GFPT2: A novel biomarker in mesothelioma for diagnosis and prognosis and its molecular mechanism in malignant progression.

BACKGROUND: Mesothelioma (MESO) is an insidious malignancy with a complex diagnosis and a poor prognosis. Our study unveils Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) as a valuable diagnostic and prognostic marker for MESO, exploring its role in MESO pathogenesis. METHODS: We utilised tissue samples and clinicopathologic data to evaluate the diagnostic and prognostic significance of GFPT2 as a biomarker for MESO. The role of GFPT2 in the malignant progression of MESO was investigated through in vitro and in vivo experiments. The activation of NF-κB-p65 through O-GlcNAcylation at Ser75 was elucidated using experiments like HPLC-QTRAP-MS/MS and mass spectrometry analysis. RESULTS: The study demonstrates that GFPT2 exhibits a sensitivity of 92.60% in diagnosing MESO. Overexpression of it has been linked to an unfavourable prognosis. Through rigorous verification, we have confirmed that elevated GFPT2 levels drive malignant proliferation, invasiveness, and metastasis in MESO. At the molecular level, GFPT2 augments p65 O-GlcNAcylation, orchestrating its nuclear translocation and activating the NF-κB signalling pathway. CONCLUSIONS: Our insights suggest GFPT2's potential as a distinctive biomarker for MESO diagnosis and prognosis, and as an innovative therapeutic target, offering a new horizon for identification and treatment strategies in MESO management.

Acupuncture Therapy on Dysphagia in Patients with Parkinson's Disease: A Randomized Controlled Study.

OBJECTIVE: To explore the effect of acupuncture therapy on dysphagia in patients with Parkinson's disease. METHODS: This randomized controlled study lasted 42 days and included 112 patients with Parkinson's disease and dysphagia. Participants were randomly assigned to the experimental and control groups (56 cases each group) using the completely randomized design, all under routine treatment. The experimental group was given acupuncture therapy. The primary outcome was Penetration-Aspiration Scale (PAS). The secondary outcomes were (1) Standardized Swallowing Assessment (SSA), and (2) nutritional status including body mass index (BMI), serum albumin, prealbumin, and hemoglobin. Adverse events were recorded as safety indicators. RESULTS: One participant quitted the study midway. There were no significant differences in baseline assessment (P>0.05). After treatment, both groups showed significant improvement in PAS, SSA and nutritional status except for BMI of the control group. There were significant differences between the two groups in the PAS for both paste and liquid, SSA (25.18±8.25 vs. 20.84±6.92), BMI (19.97±3.34 kg/m2vs. 21.26 ±2.38 kg/m2), serum albumin (35.16 ±5.29 g/L vs. 37.24 ±3.98 g/L), prealbumin (248.33 ±27.72 mg/L vs. 261.39 ±22.10 mg/L), hemoglobin (119.09±12.53 g/L vs. 126.67±13.97 g/L) (P<0.05). There were no severe adverse events during the study. CONCLUSION: The combination of routine treatment and acupuncture therapy can better improve dysphagia and nutritional status in patients with Parkinson's disease, than routine treatment solely. (registration No. CLINICALTRIAL: gov NCT06199323).

RNA editing in response to COVID-19 vaccines: unveiling dynamic epigenetic regulation of host immunity.

Background: COVID-19 vaccines are crucial for reducing the threat and burden of the pandemic on global public health, yet the epigenetic, especially RNA editing in response to the vaccines remains unelucidated. Results: Our current study performed an epitranscriptomic analysis of RNA-Seq data of 260 blood samples from 102 healthy and SARS-CoV-2 naïve individuals receiving different doses of the COVID-19 vaccine and revealed dynamic, transcriptome-wide adenosine to inosine (A-to-I) RNA editing changes in response to COVID-19 vaccines (RNA editing in response to COVID-19 vaccines). 5592 differential RNA editing (DRE) sites in 1820 genes were identified, with most of them showing up-regulated RNA editing and correlated with increased expression of edited genes. These deferentially edited genes were primarily involved in immune- and virus-related gene functions and pathways. Differential ADAR expression probably contributed to RNA editing in response to COVID-19 vaccines. One of the most significant DRE in RNA editing in response to COVID-19 vaccines was in apolipoprotein L6 (APOL6) 3' UTR, which positively correlated with its up-regulated expression. In addition, recoded key antiviral and immune-related proteins such as IFI30 and GBP1 recoded by missense editing was observed as an essential component of RNA editing in response to COVID-19 vaccines. Furthermore, both RNA editing in response to COVID-19 vaccines and its functions dynamically depended on the number of vaccine doses. Conclusion: Our results thus underscored the potential impact of blood RNA editing in response to COVID-19 vaccines on the host's molecular immune system.

Sex differences in functional and structural alterations of hippocampus region in chronic pain: a DTI and resting-state fMRI study.

Introduction: It is well known that there are significant differences in the prevalence of chronic pain between males and females. Human and animal imaging studies have shown that chronic pain profoundly alters the structure and function of brain regions. However, there is limited research on the sex-specific mechanisms underlying the brain plasticity and adaptive changes associated with chronic pain. In this article, we conducted a multimodal study to evaluate how nerve injury-induced chronic pain affects the brain. Methods: Male and female Sprague-Dawley (SD) rats with spared nerve injury (SNI) model underwent resting-state functional magnetic resonance imaging (rs-fMRI) (male sham group: n = 18; male SNI group: n = 18; female sham group: n = 20; female SNI group: n = 18) and magnetic resonance diffusion tensor imaging (DTI) (male sham group: n = 23; male SNI group: n = 21; female sham group: n = 20; female SNI group: n = 21) scanning. ICA method, Fractional amplitude of low-frequency fluctuations (fALFF), immunofluorescence staining, and graph theory analysis was utilized to extract the rs-fMRI changes of brain regions of each group. Results: Using SNI model, which promotes long-lasting mechanical allodynia, we found that neuropathic pain deeply modified the intrinsic organization of the brain functional network in male and female rats (main effect of operation: F = 298.449, P < 0.001). 64 independent components (ICs) in the brain were divided and assigned to 16 systems. In male rats, we observed significant alterations in the microstructure of the hippocampal cornu ammonis 1 and cornu ammonis 2 (CA1/CA2) region, as indicated by increased mean diffusivity (MD) (CA1_L: P = 0.02; CA1_R: P = 0.031; CA2_L: P = 0.035; CA2_R: P = 0.015) and radial diffusivity (RD) (CA1_L: P = 0.028; CA1_R: P = 0.033; CA2_L: P = 0.037; CA2_R: P = 0.038) values, along with enhanced activating transcription factor 3 (ATF3) expression. Conversely, in female rats, we found significant increases in the fractional amplitude of low frequency fluctuations (fALFF) value within the hippocampal dentate gyrus (DG) (F = 5.419, P = 0.023), accompanied by elevated c-Fos signal (F = 6.269, P = 0.031). Furthermore, graph theory analysis revealed notable differences in the small-world network of the hippocampal system in female rats, characterized by reduced small-world attributes and increased inter-nodal transmission efficiency. Discussion: Our study indicates sex differences in structural and functional alterations in the hippocampal system in rats under chronic pain conditions. The results suggest that the hippocampus system plays an important role in the different mechanisms of chronic pain in different sexes. These findings provide reliable insights to explore the complex mechanisms underlying sex differences in chronic pain.

Unveiling the cytotoxicity of a new gold(I) complex towards hepatocellular carcinoma by inhibiting TrxR activity.

Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is an aggressive malignancy with limited therapeutic options. In this study, we assess a collection of newly designed gold(I) phosphine complexes. Remarkably, the compound GC002 exhibits the greatest toxicity to HCC cells and outperforms established medications, such as sorafenib and auranofin, in terms of antitumor efficacy. GC002 triggers irreversible necroptosis in HCC cells by increasing the intracellular accumulation of reactive oxygen species (ROS). Mechanistically, GC002 significantly suppresses the activity of thioredoxin reductase (TrxR), which plays a crucial role in regulating redox homeostasis and is often overexpressed in HCC by binding directly to the enzyme. Our in vivo xenograft study confirms that GC002 possesses remarkable antitumor activity against HCC without severe side effects. These findings not only highlight the novel mechanism of controlling necroptosis via TrxR and ROS but also identify GC002 as a promising candidate for the further development of antitumor agents targeting HCC.

Dose-response relationship between awake prone-positioning duration and PaO2/FiO2 changes and risk of disease aggravation in patients with severe COVID-19: A prospective cohort study.

BACKGROUND: Patients not mechanically ventilated often fail to achieve the recommended duration of awake prone positioning due to treatment interruption and discomfort. Few studies have investigated the link between treatment outcome and prone-positioning duration, the inability to accurately guide patients to perform awake prone positioning. OBJECTIVES: The aim of this study was to characterise and explore the relationship between awake prone-positioning duration with the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2 [P/F]) changes and the risk of disease aggravation. METHODS: A prospective cohort study; dose-response relationship was used. Awake prone positioning was performed on patients with severe Corona Virus Disease 2019 (COVID-19) for 5 consecutive days from 1 February to 21 March 2023. Linear and logistic regression models were utilised to assess the association between prone-positioning duration with P/F changes and risk of disease aggravation, respectively. Meanwhile, the restricted cubic spline was used to evaluate the dose-response relationships. RESULTS: A total of 408 patients with severe COVID-19 were analysed. The daily prone positioning duration was 4.57 ± 2.74 h/d, and the changes in P/F were 67.63 ± 69.17 mmHg. On the sixth day of hospitalisation, the condition of 52 (12.8%) patients deteriorated. There was a positive, nonlinear dose-response relationship (Poverall < 0.001, Pnonlinearity = 0.041) and a strong, significant positive correlation (ß = 29.286, t = 4.302, P < 0.001) between the prone-positioning duration and P/F changes. The risk of disease aggravation gradually decreases with the increase of prone-positioning duration. Nonetheless, the prone-positioning duration was not statistically associated with disease aggravation (odds ratio = 0.986, 95% confidence interval: 0.514-1.895). CONCLUSIONS: Awake prone positioning for ≥4 h/d is effective on oxygenation (not mortality/intubation) and is achievable for patients with severe COVID-19. Prolonged prone positioning is promising in improving patients' oxygenation but does not alleviate their risk of disease aggravation.

SmJAZs-SmbHLH37/SmERF73-SmSAP4 module mediates jasmonic acid signaling to balance biosynthesis of medicinal metabolites and salt tolerance in Salvia miltiorrhiza.

Salvia miltiorrhiza holds significant importance in traditional Chinese medicine. Stress-associated proteins (SAP), identified by A20/AN1 zinc finger structural domains, play crucial roles in regulating plant growth, development, resistance to biotic and abiotic stress, and hormone responses. Herein, we conducted a genome-wide identification of the SAP gene family in S. miltiorrhiza. The expression analysis revealed a significant upregulation of SmSAP4 under methyl jasmonate (MeJA) and salt stress. Overexpressing SmSAP4 in S. miltiorrhiza hairy roots increased tanshinones content while decreasing salvianolic acids content, while RNAi-silencing SmSAP4 had the opposite effect. SmSAP4 overexpression in both Arabidopsis thaliana and S. miltiorrhiza hairy roots decreased their salt stress tolerance, accompanied by increased activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), and a hindered ability to maintain the Na+ : K+ ratio. Further investigations demonstrated that MeJA alleviated the inhibitory effect of SmJAZ3 on SmSAP4 activation by SmbHLH37 and SmERF73. However, MeJA did not affect the inhibition of SmSAP4 activation by SmJAZ8 through SmbHLH37. In summary, our research reveals that SmSAP4 negatively regulates the accumulation of salvianic acid through the SmJAZs-SmbHLH37/SmERF73-SmSAP4 module and positively impacting the accumulation of tanshinones. Additionally, it functions as a negative regulator under salt stress.

Plant species diversification in the Himalaya-Hengduan Mountains region: an example from an endemic lineage of Pedicularis (Orobanchaceae) in the role of floral specializations and rapid range expansions.

The c. 270 endemic species of Pedicularis in the Himalaya-Hengduan Mountains (HHM) region exhibit high diversity in geographic distribution, elevational range and floral morphology. Many of these, including the species with the longest corolla tubes and beaked galeas, are monophyletic and represent a putative in situ radiation. In this study, we focus on the representative Clade 3 within the HHM region. We integrate the plastid phylogeny of this clade with environmental data and species distributions to infer environmental correlates of species diversity. We estimate macroevolutionary rates and reconstructed ancestral states for geographic ranges and corolla traits, and analyse patterns of range overlap and niche evolution to assess drivers of diversification in the HHM region. Our results show that the region from northwest Yunnan to southwest Sichuan is the centre of diversity for this clade of Pedicularis. Rates of diversification are associated with precipitation and multiple environmental factors. Multiple range expansions from the Sanjiang (Three Parallel Rivers) region, followed by allopatric speciation across the HHM region, contributed to early rapid diversification. Corolla traits are not significantly associated with species diversification. This study highlights the importance of integrated evidence for understanding species diversification dynamics and contributes to our understanding of the origins of the remarkable richness of plant species in the HHM region.

Analysis of the Improvement Sequence in Insomnia Symptoms and Factors Influencing the Treatment Outcomes of Smartphone-Delivered CBT in Patients with Insomnia Disorder.

Background: The effectiveness of medication combined with smartphone-delivered cognitive behavioral therapy for insomnia (CBT-I) has been well verified, but there are few studies on the sequence of remission of insomnia symptoms. This study aims to understand the sequence of symptom improvement and the factors influencing the treatment effectiveness in patients with insomnia. Methods: Smartphone-delivered CBT, as a form of Online CBT, allows for training through mobile devices at any time and place. We utilized the Good Sleep 365 app to conduct a survey, involving 2820 patients who met the baseline inclusion criteria. These patients were assessed using a general demographic questionnaire and the Pittsburgh Sleep Quality Index (PSQI) to evaluate general demographic information and insomnia symptoms, and subsequently underwent CBT training using the Good Sleep 365 app. A total of 1179 patients completed follow-ups at 4 weeks, 8 weeks, 16 weeks, and 24 weeks. Results: At 4 weeks and 8 weeks, the descending order of the reduction rates of PSQI components (excluding component 6: use of sleeping medication) was: sleep latency, subjective sleep quality, sleep efficiency, sleep disturbance, sleep maintenance, and daytime dysfunction. At 16 weeks and 24 weeks, the descending order was subjective sleep quality, sleep latency, sleep efficiency, daytime dysfunction, sleep maintenance, and sleep disturbance. There were significant differences in the reduction rates of PSQI components (excluding component 6: use of sleeping medication) both at the same follow-up times and at different follow-up times (all P<0.05). Multivariable logistic regression analysis showed that patients older than 30 years and those with a college degree or above had better treatment outcomes, whereas those with a disease duration of more than three years had worse outcomes. Conclusion: The sequence of symptom improvement in patients with insomnia changes over time, and age, educational level, and duration of disease are factors influencing treatment outcomes.

Probing the Structures and Lanthanum-Lanthanum Bonding in La2Bn- (n = 4-6) Clusters.

We report an investigation on the structures and chemical bonding in a series of di-lanthanum boron clusters, La2Bn- (n = 4-6), using photoelectron spectroscopy and theoretical calculations. Well-resolved photoelectron spectra are obtained and used to verify the global minima of the lanthanide boron clusters. The structures of La2B4- and La2B5- are found to consist of open B4 and B5 rings, respectively, around the La2 dimer equatorially. Theoretical evidence of La-La σ bonding is obtained in La2B4-, whereas the bonding in La2B5- is similar to that of an incomplete inverse sandwich without real La-La bonding. The global minimum of La2B6- is completely different, where one of the La atoms can be viewed as substituting a B atom of the B7 cluster due to the high electronic stability of the B73- borozene. The resulting lanthaborozene [LaB6]3- forms a half-sandwich structure with the second La atom, with evidence of La-La σ bonding. Lanthanide-lanthanide bonds are relatively rare in chemistry. The current work suggests that binary lanthanide boron clusters provide interesting systems to study lanthanide-lanthanide bonding.

Improvement effect of compound Ento-PB on oxazolone-induced ulcerative colitis in rats.

PURPOSE: To investigate the impact of the Chinese medicine compound Ento-PB on oxazolone (OXZ)-induced ulcerative colitis (UC) in rats. METHODS: UC rats induced by OXZ were treated with Ento-PB. The damage to the colon was assessed using several measures, including the disease activity index (DAI), colon length, colon weight/length ratio, colonic mucosal damage index, and histological score. The levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), epidermal growth factor (EGF), inducible nitric oxide synthase, and total nitric oxide synthase (tNOS) in rat serum, as well as the levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) in rat colon tissue, were determined using enzyme-linked immunosorbent assay and conventional kits. RESULTS: After being treated with Ento-PB, the DAI score and macroscopic lesion score of OXZ-induced UC rats were significantly reduced. Ento-PB prevented the shortening of rat colons, reduced the ratio of colon weight to length, and improved colon tissue lesions. Meanwhile, Ento-PB could significantly inhibit the activities of proinflammatory cytokines TNF-α, IL-13, and MPO, as well as tNOS and iNOS, while upregulating the expression of anti-inflammatory cytokines IL-4 and IL-10. Moreover, a significant increase in the expression level of EGF was observed in UC rats treated with Ento-PB, indicating that Ento-PB could enhance the repair of damaged intestinal epithelial tissue. CONCLUSIONS: Ento-PB demonstrates significant anti-UC activities in OXZ-induced UC rats by regulating the expression levels of inflammatory factors and promoting the repair of colon tissue. This study provides scientific evidence to support the further development of Ento-PB.

Integration of induction, system optimization and genetic transformation in Veratrum californicum var. vitro cultures to enhance the production of cyclopamine and veratramine.

Cyclopamine, a compound found in wild Veratrum has shown promising potential as a lead anti-cancer drug by effectively blocking cancer signaling pathways. However, its complex chemical structure poses challenges for artificial synthesis, thus limiting its supply and downstream drug production. This study comprehensively utilizes induction, system optimization, and transgenic technologies to establish an efficient suspension culture system for the high-yield production of cyclopamine and its precursor, veratramine. Experimental results demonstrate that methyl jasmonate (MeJA) effectively promotes the content of veratramine and cyclopamine in Veratrum californicum var. callus tissue, while yeast extract (YE) addition significantly increases cell biomass. The total content of veratramine and cyclopamine reached 0.0638 mg after synergistic treatment of suspension system with these two elicitors. And the content of the two substances was further increased to 0.0827 mg after the optimization by response surface methodology. Subsequently, a genetic transformation system for V. californicum callus was established and a crucial enzyme gene VnOSC1, involved in the steroidal alkaloid biosynthesis pathway, was screened and identified for genetic transformation. Combined suspension culture and synergistic induction system, the total content of the two substances in transgenic suspension system was further increased to 0.1228 mg, representing a 276.69% improvement compared to the initial culture system. This study proposes a complete and effective genetic transformation and cultivation scheme for V. californicum tissue cells, achieving milligram-level production of the anticancer agent cyclopamine and its direct precursor veratramine for the first time. It provides a theoretical basis for the industrial-scale production of these substances.

Apoptotic vesicles (apoVs) derived from fibroblast-converted hepatocyte-like cells effectively ameliorate liver fibrosis.

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs.

Protein-Induced DNA Dumbbell Amplification (PINDA) and its applications to food hazards detection.

Quantification of trace amounts of proteins is technically challenging because proteins cannot be directly amplified like nucleic acids. To improve the analytical sensitivity and to complement conventional protein analysis methods, we developed a highly sensitive and homogeneous detection strategy called Protein-Induced DNA Dumbbell Amplification (PINDA). PINDA combines protein recognition with exponential nucleic acid amplification by using protein binding probes made of DNA strands conjugated to protein affinity ligands. When a pair of probes bind to the same target protein, complementary nucleic acid sequences that are conjugated to each probe are brought into close proximity. The increased local concentration of the probes results in the formation of a stable dumbbell structure of the nucleic acids. The DNA dumbbell is readily amplifiable exponentially using techniques such as loop-mediated isothermal amplification. The PINDA assay eliminates the need for washing or separation steps, and is suitable for on-site applications. Detection of the model protein, thrombin, has a linear range of 10 fM-100 pM and detection limit of 10 fM. The PINDA technique is successfully applied to the analysis of dairy samples for the detection of ß-lactoglobulin, a common food allergen, and Salmonella enteritidis, a foodborne pathogenic bacterium. The PINDA assay can be easily modified to detect other targets by changing the affinity ligands used to bind to the specific targets.

N-terminus GTPase domain of the cytoskeleton protein FtsZ plays a critical role in its adaptation to high hydrostatic pressure.

Studies in model microorganisms showed that cell division is highly vulnerable to high hydrostatic pressure (HHP). Disassembly of FtsZ filaments induced by HHP results in the failure of cell division and formation of filamentous cells in E. coli. The specific characteristics of FtsZ that allow for functional cell division in the deep-sea environments, especially in obligate piezophiles that grow exclusively under HHP condition, remain enigmatic. In this study, by using a self-developed HHP in-situ fixation apparatus, we investigated the effect of HHP on FtsZ by examining the subcellular localization of GFP-tagged FtsZ in vivo and the stability of FtsZ filament in vitro. We compared the pressure tolerance of FtsZ proteins from pressure-sensitive strain Shewanella oneidensis MR-1 (FtsZSo) and obligately piezophilic strain Shewanella benthica DB21MT-2 (FtsZSb). Our findings showed that, unlike FtsZSo, HHP hardly affected the Z-ring formation of FtsZSb, and filaments composed of FtsZSb were more stable after incubation under 50 MPa. By constructing chimeric and single amino acid mutated FtsZ proteins, we identified five residues in the N-terminal GTPase domain of FtsZSb whose mutation would impair the Z-ring formation under HHP conditions. Overall, these results demonstrate that FtsZ from the obligately piezophilic strain exhibits superior pressure tolerance than its homologue from shallow water species, both in vivo and in vitro. Differences in pressure tolerance of FtsZ are largely attributed to the N-terminal GTPase domain. This represents the first in-depth study of the adaptation of microbial cytoskeleton protein FtsZ to high hydrostatic pressure, which may provide insights into understanding the complex bioprocess of cell division under extreme environments.

A drug delivery system of HIF-1α siRNA nanoparticles loaded by mesenchymal stem cells on choroidal neovascularization.

Aim: To assess mesenchymal stem cells (MSCs) as carriers for HIF-1α siRNA-loaded nanoparticles (NPs) for targeted therapy of experimental choroidal neovascularization (CNV).Materials & methods: A poly (lactic-co-glycolic acid) (PLGA)-core/lipid-shell hybrid NP was designed. The transfection efficacy of MSCs with the hybrid NPs was assessed. Mice were intravenously injected with MSCs after laser photocoagulation and CNV was assessed at 7 days post-injection.Results & conclusion: The transfection efficiency of hybrid NPs into MSCs was 72.7%. HIF-1α mRNA expression in 661w cells co-cultured with MSC-hybrid-siRNA NPs was significantly lower. Intravenous delivery of MSC-hybrid-siRNA NPs greatly reduced CNV area and length. Intravenous injection of MSC-hybrid-siRNA NPs achieved therapeutic efficacy in reducing CNV area. The MSC-mediated homing enabled targeted inhibition of ocular angiogenesis.

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Epimedin A inhibits the PI3K/AKT/NF-κB signalling axis and osteoclast differentiation by negatively regulating TRAF6 expression.

BACKGROUND: Epimedin A (EA) has been shown to suppress extensive osteoclastogenesis and bone resorption, but the effects of EA remain incompletely understood. The aim of our study was to investigate the effects of EA on osteoclastogenesis and bone resorption to explore the corresponding signalling pathways. METHODS: Rats were randomly assigned to the sham operation or ovariectomy group, and alendronate was used for the positive control group. The therapeutic effect of EA on osteoporosis was systematically analysed by measuring bone mineral density and bone biomechanical properties. In vitro, RAW264.7 cells were treated with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) to induce osteoclast differentiation. Cell viability assays, tartrate-resistant acid phosphatase (TRAP) staining, and immunofluorescence were used to elucidate the effects of EA on osteoclastogenesis. In addition, the expression of bone differentiation-related proteins or genes was evaluated using Western blot analysis or quantitative polymerase chain reaction (PCR), respectively. RESULTS: After 3 months of oral EA intervention, ovariectomized rats exhibited increased bone density, relative bone volume, trabecular thickness, and trabecular number, as well as reduced trabecular separation. EA dose-dependently normalized bone density and trabecular microarchitecture in the ovariectomized rats. Additionally, EA inhibited the expression of TRAP and NFATc1 in the ovariectomized rats. Moreover, the in vitro results indicated that EA inhibits osteoclast differentiation by suppressing the TRAF6/PI3K/AKT/NF-κB pathway. Further studies revealed that the effect on osteoclast differentiation, which was originally inhibited by EA, was reversed when the TRAF6 gene was overexpressed. CONCLUSIONS: The findings indicated that EA can negatively regulate osteoclastogenesis by inhibiting the TRAF6/PI3K/AKT/NF-κB axis and that ameliorating ovariectomy-induced osteoporosis in rats with EA may be a promising potential therapeutic strategy for the treatment of osteoporosis.

Serological Investigation into the Infected Genotypes of Patients with Japanese Encephalitis in the Coastal Provinces of China.

Objective: Genotypes (G) 1, 3, and 5 of the Japanese encephalitis virus (JEV) have been isolated in China, but the dominant genotype circulating in Chinese coastal areas remains unknown. We searched for G5 JEV-infected cases and attempted to elucidate which JEV genotype was most closely related to human Japanese encephalitis (JE) in the coastal provinces of China. Methods: In this study, we collected serum specimens from patients with JE in three coastal provinces of China (Guangdong, Zhejiang, and Shandong) from 2018 to 2020 and conducted JEV cross-neutralization tests against G1, G3, and G5. Results: Acute serum specimens from clinically reported JE cases were obtained for laboratory confirmation from hospitals in Shandong (92 patients), Zhejiang (192 patients), and Guangdong (77 patients), China, from 2018 to 2020. Seventy of the 361 serum specimens were laboratory-confirmed to be infected with JEV. Two cases were confirmed to be infected with G1 JEV, 32 with G3 JEV, and two with G5 JEV. Conclusion: G3 was the primary infection genotype among JE cases with a definite infection genotype, and the infection caused by G5 JEV was confirmed serologically in China.

Overcoming Microstructural Defects at the Buried Interface of Formamidinium-Based Perovskite Solar Cells.

Since the advent of formamidinium (FA)-based perovskite photovoltaics (PVs), significant performance enhancements have been achieved. However, a critical challenge persists: the propensity for void formation in the perovskite film at the buried perovskite-interlayer interface has a deleterious effect on device performance. With most emerging perovskite PVs adopting the p-i-n architecture, the specific challenge lies at the perovskite-hole transport layer (HTL) interface, with previous strategies to overcome this limitation being limited to specific perovskite-HTL combinations; thus, the lack of universal approaches represents a bottleneck. Here, we present a novel strategy that overcomes the formation of such voids (microstructural defects) through a film treatment with methylammonium chloride (MACl). Specifically, our work introduces MACl via a sequential deposition method, having a profound impact on the microstructural defect density at the critical buried interface. Our technique is independent of both the HTL and the perovskite film thickness, highlighting the universal nature of this approach. By employing device photoluminescence measurements and conductive atomic force microscopy, we reveal that when present, such voids impede charge extraction, thereby diminishing device short-circuit current. Through comprehensive steady-state and transient photoluminescence spectroscopy analysis, we demonstrate that by implementing our MACl treatment to remedy these voids, devices with reduced defect states, suppressed nonradiative recombination, and extended carrier lifetimes of up to 2.3 µs can be prepared. Furthermore, our novel treatment reduces the stringent constraints around antisolvent choice and dripping time, significantly extending the processing window for the perovskite absorber layer and offering significantly greater flexibility for device fabrication.

Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer.

The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.