Matching actions to needs: shifting policy responses to the changing health needs of Chinese children and adolescents.

China is home to the second largest population of children and adolescents in the world. Yet demographic shifts mean that the government must manage the challenge of fewer children with the needs of an ageing population, while considering the delicate tension between economic growth and environmental sustainability. We mapped the health problems and risks of contemporary school-aged children and adolescents in China against current national health policies. We involved multidisciplinary experts, including young people, with the aim of identifying actionable strategies and specific recommendations to promote child and adolescent health and wellbeing. Notwithstanding major improvements in their health over the past few decades, contemporary Chinese children and adolescents face distinct social challenges, including high academic pressures and youth unemployment, and new health concerns including obesity, mental health issues, and sexually transmitted infections. Inequality by gender, geography, and ethnicity remains a feature of health risks and outcomes. We identified a mismatch between current health determinants, risks and outcomes, and government policies. To promote the health of children and adolescents in China, we recommend a set of strategies that target government-led initiatives across the health, education, and community sectors, which aim to build supportive and responsive families, safe communities, and engaging and respectful learning environments. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Identification of RNA methylation-related lncRNAs for prognostic assessment and immunotherapy in bladder cancer-based on single cell/Bulk RNA sequencing data.

Bladder cancer is a malignancy characterized by significant heterogeneity. RNA methylation has received an increasing amount of attention in recent years. RNA data were collected from the GEO database, and cell subsets were classified according to specific cell markers. Epithelial, immunological, and fibroblast cells were clustered individually to explore the tumor heterogeneity. To distinguish between malignant and benign cells, the InferCNV R package was employed. The monocle2 R package was used for pseudotime analysis. The Decouple R package was used for transcription factor analysis of each cell subgroup, and PROGENy was used to predict the activity of pathways related to tumors. The target lncRNA was screened for model construction. In addition, the qPCR experiment was used to detect the transcription level of lncRNA. Epithelial cells, fibroblasts, and T cells significantly differ in tumor and normal tissues. The lncRNAs related to m6A/m5C/m1A were intersected to construct the model. Finally, six model lncRNAs (PSMB8-AS1, THUMPD3-AS1, U47924.27, XXbac-B135H6.15, MIR99AHG, and C14orf132) were screened. High-risk individuals were shown to have a better prognosis. qPCR experiments showed that the model lncRNA was differentially expressed between normal and tumor cells. Immunotherapy will be more effective in treating individuals with lower risk than those with higher risk using 4 candidate drugs. The prognostic m6A/m5C/m1A-related lncRNA model was constructed for evaluating the clinical outcomes of bladder cancer patients and guiding clinical medication.

Unveiling Anoikis-related genes: A breakthrough in the prognosis of bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy worldwide. Anoikis remains a new form of cell death. It is necessary to explore Anoikis-related genes in the prognosis of BLCA. METHODS: We obtained RNA expression profiles from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases for dimensionality reduction analysis and isolated epithelial cells, T cells and fibroblasts for copy number variation analysis, pseudotime analysis and transcription factor analysis based on R package. We integrated machine-learning algorithms to develop the artificial intelligence-derived prognostic signature (AIDPS). RESULTS: The performance of AIDPS with clinical indicators was stable and robust in predicting BLCA and showed better performance in every validation dataset compared to other models. Mendelian randomization analysis was conducted. Single nucleotide polymorphism (SNP) sites of rs3100578 (HK2) and rs66467677 (HSP90B1) exhibited significant correlation of bladder problem (not cancer) and bladder cancer, whereasSNP sites of rs3100578 (HK2) and rs947939 (BAD) had correlation between bladder stone and bladder cancer. The immune infiltration analysis of the TCGA-BLCA cohort was calculated via the ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) algorithm which contains stromal, immune and estimate scores. We also found significant differences in the IC50 values of Bortezomib_1191, Docetaxel_1007, Staurosporine_1034 and Rapamycin_1084 among the high- and low-risk groups. CONCLUSIONS: In conclusion, these findings indicated Anoikis-related prognostic genes in BLCA and constructed an innovative machine-learning model of AIDPS with high prognostic value for BLCA.

Investigating the prognostic role of lncRNAs associated with disulfidptosis-related genes in clear cell renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC). METHODS: Three sets of ccRCC cohorts, ICGC_RECA-EU (n = 91), GSE76207 (n = 32) and TCGA-KIRC (n = 607), were included in our study, the batch effect of which was removed using the "combat" function. Correlation was calculated using the "rcorr" function of the "Hmisc" package for Pearson analysis, which was visualized using the "pheatmap" package. Principal component analysis was performed by the "vegan" package, visualized using the "scatterplot3d" package. Long non-coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups. RESULTS: A total of 1822 disulfidptosis-related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis-related lncRNAs, namely, AP000439.3, RP11-417E7.1, RP11-119D9.1, LINC01510, SNHG3, AC156455.1, RP11-291B21.2, EMX2OS, AC093850.2, HAGLR and RP11-389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy. CONCLUSION: We developed a prognosis predicting model based on 11 selected disulfidptosis-related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.

Cucurbitacin I exerts its anticancer effects by inducing cell cycle arrest via the KAT2a-ube2C/E2F1 pathway and inhibiting HepG2-induced macrophage M2 polarization.

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally, particularly prevalent in China, where it accounts for nearly half of the world's new cases and deaths each year, but has limited therapeutic options. This study systematically investigated the impact of cucurbitacin I on HCC cell lines including SK-Hep-1, Huh-7, and HepG2. The results revealed that cucurbitacin I not only inhibited cell proliferation, cell migration and colony formation, but also induced apoptosis in HCC cells. The apoptotic induction was accompanied by a decrease in the expression of the anti-apoptotic factor B-cell lymphoma 2 (Bcl2), and an elevation in the expression levels of pro-apoptotic factors, including tumor protein p53 (P53), bcl2 associated X-apoptosis regulator (Bax), and caspase3 (Cas3). Additionally, cucurbitacin I caused cell cycle arrest by modulating the lysine acetyltransferase 2A (KAT2A)-E2F transcription factor 1 (E2F1)/Ubiquitin-conjugating enzyme E2 C (UBE2C) signaling axis. In terms of regulation on tumor microenvironment, cucurbitacin I was demonstrated the ability to inhibit HCC cell-induced M2 polarization of macrophages. This comprehensive study unveils the multifaceted anti-cancer mechanisms of cucurbitacin I, providing robust support for its potential application in the treatment of HCC, offering new avenues for the future development of HCC treatment strategies.

A Biomimetic Se-nHA/PC Composite Microsphere with Synergistic Immunomodulatory and Osteogenic Ability to Activate Bone Regeneration in Periodontitis.

Accumulation of reactive oxygen species (ROS) in periodontitis exacerbates the destruction of alveolar bone. Therefore, scavenging ROS to reshape the periodontal microenvironment, alleviate the inflammatory response and promote endogenous stem cell osteogenic differentiation may be an effective strategy for treating bone resorption in periodontitis. In this study, sericin-hydroxyapatite nanoparticles (Se-nHA NPs) are synthesized using a biomimetic mineralization method. Se-nHA NPs and proanthocyanidins (PC) are then encapsulated in sericin/sodium alginate (Se/SA) using an electrostatic injection technique to prepare Se-nHA/PC microspheres. Microspheres are effective in scavenging ROS, inhibiting the polarization of macrophages toward the M1 type, and inducing the polarization of macrophages toward the M2 type. In normal or macrophage-conditioned media, the Se-nHA/PC microspheres effectively promoted the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). Furthermore, the Se-nHA/PC microspheres demonstrated anti-inflammatory effects in a periodontitis rat model by scavenging ROS and suppressing pro-inflammatory cytokines. The Se-nHA/PC microspheres are also distinguished by their capacity to decrease alveolar bone loss, reduce osteoclast activity, and boost osteogenic factor expression. Therefore, the biomimetic Se-nHA/PC composite microspheres have efficient ROS-scavenging, anti-inflammatory, and osteogenic abilities and can be used as a multifunctional filling material for inflammatory periodontal tissue regeneration.

Cardiac computed tomography angiography for assessment of endothelial insufficiency of left atrial appendage disc-like occluder.

INTRODUCTION: This study was performed to explore the diagnostic value of cardiac computed tomography angiography (CCTA) for endothelial insufficiency (EIS) of a left atrial appendage (LAA) disc-like occluder. METHODS: Fifty-nine patients with nonvalvular atrial fibrillation who underwent placement of an LAA disc-like occluder (LAmbre; Lifetech Scientific) in our hospital were retrospectively analyzed. Patients who were found to have contrast agent entering the LAA at the 3-month postoperative CCTA examination underwent Hounsfield unit (HU) measurement of the LAA and construction of a three-dimensional (3D) model of the device for preliminary discernment between peri-device leakage (PDL) and EIS. These patients were then further examined by transesophageal echocardiography (TEE) to check for concordance with the computed tomography (CT) findings. According to the CT and TEE results, all patients were divided into the PDL group, total endothelialization group, and EIS group. The endothelial conditions and other implantation-related results were also tracked at the 6-month follow-up. RESULTS: All 59 patients underwent successful implantation of the LAmbre LAA closure device with no severe adverse events during the procedure. Thirty-five patients were found to have contrast agent entering the LAA at the 3-month postoperative CCTA follow-up. Based on the CT HU measurement and the 3D construction analysis results, these 35 patients were divided into the PDL group (19 patients) and the EIS group (16 patients). In the PDL group, the contrast agent infiltrated from the shoulder along the periphery of the occluder on two-dimensional (2D) CT images, and the 3D model showed a gap between the LAA and the device cover. However, the CCTA images of the other 16 patients in the EIS group showed that the contrast agent in the occluder on the 2D CTA images and 3D construction model confirmed the absence of a gap between the LAA and the device cover. TEE confirmed all of the CT results. The 6-month follow-up results showed that 14 of 19 patients in the EIS group achieved total endothelialization, whereas this number in the PDL group was only five of 19 patients. CONCLUSION: CCTA can replace TEE for examination of the endothelialization status, and patients with EIS have a higher chance of endothelialization than patients with PDL.

Trends and socioeconomic inequality of the burden of congenital abnormalities of the kidney and urinary tract among children and adolescents.

BACKGROUND: Although congenital abnormalities of the kidney and urinary tract (CAKUT) is the leading cause of childhood onset chronic kidney disease (CKD) and kidney failure, comprehensive information on the disease burden among children and adolescents globally is lacking. We aim to report the trends and socioeconomic inequality of CAKUT burden for people aged 0-24 years from 1990 to 2019·. METHODS: We reported the prevalence, mortality and disability-adjusted life-years (DALYs) for CAKUT based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, quantified the association of disease burden and socio-demographic index (SDI), calculated the slope index of inequality (SII) the relative index of inequality (RII) and concentration index. RESULTS: In 2019, the global prevalence, mortality, and DALYs of CAKUT among individuals aged 0-24 years were 167.11 (95%Confident Interval 166.97, 167.25), 0.30 (0.29, 0.30), and 32.22 (32.16, 32.29) per 100 000 population. The greatest prevalence, mortality and DALYs were recorded in the 0-4 year age group. The greatest mortality and DALYs were recorded in low SDI countries and territories. During 1990 to 2019, the prevalence, mortality and DALYs decreased globally, while in low and low-middle countries and territories the reduction was much less slower. India, Nigeria and Pakistan had the highest DALYs. Saudi Arabia and China exhibited a markedly decrease of CAKUT burden. Globally for every 0.1 increase in SDI, there was a 20.53% reduction in mortality, a 16.31% decrease in DALYs, but a 0.38% rise in prevalence. CONCLUSIONS: Inequality for disease burden of varying SDI was increasing globally. Thus, specific preventive and health service measures are needed to reduce the global burden from CAKUT.

Minisci-Type Dehydrogenative Coupling of N-Heteroaromatic Rings with Inert C(sp3)-H Enabled by a Visible-Light-Catalyzed Intermolecular Hydrogen Atom Transfer Process.

The Minisci-type dehydrogenative coupling of N-heteroaromatic rings with inert C-H or Si-H partners via visible-light-catalyzed hydrogen atom transfer has been reported. This methodology allows the coupling reactions to be carried out in water as a solvent under air atmospheric conditions with visible-light illumination. A wide range of inert C-H and Si-H partners could be directly coupled with various N-aromatic heterocycles to deliver products in good to excellent yields.

LncRNA KIFAP3-5:1 inhibits epithelial-mesenchymal transition of renal tubular cell through PRRX1 in diabetic nephropathy.

Long noncoding RNAs play an important role in several pathogenic processes in diabetic nephropathy, but the relationship with epithelial-mesenchymal transition in DN is unclear. Herein, we found that KIFAP3-5:1 expression was significantly down-regulated in DN plasma samples, db/db mouse kidney tissues and high glucose treated renal tubular epithelial cells compared to normal healthy samples and untreated cells. Overexpression of KIFAP3-5:1 improved renal fibrosis in db/db mice and rescued epithelial-mesenchymal transition of high glucose cultured renal tubular epithelial cells. The silence of KIFAP3-5:1 will exacerbate the progression of EMT. Mechanistically, KIFAP3-5:1 was confirmed to directly target to the -488 to -609 element of the PRRX1 promoter and negatively modulate PRRX1 mRNA and protein expressions. Furthermore, rescue assays demonstrated that the knockdown of PRRX1 counteracted the KIFAP3-5:1 low expression-mediated effects on EMT in hRPTECs cultured under high glucose. The plasma KIFAP3-5:1 of DN patients is highly correlated with the severity of renal dysfunction and plays an important role in the prediction model of DN diseases. These findings suggested that KIFAP3-5:1 plays a critical role in regulation of renal EMT and fibrosis through suppress PRRX1, and highlight the clinical potential of KIFAP3-5:1 to assist in the diagnosis of diabetic nephropathy.

Associations of school physical activity environment with comorbid obesity and myopia in children and adolescents: Findings from a Chinese national follow-up study.

BACKGROUND: Overweight and obesity (OWOB) and myopia have become two of the most important issues affecting the health of children and adolescents worldwide. Despite the recognition that the school physical activity (PA) environment is a critical factor for preventing and controlling overweight, obesity (OWOB), and myopia in children and adolescents, research on OWOB and myopia as a comorbidity remains unexplored, with evidence for effective strategies still being inconclusive. Hence, this study aimed to assess the prevalence and progression of comorbid OWOB/myopia and each condition alone, and to explore the association with school PA environment. METHODS: A total of 9814 children and adolescents aged 6-18 years were included from the Chinese National Survey on Students' Constitution and Health follow-up survey conducted from November 2019 to November 2020 in China. Anthropometric measurements, unaided distance vision acuity and non-cycloplegic refraction data were collected to assess OWOB and myopia, while eight indicators from questionnaires for children and adolescents aged 9-18 years were investigated to assess school PA environment. We calculated the one-year incidence and progression rates of comorbid OWOB/myopia, OWOB alone, and myopia alone. Mixed effect logistic regression was evaluated the association between school PA environment and incidence and progression of comorbid OWOB/myopia, OWOB, and myopia. RESULTS: The prevalence of comorbid OWOB/myopia increased from 11.1% in 2019 to 17.9% in 2020, and the incidence of comorbid OWOB/myopia was 10.9%. Children and adolescents experiencing an unfavorable school PA environment had a higher risk of the incidence of comorbid OWOB/myopia compared to a favorable school environment (OR = 1.85, 95% CI: 1.42-2.42). Similar findings were seen in the incidence of obesity (OR = 1.86, 95% CI: 1.26-2.75). Children and adolescents in an unfavorable school PA environment had a higher risk of myopia progression (OR = 1.29, 95% CI: 1.01-1.65). CONCLUSIONS: Obesity and myopia and their comorbidity have been serious among children and adolescents in China. A favorable school PA environment might mitigate the risk of comorbid OWOB/myopia, OWOB, and myopia progression.

Hypoxia-based critical gene biomarkers as prognostic reporters for gastric adenocarcinoma.

BACKGROUND: Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients. METHODS: Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non-negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package "oncoPredict" was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression. RESULTS: Hypoxia-score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution-based algorithms for immune infiltration, Hypoxia-score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high-risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low-risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia-score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia-score in single-cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single-cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees. CONCLUSION: The Hypoxia-score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.

Coordinating single-cell and bulk RNA-seq in deciphering the intratumoral immune landscape and prognostic stratification of prostate cancer patients.

INTRODUCTION: Prostate cancer is a common cancer among male population. The aberrant expression of histone modifiers has been identified as a potential driving force in numerous cancer types. However, the mechanism of histone modifiers in the development of prostate cancer remains unknown. METHODS: Expression profiles and clinical data were obtained from GSE70769, GSE46602, and GSE67980. Seruat R package was utilized to calculate the gene set enrichment of the histone modification pathway and obtain the Histone score. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were employed to identify marker genes with prognostic value. Kaplan-Meier survival analysis was conducted to assess the efficacy of the prognostic model. In addition, microenvironment cell populations counter (MCPcounter), single-sample gene set enrichment analysis (ssGSEA), and xCell algorithms were employed for immune infiltration analysis. Drug sensitivity prediction was performed using oncoPredict R package. RESULTS: We screened differentially expressed genes (DEGs) between Histone-high score (Histone-H) and Histone-low score (Histone-L) groups, which were enriched in RNA splicing and DNA-binding transcription factor binding pathways. We retained four prognostic marker genes, including TACC3, YWHAH, TAF1C and TTLL5. The risk model showed significant efficacy in stratification of the prognosis of prostate cancer patients in both internal and external cohorts (p < .0001 and p = .032, respectively). In addition, prognostic gene YWHAH was infiltrated in abundance of fibroblasts and highly correlated with Entinostat_1593 drug sensitivity score and the value of risk score. CONCLUSION: We innovatively developed a histone modification-related prognostic model with high prognostic potency and identified YWHAH as possible diagnostic and therapeutic biomarkers for prostate cancer. It provides novel insights to address prostate cancer and enhance clinical outcomes, thereby opening up a new avenue for customized treatment alternatives.

LHFPL2 Serves as a Potential Biomarker for M2 Polarization of Macrophages in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the kidney, presenting significant challenges for clinical diagnosis and treatment. Macrophages play crucial roles in RCC, promoting tumor progression and warranting further investigation. Previous studies have identified LHFPL2 as a transmembrane protein associated with reproduction, but its relationship with tumors or macrophages has not been discussed. This study utilized transcriptomic sequencing data from 609 KIRC patients in the TCGA database and single-cell sequencing data from 34,326 renal carcinoma cells for subsequent analysis. We comprehensively evaluated the expression of LHFPL2 and its relationship with clinical features, tumor prognosis, immune infiltration, and mutations. Additionally, we further assessed the correlation between LHFPL2 and macrophage M2 polarization using single-cell data and explored its potential as a cancer therapeutic target through molecular docking. The results demonstrated that LHFPL2 is upregulated in RCC and associated with poor survival rates. In clinical staging, the proportion of malignant and high-metastasis patients was higher in the high-LHFPL2 group than in the low-LHFPL2 group. Furthermore, we found that LHFPL2 influences RCC immune infiltration, with its expression positively correlated with various immune checkpoint and M2-related gene expressions, positively associated with M2 macrophage infiltration, and negatively correlated with activated NK cells. Moreover, LHFPL2 showed specific expression in macrophages, with the high-expression subgroup exhibiting higher M2 polarization, hypoxia, immune evasion, and angiogenesis scores, promoting tumor progression. Finally, we predicted several potential drugs targeting LHFPL2, such as conivaptan and nilotinib. Our analysis elaborately delineates the immune characteristics of LHFPL2 in the tumor microenvironment and its positive correlation with macrophage M2 polarization, providing new insights into tumor immunotherapy. We also propose potential FDA-approved drugs targeting this gene, which should be tested for their binding effects with LHFPL2 in future studies.

Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data.

Hepatocellular carcinoma (HCC) is a highly detrimental cancer type and has limited therapeutic options, posing significant threats to human health. The development of HCC has been associated with a disorder in bile acid (BA) metabolism. In this study, we employed an integrative approach, combining various datasets and omics analyses, to comprehensively characterize the tumor microenvironment in HCC based on genes related to BA metabolism. Our analysis resulted in the classification of HCC samples into four subtypes (C1, C2a, C2b, and C3). Notably, subtype C2a, characterized by the highest bile acid metabolism score (BAMS), exhibited the highest survival probability. This subtype also demonstrated increased immune cell infiltration, lower cell cycle scores, reduced AFP levels, and a lower risk of metastasis compared to subtypes C1 and C3. Subtype C1 displayed poorer survival probability and elevated cell cycle scores. Importantly, the identified subtypes based on BAMS showed potential relevance to the gene expression of drug targets in currently approved drugs and those under clinical research. Genes encoding VEGFR (FLT4 and KDR) and MET were elevated in C2, while genes such as TGFBR1, TGFB1, ADORA3, SRC, BRAF, RET, FLT3, KIT, PDGFRA, and PDGFRB were elevated in C1. Additionally, FGFR2 and FGFR3, along with immune target genes including PDCD1 and CTLA4, were higher in C3. This suggests that subtypes C1, C2, and C3 might represent distinct potential candidates for TGFB1 inhibitors, VEGFR inhibitors, and immune checkpoint blockade treatments, respectively. Significantly, both bulk and single-cell transcriptome analyses unveiled a negative correlation between BA metabolism and cell cycle-related pathways. In vitro experiments further confirmed that the treatment of HCC cell lines with BA receptor agonist ursodeoxycholic acid led to the downregulation of the expression of cell cycle-related genes. Our findings suggest a plausible involvement of BA metabolism in liver carcinogenesis, potentially mediated through the regulation of tumor cell cycles and the immune microenvironment. This preliminary understanding lays the groundwork for future investigations to validate and elucidate the specific mechanisms underlying this potential association. Furthermore, this study provides a novel foundation for future precise molecular typing and the design of systemic clinical trials for HCC therapy.

Multi-model assessment of potential natural vegetation to support ecological restoration.

Ecological restoration is imperative for controlling desertification. Potential natural vegetation (PNV), the theoretical vegetation succession state, can guides near-natural restoration. Although a rising transition from traditional statistical methods to advanced machine learning and deep learning is observed in PNV simulation, a comprehensive comparison of their performance is still unexplored. Therefore, we overview the performance of PNV mapping in terms of 12 commonly used methods with varying spatial scales and sample sizes. Our findings indicate that the methodology should be carefully selected due to the variation in performance of different model types, with Area Under the Curve (AUC) values ranging from 0.65 to 0.95 for models with sample sizes up to 80% of the total sample size. Specifically, semi-supervised learning performs best with small sample sizes (i.e., 10 to 200), while Random Forest, XGBoost, and artificial neural networks perform better with large sample sizes (i.e., over 500). Further, the performance of all models tends to improve significantly as the sample size increases and the grain size of the crystals becomes smaller. Take the downstream Tarim River Basin, a hyper-arid region undergoing ecological restoration, as a case study. We showed that its potential restored areas were overestimated by 2-3 fold as the spatial scale became coarser, revealing the caution needed while planning restoration projects at coarse resolution. These findings enhance the application of PNV in the design of restoration programs to prevent desertification.

24-H movement behaviors and physical fitness in preschoolers: A compositional and isotemporal reallocation analysis.

Background/Objectives: This study examined the relationships between 24-h movement behaviors and physical fitness (PF) in preschool children. Methods: The study was conducted on 474 children aged 3-6 years in Zhuhai. Physical activity (PA) and sedentary behavior (SB) were collected by the accelerometer, and sleep time was assessed through the parent-report questionnaire. Balance, cardiorespiratory fitness (CRF), flexibility, muscle strength, muscular endurance, and speed-agility were measured using a balance beam test, 20 m shuttle run test, sit and reach test, handgrip test, sit-ups, and 4 × 10 m shuttle run test respectively. The compositional data analysis was used to examine the association between 24-h movement behaviors and PF, and the compositional isotemporal substitution analysis was used for the time reallocation. Results: The daily composition, adjusted for age, gender, and body mass index (BMI), was significantly associated with CRF (p < 0.001, r2 = 0.20), flexibility (p < 0.001, r2 = 0.07), muscular strength (p < 0.001, r2 = 0.37), muscular endurance (p < 0.001, r2 = 0.26), and speed-agility (p < 0.001, r2 = 0.26). The addition of moderate-to-vigorous PA (MVPA) at the expense of SB and sleep, MVPA at the cost of sleep, was associated with significant muscular strength and speed-agility improvements respectively. The impact of SB and sleep replacing MVPA is stronger than MVPA replacing SB and sleep on muscular strength. Conclusion: These findings offer useful insight for the replacement of movement behaviors within the recommended range to facilitate PF development in early childhood.

GhBZR3 suppresses cotton fiber elongation by inhibiting very-long-chain fatty acid biosynthesis.

The BRASSINAZOLE-RESISTANT (BZR) transcription factor is a core component of brassinosteroid (BR) signaling and is involved in the development of many plant species. BR is essential for the initiation and elongation of cotton fibers. However, the mechanism of BR-regulating fiber development and the function of BZR is poorly understood in Gossypium hirsutum L. (cotton). Here, we identified a BZR family transcription factor protein referred to as GhBZR3 in cotton. Overexpression of GhBZR3 in Arabidopsis caused shorter root hair length, hypocotyl length, and hypocotyl cell length, indicating that GhBZR3 negatively regulates cell elongation. Pathway enrichment analysis from VIGS-GhBZR3 cotton plants found that fatty acid metabolism and degradation might be the regulatory pathway that is primarily controlled by GhBZR3. Silencing GhBZR3 expression in cotton resulted in taller plant height as well as longer fibers. The very-long-chain fatty acid (VLCFA) content was also significantly increased in silenced GhBZR3 plants compared with the wild type. The GhKCS13 promoter, a key gene for VLCFA biosynthesis, contains two GhBZR3 binding sites. The results of yeast one-hybrid, electrophoretic mobility shift, and luciferase assays revealed that GhBZR3 directly interacted with the GhKCS13 promoter to suppress gene expression. Taken together, these results indicate that GhBZR3 negatively regulates cotton fiber development by reducing VLCFA biosynthesis. This study not only deepens our understanding of GhBZR3 function in cotton fiber development, but also highlights the potential of improving cotton fiber length and plant growth using GhBZR3 and its related genes in future cotton breeding programs.

Reading Braille by Touch Recruits Posterior Parietal Cortex.

Blind readers use a tactile reading system consisting of raised dot arrays: braille/⠃⠗⠇. How do human brains implement reading by touch? The current study looked for signatures of reading-specific orthographic processes in braille, separate from low-level somatosensory responses and semantic processes. Of specific interest were responses in posterior parietal cortices (PPCs), because of their role in high-level tactile perception. Congenitally blind, proficient braille readers read real words and pseudowords by touch while undergoing fMRI. We leveraged the system of contractions in English braille, where one braille cell can represent multiple English print letters (e.g., "ing" ⠬, "one" ⠐⠕), making it possible to separate physical and orthographic word length. All words in the study consisted of four braille cells, but their corresponding Roman letter spellings varied from four to seven letters (e.g., "con-c-er-t" ⠒⠉⠻⠞. contracted: four cells; uncontracted: seven letters). We found that the bilateral supramarginal gyrus in the PPC increased its activity as the uncontracted word length increased. By contrast, in the hand region of primary somatosensory cortex (S1), activity increased as a function of a low-level somatosensory feature: dot-number per word. The PPC also showed greater response to pseudowords than real words and distinguished between real and pseudowords in multivariate-pattern analysis. Parieto-occipital, early visual and ventral occipito-temporal, as well as prefrontal cortices also showed sensitivity to the real-versus-pseudoword distinction. We conclude that PPC is involved in orthographic processing for braille, that is, braille character and word recognition, possibly because of braille's tactile modality.

Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells.

BACKGROUND: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. METHODS: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. RESULTS: Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. CONCLUSION: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment.