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Abstract Background Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, disrupting ion transport. This results in organ damage and reduced life expectancy. Main body of the abstract Recent therapeutic advances targeting CFTR dysfunction have transformed treatment. CFTR modulator drugs directly target molecular defects underlying CF. Ivacaftor was the first approved potentiator benefiting gating mutations. Correctors like lumacaftor/ivacaftor and newer triple therapy combinations more effectively address the prevalent F508del mutation by improving CFTR processing. Gene and mRNA therapies also show promise, with preclinical studies editing CFTR in stem cell-derived epithelia and mRNA supplementation stabilizing acute exacerbations. Short conclusion Targeting CFTR dysfunction through small molecules, gene editing, and cell-based therapies represents a paradigm shift from symptom management to addressing genetic causes. Expanding access to innovative treatments across all patient subgroups may modify disease progression. While awaiting genetic cures, emerging strategies provide hope that CF outcomes can transition from early lethality to a chronic condition with an improved life expectancy and quality of life.

Abstract Background Visual quality after corneal refractive surgery is linked to the postoperative effective optical zone (EOZ). This study aims to compare long-term changes in the EOZ following small incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (FS-LASIK) for moderate and high myopia. Methods This study included 42 patients (72 eyes) who underwent either SMILE (36 eyes) or FS-LASIK (36 eyes). A custom software program based on the tangential curvature difference map of the Pentacam HR (Oculus Optikgeräte GmbH) was used to define the EOZ at 3 and 7 years postoperatively. The EOZ, its chronological changes compared to the programmed optical zone (POZ), and the corneal wavefront aberrations following SMILE and FS-LASIK were analyzed. Correlations between the EOZ changes and relevant parameters were evaluated. Results Three years postoperatively, EOZ following SMILE and FS-LASIK were 5.13 ± 0.27 mm and 4.70 ± 0.24 mm (P

Abstract Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease leading to destruction of insulin-producing pancreatic beta cells. Both genetic and environmental factors contribute to pathogenesis. The incidence of T1D is increasing worldwide, with significant geographic and ethnic variations. Patients present with symptoms of hyperglycemia and diabetes complications. Main body In T1D, autoreactive T cells and autoantibodies destroy beta cells, causing insulin deficiency. Exogenous insulin therapy is essential but cannot replicate normal physiology. Management requires intensive lifestyle education on diet, exercise, glucose monitoring and avoiding complications, in addition to insulin. Novel therapies like immunotherapy, cell transplantation, artificial pancreas devices and AI algorithms aim to improve care. Strategies for reversing T1D involve combination immunotherapies to block autoimmunity and regenerate beta cells via stem cells or xenotransplantation. Conclusion While type 1 diabetes remains challenging, ongoing research provides hope. Elucidating individualized disease mechanisms and translating findings into precision prevention and treatment approaches are critical to improving long-term outcomes. Innovative and multi-targeted therapies may fundamentally change the trajectory of T1D.

Purpose: To investigate the refractive and ocular biometric characteristics of children with mild hyperopia and distinguish between non-myopic and pseudomyopic eyes before cycloplegia. Methods: The eligible children underwent refractive error measurements using a NIDEK autorefractor before and after the administration of 0.5 % tropicamide. Ocular biometric parameters, including axial length (AL), anterior chamber depth (ACD), and lens thickness (LT), were measured using the IOLMaster 700 before cycloplegia. We performed comparative analyses between the non-myopic and pseudomyopic groups, categorized based on whether the spherical equivalent (SE) before cycloplegia exceeded −0.50 diopters (D). Univariable and multivariable regression analyses were performed to control for confounding factors. Results: The final analysis included 968 eyes. The participants with pseudomyopia were more likely to be boys (P = 0.029), younger (P = 0.004), less hyperopic (P

Abstract Dysregulated activation of Wnt/β-catenin signaling pathway is a frequent or common event during advanced progression of multiple cancers. With this signaling activation, it enhances their tumorigenic growth and facilitates metastasis and therapy resistance. Advances show that this signaling pathway can play dual regulatory roles in the control of cellular processes epithelial-mesenchymal transition (EMT) and cancer stemness in cancer progression. Aberrant activation of Wnt/β-catenin signaling pathway is shown to be common in prostate cancer and also castration-resistant prostate cancer (CRPC). However, the transcriptional regulators of this pathway in prostate cancer are still not well characterized. NURR1 (NR4A2) is an orphan nuclear receptor and plays an important role in the development of dopaminergic neurons. Previously, we have shown that NURR1 exhibits an upregulation in isolated prostate cancer stem-like cells (PCSCs) and a xenograft model of CRPC. In this study, we further confirmed that NURR1 exhibited an upregulation in prostate cancer and also enhanced expression in prostate cancer cell lines. Functional and molecular analyses showed that NURR1 could act to promote both in vitro (cancer stemness and EMT) and also in vivo oncogenic growth of prostate cancer cells (metastasis and castration resistance) via its direct transactivation of CTNNB1 (β-catenin) and activation of β-catenin to mediate the activation of Wnt/β-catenin signaling pathway. Moreover, we also demonstrated that NURR1 activity in prostate cancer cells could be modulated by small molecules, implicating that NURR1 could be a potential therapeutic target for advanced prostate cancer management.

Abstract Background Liver fibrosis results from chronic liver injury and is characterized by excessive deposition of extracellular matrix proteins including collagen. It can progress to cirrhosis and liver failure. Main body of the abstract Multiple cellular signaling pathways drive hepatic stellate cell activation and fibrogenesis. Advances in biomarkers, imaging modalities, and omics platforms enable noninvasive diagnosis and staging of liver fibrosis. Emerging antifibrotic approaches include medications like pirfenidone, obeticholic acid, and monoclonal antibodies targeting pro-fibrotic mediators. Cell therapies using mesenchymal stem cells demonstrate antifibrotic potential through paracrine immunosuppression. Tissue-engineered liver grafts and biomaterial carriers for localized drug delivery are promising technologies. Microfluidic liver-on-a-chip platforms with patient-derived cells provide unprecedented models to study human liver fibrosis and test drug candidates. Short conclusion Significant progress has elucidated mechanisms underlying liver fibrogenesis and uncovered novel therapeutic targets. Ongoing challenges include translating preclinical findings, improving antifibrotic efficacy, and enabling personalized precision medicine approaches. Further research into combinatorial therapies, biomarkers, and tissue engineering technologies will advance the treatment of liver fibrosis from all causes.

Abstract Background Hepatocellular carcinoma (HCC) is a common type of liver cancer, with a high mortality rate. Hepatocellular carcinoma is a type of liver cancer that can be effectively managed through early detection and accurate diagnosis, followed by a personalized treatment plan that may include surgical resection, liver transplantation, minimally-invasive techniques, immunotherapy, or targeted therapy depending on the stage and severity of the cancer. Main body of the abstract This paper discusses recent advances in the early detection, management, and prevention of HCC. The use of newer imaging techniques, such as Magnetic resonance imaging (MRI) and contrast-enhanced ultrasound, along with image segmentation technology and deep learning models, have greatly enhanced the accuracy of HCC detection and diagnosis. Minimally-invasive techniques, such as thermal ablation and radiofrequency ablation, have allowed for more precise and targeted destruction of tumors, while Nanoparticles, immunotherapy and targeted therapy have shown promise in the management of advanced stage HCC. The use of Artificial intelligence (AI) and machine learning has revolutionized HCC research, aiding in the identification of high-risk patients and predicting outcomes. Lifestyle modifications, such as weight management, alcohol avoidance, and hepatitis B vaccinations, can play a critical role in preventing HCC development. Short conclusion Recent advances in early detection, management, and prevention of HCC have shown promise in improving patient outcomes. The use of newer imaging techniques, minimally-invasive techniques, immunotherapy, targeted therapy, and AI and machine learning have greatly enhanced HCC research and management, while lifestyle modifications can play a critical role in prevention. However, further research is required to fully understand the potential benefits of nanoparticles, traditional Chinese medicine and herbal medicines in HCC treatment. Graphical Abstract

Abstract Background Tobacco smoking remains a major preventable cause of disease and death worldwide. Combustible cigarettes release thousands of chemicals that can initiate inflammatory pathways leading to smoking-related illness. This review aims to synthesize current scientific knowledge on mechanisms of smoking-induced disease, epidemiological trends, and clinical strategies from recent literature. Main body of the abstract At the cellular level, cigarette smoke triggers oxidative stress through reactive oxygen species (ROS), causing DNA damage. This provokes inflammatory signaling cascades mediated by damage-associated molecular patterns (DAMPs), receptors like RAGE and TLRs, and downstream cytokines. Smoking also disrupts apoptosis and autophagy. In the lungs, oxidative stress and inflammation from smoking play central roles in COPD pathogenesis. Smoking-induced oxidative DNA damage, chronic inflammation, and impaired immunity combine to promote lung carcinogenesis. For cardiovascular disease, smoking triggers endothelial dysfunction, platelet activation, and atherogenesis through oxidized LDL and effects on nitric oxide and adhesion molecules. Short conclusion Given the unequivocal evidence of health risks, smoking cessation is critical to reducing preventable death and disability. Both counseling and pharmacotherapy have proven efficacy for quitting, but efficacy remains limited long-term. Emerging nicotine products like e-cigarettes have unknown impacts on cessation and population health. Comprehensive efforts encompassing prevention, screening, treatment innovation, harm reduction, and policy reform focused on curbing smoking-attributable morbidity and mortality are warranted.

Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its remodeling, while tissue inhibitor of matrix MMP-2 (TIMP-2) inhibits active MMP-2. The present study aimed to look into how refractive development and the expression of MMP-2 and TIMP-2 in the guinea pigs' remodeled sclerae are affected by artificial light with varying spectral compositions. Three weeks old guinea pigs were randomly assigned to groups exposed to five different types of light: natural light, LED light with a low color temperature, three full spectrum artificial lights, i.e. E light (continuous spectrum in the range of ~390-780 nm), G light (a blue peak at 450 nm and a small valley 480 nm) and F light (continuous spectrum and wavelength of 400 nm below filtered). A-scan ultrasonography was used to measure the axial lengths of their eyes, every two weeks throughout the experiment. Following twelve weeks of exposure to light, the sclerae were observed by optical and transmission electron microscopy. Immunohistochemistry, Western blot and RT-qPCR were used to detect the MMP-2 and TIMP-2 protein and mRNA expression levels in the sclerae. After four, six, eight, ten, and twelve weeks of illumination, the guinea pigs in the LED and G light groups had axial lengths that were considerably longer than the animals in the natural light group while the guinea pigs in the E and F light groups had considerably shorter axial lengths than those in the LED group. Following twelve weeks of exposure to light, the expression of the scleral MMP-2 protein and mRNA were, from low to high, N group, E group, F group, G group, LED group; however, the expression of the scleral TIMP-2 protein and mRNA were, from high to low, N group, E group, F group, G group, LED group. The comparison between groups was statistically significant (p

Vascular dementia (VD), a chronic syndrome of acquired intellectual impairment resulting from cerebrovascular diseases, is closely linked to neuronal autophagy and apoptosis. As a standardized extract from Ginkgo biloba L. leaves, EGb761 is widely applied for treating cerebrovascular diseases owing to its neuroprotective effects, with on-going research exploring its therapeutic mechanisms. Rat model of VD and SH-SY5Y cell model with OGD/R injury was applied for this study. Results showed that EGb761 reduces OGD/R-elicited apoptosis and autophagosome production, whereas improving the viability of hippocampal neurons. EGb761 treatment led to a decrease in the ratios of p-AMPK/AMPK, Bax/Bcl-2, cleaved caspase-3/caspase-3, cleaved caspase-9/caspase-9, LC3-II/LC3-I, and level of Beciln-1, as well as enhancing the proportion of p-mTOR/mTOR. Additionally, EGb761 indicated a protective effect on rats' cognitive function. These results demonstrated EGb761′s specific therapeutic mechanism in preventing apoptosis and autophagy in VD models and improving cognitive functioning in VD rats through AMPK-mTOR signalling.

Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia resulting from inadequate insulin signaling. Current management relies on biomarkers such as hemoglobin A1c (HbA1c) to guide therapy, but emerging tools offer opportunities to transform care through more personalized approaches. Molecular biomarkers, including microRNAs, metabolites, and proteins, may enable better prediction of disease course and risk of complications in individuals. Genomic medicine leverages knowledge of genetic architecture to guide tailored prevention and treatment based on an individual’s genomic profile. Stem cell research differentiates functional insulin-secreting cells for transplantation into patients as an alternative to exogenous insulin. Gene silencing techniques such as RNA interference can restore defective insulin production and secretion pathways by inhibiting dysregulated gene expression. Artificial intelligence applications automate glucose monitoring, insulin delivery, diagnostic screening for complications, and digital health coaching. Despite barriers to translation, these technologies have disruptive potential for predictive, preventive, precise, and participatory care paradigms in diabetes management. Continued research on molecular biomarkers, pharmacogenomics, stem cell therapies, gene editing, and artificial intelligence (AI) aims to improve patient outcomes through more personalized approaches tailored to the specific biological vulnerabilities underlying each individual’s diabetes.

Abstract Background Long noncoding RNAs (lncRNAs) play a key role in the occurrence and progression of myopia. However, the function of lncRNAs in retinal ganglion cells (RGCs) in the pathogenesis of myopia is still unknown. The aim of our study was to explore the lncRNA-mediated competing endogenous RNA (ceRNA) network in RGCs during the development of myopia. Methods RNA sequencing was performed to analyze lncRNA and mRNA expression profiles in RGCs between guinea pigs with form-deprived myopia (FDM) and normal control guinea pigs, and related ceRNA networks were constructed. Then, potentially important genes in ceRNA networks were verified by qRT‒PCR, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore biological functions in the RGCs of FDM guinea pigs. The important genes and related signaling pathways were further verified by qRT‒PCR, immunohistochemistry, immunofluorescence and Western blot in myopia in FDM guinea pigs, FDM mice, and highly myopic adults. Results The distribution of RGCs was uneven, the number of RGCs was decreased, and RGC apoptosis was increased in FDM guinea pigs. In total, 873 lncRNAs and 2480 mRNAs were determined to be differentially expressed genes in RGCs from normal control and FDM guinea pigs. Via lncRNA-mediated ceRNA network construction and PCR verification, we found that lncRNA-XR_002792574.1 may be involved in the development of myopia through the miR-760-3p/Adcy1 pathway in RGCs. Further verification in FDM guinea pigs, FDM mice, and highly myopic adults demonstrated that the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis in RGCs might be related to cGMP/PKG, the apelin signaling pathway and scleral remodeling. Conclusion We demonstrated that the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis in RGCs might be related to myopia. On the one hand, the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis might inhibit the cGMP/PKG and apelin signaling pathways in RGCs, thereby causing RGC damage in myopia. On the other hand, the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis may cause myopic scleral remodeling through the ERK-MMP-2 pathway. These findings may reveal novel potential targets in myopia and provide reference value for exploration and development of gene editing therapeutics for hereditary myopia.

Tunnel disease detection and maintenance are critical tasks in urban engineering, and are essential for the safety and stability of urban transportation systems. Water stain detection presents unique challenges due to its variable morphology and scale, which leads to insufficient multiscale contextual information extraction and boundary information loss in complex environments. To address these challenges, this paper proposes a method called Deep Aggregation Network with Edge Information Supplement (DAEiS-Net) for detecting tunnel water stains. The proposed method employs a classic encoder–decoder architecture. Specifically, in the encoder part, a Deep Aggregation Module (DAM) is introduced to enhance feature representation capabilities. Additionally, a Multiscale Cross-Attention Module (MCAM) is proposed to suppress noise in the shallow features and enhance the texture information of the high-level features. Moreover, an Edge Information Supplement Module (EISM) is designed to mitigate semantic gaps across different stages of feature extraction, improving the extraction of water stain edge information. Furthermore, a Sub-Pixel Module (SPM) is proposed to fuse features at various scales, enhancing edge feature representation. Finally, we introduce the Tunnel Water Stain Dataset (TWS), specifically designed for tunnel water stain segmentation. Experimental results on the TWS dataset demonstrate that DAEiS-Net achieves state-of-the-art performance in tunnel water stain segmentation.

Bacillus Calmette–Guérin (BCG) immunotherapy has been a cornerstone treatment for non-muscle-invasive bladder cancer for decades and still faces challenges, such as severe immune adverse reactions, which reduce its use as a first-line treatment. This review examines BCG therapy’s history, mechanisms, and current status, highlighting how nanotechnology and bioengineering are revitalizing its application. We discuss novel nanocarrier systems aimed at enhancing BCG’s efficacy while mitigating specific side effects. These approaches promise improved tumor targeting, better drug loading, and an enhanced stimulation of anti-tumor immune responses. Key strategies involve using materials such as liposomes, polymers, and magnetic particles to encapsulate BCG or functional BCG cell wall components. Additionally, co-delivering BCG with chemotherapeutics enhances drug targeting and tumor-killing effects while reducing drug toxicity, with some studies even achieving synergistic effects. While most studies remain experimental, this research direction offers hope for overcoming BCG’s limitations and advancing bladder cancer immunotherapy. Further elucidation of BCG’s mechanisms and rigorous safety evaluations of new delivery systems will be crucial for translating these innovations into clinical practice.

We propose a shape-preserving building model reconstruction method that involves simplifying the original building mesh to accommodate various building shapes and complexities. To achieve this, we apply a structure-aware segmentation technique to parse the ubiquitous building points into building geometric primitives and building structural points, i.e., anchor points. After that, we generate dense building meshes from building semantic points in a topology-aware manner. As the geometric primitive semantics are assigned to the building points during the structure-aware segmentation process, these primitive semantics of the building points can be explicitly transferred into the created building meshes. To offer lightweight and accurate building models with enriched semantics, we leverage the building structural points as constraints for the subsequent edge collapse simplification algorithm. This algorithm effectively decimates irrelevant vertices and meshes, while preserving the essential building structural contours. The entire simplification process is performed in a shape-preserving manner, granting us flexible control over the imposition of different degrees of strength regarding various geometric primitives during the simplification. We conduct qualitative and quantitative analyses to evaluate the effectiveness of our method on both individual building models and a large-scale urban scene. Additionally, we extensively compare our proposed shape-preserving algorithm with other state-of-the-art mesh decimation methods to demonstrate our superiority.

BackgroundMyopia poses a global health concern and is influenced by both genetic and environmental factors. The incidence of myopia tends to increase during infectious outbreaks, such as the COVID-19 pandemic. This study examined the screen-time behaviors among Chinese children and adolescents and investigated the efficacy of artificial intelligence (AI)-based alerts in modifying screen-time practices.MethodsA cross-sectional analysis was performed using data from 6,716 children and adolescents with AI-enhanced tablets that monitored and recorded their behavior and environmental light during screen time.ResultsThe median daily screen time of all participants was 58.82 min. Among all age groups, elementary-school students had the longest median daily screen time, which was 87.25 min and exceeded 4 h per week. Children younger than 2 years engaged with tablets for a median of 41.84 min per day. Learning accounted for 54.88% of participants’ screen time, and 51.03% (3,390/6,643) of the participants used tablets for 1 h at an average distance

Abstract Background The most common site of metastasis in colorectal cancer (CRC) is the liver and liver metastases occur in more than 50% of patients during diagnosis or treatment. The occurrence of metastasis depends on a series of events known as the invasive-metastasis cascade. Currently, the underlying genes and pathways regulating metastasis initiation in the liver microenvironment are unknown. Methods We performed systematic CRISPR/Cas9 screening using an in vivo mouse model of CRC liver metastasis to identify key regulators of CRC metastasis. We present the full results of this screen,which included a list of genes that promote or repress CRC liver colonization. By silencing these genes individually, we found that chondroitin sulfate synthase 1 (CHSY1) may be involved in CRC metastasis. We verified the function of CHSY1 and its involvement in liver metastasis of CRC through in vivo and in vitro experiments. Result The results of TCGA and CRISPR/Cas9 showed that CHSY1 was overexpressed in CRC primary and liver metastasis tissues and indicated a worse clinical prognosis. In vitro and in vivo experiments confirmed that CHSY1 facilitated the liver metastasis of CRC and CHSY1 induced CD8+ T cell exhaustion and upregulated PD-L1 expression. The metabolomic analysis indicated that CHSY1 promoted CD8+ T cell exhaustion by activating the succinate metabolism pathway leading to liver metastasis of CRC. Artemisinin as a CHSY1 inhibitor reduced liver metastasis and enhanced the effect of anti-PD1 in CRC. PLGA-loaded Artemisinin and ICG probe reduced liver metastasis and increased the efficiency of anti-PD1 treatment in CRC. Conclusion CHSY1 could promote CD8+ T cell exhaustion through activation of the succinate metabolic and PI3K/AKT/HIF1A pathway, leading to CRC liver metastasis. The combination of CHSY1 knockdown and anti-PD1 contributes to synergistic resistance to CRC liver metastasis. Artemisinin significantly inhibits CHSY1 activity and in combination with anti-PD1 could synergistically treat CRC liver metastases. This study provides new targets and specific strategies for the treatment of CRC liver metastases, bringing new hope and benefits to patients.

Abstract Severe hypoxia would aggravate the acute kidney injury (AKI) in high-altitude areas and continuous renal replacement therapy (CRRT) has been used to treat critically ill patients with AKI. However, the characteristics and outcomes of CRRT in critically ill patients at AKI in high altitudes and the optimal timing of CRRT initiation remain unclear. 1124 patients were diagnosed with AKI and treated with CRRT in the ICU, comprising a high-altitude group (n = 648) and low-altitude group (n = 476). Compared with the low-altitude group, patients with AKI at high altitude showed longer CRRT (4.8 vs. 3.7, P = 0.036) and more rapid progression of AKI stages (P 0.05). Referring to the analysis of survival and kidney recovery curves, a higher mortality but a lower possibility of renal recovery was observed in the high-altitude group (P

Abstract Background Helicobacter pylori (H. pylori) is a bacterial infection that is prevalent and affects more than half of the world's population, causing stomach disorders such as gastritis, peptic ulcer disease, and gastric cancer. Main body The diagnosis of H. pylori infection relies on invasive and non-invasive techniques emerging artificial intelligence, and antibiotic therapy is available, but antibiotic resistance is a growing concern. The development of a vaccine is crucial in preventing H. pylori-associated diseases, but it faces challenges due to the bacterium's variability and immune escape mechanisms. Despite the challenges, ongoing research into H. pylori's virulence factors and immune escape mechanisms, as well as the development of potential vaccine targets, provides hope for more effective management and prevention of H. pylori-associated diseases. Recent research on H. pylori's immune escape mechanisms and novel immune checkpoint inhibitors could also lead to biomarkers for early cancer detection. Therefore, experts have suggested a combination of traditional and herbal medicine with artificial intelligence to potentially eradicate H. pylori. Short conclusion H. pylori infection remains a significant global health problem, but ongoing research into its properties and advanced technologies in addition to the combination of traditional and herbal medicine with artificial intelligence may also lead to the eradication of H. pylori-associated diseases. Graphical abstract

Auxins play crucial regulatory roles in plants coping with cadmium (Cd) stress. However, the regulatory mechanism by which auxins alleviate Cd toxicity in tomato seedlings remains unclear. Here, we demonstrate that exposure to Cd stress leads to dynamic changes in the auxin response in tomato roots, characterized by an initial increase followed by a subsequent weakening. Under Cd stress, tomato seedlings show primary root- and hypocotyl-growth inhibition, accompanied by the accumulation of Cd and reactive oxygen species (ROS) in the roots. The exogenous application of 1-naphthylacetic acid (NAA) does not mitigate the inhibitory effect of Cd toxicity on primary root growth, but it does significantly enhance lateral root development under Cd stress. Auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA) and 2,3,5-triiodobenoic acid (TIBA), aggravate the growth inhibition of primary roots caused by Cd stress. Additionally, lateral root development was inhibited by NPA. However, applying auxin synthesis inhibitors L-kynurenine (kyn) and yucasin alleviated the tomato root growth inhibition caused by Cd stress; between them, the effect of yucasin was more pronounced. Yucasin mitigates Cd toxicity in tomato seedlings by reducing Cd2+ absorption and auxin accumulation, strengthening ROS scavenging, and reducing cell death in roots. These observations suggest that yucasin potentially mitigates Cd toxicity and improves the tolerance of tomato seedlings to Cd stress.

Sinojackia Hu. comprises five to eight Chinese endemic species with high ornamental and medicinal value. However, the generic limits, interspecific relationships and evolutionary history of the genus remain unresolved. In this study, we newly sequenced three plastomes of S. oblongicarpa and compared them with those of the other congeneric species to explore the taxonomic delimitation of the species and the evolutionary history of the genus. The plastome structure of Sinojackia species was extremely conserved in terms of number of genes, sequence length, and GC content. The codon usage patterns revealed that natural selection may be the main factor shaping codon usage bias. Our phylogenetic tree shows that Sinojackia is monophyletic and can be divided into two clades. Sinojackia oblongicarpa as a distinct species is supported for it is distantly related to S. sarcocarpa. The evolutionary analysis of morphological features indicates that the woody mesocarp is an ancestral feature. Sinojackia originated in central Southeast China during the early Miocene. In this period, it experienced elevated diversification and migrated from central Southeast China to the Hunan Province and the Sichuan Province with the development of the Asian monsoon and East Asian flora. Glacial–interglacial interactions with the monsoon climate may provide favorable expansion conditions for Sinojackia on a small scale.

The COVID-19 pandemic has reshaped our daily lives and the way we interact with urban green–blue spaces (UGBS), particularly in the economically challenged regions of Northwest China. Our study, utilizing surveys and social media, delves into the pandemic’s impact on UGBS engagement in this area, offering critical insights for urban planning amidst a global health crisis. We found a gender-balanced but preference-specific engagement in UGBS, with women and married couples in the Chengguan District of Lanzhou city showing affinity. Moreover, educational levels and proximity to academic institutions emerged as key factors influencing UGBS use, pointing to the importance of educational attainment in engagement diversity. Enhancing safety, creating child-friendly and leisure facilities for families, and designing vibrant spaces for socializing are vital, and placing UGBS near educational districts could also promote environmental awareness and scientific learning. Furthermore, the pandemic has reshaped public priorities, elevating the value of accessible, safe UGBS. This shift is evidenced by varied motivations for UGBS visits, with an emphasis on health, nature connectivity, and leisure. Women, older adults, and families, each with their distinct reasons, were drawn to UGBS for activities ranging from recreation to relaxation. Our findings advocate for the creation of multifunctional UGBS that cater to these varied interests, incorporating features such as air-purifying plants, scenic pathways, and zones for family activities, all underpinned by enhanced safety and accessibility. The study also highlights distinct transportation preferences among residents of Chengguan’s northern and southern parts, suggesting a tailored approach to urban infrastructure that accommodates pedestrian access and public transit use. To prevent overcrowding, adjusting facility hours and event timings based on peak visitation times is recommended. Moreover, improving walkways and public transport connectivity is essential not just for convenience but also for ensuring that these green spaces are equitable and financially accessible, fostering inclusive access to these essential urban areas. During the pandemic, social media revealed a growing search for spiritual fulfillment within UGBS, highlighting their importance in societal well-being and coping mechanisms. In response, there’s a compelling opportunity for UGBS to evolve by incorporating designated areas for spiritual relaxation, along with mental health support services. By actively monitoring social media feedback and trends, these spaces can adapt and refine their offerings, ensuring that they meet the community’s changing needs more effectively. Our study highlights the importance of tailoring UGBS to meet diverse community needs, especially during crises. It emphasizes creating multifunctional, accessible UGBS that reflect demographic trends, transportation habits, and public preferences, aiming to boost community resilience and well-being. Drawing from research conducted amidst a worldwide crisis, our study provides key recommendations for the future evolution of UGBS, urging the creation of inclusive environments that bolster the health and well-being of urban populations.

Abstract Importance Both the morbidity and mortality of prostate cancer are increasing worldwide. Updated evaluations of prostate cancer burden and its global, regional and national patterns are essential for formulating effective preventive strategies. Objective To investigate prostate cancer incidence, mortality, and disability-adjusted life years (DALYs) between 1990 and 2019 to facilitate preventive measures and control planning. Methods Annual incident cases, deaths, DALYs, age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and age-standardized DALYs rates (ASDRs) of prostate cancer between 1990 and 2019 were derived from the Global Burden of Diseases study 2019. Percentage changes in incident cases, deaths and DALYs and estimated annual percentage changes (EAPCs) in ASIRs, ASMRs and ASDRs were calculated to quantify temporal trends. Correlations between EAPCs and socio-demographic index (SDI) and universal health coverage index (UHCI) were evaluated by Pearson correlation analyses. Results Globally, the number of incident cases, deaths, and DALYs of prostate cancer increased by 116.11%, 108.94%, and 98.25% from 1990 to 2019, respectively. The ASIR increased by an average of 0.26% (95% CI: 0.14%, 0.37%) per year between 1990 and 2019, while the ASMR and ASDR decreased by an average of – 0.75% (95% CI: – 0.84%, – 0.67%) and – 0.71% (95% CI: – 0.78%, – 0.63%) per year in this period, respectively. Epidemic trends in the burdens of prostate cancer were not uniform throughout different groups of SDI or geography. The burdens of prostate cancer varied across SDI regions, with an increasing trend in ASIR, ASMR, and ASDR in low and low-middle SDI regions between 1990 and 2019. A significant positive correlation between the EAPC in ASIR and UHCI was observed in countries with a UHCI

The increasing global demand for sustainable urban development has led to the widespread adoption of Green Infrastructure (GI) worldwide. However, there remains a lack of understanding regarding public support for implementing GI specifically at industrial sites. This study focuses on promoting industrial GI (IGI) and examines residents' willingness to pay (WTP) for GI installation and the nonmarket value of GI is estimated using the travel cost method (TCM). Among respondents residing in neighborhoods surrounding industrial areas, a significant proportion (90%) expressed their WTP for GI promotion. The aggregated annual WTP for IGI and Neighbourhood GI (NGI) were estimated to be approximately CNY 16.2 million and CNY 21.9 million, respectively. Moreover, the annual nonmarket value provided by IGI and NGI to human well-being was estimated to be around CNY 4.5 million and CNY 20.7 million, respectively. The study reveals that middle-aged and middle-income groups exhibit a higher propensity for WTP, with specific GI measures such as rain gardens, vegetated swales, trees, and naturalized landscaping receiving greater WTP intentions. The primary challenges identified for promoting IGI include cost, policy, and maintenance considerations. This study recommends customizing planning approaches for IGI promotion, considering diverse demographics, including constructing youth apartments near industrial areas, implementing age-friendly design features, and enhancing landscape design in elderly communities. Disseminating GI knowledge through media and partnering with local organizations for awareness enhancement is essential for encouraging higher WTP. The effectiveness of water features and pedestrian-friendly areas in improving and promoting IGI spaces is also highlighted. These findings offer valuable insights to policymakers and city planners, facilitating the identification of more effective GI designs for promoting sustainable urban environments that align with societal preferences and demands.

Spatially explicit information on the distribution of dominant tree species groups and aboveground biomass (AGB) in forested areas is essential for developing targeted forest management and biodiversity conservation measures, as well as assessing forest carbon sequestration capacity. There is a shortage of continuously updated 30-m spatial resolution products for mapping dominant tree species groups. The vast majority of remote sensing-based AGB estimation approaches have relatively low accuracy for dominant tree species groups or forest types and are unsuitable for AGB modeling. Therefore, this study aims to develop an integrated framework that considers the phenological characteristics of different tree species to improve the mapping accuracies of forest dominant tree groups and corresponding AGB estimates. Thirty-meter resolution maps of dominant tree species groups were created using machine learning algorithms and phenological parameters. Features extracted from optical and radar images and phenological characteristics were used to construct AGB estimation models in a temporally consistent manner to improve the AGB estimation accuracy and perform dynamic AGB monitoring. The proposed method accurately characterized the dynamic distribution of the dominant tree species groups in the study area. The traditional AGB model that does not consider different forest types or species had an R2 value of 0.52, whereas the proposed model that considers phenology and forest types had an R2 value of 0.67. This result indicates that incorporating information on phenology and dominant species improves the accuracy of AGB estimations. The AGB in most regions was 30–55 t/ha, showing that the majority of the forests were young or middle-aged stands, and the areal percentage of AGB greater than 30 t/ha increased during the study period, suggesting an improvement in forest quality. Furthermore, the oak AGB was the highest, indicating that oak afforestation should be encouraged to enhance the carbon sequestration capacity of future forest ecosystems. The results provide new insights for researchers and managers to understand the trends of forest development and forest health, as well as technical information and a database for formulating more rational forest management strategies.

Abstract Background In response to the coronavirus disease 2019 (COVID-19) pandemic, the Chinese government implemented the dynamic COVID-zero strategy. We hypothesized that pandemic mitigation measures might have reduced the incidence, mortality rates, and case fatality ratios (CFRs) of the human immunodeficiency virus (HIV) in 2020–2022. Method We collected HIV incidence and mortality data from the website of the National Health Commission of the People’s Republic of China from January 2015 to December 2022. We compared the observed and predicted HIV values in 2020–2022 with those in 2015–2019 using a two-ratio Z-test. Results From January 1, 2015, to December 31, 2022, a total of 480,747 HIV incident cases were reported in mainland China, of which 60,906 (per year) and 58,739 (per year) were reported in 2015–2019 (pre-COVID-19 stage) and 2020–2022 (post-COVID-19 stage), respectively. The average yearly HIV incidence decreased by 5.2450% (from 4.4143 to 4.1827 per 100,000 people, p

Abstract Background Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. Methods Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models. Results Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis. Conclusion Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

Background: Little is known about changes in astigmatism during atropine treatment. We aimed to explore the effects of atropine 0.01% eye drops on both spherical and cylindrical refractive errors in myopic children. Methods: Children aged 6–14 years with myopia ≥ −6.00 D and −2.00 D in at least one eye were enrolled. Subjects were randomised either to receive atropine 0.01% once nightly with single-vision lenses or simply to wear single-vision lenses and were followed up at 3-month intervals. Cycloplegic refraction and axial length were measured. The magnitude and direction of total astigmatism (TA), corneal astigmatism (CA), and residual astigmatism (RA) were evaluated. Results: Overall, 119 eyes (69 eyes in the atropine group and 50 eyes in the control group) were included in the final analyses after 9 months. Atropine-treated eyes showed significantly less progression of myopia than did control eyes (spherical equivalent: −0.35 ± 0.33 vs. −0.56 ± 0.49 D, p = 0.001; axial length: 0.20 ± 0.19 vs. 0.33 ± 0.19 mm, p

Abstract Background Midazolam (MDZ) is an anaesthetic that is widely used for anxiolysis and sedation. More recently, MDZ has also been described to be related to the outcome of various types of carcinomas. However, how MDZ influences the progression of hepatocellular carcinoma (HCC) and its effects on the biological function and tumour immune microenvironment of this type of tumour remain unknown. Methods The effects of MDZ on the proliferation, invasion, and migration of HCC cell lines were examined in vitro using the Cell Counting Kit 8 (CCK8), 5-ethynyl-2ʹ-deoxyuridine (EdU), Transwell, and wound healing assays. Additionally, western blotting was employed to confirm that PD-L1 was expressed. Chromatin immunoprecipitation-seq (ChIP-seq) analysis was used to pinpoint the transcriptional regulation regions of NF-κB and programmed death-ligand 1 (PD-L1). A C57BL/6 mouse model was used to produce subcutaneous HCC tumors in order to evaluate the in vivo performance of MDZ. Mass spectrometry was also used to assess changes in the tumour immunological microenvironment following MDZ injection. Results The HCC-LM3 and Hep-3B cell lines’ proliferation, invasion, and migration were controlled by MDZ, according to the results of the CCK8, EdU, Transwell, and wound healing assays. PD-L1 expression was shown by ChIP-seq analysis to be boosted by NF-κB, and by Western blotting analysis, it was shown that MDZ downregulated the expression of NF-κB. Additionally, in vivo tests revealed that intraperitoneal MDZ injections reduced HCC tumor development and enhanced the effectiveness of anti-PD-1 therapy. The CD45+ immune cell proportions were higher in the MDZ group than in the PBS group, according to the mass spectrometry results. Injection of MDZ resulted in a decrease in the proportions of CD4+ T cells, CD8+ T cells, natural killer (NK) cells, monocytes, Tregs, and M2 macrophages and a rise in the proportion of dendritic cells. Additionally, the concentrations of the cytokines IFN-g and TNF-a were noticeably raised whereas the concentrations of the CD8+ T-cell fatigue markers ICOS, TIGIT, and TIM3 were noticeably lowered. Conclusion According to this study, MDZ inhibited the progression of HCC by inhibiting the NF-κB pathway and reducing the exhaustion of CD8+ T cells. In clinical practice, MDZ combined with anti-PD-1 therapy might contribute to synergistically improving the antitumor efficacy of HCC treatment.

Background: The prominent mitochondrial metabolic changes of the atrium reportedly have significant impact on electrical signals and structural remodeling which play important roles in the occurrence and development of atrial fibrillation (AF). However, the mechanism is not completely known.Objective: This study was aimed to explore the mitochondrial metabolism reprogrammed in AF patients by integrating metabolomics as well as proteomics of human atrium tissues.Methods and Results: Left atrial tissue samples were harvested from 10 non-valvular AF patients and 10 matched samples from healthy donors for transplantation. In metabolomics analysis, 113 metabolites were upregulated and 10 metabolites were downregulated in AF, where multiple pathways related to mitochondrial energy metabolism were enriched. Correlation analysis between the differentially expressed proteins and metabolites identified several hub proteins related to mitochondrial function including Glycerol-3-phosphate dehydrogenase 2 (GPD2), Synemin (SYNM), Plectin (PLEC), with MCC score of 27, 17, 16, respectively, which have the most interactions with the dysregulated metabolites and ranked at the top in network string interactions scored by MCC method. All 330 differentially expressed proteins including 225 upregulated and 105 downregulated molecules were revealed and analyzed, which identified the downregulation of GPD2 (p = 0.02 and FC = 0.77), PLEC (p < 0.001 and FC = 0.71) and SYNM (p = 0.04 and FC = 0.76) in AF patients. Gene Set Variation Analysis (GSEA) showed mitochondrial metabolism-associated pathways including oxidative phosphorylation (NES: −1.73) and ATP biosynthetic process (NES: −2.29), were dramatically diversified in human AF. In GSVA, the expression levels of GPD2, PLEC, and SYNM were demonstrated to be associated with multiple metabolic pathways related to mitochondrial function (e.g., lipid metabolism and AMP activated protein kinase signaling) and cardiac structural and electrical remodeling (e.g., contractile fiber, ion homeostasis), which were proven vital in the development and maintenance of AF.Conclusion: In all, this study provides new insights into understanding the mechanisms of AF progression, especially the reprogramming mitochondrial metabolism, and identifies several genes related to mitochondrial function as novel targets for AF, which may be involved in the occurrence and development of AF.

Prostate cancer (PCa) is a prevalent malignant disease and the primary reason for cancer-related mortality among men globally. GLIS1 (GLIS family zinc finger 1) is a key regulator in various pathologies. However, the expression pattern, clinical relevance, and immunomodulatory function of GLIS1 in PCa remain unclear. In this study, GLIS1 was discovered to serve as a key gene in PCa by integrating mRNA and miRNA expression profiles from GEO database. We systematically explored the expression and prognostic values of GLIS1 in cancers using multiple databases. Additionally, we examined the functions of GLIS1 and the relationship between GLIS1 expression levels and immune infiltration in PCa. Results showed that GLIS1 was differentially expressed between normal and tumor tissues in various cancer types and was significantly low-expressed in PCa. Low GLIS1 expression was associated with poor PCa prognosis. GLIS1 was also involved in the activation, proliferation, differentiation, and migration of immune cells, and its expression showed a positive correlation with the infiltration of various immune cells. Moreover, GLIS1 expression was positively associated with various chemokines/chemokine receptors, indicating the involvement in regulating immune cell migration. In summary, GLIS1 is a potential prognostic biomarker and a therapeutic target to modulate anti-tumor immune response in PCa.

Abstract Purpose The aim of this study was to identify trends and focuses in the field of Fuchs endothelial corneal dystrophy (FECD) research. Methods A bibliometric analysis based on the Web of Science Core Collection was conducted. All publications related to FECD from 2001 to 2020 were extracted and analyzed. VOSviewer v.1.6.17 was used to construct a visualization map and evaluate the trends and focuses in FECD research. Results A total of 1,041 publications were extracted. The rate of global publications has steadily increased. The United States produced the highest number of publications (461), the highest number of citations (18,757), and the highest H index (69). Melles GRJ published the highest number of papers (60), and Price FW had the highest number of citations (4,154) in the FECD research field. The highest number of publications came from the journal Cornea (279). Keywords were classified into four clusters: (1) corneal transplantation surgery, (2) surgical techniques and instruments, (3) corneal parameter measurement, and (4) genetic and molecular pathomechanisms. The average appearing years (AAYs) of the keywords were evaluated. Recently appearing keywords included “Tcf4 gene” (AAY of 2018.3), “ctg18.1” (AAY of 2017.2), “trinucleotide repeat expansion” (AAY of 2018.3), “rock inhibitor” (AAY of 2017.4), and “descemetorhexis” (AAY of 2017.4). Conclusions The United States has a dominant position in FECD research. Although corneal transplantation surgery has been the most mainstream area of FECD research field for a long time, gene mutations such as the TCF4 CTG trinucleotide repeat expansion, nonsurgical interventions such as rho-associated kinase inhibitors, and newer surgical methods such as descemetorhexis without endothelial keratoplasty are potential research hotspots.

Abstract Background Accumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood. Methods The regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model. Results Endothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs. Conclusions Enhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the TMPRSS2:ERG fusion gene.

Obesity, a chronic metabolic disease with a complex pathophysiology, is caused by several variables. High-fat diets lead to the disruption of the gut microbiota and impaired gut barrier function in obese people. The dysbiosis and its metabolites through the intestinal barrier lead to an imbalance in energy metabolism and inflammatory response, which eventually contributes to the development of chronic diseases such as diabetes, hypertension, and cardiovascular disease. Current medicines are therapeutic to obesity in the short term; however, they may bring significant physical and emotional problems to patients as major side effects. Therefore, it is urgent to explore new therapeutic methods that have definite efficacy, can be taken for a long time, and have mild adverse effects. Numerous studies have demonstrated that traditional Chinese medicine (TCM) can control the gut microbiota in a multi-targeted and comprehensive manner, thereby restoring flora homeostasis, repairing damaged intestinal mucosal barriers, and eventually curbing the development of obesity. The active ingredients and compounds of TCM can restore the normal physiological function of the intestinal mucosal barrier by regulating gut microbiota to regulate energy metabolism, inhibit fat accumulation, affect food appetite, and reduce intestinal mucosal inflammatory response, thereby effectively promoting weight loss and providing new strategies for obesity prevention and treatment. Although there are some studies on the regulation of gut microbiota by TCM to prevent and treat obesity, all of them have the disadvantage of being systematic and comprehensive. Therefore, this work comprehensively describes the molecular mechanism of obesity mediated by gut microbiota based on the research state of obesity, gut microbiota, and TCM. A comprehensive and systematic summary of TCM targeting the regulation of gut microbiota for the treatment of obesity should be conducted in order to provide new strategies and ideas for the treatment of obesity.

BackgroundA microneedle patch loaded with Atractylodes macrocephala Rhizoma water extract was prepared for the treatment of mammary gland hyperplasia. To explore the relationship between Mammary gland hyperplasia and intestinal flora.Materials and methodsPreparation of the microneedle patch by micromolding method, the prescription of the microneedle was optimized by the Box-Behnken Design response surface test, and the micro-morphology, penetration, toughness, and brittleness were investigated. In vitro release of drug-loaded microneedles was measured by diffusion cell method. The rat model of mammary gland hyperplasia was prepared by the combination of estradiol benzoate-progesterone, and the microneedle patch of Atractylodes macrocephala Rhizoma aqueous extract was used for intervention treatment. The change of levels in E2, P, and PRL in rat serum was determined. The intestinal contents of rats were collected and the changes in intestinal flora in MGH rats were analyzed by 16s rRNA high-throughput sequencing.ResultsThe optimized microneedle formula is a PVA concentration of 6.0%, HA concentration of 15.5%, and PVPK30 concentration of 16.0%. The prepared microneedle tip loaded with Atractylodes macrocephala Rhizoma aqueous extract has complete, sharp, and no bubbles and the needle rate of the microneedle array is in the range of 95%~100%. The bending rate of the microneedle is about 12.7%, and it has good flexibility, and the microneedle can puncture 4 layers of ParafilmⓇ membrane smoothly, and the puncture rate is more than 96%. The in vitro release of the microneedle was characterized by rapid release. The results of animal experiments showed that Atractylodes macrocephala Rhizoma aqueous extract microneedle patch could significantly reduce the E2 level, significantly reduce the PRL level, and significantly increase the P level. At the same time, it can regulate the abundance and diversity of intestinal flora in MGH rats, improve the intestinal flora disorder caused by mammary gland hyperplasia, and balance the community structure.ConclusionThe prepared microneedle containing Atractylodes macrocephala Rhizoma aqueous extract has good toughness and brittle strength, can penetrate the skin and enter the dermis, and effectively deliver drugs to play a role in the treatment of mammary gland hyperplasia.

Background GLI-similar 1 (GLIS1) is one of of Krüppel-like zinc finger proteins, which are either stimulators or inhibitors of genetic transcription. Nevertheless, its effects on T cell were elusive.Methods In this study, we intend to explore the effects of GLIS1 on modulating the anticancer potency of CD8+ T cells in hepatocellular carcinoma (HCC). The expression of GLIS1 in CD8 peripheral blood mononuclear cell and CD8 tumor-infiltrating lymphocytes of HCC tissues was validated by quantificational real-time-PCR and flow cytometry. The anticancer potency of CD8+ T cells with GLIS1 knock down was confirmed in C57BL/6 mouse model and HCC patient-derived xenograft mice model. GLIS1–/– C57BL/6 mice was applied to explore the effects GLIS1 on tumor immune microenvironment. Chromatin immunoprecipitation and RNA transcriptome sequencing analysis were both performed in GLIS1-knock down of CD8+ T cells.Results GLIS1 was upregulated in exhausted CD8+ T cells in HCC. GLIS1 downregulation in CD8+ T cells repressed cancer development, elevated the infiltrate ability of CD8+ T cells, mitigated CD8+ T cell exhaustion and ameliorated the anti-PD1 reaction of CD8+ T cells in HCC. The causal link beneath this included transcriptional regulation of SGK1-STAT3-PD1 pathway by GLIS1, thereby maintaining the abundant PD1 expression on the surface of CD8+ T cells.Conclusion Our study revealed that GLIS1 promoted CD8+ T cell exhaustion in HCC through transcriptional regulating SGK1-STAT3-PD1 pathway. Downregulating the expression of GLIS1 in CD8+ T cells exerted an effect with anti-PD1 treatment synergistically, revealing a prospective method for HCC immune therapy.

The purpose of the study was to investigate the effect of artificial light with different spectral composition and distribution on axial growth in guinea pigs. Three-week-old guinea pigs were randomly assigned to groups exposed to natural light, low color temperature light-emitting diode (LED) light, two full spectrum artificial lights (E light and Julia light) and blue light filtered light with the same intensity. Axial lengths of guinea pigs’ eyes were measured by A-scan ultrasonography prior to the experiment and every 2 weeks during the experiment. After light exposure for 12 weeks, retinal dopamine (DA), dihydroxy-phenylacetic acid (DOPAC) levels and DOPAC/DA ratio were analyzed by high-pressure liquid chromatography electrochemical detection and retinal histological structure was observed. Retinal melanopsin expression was detected using Western blot and immunohistochemistry. After exposed to different kinds of light with different spectrum for 4 weeks, the axial lengths of guinea pigs’ eyes in LED group and Julia light group were significantly longer than those of natural light group. After 6 weeks, the axial lengths in LED light group were significantly longer than those of E light group and blue light filtered group. The difference between axial lengths in E light group and Julia light group showed statistical significance after 8 weeks (p

Objective: To prepare acetylated Taraxacum mongolicum polysaccharide from Taraxacum mongolicum Hand.-Mazz, and study its structural characteristics, antioxidant activity and antibacterial activity. Methords: The structure of the polysaccharide extracted by water extraction and then alcohol precipitation method was modified by acetic anhydride method to obtain its acetylated. Infraed spectroscopy, scanning electron microscope and X-ray powder diffraction were used to structural characteristics of the polysaccharide and its acetylated. On the basis, the antioxidant activities were evaluated by 1,1-Dipheny1-2-picrylhydrazyl (DPPH) free radicals, superoxide anion free radicals, hydroxyl free radicals and reducing power scavenging abilities using chemical model method, and the anti-bacteria tests was evaluated through the paper method in vitro. Results: The extraction yield of purified dandelion polysaccharide was 68.75%. Infraed spectroscopy, scanning electron microscope and X-ray powder diffraction of characterization confirmed the successful synthesis of acetylated. The basic structure framework of polysaccharide was not changed after being modified with acetylated. In the concentration range of 0.1～2.0 mg/mL, IC50 values were 5.393±0.941 and 2.153±0.093 mg/mL for pure polysaccharide and acetylated polysaccharides against 1,1-dipheny1-2-picryl-hydrazyl (DPPH) free radicals, respectively, 6.513±0.500 and 2.092±0.825 mg/mL against superoxide anion, respectively, 0.626±0.034 and 0.322±0.010 mg/mL against hydroxyl radical, respectively, and the maximum scanning rates were 0.138±0.019 and 0.239±0.022 reducing power, respectively. As the concentration increased, the antioxidant activity of acetylated polysaccharides increased gradually. In addition, the antibacterial airyctivity of the acetylated polysaccharides was stronger than the unmodified polysaccharides, and the antibaterial activity with the increase of polysaccharide cincentration. Conclusion: The structural stability of purified Taraxacum mongolicum polysaccharide was increased after being modified with acetylated, leading to a significant increase in the antioxidant activity and antibiacterial in vitro.

Mining electric shovels (MES) are one of the key pieces of equipment for mining, and their comprehensive performance plays an important role in mining efficiency. Based on the screw theory, this paper proposes a comprehensive configuration method for an MES working device and selects a new mining electric shovel working device with a larger excavation range, taking the working device as an example for dimensional optimization and simulation analysis. Firstly, based on the closed-loop vector equation, the position inverse solution of the mechanism is analyzed, and the correctness of the position equation is verified by the simulation and by numerical solutions. Then, the constraints of the mechanism are analyzed, and the numerical method and the position equation are combined to solve for the workspace of the mechanism. The dimensional parameters of the mechanism are optimized by genetic algorithms. The workspace of the optimized working device is increased by 13.4789%. Finally, the mining results of the two MES, the working devices, are simulated and verified by experiment. It is shown that the experimental results are basically consistent with the simulation results. The excavation quality difference of the two working devices are 2.02% and 2.20%, which verifies the correctness of the kinematics equation of the working device and the feasibility of the new working device.

Abstract Background Accurate staging in individuals infected with hepatitis C is imperative to understand their long-term risk for liver-related complications. Liver biopsy has a traditional role to determine the levels of liver fibrosis specifically in hepatitis C virus patients. However, the development of non-invasive options has reduced the utilization of biopsy in this population. Main body of the abstract Detecting fibrosis levels through blood samples is already an acceptable alternative to biopsy; however, the optimal non-invasive panel has yet to be defined. Our study indicated hyaluronic acid, collagen oligomeric matrix protein, collagen type IV, and liver fibrosis scoring systems to distinguish fibrosis patients from the non-fibrosis group. Short conclusion The combination of these novel biomarkers, H. A, CO-IV, and Comp tests, could be used to accurately stage individuals with hepatitis C.

Background: Biometric parameters play an important role in studies on myopia. This study aimed to explore the application of a commercially available two-dimensional visualized swept-source optical coherence tomography (OCT) system, for in vivo biometric measurement in multiple myopia model species. Methods: In this study, chickens, guinea pigs, and C57BL/6 mice underwent eye imaging with the commercially available OCT (CASIA2), and the original images were used to calculate the central corneal thickness, anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), and axial length (AL). The retinal thickness and choroidal thickness were also calculated in chicken eyes. The repeatability of the biometric measurement outcomes was analyzed. Results: Excellent repeatable AL measurements were obtained for all three species, with an intraclass correlation coefficient (ICC) of ≥0.941 and a within-subject standard deviation of ≤0.055. Excellent repeatability was found in chicken eyes for ACD, LT, and VCD, with an ICC of ≥0.932; in guinea pig eyes for ACD and VCD, with an ICC of ≥0.934; and in mouse eyes for LT, with an ICC of ≥0.941. Conclusions: It is effective to use commercially available OCT to measure biometric parameters in chickens, guinea pigs, and C57BL/6 mice. This methodology could potentially increase the accuracy and efficiency of future myopia animal experiments.

Background/aimsTo evaluate the influence of cycloplegia on lens refractive parameters in 6–12-year-old children with myopia and hyperopia for exploring the pathogenesis of myopia.MethodsOne hundred eyes of 100 patients (50 boys) were included. In the myopic group, 50 subjects (25 boys and 25 right eyes) were enrolled with a mean age of 9.20 ± 1.69 years. IOLMaster 700 measurements were performed pre- and post-cycloplegia. The pictures were marked using semi-automatic software. The lens curvature and power were obtained using MATLAB image processing software. Paired and independent sample t-tests were used for data analysis. Statistical significance was set at P < 0.05.ResultsAnterior and posterior lens curvature radius in myopic eyes were larger than those in hyperopic eyes, both pre- and post-cycloplegia (both P < 0.001). The refractive power in myopic eyes was lower than that in hyperopic eyes without cycloplegia, both pre- and post-cycloplegia (both P < 0.001). The changes in anterior lens curvature and refractive power between pre- and post-cycloplegia in hyperopic eyes were larger than those in myopic eyes (both P < 0.05). No significant difference was found in the change in posterior lens curvature and refractive power after cycloplegia in hyperopic and myopic eyes (P > 0.05).ConclusionAnterior and posterior surfaces of the lens were flatter, and the refractive power was lower in the myopia group than in the hyperopia group. Myopic and hyperopic patients showed a tendency for lens flattening and refractive power decrease after cycloplegia. Hyperopic patients had more changes in anterior lens curvature and refractive power after cycloplegia.

Abstract Introduction Nowadays, emerging SARS‐CoV‐2 Omicron, the novel highly mutated VOC, has quickly spread as the dominant variant in over 190 countries worldwide through the first part of 2022, which is influencing the infectivity, transmissibility, pathogenicity, and severity of COVID‐19 pandemic. Additionally, clinical cases and experimental studies have reported that Omicron variant likely leads to weakened immune protection elicited by infection, antibody therapies, and vaccines. The new wave, from late February, 2022, was escalated abruptly by higher levels of transmission of Omicron BA.2 sublineage in China. Methods and Results Following a systematic database search, this review summarizes the salient features of Omicron sublineages, and their impact on transmissibility, disease severity as well as the efficacy of the available vaccines and treatment against the Omicron. Conclusion We hope this study will provide a scientific reference for alleviating the burden of COVID‐19.

B cells, which consist of two well-defined populations: B1 and B2 cells, which can produce antibodies that are essential for host protection against infections, through virus neutralization, opsonization and antibody-dependent cellular cytotoxicity. Epigenetic modifications, such as DNA methylation and histone modification could regulate immune cell differentiation and functions. In this study, we found a significant reduction of GC response in the B cell specific knockout of H3K36 methyltransferase NSD1 (Mb1-Cre+ NSD1fl/fl, NSD1B KO) mice compared with the wildtype control (Mb1-Cre+ NSD1+/+, NSD1B WT). We also demonstrated reduced production of high-affinity antibody, but increased production of low-affinity antibody in the NSD1B KO mice. Further analysis revealed that loss of NSD1 promoted the development of B1 cells by increasing the expression of Rap1b and Arid3a. In conclusion, our data suggest that NSD1 plays an important role in regulation the development of B1 and B2 cells, and the process of germinal center formation and high-affinity antibody production.

BackgroundAt present, the incidence of alcoholic fatty liver disease (AFLD) is increasing year by year, and numerous studies have confirmed that liver diseases are closely related to intestinal flora. Seabuckthorn and Astragalus membranaceus, as traditional Chinese medicine (TCM) with the homology of medicine and food, have good liver protection, and their polysaccharides can regulate the intestinal flora. Here, we studied the effects of HRP, APS and the combination of the two polysaccharides on the intestinal flora of AFLD mice, which provided scientific basis for the treatment of AFLD with the two polysaccharides.Materials and methodsThirty Kunming (KM) mice were randomly divided into the control group (Con), the model group (Mod), the HRP treatment group (HRP), the APS treatment group (APS), and HRP+APS treatment group (HRP+APS), with six mice in each group. The AFLD model was constructed by continuous intragastric administration of 42% vol Niulanshan ethanol solution for 28 days, and the mice in each polysaccharide group were given corresponding drugs. The levels of AST, ALT, TC and TG in serum of mice were measured. 16S rRNA amplicon sequencing technique was used to determine the diversity and richness of intestinal flora, and the relative abundance of intestinal flora at phylum level and genus level of the mice in each group.ResultsHRP, APS and HRP+APS could reduce the serum levels of AST, ALT, TC and TG in mice. In addition, HRP, APS and HRP + APS restored the diversity, relative abundance and community structure of intestinal mucosa bacteria in AFLD mice to a certain extent. Specifically, HRP, APS and HRP+APS remarkably decreased the ratio of Firmicutes to Bacteroidetes, and ultimately increased the abundance of beneficial bacteria and reduced the abundance of pathogenic bacteria.ConclusionHRP, APS, and HRP+APS can improve the intestinal microecology of AFLD model mice, alleviate liver injury, and maintain normal intestinal function in different degrees.

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

BackgroundProstate cancer (PCa) is among the leading causes of cancer death worldwide. Ferroptosis refers to an iron-dependent form of regulated cell death and is involved in prostate tumorigenesis. A few ferroptosis-related gene signatures have been developed to predict the prognosis for PCa patients. However, previous signatures were typically established based on biochemical recurrence-free survival, which has proven not to be a good surrogate for overall survival (OS). This study aimed to construct a novel ferroptosis-related gene prognostic index (FRGPI) to predict disease-free survival (DFS) and response to immunotherapy for PCa patients after radical prostatectomy.MethodsGene expression and clinicopathological data on PCa patients were obtained from the TCGA database. Ferroptosis-related hub genes associated with DFS of PCa patients were identified by an in-depth bioinformatics analysis using a novel and comprehensive algorithm based on functional enrichment, consensus clustering, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network construction. The FRGPI was established on the basis of the genes selected using multivariate cox regression analysis and further validated in two additional PCa cohorts. Next, the clinicopathological, molecular, and immune profiles were characterized and compared between FRGPI-high and FRGPI-low subgroups. Finally, the predictive role of the FRGPI in response to immunotherapy was estimated using a metastatic urothelial cancer cohort treated with an anti-PD-L1 agent.ResultsThe FRGPI was constructed based on four genes (E2F1, CDC20, TYMS, and NUP85), and FRGPI-high patients had worse DFS than FRGPI-low patients. Multivariate cox regression analysis revealed that FRGPI could act as an independent prognostic factor for PCa patients after radical prostatectomy. A prognostic nomogram comprising the FRGPI and other clinicopathological parameters was established to predict the DFS for PCa patients quantitatively. In addition, comprehensive results demonstrated that high FRGPI scores showed a significantly positive correlation with worse clinicopathological features, higher mutation counts, increased frequency of copy number variations (CNVs), higher homologous recombination deficiency (HRD) and immune scores, higher mRNAsi, and more importantly, enhanced sensitivity to immunotherapy.ConclusionsFRGPI is not only a promising and robust prognostic biomarker, but also a potential indicator of immunotherapeutic outcomes for PCa patients after radical prostatectomy.

Aim: To evaluate the effects of 0.5% tropicamide on anterior segment parameters with the CASIA2 imaging device in emmetropic, myopic, and hyperopic eyes.Methods: In this prospective study, a total of 125 subjects (34 emmetropic subjects, 57 myopic subjects, and 34 hyperopic subjects) at the Shanghai Eye and ENT Hospital of Fudan University were recruited from June 2021 to September 2021. The 0.5% tropicamide solution was used once every 5 min a total of 5 times for cycloplegia. The anterior segment parameters were recorded by CASIA2 before and after cycloplegia. Changes in anterior segment parameters were compared among the three refractive groups.Results: Crystalline lens rise (CLR) and crystalline lens thickness (CLT) significantly decreased in all three refractive groups after cycloplegia (all p < 0.01). The anterior radius of lens (ARL) and anterior chamber depth (ACD) significantly increased in all three refractive groups after cycloplegia (all p < 0.01). Posterior radius of lens (PRL) significantly increased in hyperopic eyes after cycloplegia (p < 0.01) while it remained unchanged in emmetropic eyes and myopic eyes. Central corneal thickness (CCT), anterior chamber width (ACW), lens decentration (LD), and lens tilt (LT) remained unchanged after cycloplegia in all three refractive groups (all p > 0.05). Changes in CLR, CLT, ARL, PRL, and ACD in hyperopic eyes were greater than those in emmetropic eyes and myopic eyes (all p < 0.05).Conclusion: Apart from various changes in anterior segment parameters after application by 0.5% tropicamide in all three refractive groups, significant changes in CLR, CLT, ARL, PRL, and ACD in hyperopic eyes should be noted for proper clinical interpretation.

ABSTRACT Hypothesis: Endoclip can be used as fiducial marker in urology. Objective: To assess the feasibility, cost effectiveness and reliability of endoclips as novel fiducial markers in precision radiotherapy, as part of a trimodality bladder-preserving treatment (TBPT) of muscle-invasive bladder carcinoma. Materials and Methods: This retrospective study was performed at Weifang People's Hospital (Weifang, China) from January 2015 to June 2018. A total of 15 patients underwent TBPT. Endoclips were applied to healthy edges of the resected bladder wall as novel fiducial markers. Radio-sensitizing chemotherapy and routine precision radiotherapy were given. The number and position of the endoclips during radiotherapy sessions were monitored. Complications and tumor recurrence were analyzed. Results: The mean age (±standard deviation) of the patients was 67±10 years (range 46-79). There were 3 females and 12 males. Forty-nine endoclips were applied in all patients (3.3±0.8). The tumor was completely visibly resected in all patients. The number of endoclips remained the same through the planned last radiotherapy session (3.3±0.8), i.e., none were lost. All endoclips were removed after the last radiotherapy session. The average number of follow-up months was 38.9±13.2 (range 11-52). There were no procedure-related complications at discharge or follow-up. At one-year, overall recurrence-free survival was 93.3%. Two patients had recurrences at 18 months and 10 months after TBPT, respectively, and salvage radical cystectomy was performed with no further recurrences. Another patient died due to metastasis 9 months after the completion of therapy. Conclusions: Endoclips are reliable, safe and cost-effective as novel fiducial markers in precision-radiotherapy post-TBPT.