IGF2BP2 regulates the inflammation of fibroblast-like synoviocytes via GSTM5 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with an unknown etiology. RA cannot be fully cured and requires lengthy treatment, imposing a significant burden on both individuals and society. Due to the lack of specific drugs available for treating RA, exploring a key new therapeutic target for RA is currently an important task. Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the progression of RA, which release interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α resulting in abnormal inflammatory reaction in the synovium. A previous study has highlighted the correlation of m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) with inflammation-related diseases in human. However, the role of IGF2BP2 in the inflammatory reaction of FLSs during RA progression has not been assessed. In this study, IGF2BP2 expression was decreased in the synovial tissues of RA patients and collagen-induced arthritis (CIA) rats. Intra-articular injection of an adeno-associated virus (AAV) vector overexpressing IGF2BP2 relieved paw swelling, synovial hyperplasia and cartilage destruction in CIA rats. IGF2BP2 overexpression also inhibited lipopolysaccharide (LPS)-mediated RA fibroblast-like synoviocytes (RA-FLSs) migration and invasion accompanied by a decreased level of inflammatory factors in vitro. Conversely, IGF2BP2 suppression promoted RA-FLSs migration and invasion with an elevated level of inflammatory factors in vitro. The sequencing result showed that glutathione S-transferase Mu 5 (GSTM5), a key antioxidant gene, was the target mRNA of IGF2BP2. Further experiments demonstrated that IGF2BP2 strengthened the stability of GSTM5 mRNA, leading to weakened inflammatory reaction and reduced expression of matrix metalloproteinase 9 and 13 (MMP9, MMP13). Therefore, IGF2BP2-GSTM5 axis may represent a potential therapeutic target for RA treatment.

Addressing the Carbonate Issue: Electrocatalysts for Acidic CO2 Reduction Reaction.

Electrochemical CO2 reduction reaction (CO2RR) powered by renewable energy provides a promising route to CO2 conversion and utilization. However, the widely used neutral/alkaline electrolyte consumes a large amount of CO2 to produce (bi)carbonate byproducts, leading to significant challenges at the device level, thereby impeding the further deployment of this reaction. Conducting CO2RR in acidic electrolytes offers a promising solution to address the "carbonate issue"; however, it presents inherent difficulties due to the competitive hydrogen evolution reaction, necessitating concerted efforts toward advanced catalyst and electrode designs to achieve high selectivity and activity. This review encompasses recent developments of acidic CO2RR, from mechanism elucidation to catalyst design and device engineering. This review begins by discussing the mechanistic understanding of the reaction pathway, laying the foundation for catalyst design in acidic CO2RR. Subsequently, an in-depth analysis of recent advancements in acidic CO2RR catalysts is provided, highlighting heterogeneous catalysts, surface immobilized molecular catalysts, and catalyst surface enhancement. Furthermore, the progress made in device-level applications is summarized, aiming to develop high-performance acidic CO2RR systems. Finally, the existing challenges and future directions in the design of acidic CO2RR catalysts are outlined, emphasizing the need for improved selectivity, activity, stability, and scalability.

Long-term efficacy, safety and biocompatibility of a novel sirolimus eluting iron bioresorbable scaffold in a porcine model.

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Cultivation of microalgae in food processing effluent for pollution attenuation and astaxanthin production: a review of technological innovation and downstream application.

Valorization of food processing effluent (FPE) by microalgae cultivation for astaxanthin production is regarded as a potential strategy to solve the environmental pollution of food processing industry and promote the development of eco-friendly agriculture. In this review paper, microalgal species which have the potential to be employed for astaxanthin in FPE were identified. Additionally, in terms of CO2 emission, the performances of microalgae cultivation and traditional methods for FPE remediation were compared. Thirdly, an in-depth discussion of some innovative technologies, which may be employed to lower the total cost, improve the nutrient profile of FPE, and enhance the astaxanthin synthesis, was provided. Finally, specific effects of dietary supplementation of algal astaxanthin on the growth rate, immune response, and pigmentation of animals were discussed. Based on the discussion of this work, the cultivation of microalgae in FPE for astaxanthin production is a value-adding process which can bring environmental benefits and ecological benefits to the food processing industry and agriculture. Particularly, technological innovations in recent years are promoting the shift of this new idea from academic research to practical application. In the coming future, with the reduction of the total cost of algal astaxanthin, policy support from the governments, and further improvement of the innovative technologies, the concept of growing microalgae in FPE for astaxanthin will be more applicable in the industry.

Evaluation of the consistency of the MRI- based AI segmentation cartilage model using the natural tibial plateau cartilage.

OBJECTIVE: The study aims to evaluate the accuracy of an MRI-based artificial intelligence (AI) segmentation cartilage model by comparing it to the natural tibial plateau cartilage. METHODS: This study included 33 patients (41 knees) with severe knee osteoarthritis scheduled to undergo total knee arthroplasty (TKA). All patients had a thin-section MRI before TKA. Our study is mainly divided into two parts: (i) In order to evaluate the MRI-based AI segmentation cartilage model's 2D accuracy, the natural tibial plateau was used as gold standard. The MRI-based AI segmentation cartilage model and the natural tibial plateau were represented in binary visualization (black and white) simulated photographed images by the application of Simulation Photography Technology. Both simulated photographed images were compared to evaluate the 2D Dice similarity coefficients (DSC). (ii) In order to evaluate the MRI-based AI segmentation cartilage model's 3D accuracy. Hand-crafted cartilage model based on knee CT was established. We used these hand-crafted CT-based knee cartilage model as gold standard to evaluate 2D and 3D consistency of between the MRI-based AI segmentation cartilage model and hand-crafted CT-based cartilage model. 3D registration technology was used for both models. Correlations between the MRI-based AI knee cartilage model and CT-based knee cartilage model were also assessed with the Pearson correlation coefficient. RESULTS: The AI segmentation cartilage model produced reasonably high two-dimensional DSC. The average 2D DSC between MRI-based AI cartilage model and the tibial plateau cartilage is 0.83. The average 2D DSC between the AI segmentation cartilage model and the CT-based cartilage model is 0.82. As for 3D consistency, the average 3D DSC between MRI-based AI cartilage model and CT-based cartilage model is 0.52. However, the quantification of cartilage segmentation with the AI and CT-based models showed excellent correlation (r = 0.725; P values < 0.05). CONCLUSION: Our study demonstrated that our MRI-based AI cartilage model can reliably extract morphologic features such as cartilage shape and defect location of the tibial plateau cartilage. This approach could potentially benefit clinical practices such as diagnosing osteoarthritis. However, in terms of cartilage thickness and three-dimensional accuracy, MRI-based AI cartilage model underestimate the actual cartilage volume. The previous AI verification methods may not be completely accurate and should be verified with natural cartilage images. Combining multiple verification methods will improve the accuracy of the AI model.

Psychological distress and mental health care utilization among Black survivors of adolescent and young adult cancer.

BACKGROUND: Survivors of adolescent and young adult (AYA) cancer experience significant psychological distress and encounter barriers to accessing mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes among AYA survivors, and none have compared outcomes within a racially minoritized population. METHODS: National Health Interview Survey data (2010-2018) were analyzed that identified non-Hispanic Black (hereafter, Black) survivors of AYA cancer and age- and sex-matched Black noncancer controls. Sociodemographic factors, chronic health conditions, modifiable behaviors (smoking and alcohol use), and psychological outcomes were assessed with χ2 tests. Logistic regression models, adjusted for survey weights, were used to evaluate the odds of psychological distress by cancer status after adjusting for covariates. Interactions between variables and cancer status were investigated. RESULTS: The study included 334 Black survivors of AYA cancer and 3340 Black controls. Compared to controls, survivors were more likely to report moderate/severe distress (odds ratio [OR], 1.64; p < .001), use mental health care (OR, 1.53; p = .027), report an inability to afford mental health care (OR, 3.82; p < .001), and use medication for anxiety and/or depression (OR, 2.16; p = .001). Forty-one percent of survivors reported moderate/severe distress, and only 15% used mental health care. Among survivors, ages 18-39 years (vs. 40-64 years) and current smoking (vs. never smoking) were associated with the presence of moderate/severe distress. Among survivors with distress, high poverty status was associated with reduced utilization of mental health care. CONCLUSIONS: A cancer diagnosis for a Black AYA is associated with greater psychological distress within an already vulnerable population.

Supportive Care Needs in Chinese, Vietnamese, and Korean Americans With Metastatic Cancer: Mixed Methods Protocol for the DAWN Study.

BACKGROUND: Asian Americans with metastatic cancer are an understudied population. The Describing Asian American Well-Being and Needs in Cancer (DAWN) Study was designed to understand the supportive care needs of Chinese-, Vietnamese-, and Korean-descent (CVK) patients with metastatic cancer. OBJECTIVE: This study aims to present the DAWN Study protocol involving a primarily qualitative, convergent, mixed methods study from multiple perspectives (patients or survivors, caregivers, and health care professionals). METHODS: CVK Americans diagnosed with solid-tumor metastatic cancer and their caregivers were recruited nationwide through various means (registries, community outreach newsletters, newspapers, radio advertisements, etc). Potentially eligible individuals were screened and consented on the web or through a phone interview. The study survey and interview for patients or survivors and caregivers were provided in English, traditional/simplified Chinese and Cantonese/Mandarin, Vietnamese, and Korean, and examined factors related to facing metastatic cancer, including quality of life, cultural values, coping, and cancer-related symptoms. Community-based organizations assisted in recruiting participants, developing and translating study materials, and connecting the team to individuals for conducting interviews in Asian languages. Health care professionals who have experience working with CVK patients or survivors with metastatic solid cancer were recruited through referrals from the DAWN Study community advisory board and were interviewed to understand unmet supportive care needs. RESULTS: Recruitment began in November 2020; data collection was completed in October 2022. A total of 66 patients or survivors, 13 caregivers, and 15 health care professionals completed all portions of the study. We completed data management in December 2023 and will submit results for patients or survivors and caregivers to publication outlets in 2024. CONCLUSIONS: Future findings related to this protocol will describe and understand the supportive care needs of CVK patients or survivors with metastatic cancer and will help develop culturally appropriate psychosocial interventions that target known predictors of unmet supportive care needs in Chinese, Vietnamese, and Korean Americans with metastatic cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50032.

Pricing strategy research in the dual-channel pharmaceutical supply chain considering service.

In the context of developing a new era, the pharmaceutical supply chain market has gradually transformed from a seller's market to a buyer's market. The closer the consumers are, the greater the market pricing power, so the pharmaceutical market power of manufacturers and retailers has also changed. This study considers the effect of service on the pricing strategy of the pharmaceutical platform supply chain. The study aimed to coordinate optimization, and the coordination strategy of the pharmaceutical platform supply chain of complementary products is discussed mainly by researching the price and service factors. Various situations are studied by hypothesis and model solving. This study uses Stackelberg game decision-making. Manufacturers are at the forefront of platform supply chain decisions. The research found that the price was lower under centralized decision-making than under decentralized decision-making. Coordination between price and service levels needs attention in the pharmaceutical platform supply chain of complementary products, and the service level should be controlled within a certain range. Only by improving the service level can enterprises maximize profits, providing a theoretical basis for pharmaceutical supply chain pricing strategy research. Supply chain members must strive to improve service levels to improve medical supply consumers' (patients) psychological satisfaction level. Service levels do not fully mitigate channel conflict. Therefore, pharmaceutical complements have become a way to alleviate the conflicts in the pharmaceutical platform supply chain.

Comparison of the osteogenic potential of fibroblasts from different sources.

OBJECTIVE: With the growing interest in the role of fibroblasts in osteogenesis, this study presents a comparative evaluation of the osteogenic potential of fibroblasts derived from three distinct sources: human gingival fibroblasts (HGFs), mouse embryonic fibroblasts (NIH3T3 cells), and mouse subcutaneous fibroblasts (L929 cells). MC3T3-E1 pre-osteoblast cells were employed as a positive control for osteogenic behavior. DESIGN: Our assessment involved multiple approaches, including vimentin staining for cell origin verification, as well as ALP and ARS staining in conjunction with RT-PCR for osteogenic characterization. RESULTS: Our findings revealed the superior osteogenic differentiation capacity of HGFs compared to MC3T3-E1 and NIH3T3 cells. Analysis of ALP staining confirmed that early osteogenic differentiation was most prominent in MC3T3-E1 cells at 7 days, followed by NIH3T3 and HGFs. However, ARS staining at 21 days demonstrated that HGFs produced the highest number of calcified nodules, indicating their robust potential for late-stage mineralization. This late-stage osteogenic potential of HGFs was further validated through RT-PCR analysis. In contrast, L929 cells displayed no significant osteogenic differentiation potential. CONCLUSIONS: In light of these findings, HGFs emerge as the preferred choice for seed cells in bone tissue engineering applications. This study provides valuable insights into the potential utility of HGFs in the fields of bone tissue engineering and regenerative medicine.

Lysosome-Related Genes and RNF19B as Prognostic Markers for Survival and Immunotherapy Efficacy in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) poses a considerable worldwide health concern due to its associated high risk of death. The heterogeneity of HCC poses challenges in developing practical risk stratification tools and identifying prognostic markers for personalized targeted treatments. Recently, lysosomes were shown to be crucial contributors to numerous cellular activities, including tumor initiation and regulating immune responses. Here, we aimed to construct a reliable prognostic signature based on lysosome-related genes and determine its association with the immune microenvironment. METHODS: We comprehensively analyzed lysosome-related genes in HCC to investigate their influence on patient survival and the tumor immune microenvironment. A prognostic signature comprising 14 genes associated with lysosomes was created to estimate the survival outcomes of individuals with HCC. Additionally, we verified the prognostic importance of Ring Finger Protein 19B (RNF19B) in HCC patients through multiplex immunohistochemistry analysis. RESULTS: Our constructed lysosome-related prediction model could significantly discriminate between HCC patients with good and poor survival outcomes (P < 0.05). We also found that elevated RNF19B expression was linked to unfavorable prognostic outcomes and showed a connection with specific clinicopathological characteristics. Moreover, it was observed that RNF19B could facilitate the transformation of macrophages into M2-polarized macrophages and showed a significant positive correlation with PD-1 and CTLA-4. CONCLUSION: In summary, our study proposes that the expression of lysosome-related genes is associated with the immune microenvironment, serving as a predictor for HCC patients' survival. Meanwhile, RNF19B was identified as a novel prognostic marker for predicting OS and immunotherapy effects in HCC patients.

ZIF-8-Encapsulated Pexidartinib Delivery via Targeted Peptide-Modified M1 Macrophages Attenuates MDSC-Mediated Immunosuppression in Osteosarcoma.

Adoptive cellular therapy is a promising strategy for cancer treatment. However, the effectiveness of this therapy is limited by its intricate and immunosuppressive tumor microenvironment. In this study, a targeted therapeutic strategy for macrophage loading of drugs is presented to enhance anti-tumor efficacy of macrophages. K7M2-target peptide (KTP) is used to modify macrophages to enhance their affinity for tumors. Pexidartinib-loaded ZIF-8 nanoparticles (P@ZIF-8) are loaded into macrophages to synergistically alleviate the immunosuppressive tumor microenvironment synergistically. Thus, the M1 macrophages decorated with KTP carried P@ZIF-8 and are named P@ZIF/M1-KTP. The tumor volumes in the P@ZIF/M1-KTP group are significantly smaller than those in the other groups, indicating that P@ZIF/M1-KTP exhibited enhanced anti-tumor efficacy. Mechanistically, an increased ratio of CD4+ T cells and a decreased ratio of MDSCs in the tumor tissues after treatment with P@ZIF/M1-KTP indicated that it can alleviate the immunosuppressive tumor microenvironment. RNA-seq further confirms the enhanced immune cell function. Consequently, P@ZIF/M1-KTP has great potential as a novel adoptive cellular therapeutic strategy for tumors.

Review of the subgenus Tarpheion of the genus Blacus Nees (Hymenoptera, Braconidae, Brachistinae) from China, with description of nine new species and eight new records.

An updated key to the currently known species of the subgenus Tarpheion van Achterberg, 1976 (Hymenoptera, Braconidae, Blacus) in China is provided. Nine new species are proposed, B. (T.) adelphius sp. nov., B. (T.) frontalis sp. nov., B. (T.) gilvus sp. nov., B. (T.) hainanensis sp. nov., B. (T.) parilis sp. nov., B. (T.) reticulatus sp. nov., B. (T.) sculptilis sp. nov., B. (T.) tanae sp. nov., and B. (T.) wuyishanensis sp. nov. Eight species, B. (T.) achterbergi Haeselbarth, 1976, B. (T.) albiventris van Achterberg, 1988, B. (T.) angichorus van Achterberg, 1988, B. (T.) antennalis van Achterberg, 1988, B. (T.) apicalis van Achterberg, 1976, B. (T.) artomandibularis van Achterberg, 1976, B. (T.) bicolor van Achterberg, 1988, and B. (T.) soror van Achterberg, 1988, are newly recorded from China.

The only species of Calvisia (Phasmatodea, Necrosciinae) from China, with a new synonymy and additional descriptions.

Calvisia is a colorful winged stick insect genus consisting of 6 subgenera and 44 species widely distributed in temperate and tropical Asia. C. medogensis syn. nov. was discovered in Mdog, Xizang (Tibet), China and is so far the only species recorded from China. We here propose that C. medogensis syn. nov. is a synonym of C. fuscoalata after checking type specimens of both species. New materials studied are deposited in Yunnan Agricultural University, China (YNAU).

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Role of keystone drives polycyclic aromatic hydrocarbons degradation and humification especially combined with aged contaminated soil in co-composting.

Accumulation of persistent organic pollutants polycyclic aromatic hydrocarbons (PAHs) in soil has become a global problem. Composting is considered one of the more economical methods of soil remediation and is important for the resourceful use of wastes. Agroforestry waste is produced in huge amounts and is utilized at low rates, hence there is an urgent need to manage it. Here, leaf (LVS) or rice straw (SVS) was co-composting with aged contaminated soil to investigate bacteria interaction to PAHs degradation and humus formation. The degradation rate of high molecular weight PAHs (HMW-PAHs) in LVS and SVS reached 58.9% and 52.5%, and the low molecular weight PAHs (LMW-PAHs) were 77.5% and 65%. Meanwhile, the humus increased by 44.8% and 60.5% in LVS and SVS at the end of co-composting. The topological characteristics and community assembly of the bacterial community showed that LVS had higher complexity and more keystones than SVS, suggesting that LVS might more beneficial for the degradation of PAHs. The stability of the co-occurrence network and stochastic processes (dispersal limitation) dominated community assembly made SVS beneficial for humus formation. Mantel test and structural equation models indicated that the transformation of organic matter was important for PAHs degradation and humus formation. Degradation of HMW-PAHs led to bacterial succession, which affected the formation of precursors and ultimately increased the humus content. This study provided potential technology support for improving the quality of agroforestry organic waste composting and degrading PAHs in aged contaminated soil.

Spatial disparities and internal subsystems'coupling coordination analysis of green development in Chinese animal husbandry.

This study establishes an indicator system encompassing economic, social, and environmental dimensions to assess the level of green development in animal husbandry from 2010 to 2020. It further examines the coupling coordination degree within each dimension. The Dagum Gini coefficient is employed to scrutinize the regional disparities in coupling coordination degree of the economic benefit, social benefit, and environmental benefit of the green development in Chinese animal husbandry. Additionally, Moran's I is utilized to identify the degree of spatial autocorrelation and aggregation types. The results demonstrate the following: (1) From 2010 to 2020, the level of green development in the animal husbandry in China has steadily improved. Among the three dimensions, economic benefits exhibit the highest performance, followed by environmental benefits and social benefits. There are obvious regional disparities in the green development of animal husbandry, which are "strong in north and weak in south" and "strong in west and weak in east." The Gini coefficient for green development in the animal husbandry in China experienced a fluctuating upward trend. (2) From 2010 to 2020, the overall coupling coordination degree of the economic benefit, social benefit, and environmental benefit of green development in the animal husbandry in China remains at a rudimentary level and demonstrates a steady upward trend. Spatially, it manifests an agglomeration pattern primarily centered around Beijing, with the northeastern region being the main focus. (3) The Gini coefficient for the coupling coordination degree experienced a slight fluctuating upward trend. In terms of inter-regional disparities, significant differences are observed between the northeastern region and the central region, as well as between the northeastern region and the eastern region. In terms of contribution to disparities, inter-regional contributions were the most substantial, followed by super-variable density, with intra-regional contributions being the smallest. (4) The coupling coordination degree displayed spatial autocorrelation, with "high-high" aggregation areas predominantly concentrated in the northeastern region.

S-nitrosoglutathione reductase-dependent p65 denitrosation promotes osteoclastogenesis by facilitating recruitment of p65 to NFATc1 promoter.

Osteoclasts, the exclusive bone resorptive cells, are indispensable for bone remodeling. Hence, understanding novel signaling modulators regulating osteoclastogenesis is clinically important. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) is a master transcription factor in osteoclastogenesis, and binding of NF-κB p65 subunit to NFATc1 promoter is required for its expression. It is well-established that DNA binding activity of p65 can be regulated by various post-translational modifications, including S-nitrosation. Recent studies have demonstrated that S-nitrosoglutathione reductase (GSNOR)-mediated protein denitrosation participated in cell fate commitment by regulating gene transcription. However, the role of GSNOR in osteoclastogenesis remains unexplored and enigmatic. Here, we investigated the effect of GSNOR-mediated denitrosation of p65 on osteoclastogenesis. Our results revealed that GSNOR was up-regulated during osteoclastogenesis in vitro. Moreover, GSNOR inhibition with a chemical inhibitor impaired osteoclast differentiation, podosome belt formation, and bone resorption activity. Furthermore, GSNOR inhibition enhanced the S-nitrosation level of p65, precluded the binding of p65 to NFATc1 promoter, and suppressed NFATc1 expression. In addition, mouse model of lipopolysaccharides (LPS)-induced calvarial osteolysis was employed to evaluate the therapeutic effect of GSNOR inhibitor in vivo. Our results indicated that GSNOR inhibitor treatment alleviated the inflammatory bone loss by impairing osteoclast formation in mice. Taken together, these data have shown that GSNOR activity is required for osteoclastogenesis by facilitating binding of p65 to NFATc1 promoter via promoting p65 denitrosation, suggesting that GSNOR may be a potential therapeutic target in the treatment of osteolytic diseases.

Shigella induces stress granule formation by ADP-riboxanation of the eIF3 complex.

Under stress conditions, translationally stalled mRNA and associated proteins undergo liquid-liquid phase separation and condense into cytoplasmic foci called stress granules (SGs). Many viruses hijack SGs for their pathogenesis; however, whether pathogenic bacteria also exploit this pathway remains unknown. Here, we report that members of the OspC family of Shigella flexneri induce SG formation in infected cells. Mechanistically, the OspC effectors target multiple subunits of the host translation initiation factor 3 complex by ADP-riboxanation. The modification of eIF3 leads to translational arrest and thus the formation of SGs. Furthermore, OspC-mediated SGs are beneficial for S. flexneri replication within infected host cells, and bacterial strains unable to induce SGs are attenuated for virulence in a murine model of infection. Our findings reveal a mechanism by which bacterial pathogens induce SG assembly by inactivating host translational machinery and promote bacterial proliferation in host cells.

Age-related differences in long-term potentiation-like plasticity and short-latency afferent inhibition and their association with cognitive function.

Background: The neurophysiological differences in cortical plasticity and cholinergic system function due to ageing and their correlation with cognitive function remain poorly understood. Aims: To reveal the differences in long-term potentiation (LTP)-like plasticity and short-latency afferent inhibition (SAI) between older and younger individuals, alongside their correlation with cognitive function using transcranial magnetic stimulation (TMS). Methods: The cross-sectional study involved 31 younger adults aged 18-30 and 46 older adults aged 60-80. All participants underwent comprehensive cognitive assessments and a neurophysiological evaluation based on TMS. Cognitive function assessments included evaluations of global cognitive function, language, memory and executive function. The neurophysiological assessment included LTP-like plasticity and SAI. Results: The findings of this study revealed a decline in LTP among the older adults compared with the younger adults (wald χ2=3.98, p=0.046). Subgroup analysis further demonstrated a significant reduction in SAI level among individuals aged 70-80 years in comparison to both the younger adults (SAI(N20): (t=-3.37, p=0.018); SAI(N20+4): (t=-3.13, p=0.038)) and those aged 60-70 (SAI(N20): (t=-3.26, p=0.025); SAI(N20+4): (t=-3.69, p=0.006)). Conversely, there was no notable difference in SAI level between those aged 60-70 years and the younger group. Furthermore, after employing the Bonferroni correction, the correlation analysis revealed that only the positive correlation between LTP-like plasticity and language function (r=0.61, p<0.001) in the younger group remained statistically significant. Conclusions: During the normal ageing process, a decline in synaptic plasticity may precede cholinergic system dysfunction. In individuals over 60 years of age, there is a reduction in LTP-like plasticity, while a decline in cholinergic system function is observed in those over 70. Thus, the cholinergic system may play a vital role in preventing cognitive decline during normal ageing. In younger individuals, LTP-like plasticity might represent a potential neurophysiological marker for language function.