYP2B6 primarily catalyzed their formation. In humans, M7-1 was shown to undergo glucuronidation at the 4-position and 1-position by multiple UDP-glucuronosyltransferases (UGTs) to produce M5-1 and M5-3, respectively, or was metabolized to M3 by cytosolic sulfotransferases. M7-2 was glucuronidated at the ω position by UGT1A9, 2B4, and 2B7 to form M5-2. UGT1A9 predominantly catalyzed the glucuronidation of HSK3486 (M4). The CLint,u values for M4 formation in human liver and kidney microsomes were 1028 and 3407 µl/min/mg, respectively. In vitro to in vivo extrapolation analysis suggested that renal glucuronidation contributed approximately 31.4% of the combined clearance. In addition to HSK3486 glucuronidation (M4), 4-hydroxylation (M7-1) was identified as another crucial oxidative metabolic pathway (fCL: 34.5%). Further attention should be paid to the impact of CYP2B6- and UGT1A9-mediated drug interactions and gene polymorphisms on the exposure and efficacy of HSK3486. SIGNIFICANCE STATEMENT: This research elucidates the major oxidative metabolic pathways of HSK3486 (the formation of three monohydroxylated metabolites: M7-1, M7-2, M7-3) as well as definitive structures and formation pathways of these monohydroxylated metabolites and their glucuronides or sulfate in humans. This research also identifies major metabolizing enzymes responsible for the glucuronidation (UGT1A9) and oxidation (CYP2B6) of HSK3486 and characterizes the mechanism of extrahepatic metabolism. The above information is helpful in guiding the safe use of HSK3486 in the clinic.

Preparation of Ag@lignin nanotubes for the development of antimicrobial biodegradable films from corn straw.

Current environmental and energy issues have attracted considerable attention from industries, governments, and academia. Developing alternative diverse petrochemical-based plastics with biodegradable packaging materials from renewable resources is critical for ensuring both sustainability and safety. In this study, biodegradable films are fabricated from corn straw via a facile sol-gel process. Furthermore, these films are imbued with antimicrobial properties by coupling with silver@lignin nanotube hybrid antibacterial agents, formed via the in situ reduction of silver ions into elemental silver by lignin (mild reducing agent), followed by the self-assembly of lignin molecules into nanotubes assisted by an aqueous silver nitrate electrolyte solution. The developed antibacterial corn straw film exhibits strong mechanical and antibacterial properties, with a tensile strength and elongation at break of 68.7 MPa and 11.3 %, respectively, under optimum conditions and antibacterial activity against Escherichia coli and Staphylococcus aureus of 99.9 % and 97.2 %, respectively. The as-prepared corn straw films exhibit high hydrophobicity and ultraviolet resistance. The morphology, structure, and thermal properties of the corn straw films were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive spectroscopy, X-ray diffraction, and thermogravimetric analysis. This study provides a straw-based biodegradable packaging film with antimicrobial properties.

Reprogramming of 3D chromatin domains by antagonizing the ß-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer.

The therapeutic potential of targeting the ß-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a ß-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this ß-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the ß-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the ß-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.

Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations.

An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We found the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.

Application fruit tree hole storage brick fertilizer is beneficial to increase the nitrogen utilization of grape under subsurface drip irrigation.

It is very important to promote plant growth and decrease the nitrogen leaching in soil, to improve nitrogen (N) utilization efficiency. In this experiment, we designed a new fertilization strategy, fruit tree hole storage brick (FTHSB) application under subsurface drip irrigation, to characterise the effects of FTHSB addition on N absorption and utilization in grapes. Three treatments were set in this study, including subsurface drip irrigation (CK) control, fruit tree hole storage brick A (T1) treatment, and fruit tree hole storage brick B (T2) treatment. Results showed that the pore number and size of FTHSB A were significantly higher than FTHSB B. Compared with CK, T1 and T2 treatments significantly increased the biomass of different organs of grape, N utilization and 15N content in the roots, stems and leaves, along with more prominent promotion at T1 treatment. When the soil depth was 15-30 cm, the FTHSB application significantly increased the soil 15N content. But when the soil depth was 30-45 cm, it reduced the soil 15N content greatly. T1 and T2 treatments obviously increased the activities of nitrite reductase (NR) and glutamine synthetase (GS) in grape leaves, also the urease activity(UR) in 30 cm of soil. Our findings suggest that FTHSB promoted plant N utilization by reducing N loss in soil and increasing the enzyme activity related to nitrogen metabolism. In addition, this study showed that FTHSB A application was more effective than FTHSB B in improving nitrogen utilization in grapes.

LC-MS-based untargeted metabolomics reveals the mechanism underlying prostate damage in a type 2 diabetes mouse model.

Type 2 diabetes mellitus (T2DM) can cause prostate damage and affect male reproductive function, but the underlying mechanisms are not completely understood. In this study, we used liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics to identify endogenous metabolites in the prostate of a T2DM mouse model. The selected endogenous metabolites were then subjected to bioinformatics analysis and metabolic pathway studies to understand their role in the development of T2DM-induced prostate damage. We used male homozygous BTBR ob/ob mice (n = 12) and BTBR WT mice (n = 11) in this study. We monitored changes in blood glucose, body weight, prostate weight, and prostate index, as well as performed hematoxylin and eosin (H&E) staining and observed that the prostate of the BTBR ob/ob was damaged. We then used ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) for metabolomics analysis. The stability of the model was validated using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). Using variable importance in projection (VIP) > 1, false discovery rate (FDR) < 0.05, and coefficient of variation (CV) < 30 as criteria, a total of 149 differential metabolites (62 upregulated and 87 downregulated) were identified between the prostates of the two groups of mice. Topological pathway analysis showed that these differential metabolites were mainly involved in sphingolipid (SP) and glycerophospholipid (GP) metabolism. In conclusion, our study not only emphasizes the damage caused by T2DM to the prostate but also provides new insights into the potential mechanisms of T2DM-induced male reproductive dysfunction.

Probucol attenuates high glucose-induced Müller cell damage through enhancing the Nrf2/p62 signaling pathway.

PURPOSE: This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action. METHODS: Primary human retinal Müller cells were incubated with high glucose (HG, 35 mM) in the present or absence of different concentrations of probucol for 24 h. Cell viability was determined using the CCK-8 method. Mitochondrial membrane potential (MMP) was measured using JC-1 staining and cell cycle by flow cytometry. The expression of nuclear factor E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit, and p62 was quantified using quantitative polymerase chain reaction and western blot. RESULTS: We found that HG inhibited cell proliferation, arrested cell cycle, and increased MMP in human Müller cells. Probucol activated the Nrf2/p62 pathway and upregulated the anti-apoptotic protein, Bcl2, and attenuated HG-mediated damage in Müller cells. CONCLUSIONS: Our results suggest that probucol may protect Müller cells from HG-induced damage through enhancing the Nrf2/p62 signaling pathway.

The immune imbalance between follicular regulatory and helper T cells in myelin oligodendrocyte glycoprotein IgG-associated disease.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a newly defined inflammatory demyelinating disease of the central nervous system. Currently, no immuno-modulatory treatment has been approved for MOGAD. We explored the function of follicular regularoty T (Tfr) and follicular helper T (Tfh) cells in patients with MOGAD. The number of circulating Tfr and Tfh cells and their expression of functional markers were accessed by flow cytometry. Circulating Tfr, Tfh, and B cells were further sorted and co-cultured in vitro to examine the influence of Tfr on Tfh-mediated B cell differentiation. In patients with MOGAD, the percentage of circulating PD-1hi Tfh cells elevated while the frequency of circulating activated Tfr cells decreased significantly. The Tfh/Tfr ratios positively correlated with the percentage of plasmblasts. In vitro, Tfh cells from patients with MOGAD exhibited a stronger capacity to promote the differentiation of plasmablasts through producing interleukin (IL)-21 than non-Tfh cells from patients, whereas Tfr cells suppressed this Tfh-mediated plasmablasts expansion, to a similar extent of IL-1 receptor antagonist (IL-1Ra). In conclusion, we revealed an immune imbalance of Tfr and Tfh cells in MOGAD. Tfr and IL-1Ra could be potential therapeutic targets in MOGAD.

Increased intraocular inflammation in retinal vein occlusion is independent of circulating immune mediators and is involved in retinal oedema.

We aim to understand the link between systemic and intraocular levels of inflammatory mediators in treatment-naïve retinal vein occlusion (RVO) patients, and the relationship between inflammatory mediators and retinal pathologies. Twenty inflammatory mediators were measured in this study, including IL-17E, Flt-3 L, IL-3, IL-8, IL-33, MIP-3ß, MIP-1α, GRO ß, PD-L1, CD40L, IFN-ß, G-CSF, Granzyme B, TRAIL, EGF, PDGF-AA, PDGF-AB/BB, TGF-α, VEGF, and FGFß. RVO patients had significantly higher levels of Flt-3 L, IL-8, MIP-3ß, GROß, and VEGF, but lower levels of EGF in the aqueous humor than cataract controls. The levels of Flt-3 L, IL-3, IL-33, MIP-1α, PD-L1, CD40 L, G-CSF, TRAIL, PDGF-AB/BB, TGF-α, and VEGF were significantly higher in CRVO than in BRVO. KEGG pathway enrichment revealed that these mediators affected the PI3K-Akt, Ras, MAPK, and Jak/STAT signaling pathways. Protein-Protein Interaction (PPI) analysis showed that VEGF is the upstream cytokine that influences IL-8, G-CSF, and IL-33 in RVO. In the plasma, the level of GROß was lower in RVO than in controls and no alterations were observed in other mediators. Retinal thickness [including central retinal thickness (CRT) and inner limiting membrane to inner plexiform layer (ILM-IPL)] positively correlated with the intraocular levels of Flt-3 L, IL-33, GROß, PD-L1, G-CSF, and TGF-α. The size of the foveal avascular zone positively correlated with systemic factors, including the plasma levels of IL-17E, IL-33, INF-ß, GROß, Granzyme B, and FGFß and circulating high/low-density lipids and total cholesterols. Our results suggest that intraocular inflammation in RVO is driven primarily by local factors but not circulating immune mediators. Intraocular inflammation may promote macular oedema through the PI3K-Akt, Ras, MAPK, and Jak/STAT signaling pathways in RVO. Systemic factors, including cytokines and lipid levels may be involved in retinal microvascular remodeling.

MEMS Resonant Cantilevers for High-Performance Thermogravimetric Analysis of Chemical Decomposition.

We investigate the MEMS resonant cantilevers for high-performance thermogravimetric analysis (TGA) of chemical decomposition, featuring high accuracy and minimized thermal lag. Each resonant cantilever is integrated with a microheater for sample heating near the free end, which is thermally isolated from the resonance excitation and readout elements at the fixed end. Combining finite element modeling and experiments, we demonstrate that the sample loading region can stabilize within ~11.2 milliseconds in response to a step heating of 500 °C, suggesting a very fast thermal response of the MEMS resonant cantilevers of more than 104 °C/s. Benefiting from such a fast thermal response, we perform high-performance TG measurements on basic copper carbonate (Cu2(OH)2CO3) and calcium oxalate monohydrate (CaC2O4·H2O). The measured weight losses better agree with the theoretical values with 5-10 times smaller thermal lags at the same heating rate, compared with those measured by using conventional TGA. The MEMS resonant cantilevers hold promise for highly accurate and efficient TG characterization of materials in various fields.

DNA Deamination Is Required for Human APOBEC3A-Driven Hepatocellular Carcinoma In Vivo.

Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3's signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as utilized in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA-editing activity is defective in promoting tumor formation. Collectively, these results demonstrate that APOBEC3A is a "master driver" that fuels tumor formation through a DNA deamination-dependent mechanism.

An integrated bioinformatic investigation of focal adhesion-related genes in glioma followed by preliminary validation of COL1A2 in tumorigenesis.

Focal adhesions (FAs) allow cells to contact the extracellular matrix, helping to maintain tension and enabling signal transmission in cell migration, differentiation, and apoptosis. In addition, FAs are associated with changes in the tumor microenvironment (TME) that lead to malignant progression and drug resistance in tumors. However, there are still few studies on the comprehensive analysis of focal adhesion-related genes (FARGs) in glioma. Expression data and clinical information of glioma samples were downloaded from public databases. Two distinct molecular subtypes were identified based on FARGs using an unsupervised consensus clustering algorithm. A scoring system consisting of nine FARGs was constructed using integrated LASSO regression and multivariate Cox regression. It not only has outstanding prognostic value but also can guide immunotherapy of glioma patients, which was verified in TCGA, CGGA, GSE16011, and IMvigor210 cohorts. The results of bioinformatics analysis, immunohistochemistry staining, and western blotting all revealed that the expression of COL1A2 was up-regulated in glioblastoma and related to poor prognosis outcomes in patients from public datasets. COL1A2 promotes the proliferation, migration, and invasion of glioblastoma cells. A positive correlation between COL1A2 and CD8 was determined in GBM specimens from eight patients. Moreover, the results of cell co-cultured assay showed that COL1A2 participated in the killing of GBM cells by Jurkat cells. Our study indicates that the FARGs have prominent application value in the identification of molecular subtypes and prediction of survival outcomes in glioma patients. Bioinformatics analysis and experimental verification provide a direction for further research on FARGs.