Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Functionalized PLGA Microsphere Loaded with Fusion Peptide for Therapy of Bone Defects.

The challenges in the treatment of extensive bone defects are infection control and bone regeneration. Bone tissue engineering is currently one of the most promising strategies. In this study, a short biopeptide with specific osteogenic ability is designed by fusion peptide technology and encapsulated with chitosan-modified poly(lactic acid-glycolic acid) (PLGA) microspheres. The fusion peptide (FP) mainly consists of an osteogenic functional sequence (P-15) and a bone-specific binding sequence (Asp-6), which can regulate bone formation accurately and efficiently. Chitosan-modified PLGA with antimicrobial and pro-healing effects is used to achieve the sustained release of fusion peptides. In the early stage, the antimicrobial and soft tissue healing effects can stop the wound infection as soon as possible, which is relevant for the subsequent bone regeneration process. Our data show that CS-PLGA@FP microspheres have antibacterial and pro-cell migration effects in vitro and excellent pro-wound-healing effects in vivo. In addition, CS-PLGA@FP microspheres promote the expression of osteogenic-related factors and show excellent bone regeneration in a rat defect model. Therefore, CS-PLGA@FP microspheres are an efficient biomaterial that can accelerate the recovery of bone defects.

gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity.

Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one ß-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 ß-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many ß-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.

FBXO22 promotes glioblastoma malignant progression by mediating VHL ubiquitination and degradation.

Glioblastoma (GBM) is the most common malignant primary brain tumor. Despite comprehensive treatment with traditional surgery, radiotherapy, and chemotherapy, the median survival rate is <14.6% and the 5-year survival rate is only 5%. FBXO22, a substrate receptor of the SCF ubiquitin ligases, has been reported to play a promoting role in melanoma, liver cancer, cervical cancer, and other cancers. However, the function of FBXO22 in GBM has not been reported. In the present study, we demonstrate that FBXO22 is highly expressed in glioma and is positively correlated with worse pathological features and shorter survival of GBM patients. We revealed that FBXO22 promotes GBM cell proliferation, angiogenesis, migration, and tumorigenesis in vitro and in vivo. In terms of mechanism, we reveal that FBXO22 decreases VHL expression by directly mediating VHL ubiquitination degradation, which ultimately increases HIF-1α and VEGFA expression. In addition, our data confirm that there are positive correlations among FBXO22, HIF-1α, and VEGFA expression, and there is a negative correlation between FBXO22 and VHL protein expression in glioma patients. Our study strongly indicates that FBXO22 is a promising diagnostic marker and therapeutic target for glioma patients.

SDCBP modulates tumor microenvironment, tumor progression and anti-PD1 efficacy in colorectal cancer.

Anti-programmed cell death 1 (aPD1) therapy has yielded limited success in patients with colorectal cancer (CRC). Syndecan binding protein (SDCBP), encodes a PDZ domain-containing protein that is essential for cellular processes, including cell adhesion, migration, and signal transduction. Here, we investigated the effect of SDCBP on tumor progression, immunotherapy, and the tumor microenvironment (TME) in CRC. High expression of SDCBP is associated with non-response to immunotherapy and correlated with poorer disease-free survival (DFS) in CRC patients. Inhibiting SDCBP by transfecting shRNA or using its inhibitor zinc pyrithione (ZnPT) hindered proliferation and metastasis while enhancing the efficacy of aPD1 treatment in a mouse xenograft model and liver metastasis model. The TME of CRC was significantly altered following ZnPT treatment characterized by a reduced amount of M2 macrophages and a heightened percentage of M1 macrophages. The co-culture system of CRC cells and macrophages provided evidence that SDCBP silencing promoted the repolarisation of M2 macrophages into M1. SDCBP promotes the proliferation, metastasis, and immunotherapy resistance of CRC. Thus, ZnPT represents an effective SDCBP inhibitor and exhibits considerable potential for combination with aPD1 to enhance immunotherapy efficacy.

The CT-guided percutaneous drainage of pancreatic pseudocyst accompanied by pseudoaneurysm: A case report.

RATIONALE: This case report discusses the CT-guided percutaneous drainage of a pancreatic pseudocyst accompanied by a pseudoaneurysm. Pancreatic pseudocysts can erode the peripancreatic artery and produce pseudoaneurysms. This is rare, but it can be life-threatening. PATIENT CONCERNS: The case presented involves a 58-year-old female who was diagnosed with pancreatic cancer and underwent surgical treatment. She presented with hematochezia, dizziness, and hypodynamic findings with no obvious cause. Imaging revealed a pancreatic pseudocyst and small arterial aneurysms. To reduce the risk of aneurysm rupture, the patient underwent transcatheter arterial coil embolization. Three days later, CT-guided catheter drainage was performed to reduce the erosion of the arterial wall caused by pancreatic fluid. DIAGNOSES: The contrast-enhanced-CT imaging showed a round, slightly high-density lesion in the cyst, suggesting the presence of a pseudoaneurysm. INTERVENTIONS: The patient was sent for another transcatheter arterial embolization with coils and n-butyl-2-cyanoacrylate. OUTCOMES: After receiving the transcatheter arterial embolization, the patient had no serious bleeding or other complications. LESSONS: Early detection and accurate assessment of pseudoaneurysms are essential for appropriate management. This case shows that contrast-enhanced CT is necessary before CT-guided percutaneous drainage of pancreatic pseudocysts. It also shows that, due to the many complications that pancreatic pseudocysts may cause, appropriate treatment of pseudocysts complicated with pseudoaneurysm has important clinical significance.

Melanoma extracellular vesicles inhibit tumor growth and metastasis by stimulating CD8 T cells.

Tumor cell-derived extracellular vesicles (EVs) play a crucial role in mediating immune responses by carrying and presenting tumor antigens. Here, we suggested that melanoma EVs triggered cytotoxic CD8 T cell-mediated inhibition of tumor growth and metastasis. Our results indicated that immunization of mice with melanoma EVs inhibited melanoma growth and metastasis while increasing CD8 T cells and serum interferon γ (IFN-γ) in vivo. In vitro experiments showed that melanoma EV stimulates dendritic cells (DCs) maturation, and mature dendritic cells induce T lymphocyte activation. Thus, tumor cell-derived EVs can generate anti-tumor immunity in a prophylactic setting and may be potential candidates for cell-free tumor vaccines.

Bioaerosols in deodorization covers of wastewater treatment plants: Emission characteristics and health risks.

Wastewater treatment plants (WWTPs) are the main source of bioaerosol emissions. The cover of deodorization within WWTPs serves not only to manage odors but also to limit the dispersion of bioaerosols. This study investigated the emission characteristics and exposure risks of bioaerosols inside deodorization covers from a WWTP in Northern China. The results revealed that the concentration of bacteria in bioaerosols ranged from 96 ± 8 to 706 ± 45 CFU/m3, with the highest concentration observed in the biochemical reaction tank. The predominant bacterial genera in bioaerosols within the odor control covers were Cetobacterium, Romboutsia, Bacteroides, Lactobacillus, and Tubricibacter, while the dominant fungal genera included Aspergillus, Alternaria, Fusarium, and Cladosporium. The main water-soluble ions in the air were NH4+, Ca2+, SO42-, and Cl-. SO42- was found to promote the survival of Cetobacterium, Brevibacterium, Fusarium, Penicillium, and Filobasidium, while Cl- exhibited inhibitory effects on most microorganisms in bioaerosols. Source tracker analysis indicated that wastewater was the primary source of bioaerosols in the biochemical reaction tank. The non-carcinogenic risk associated with bioaerosols within deodorization covers was less than 1 (2.34 × 10-9 to 3.08 × 10-2). FunGuild fungal functional prediction suggested that the abundance of animal pathogens was highest in the bioaerosols from the anaerobic sedimentation tank. BugBase phenotypic prediction showed that the abundance of potential pathogens in secondary sedimentation tank bioaerosols was the highest. This study effectively revealed the characteristics and sources of bioaerosols in the sewage and sludge treatment area under the deodorization cover, which provided a theoretical basis for enhancing the management and control of bioaerosols.

Recent progress in critical electrode and electrolyte materials for flexible zinc-ion batteries.

With the increasing popularity of flexible and wearable electronic devices, the demand for power supplies that can be easily bent or worn is also rapidly growing. However, traditional lithium ion batteries are difficult to adapt to complex wearable devices because of their unsatisfactory flexibility and thickness as well as safety issues. Zinc-ion batteries have several advantages, including low redox potential, high theoretical capacity, high safety, and abundant reserves. These features make flexible zinc-ion batteries (FZIBs) an ideal wearable energy storage device candidate. The electrochemical performance and mechanical deformability of FZIBs were pivotally determined based on the properties of their electrode and electrolyte. Herein, we summarize some recent advances from 2015 to 2023 in the design and preparation of various electrode and electrolyte materials for FZIBs with controllable morphology and structure, excellent mechanical property, and enhanced electrochemical performance. Moreover, efforts to explore the potential practical applications of FZIBs have also been considered. Finally, we present and discuss current challenges and opportunities for the development of high-performance FZIBs.

circEPB41L2 blocks the progression and metastasis in non-small cell lung cancer by promoting TRIP12-triggered PTBP1 ubiquitylation.

The metastasis of non-small cell lung cancer (NSCLC) is the leading death cause of NSCLC patients, which requires new biomarkers for precise diagnosis and treatment. Circular RNAs (circRNAs), the novel noncoding RNA, participate in the progression of various cancers as microRNA or protein sponges. We revealed the mechanism by which circEPB41L2 (hsa_circ_0077837) blocks the aerobic glycolysis, progression and metastasis of NSCLC through modulating protein metabolism of PTBP1 by the E3 ubiquitin ligase TRIP12. With ribosomal RNA-depleted RNA seq, 57 upregulated and 327 downregulated circRNAs were identified in LUAD tissues. circEPB41L2 was selected due to its dramatically reduced levels in NSCLC tissues and NSCLC cells. Interestingly, circEPB41L2 blocked glucose uptake, lactate production, NSCLC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, acting as a scaffold, circEPB41L2 bound to the RRM1 domain of the PTBP1 and the E3 ubiquitin ligase TRIP12 to promote TRIP12-mediated PTBP1 polyubiquitylation and degradation, which could be reversed by the HECT domain mutation of TRIP12 and circEPB41L2 depletion. As a result, circEPB41L2-induced PTBP1 inhibition led to PTBP1-induced PKM2 and Vimentin activation but PKM1 and E-cadherin inactivation. These findings highlight the circEPB41L2-dependent mechanism that modulates the "Warburg Effect" and EMT to inhibit NSCLC development and metastasis, offering an inhibitory target for NSCLC treatment.

PRMT1-mediated PGK1 arginine methylation promotes colorectal cancer glycolysis and tumorigenesis.

Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle, which is called the Warburg effect. However, the detailed mechanisms of abnormal activation of the glycolysis pathway in colorectal cancer are largely unknown. In this study, we reveal that the protein arginine methyltransferase 1 (PRMT1) promotes glycolysis, proliferation, and tumorigenesis in CRC cells. Mechanistically, PRMT1-mediated arginine asymmetric dimethylation modification of phosphoglycerate kinase 1 (PGK1, the first ATP-producing enzyme in glycolysis) at R206 (meR206-PGK1) enhances the phosphorylation level of PGK1 at S203 (pS203-PGK1), which inhibits mitochondrial function and promotes glycolysis. We found that PRMT1 and meR206-PGK1 expression were positively correlated with pS203-PGK1 expression in tissues from colorectal cancer patients. Furthermore, we also confirmed that meR206-PGK1 expression is positively correlated with the poor survival of patients with colorectal cancer. Our findings show that PRMT1 and meR206-PGK1 may become promising predictive biomarkers for the prognosis of patients with CRC and that arginine methyltransferase inhibitors have great potential in colorectal cancer treatment.

Polypyrimidine tract-binding protein 3/insulin-like growth factor 2 mRNA-binding proteins 3/high-mobility group A1 axis promotes renal cancer growth and metastasis.

Polypyrimidine tract-binding protein 3 (PTBP3) plays an important role in the post-transcriptional regulation of gene expression, including mRNA splicing, translation, and stability. Increasing evidence has shown that PTBP3 promotes cancer progression in several tumor types. However, the molecular mechanisms of PTBP3 in renal cell carcinoma (RCC) remain unknown. Here, tissue microarrays (TMAs) suggested that PTBP3 expression was increased in human RCC and that high PTBP3 expression was correlated with poor five-year overall survival and disease-free survival. We also showed that PTBP3 binds with HMGA1 mRNA in the 3'UTR region and let-7 miRNAs. PTBP3 interacted with IGF2BP3, and the PTBP3/IGF2BP3 axis prevented let-7 mediated HMGA1 mRNA silencing. PTBP3 promotes renal cancer cell growth and metastasis in vitro and in vivo. Taken together, our findings indicate PTBP3 serves as a regulator of HMGA1 and suggest its potential as a therapeutic agent for RCC.

The crucial role of transient tri-coordinated oxygen in the flow of silicate melts.

The transport properties of high-temperature silicate melts control magma flow and are crucial for a wide variety of industrial processes involving minerals. However, anomalous melt properties have been observed that cannot be explained by the traditional polymerization degree theory, which was derived based on quenched melts. Ab initio molecular dynamics (AIMD) simulations were conducted to investigate the flow mechanism of CaO-Al2O3-SiO2 melts under high temperature atmospheric conditions. By analyzing the dynamic structure of melted silicates and employing molecular orbital theory, we gained a fundamental understanding of the flow mechanism from a chemistry perspective. Transient tri-coordinated oxygen (TO) bonded with one Si and two Al atoms (SiOAl2) was found to be a pivotal intermediate in melt flow and atomic diffusion processes. Frequent chemical transition between TO in SiOAl2 and bridging oxygen (BO) dominated the fluidity of melted silicates. The presence of such transitions is facilitated by the unstable nature of [SiAlO2] 4-membered rings, which are susceptible to instability due to the intense repulsion between the O 2p lone pairs and the excessively bent O-Al-O angle. Additionally, the density of SiOAl2 type TO motif could serve as an indicator to determine the relationship between structure and fluidity. Our results challenge the traditional polymerization degree theory and suggest the need to reassess high-temperature liquid properties that govern processes in the Earth and industry by monitoring transient motifs.

Misdiagnosis of ß-Thalassemia Major Due to Chinese Gγ+(Aγδß)0-Thalassemia Combined with ß0-Thalassemia.

δß-thalassemia is a rare type of thalassemia characterized by increased Hb F levels, including mainly Chinese Gγ(Aγδß)0-thalassemia, Yunnanese Gγ(Aγδß)0-thalassemia, Cantonese Gγ(Aγδß)0-thalassemia in China. Due to the low rate of δß-thalassemia carriers, there are few reports of δß-thalassemia combined with ß-thalassemia causing ß-thalassemia major. Herein, we described the combination of Chinese Gγ(Aγδß)0-thalassemia and ß-thalassemia leading to ß-thalassemia major in a Chinese patient. Hemoglobin analysis was performed by capillary electrophoresis (CE). Routine genetic analysis was carried out by gap-polymerase chain reaction (Gap-PCR) and PCR and reverse dot blot (PCR-RDB). Multiple ligation-dependent probe amplification (MLPA) was used to detect the large deletion, and Gap-PCR confirmed the deletion. A CE result showed an elevated Hb F level of 98.7% and 11.7% in the proband and her mother, but the proband was diagnosed with ßCD17M/ßCD17M using routine genetic analysis. However, her father was heterozygous for CD17 in ß-globin, and her mother was detected as SEA heterozygous. The further analysis presented that the proband had actually missed the diagnosis of Chinese Gγ(Aγδß)0-thalassemia by MLPA and PCR-RDB. Finally, the genotype of the proband was corrected from ßCD17M/ßCD17M to ßCD17M/ßGγ(Aγδß)0. This is the first report of Chinese Gγ(Aγδß)0-thalassemia combined with ß-thalassemia resulting in ß-thalassemia major in China. Screening for δß-thalassemia by Hb analysis could be an effective method.

Outcomes of Upgrading to LBBP in CRT Nonresponders: A Prospective, Multicenter, Nonrandomized, Case-Control Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) nonresponders account for nearly 30% of CRT candidates. Left-bundle branch pacing (LBBP) is an alternative to CRT. OBJECTIVES: This study aimed to evaluate the feasibility, clinical efficacy, and outcomes of upgrading to LBBP in CRT nonresponders, using propensity-score matching (PSM) analysis. METHODS: CRT nonresponders were defined as those with an implantable CRT-pacemaker or CRT-defibrillator for more than 12 months who remained nonresponsive (a decrease in left ventricular end-systolic volume of <15% or a left ventricular ejection fraction [LVEF] absolute increase of <5%) after optimal medical therapy and device optimization compared with baseline. In total, 145 CRT nonresponders were prospectively enrolled and randomly divided into 2 groups: upgraded to LBBP (n = 48), and continuing biventricular pacing (BVP) (control; n = 97). PSM was performed at a 1:1 ratio, and clinical evaluation and echocardiographic assessments were compared at baseline and follow-up in paired cohorts. The primary composite endpoint for clinical outcomes (heart failure-related rehospitalization events, all-cause death, or heart transplantation) was analyzed. RESULTS: Successful upgrading to LBBP was achieved in 48/49 patients (97.96%), with a significant decrease in QRS duration (P < 0.001). In the paired LBBP group, LVEF significantly increased (baseline: 29.75% ± 7.79%; 6 months: 37.78% ± 9.25% [P < 0.001]; 12 months: 38.84% ± 12.13% [P < 0.001]) with 21/44 patients (47.73%) classified as echocardiographically responsive, whereas in the BVP control group, no significant improvement was observed (29.55% ± 6.74% vs 29.22% ± 8.10%; P = 0.840). In a multivariate logistic regression model, LV end-diastolic volume and baseline LBBB QRS morphology were independent predictors of echocardiographic response after upgrading to LBBP. At a median 24 months, the primary composite endpoint was significantly lower in the LBBP group (HR: 0.31; 95% CI: 0.14-0.72; log-rank P = 0.007). CONCLUSIONS: Upgrading to LBBP is feasible and effective in achieving significant heart function improvement and better clinical outcomes in CRT nonresponders, making it a reasonable and promising pacing strategy. (LBBP in CRT Non-Response patients; ChiCTR1900028131).

Steroidal saponins from the roots of Paris verticillata and their anti-proliferative and anti-inflammatory activities.

Thirteen previously undescribed steroidal saponins, named parisverticilloside A-M (1-13) and twenty known steroidal saponins (14-33) were isolated from ethanol extract of the roots of Paris verticillata. Their structures were identified by a series of spectroscopic methods, including 1D and 2D NMR, HR-ESI-MS, optical rotatory dispersion and chemical processes. The anti-proliferative activities of all compounds against LN229, HepG2, MDA-MB-231 and 4T1 cell lines were evaluated using the CCK8 assay with cisplatin or capecitabine as the positive control. The anti-inflammatory activities of all compounds were measured by inhibition of LPS-induced NO release from BV2 cell lines, with dexamethasone as the positive control.

Surface Modification Driven Initial Coulombic Efficiency and Rate Performance Enhancement of Li1.2 Mn0.54 Ni0.13 Co0.13 O2 Cathode.

Due to its high energy density and low cost, Li-rich Mn-based layered oxides are considered potential cathode materials for next generation Li-ion batteries. However, they still suffer from the serious obstacle of low initial Coulombic efficiency, which is detrimental to their practical application. Here, an efficient surface modification method via NH4 H2 PO4 assisted pyrolysis is performed to improve the Coulombic efficiency of Li1.2 Mn0.54 Ni0.13 Co0.13 O2 , where appropriate oxygen vacancies, Li3 PO4 and spinel phase are synchronously generated in the surface layer of LMR microspheres. Under the synergistic effect of the oxygen vacancies and spinel phase, the unavoidable oxygen release in the cycling process was effectively suppressed. Moreover, the induced Li3 PO4 nanolayer could boost the lithium-ion diffusion and mitigate the dissolution of transition metal ions, especially manganese ions, in the material. The optimally modified sample yielded an impressive initial Coulombic efficiency and outstanding rate performance.

Isoquercitrin attenuates the osteoclast-mediated bone loss in rheumatoid arthritis via the Nrf2/ROS/NF-κB pathway.

An excess of osteoclastogenesis significantly contributes to the development of rheumatoid arthritis (RA). Activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) ligand (RANKL)-induced reactive oxygen species (ROS)-to-NF-κB signaling cascade are important mechanisms regulating osteoclastogenesis; however, whether Nrf2 is involved in RANKL-induced NF-κB activation is controversial. Isoquercitrin, a natural flavonoid compound, has been shown to have Nrf2-dependent antioxidant effects inprevious studies. We sought to verify whether isoquercitrin could modulate RANKL-induced NF-κB activation by activating Nrf2, thereby affecting osteoclastogenesis. Tartrate-resistant acid phosphatase staining, F-actin ring staining and resorption pit assay suggested that isoquercitrin significantly inhibited osteoclastogenesis and osteolytic function. Mitosox staining showed that RANKL-induced ROS generation was significantly inhibited by isoquercitrin from day 3 of the osteoclast differentiation cycle. Quantitative real-time PCR, Western blot, and immunofluorescence indicated that isoquercitrin activated the Nrf2 signaling pathway and inhibited NF-κB expression. And when we used the Nrf2-specific inhibitor ML385, the inhibition of NF-κB by isoquercitrin disappeared. Moreover, we found that Nrf2 is not uninvolved in RANKL-induced NF-κB activation and may be related to the timing of ROS regulation. When we limited isoquercitrin administration to 2 days, Nrf2 remained activated and the inhibition of NF-κB disappeared. In vivo experiments suggested that isoquercitrin attenuated RA modeling-induced bone loss. Overall, isoquercitrin-activated Nrf2 blocked the RANKL-induced ROS-to-NF-κB signaling cascade response, thereby inhibiting osteoclastogenesis and bone loss. These findings provide new ideas for the treatment of RA.

Neoantigen-targeted TCR-engineered T cell immunotherapy: current advances and challenges.

Adoptive cell therapy using T cell receptor-engineered T cells (TCR-T) is a promising approach for cancer therapy with an expectation of no significant side effects. In the human body, mature T cells are armed with an incredible diversity of T cell receptors (TCRs) that theoretically react to the variety of random mutations generated by tumor cells. The outcomes, however, of current clinical trials using TCR-T cell therapies are not very successful especially involving solid tumors. The therapy still faces numerous challenges in the efficient screening of tumor-specific antigens and their cognate TCRs. In this review, we first introduce TCR structure-based antigen recognition and signaling, then describe recent advances in neoantigens and their specific TCR screening technologies, and finally summarize ongoing clinical trials of TCR-T therapies against neoantigens. More importantly, we also present the current challenges of TCR-T cell-based immunotherapies, e.g., the safety of viral vectors, the mismatch of T cell receptor, the impediment of suppressive tumor microenvironment. Finally, we highlight new insights and directions for personalized TCR-T therapy.

Regulation of Sulfur Atoms in MoSx by Magneto-Electrodeposition for Hydrogen Evolution Reaction.

Compared with crystalline molybdenum sulfide (MoS2 ) employed as an efficient hydrogen evolution reaction (HER) catalyst, amorphous MoSx exhibits better activity. To synthesize amorphous MoSx , electrodeposition serving as a convenient and time-saving method is successfully applied. However, the loading mass is hindered by limited mass transfer efficiency and the available active sites require further improvement. Herein, magneto-electrodeposition is developed to synthesize MoSx with magnetic fields up to 9 T to investigate the effects of a magnetic field in the electrodeposition processing, as well as the induced electrochemical performance. Owing to the magneto-hydrodynamic effect, the loading mass of MoSx is obviously increased, and the terminal S2- serving as the active site is enhanced. The optimized MoSx catalyst delivers outstanding HER performance, achieving an overpotential of 50 mV at a current density of 10 mA cm-2 and the corresponding Tafel slope of 59 mV dec-1 . The introduction of a magnetic field during the electrodeposition process will provide a novel route to prepare amorphous MoSx with improved electrochemical performance.