MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma. OBJECTIVES: Clarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance. METHODS: Bioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments. RESULTS: In this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostatin A (TSA), an inhibitor of HDAC1, was found to impede the MIER2/HDAC1/P53/PGC1A pathway, offering potential benefits for patients with sunitinib-resistant renal cell cancer. CONCLUSION: Our findings highlight MIER2 as a key player in anchoring HDAC1 and inhibiting PGC1A expression through the deacetylation of P53, thereby inducing lipid accumulation in RCC and promoting drug resistance. Lipid-rich RCC cells compensate for energy production and sustain their own growth in a glycolysis-independent manner, evading the cytotoxic effects of targeted drugs and ultimately culminating in the development of drug resistance.

A mitochondrion-targeted cyanine agent for NIR-II fluorescence-guided surgery combined with intraoperative photothermal therapy to reduce prostate cancer recurrence.

Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.

Nonmetallic modified zero-valent iron for remediating halogenated organic compounds and heavy metals: A comprehensive review.

Zero Valent Iron (ZVI), an ideal reductant treating persistent pollutants, is hampered by issues like corrosion, passivation, and suboptimal utilization. Recent advancements in nonmetallic modified ZVI (NM-ZVI) show promising potential in circumventing these challenges by modifying ZVI's surface and internal physicochemical properties. Despite its promise, a thorough synthesis of research advancements in this domain remains elusive. Here we review the innovative methodologies, regulatory principles, and reduction-centric mechanisms underpinning NM-ZVI's effectiveness against two prevalent persistent pollutants: halogenated organic compounds and heavy metals. We start by evaluating different nonmetallic modification techniques, such as liquid-phase reduction, mechanical ball milling, and pyrolysis, and their respective advantages. The discussion progresses towards a critical analysis of current strategies and mechanisms used for NM-ZVI to enhance its reactivity, electron selectivity, and electron utilization efficiency. This is achieved by optimizing the elemental compositions, content ratios, lattice constants, hydrophobicity, and conductivity. Furthermore, we propose novel approaches for augmenting NM-ZVI's capability to address complex pollution challenges. This review highlights NM-ZVI's potential as an alternative to remediate water environments contaminated with halogenated organic compounds or heavy metals, contributing to the broader discourse on green remediation technologies.

Characterization of Mitoribosomal Small Subunit unit genes related immune and pharmacogenomic landscapes in renal cell carcinoma.

Mitoribosomes are essential for the production of biological energy. The Human Mitoribosomal Small Subunit unit (MRPS) family, responsible for encoding mitochondrial ribosomal small subunits, is actively engaged in protein synthesis within the mitochondria. Intriguingly, MRPS family genes appear to play a role in cancer. A multistep process was employed to establish a risk model associated with MRPS genes, aiming to delineate the immune and pharmacogenomic landscapes in clear cell renal cell carcinoma (ccRCC). MRPScores were computed for individual patients to assess their responsiveness to various treatment modalities and their susceptibility to different therapeutic targets and drugs. While MRPS family genes have been implicated in various cancers as oncogenes, our findings reveal a contrasting tumor suppressor role for MRPS genes in ccRCC. Utilizing an MRPS-related risk model, we observed its excellent prognostic capability in predicting survival outcomes for ccRCC patients. Remarkably, the subgroup with high MRPS-related scores (MRPScore) displayed poorer prognosis but exhibited a more robust response to immunotherapy. Through in silico screening of 2183 drug targets and 1646 compounds, we identified two targets (RRM2 and OPRD1) and eight agents (AZ960, carmustine, lasalocid, SGI-1776, AZD8055_1059, BPD.00008900_1998, MK.8776_2046, and XAV939_1268) with potential therapeutic implications for high-MRPScore patients. Our study represents the pioneering effort in proposing that molecular classification, diagnosis, and treatment strategies can be formulated based on MRPScores. Indeed, a high MRPScore profile appears to elevate the risk of tumor progression and mortality, potentially through its influence on immune regulation. This suggests that the MRPS-related risk model holds promise as a prognostic predictor and may offer novel insights into personalized therapeutic strategies.

Social participation and health in middle-aged and older empty nesters: A study on gender differences.

Background: The growing population of middle-aged and older empty nesters is characterized by poorer health, and social participation (SP) has been shown to improve this situation. However, few studies have investigated specific performance and gender differences between SP and health. The present study aims to address these issues. Methods: A total of 1207 middle-aged and older empty nesters over 45 years old were selected from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018). Random-effects analyses were used to explore the association between changes in SP (diversity, frequency, type) and changes in health status. Health status include physical health, mental health, self-reported health (SRH). Results: Female middle-aged and olderly empty nesters have significantly poorer health and participate in SP more frequently. The higher the diversity of SP, the better the health of middle-aged and olderly empty nesters, while higher frequency is beneficial to SRH. Female's participation in sports and Internet had better mental health and SRH, and mahjong helped female's mental health. Clubs are helpful for male's SRH. Conclusions: This study reveals the specifics of the association between SP and health status of middle-aged and older empty nesters. Therefore, all aspects of SP and gender differences should be taken into account when predicting and improving the health status. Help the government to better formulate policies to better cope with the increasing empty nest phenomenon and build a harmonious and stable society.

Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke.

BACKGROUND: Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. METHODS: The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. RESULTS: We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. CONCLUSION: This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke.

Amorphous Albumin Gadolinium-Based Nanoparticles for Ultrahigh-Resolution Magnetic Resonance Angiography.

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 µm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.

Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain.

Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777 spots, allowing us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of ischemia-associated gene expression in the peri-infarct area of the ischemic hemisphere. Analysis of ligand-receptor interactions in cell communication revealed galectin-9 to cell-surface glycoprotein CD44 (LGALS9-CD44) as a critical signaling pathway after ischemic injury and identified microglia and macrophages as the main source of galectins after stroke. Extracellular vesicle-mediated Lgals9 delivery improved the long-term functional recovery in photothrombotic stroke mice. Knockdown of Cd44 partially reversed these therapeutic effects, inhibiting oligodendrocyte differentiation and remyelination. In summary, our study provides a detailed molecular and cellular characterization of the peri-infact area in a murine stroke model and revealed Lgals9 as potential treatment target that warrants further investigation.

Pressure-driven dome-shaped superconductivity in topological insulator GeBi2Te4.

The discovery of new superconductors based on topological insulators always captures special attention due to their unique structural and electronic properties. High pressure is an effective way to regulate the lattice as well as electronic states in the topological insulators, thus altering their electronic properties. Herein, we report the structural and electrical transport properties of the topological insulator GeBi2Te4by using high-pressure techniques. The synchrotron x-ray diffraction revealed that GeBi2Te4underwent two structural phase transitions fromR-3m(phase I) toC2/m(phase II) and then intoIm-3m(phase III). Superconductivity was observed at 6.6 GPa to be associated with the first structural phase transition. The superconducting transition temperatureTcreached a maximum value of 8.4 K, accompanied by theRHsign changing from negative to positive at 14.6 GPa, then gradually decreased with increasing pressure in phase III, showing a dome-shaped phase diagram. The present results provide a platform for understanding the interplay between the crystal structure and superconductivity by the regulation of pressure in the topological insulator materials.

Intratumoral and peritumoral radiomics predict pathological response after neoadjuvant chemotherapy against advanced gastric cancer.

BACKGROUND: To investigate whether intratumoral and peritumoral radiomics may predict pathological responses after neoadjuvant chemotherapy against advanced gastric cancer. METHODS: Clinical, pathological, and CT data from 231 patients with advanced gastric cancer who underwent neoadjuvant chemotherapy at our hospital between July 2014 and February 2022 were retrospectively collected. Patients were randomly divided into a training group (n = 161) and a validation group (n = 70). The support vector machine classifier was used to establish radiomics models. A clinical model was established based on the selected clinical indicators. Finally, the radiomics and clinical models were combined to generate a radiomics-clinical model. ROC analyses were used to evaluate the prediction efficiency for each model. Calibration curves and decision curves were used to evaluate the optimal model. RESULTS: A total of 91 cases were recorded with good response and 140 with poor response. The radiomics model demonstrated that the AUC was higher in the combined model than in the intratumoral and peritumoral models (training group: 0.949, 0.943, and 0.846, respectively; validation group: 0.815, 0.778, and 0.701, respectively). Age, Borrmann classification, and Lauren classification were used to construct the clinical model. Among the radiomics-clinical models, the combined-clinical model showed the highest AUC (training group: 0.960; validation group: 0.843), which significantly improved prediction efficiency. CONCLUSION: The peritumoral model provided additional value in the evaluation of pathological response after neoadjuvant chemotherapy against advanced gastric cancer, and the combined-clinical model showed the highest predictive efficiency. CRITICAL RELEVANCE STATEMENT: Intratumoral and peritumoral radiomics can noninvasively predict the pathological response against advanced gastric cancer after neoadjuvant chemotherapy to guide early treatment decision and provide individual treatment for patients. KEY POINTS: 1. Radiomics can predict pathological responses after neoadjuvant chemotherapy against advanced gastric cancer. 2. Peritumoral radiomics has additional predictive value. 3. Radiomics-clinical models can guide early treatment decisions and improve patient prognosis.

Transposable elements cause the loss of self-incompatibility in citrus.

Self-incompatibility (SI) is a widespread prezygotic mechanism for flowering plants to avoid inbreeding depression and promote genetic diversity. Citrus has an S-RNase-based SI system, which was frequently lost during evolution. We previously identified a single nucleotide mutation in Sm-RNase, which is responsible for the loss of SI in mandarin and its hybrids. However, little is known about other mechanisms responsible for conversion of SI to self-compatibility (SC) and we identify a completely different mechanism widely utilized by citrus. Here, we found a 786-bp miniature inverted-repeat transposable element (MITE) insertion in the promoter region of the FhiS2-RNase in Fortunella hindsii Swingle (a model plant for citrus gene function), which does not contain the Sm-RNase allele but are still SC. We demonstrate that this MITE plays a pivotal role in the loss of SI in citrus, providing evidence that this MITE insertion prevents expression of the S-RNase; moreover, transgenic experiments show that deletion of this 786-bp MITE insertion recovers the expression of FhiS2-RNase and restores SI. This study identifies the first evidence for a role for MITEs at the S-locus affecting the SI phenotype. A family-wide survey of the S-locus revealed that MITE insertions occur frequently adjacent to S-RNase alleles in different citrus genera, but only certain MITEs appear to be responsible for the loss of SI. Our study provides evidence that insertion of MITEs into a promoter region can alter a breeding strategy and suggests that this phenomenon may be broadly responsible for SC in species with the S-RNase system.

Protective effect of intermittent hypobaric hypoxia against radiation-induced liver damage in Sprague-Dawley rats.

BACKGROUND: Without timely and effective interventions or treatments, radiation-induced liver damage (RILD) can lead to serious consequences for the patients and their families. OBJECTIVE: To investigate the protective effect of intermittent hypobaric hypoxia preconditioning (IHHP) in RILD. METHODS: Male adult SD rats were randomly divided into 8 groups including one control group, one only irradiation group and other experimental groups. Blood routine tests and liver function tests were all assessed with abdominal venous blood. Moreover, hematoxylin eosin (HE) staining and immunohistochemistry assay were used to detect the histopathological changes and expressions of transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor α (TNF-α) and hypoxia-inducible factor 1α (HIF-1α) in radiated liver sections. RESULTS: Blood routing tests showed that RBC, WBC and Hb were all significantly increased while the differences of these results between different groups with same simulated altitude were approximate. However, liver function in the IHHP plus irradiation at 4000 m group was significantly decreased (P< 0.05) compared to only irradiation groups, and the manifestation of HE and lower positive expression of TNF-α showed improved histopathological changes in the liver section. Furthermore, no significant difference of HIF-1α expression between any two groups treated with IHHP was observed. CONCLUSION: IHHP at the altitude of 4000 m group could alleviate the radioactive liver damage by downregulating TNF-α and less strong positive expression of TGF-ß1. Furthermore, patients exposed to radiation might benefit from this treatment to prevent or reduce the RILD.

Immunosuppressive MFAP2+ cancer associated fibroblasts conferred unfavorable prognosis and therapeutic resistance in gastric cancer.

PURPOSE: To explore the predictive merit of MFAP2+ cancer associated fibroblasts (CAFs) infiltration for clinical outcomes and adjuvant chemotherapy or immunotherapy responsiveness in gastric cancer (GC). METHODS: In this study, several independent cohorts were included respectively to dissect the relationship of clinical outcomes, therapeutic responses and tumor microenvironment with different MFAP2+ CAFs infiltration. Drug sensitivity analysis was conducted to predict the relationship between MFAP2+ CAFs infiltration and targeted drug response. Kaplan-Meier curves and the log-rank test were used to compare clinical outcomes of patients with different MFAP2+ CAFs infiltration. RESULTS: High MFAP2+ CAFs infiltration yielded inferior prognosis in terms of overall survival, progress free survival and recurrence free survival in GC. Patients with low MFAP2+ CAFs infiltration were more likely to gain benefit from adjuvant therapy. Moreover, low MFAP2+ CAFs infiltration could predict a promising response to immunotherapy in GC patients. MFAP2+ CAFs with immunosuppressive features were highly relevant to immune evasive contexture characterized by the dysfunction of CD8+ T cells. We found that MFAP2+ CAFs communicated with T cells, B cells and Macrophages through releasing macrophage migration inhibitor factor (MIF), which further suggested that MFAP2+ CAFs might promote therapeutic resistance through regulating T cells dysfunction and M2 macrophages polarization. CONCLUSION: Immunosuppressive MFAP2+ CAFs constructed an immune evasive tumor microenvironment characterized by incapacitated immune effector cells, consequently predicting inferior clinical outcomes and response on adjuvant therapy and immunotherapy in patients with GC. The potential of immunosuppressive MFAP2+ CAFs as a therapeutic target for GC deserved thoroughly exploration.

LncRNA-CCAT5-mediated crosstalk between Wnt/ß-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity.

BACKGROUND: Although the constitutively activated Wnt/ß-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis. METHODS: LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant ß-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD. RESULTS: We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the ß-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and ß-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnthigh GC, but not Wntlow GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnthigh PDX mice. CONCLUSIONS: We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.

Prognostic significance of PD-L1 expression in pancreatic cancer: evidence from an updated meta-analysis.

Recent studies revealed that programmed cell death ligand 1 (PD-L1) expression was associated with unfavorable prognosis in various solid tumors, but its clinical relevance for pancreatic cancer has not yet been well established. This meta-analysis summarizes the potential prognostic value of PD-L1 in pancreatic cancer. A quantitative meta-analysis was performed by a systematic search of databases including PubMed, EMBASE, Web of Science, Cochrane library, Scopus and Ovid for eligible studies on the prognostic significance of PD-L1 in pancreatic cancer patients. Pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated to evaluate the strength of the link between PD-L1 expression and clinical prognosis of patients. Seventeen eligible studies with 2669 patients were included in our study. A significant association was observed between PD-L1 abundance and poor overall survival (OS) of patients with pancreatic cancers, with a pooled hazard ratio (HR) of 1.902, 95% CI: 1.657-2.184. Sensitivity analysis confirmed the reliability of our results. Subgroup analysis shows that differences in regions and detection methods of PD-L1 did not change the overall predictive value of PD-L1 for poor prognosis in pancreatic cancer patients. This meta-analysis indicated that the expression of PD-L1 is associated with a worse OS in pancreatic cancer patients. Additionally, PD-L1 may act as a potential parameter for predicting poor prognosis and thus providing a promising target for anticancer therapy in pancreatic cancer.

Ebola virus VP35 perturbs type I interferon signaling to facilitate viral replication.

As one of the deadliest viruses, Ebola virus (EBOV) causes lethal hemorrhagic fevers in humans and nonhuman primates. The suppression of innate immunity leads to robust systemic virus replication of EBOV, leading to enhanced transmission. However, the mechanism of EBOV-host interaction is not fully understood. Here, we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis, which are highly clustered to Jak-STAT signaling. EBOV VP35 and VP30 were found to inhibit type I interferon (IFN) signaling. Moreover, exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1, and suppresses nuclear translocation of STAT1. Using serial truncated mutations of VP35, N-terminal 1-220 amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling. Remarkably, VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus (BDBV) and Marburg virus (MARV), resulting in stable replication to facilitate the pathogenesis. Altogether, this study enriches understanding on EBOV evasion of innate immune response, and provides insights into the interplay between filoviruses and host.

Association of Public Sports Space Perception with Health-Related Quality of Life in Middle-Aged and Older Adults-Evidence from a Survey in Shandong, China.

Creating a healthy living environment for middle-aged and older adults is a key strategy for countries to address the aging challenge, but the effects of such an environment on the health-related quality of life (HRQoL) of middle-aged and older adults remain underexplored. This study aimed to examine the link between public sports facilities and the HRQoL of middle-aged and older adult residents in communities. A total of 1169 respondents (average age: 66.84; male: 46.19%) were selected from the Shandong, China. This study measured respondents 'physical activity (PA) using the International Physical Activity Questionnaire, the HRQoL of respondents using the 36-item Short Form Health Survey, and the Public Sports Space Perception Scale for respondents' public sports space perception. Correlation analysis and logistic regression analysis were employed to test the relationship among public sports space perception, physical activity (PA), and HRQoL. The mediating role of PA was conducted using the PROCESS macro for SPSS. The results revealed that public sports space perception only influenced the HRQoL of middle-aged and older adults through light-intensity PA (PCS: B = 0.09, 95% CI 0.01, 0.03; MCS: B = 0.02, 95% CI 0.01, 0.05) among light-intensity PA, moderate-intensity PA, vigorous-intensity PA., and this mediation model varied across different age groups of middle-aged and older adults. Moreover, digital inclusion only moderated the psychological aspect of HRQoL of middle-aged and older adults (p < 0.05). This study provided empirical evidence for enhancing the HRQoL of middle-aged and older adults and offered useful insights for the planning and design of public sports facilities and the formulation of health management policies for middle-aged and older adults.

Therapeutic potential and protective role of GRK6 overexpression in pulmonary arterial hypertension.

Abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a key mechanism in the development of pulmonary arterial hypertension (PAH). Signal transducer and activator of transcription 3 (STAT3) signalling plays a critical role in modulating PASMC proliferation, and G-protein-coupled receptor kinase 6 (GRK6) regulates the STAT3 pathway. However, the mechanism underlying the relationship between GRK6 and PAH remains unclear. In this study, we aimed to investigate the role of GRK6 in PAH and determine its potential as a therapeutic target. We utilised hypoxia- and SU5416-induced PAH mouse models and a monocrotaline-induced PAH rat model to analyse the involvement of GRK6. We conducted gain- and loss-of-function experiments using mouse PASMCs. Modulation of GRK6 expression was achieved via a lentiviral vector in vitro and an adeno-associated virus serotype 1 encoding GRK6 in vivo. GRK6 was significantly downregulated in the lung tissues of PAH mice and rats, predominantly in PASMCs. Knockout of GRK6 exacerbated PAH, while both therapeutic and prophylactic overexpression of GRK6 alleviated PAH, as evidenced by a reduction in right ventricular systolic pressure, right ventricular wall to left ventricular wall plus ventricular septum ratio, pulmonary vascular media thickness, and pulmonary vascular muscularisation. Mechanistically, GRK6 overexpression attenuated hypoxia-induced PASMC proliferation and STAT3 phosphorylation. Conversely, knockdown of GRK6 promoted hypoxia-induced proliferation, which was mitigated by a STAT3 inhibitor. Our findings highlight the potential protective and beneficial roles of GRK6 in PAH; we propose a lung-targeted GRK6 gene therapy utilizing adeno-associated virus serotype 1 as a potential treatment approach for patients with PAH.

Polarization-maintaining photonic crystal fiber with high Brillouin gain coefficient for Brillouin lasers.

Stimulated Brillouin scattering (SBS) is effective for realizing a laser with an ultra-narrow linewidth. Although photonic crystal fiber (PCF) is considered an excellent medium to achieve SBS, it does not meet the requirements of low loss, large birefringence, and ease of fabrication. We propose a polarization-maintaining PCF (PM-PCF) structure and theoretically analyze the effects of the geometric structural parameters of the PM-PCF on various optical properties. Our theoretical analysis and experimental results contribute to the advancement of the field of ultra-narrow linewidth fiber lasers, distributed fiber sensing, and fiber-optic gyroscopes related to SBS.