Deep learning-based automatic measurement system for patellar height: a multicenter retrospective study.

BACKGROUND: The patellar height index is important; however, the measurement procedures are time-consuming and prone to significant variability among and within observers. We developed a deep learning-based automatic measurement system for the patellar height and evaluated its performance and generalization ability to accurately measure the patellar height index. METHODS: We developed a dataset containing 3,923 lateral knee X-ray images. Notably, all X-ray images were from three tertiary level A hospitals, and 2,341 cases were included in the analysis after screening. By manually labeling key points, the model was trained using the residual network (ResNet) and high-resolution network (HRNet) for human pose estimation architectures to measure the patellar height index. Various data enhancement techniques were used to enhance the robustness of the model. The root mean square error (RMSE), object keypoint similarity (OKS), and percentage of correct keypoint (PCK) metrics were used to evaluate the training results. In addition, we used the intraclass correlation coefficient (ICC) to assess the consistency between manual and automatic measurements. RESULTS: The HRNet model performed excellently in keypoint detection tasks by comparing different deep learning models. Furthermore, the pose_hrnet_w48 model was particularly outstanding in the RMSE, OKS, and PCK metrics, and the Insall-Salvati index (ISI) automatically calculated by this model was also highly consistent with the manual measurements (intraclass correlation coefficient [ICC], 0.809-0.885). This evidence demonstrates the accuracy and generalizability of this deep learning system in practical applications. CONCLUSION: We successfully developed a deep learning-based automatic measurement system for the patellar height. The system demonstrated accuracy comparable to that of experienced radiologists and a strong generalizability across different datasets. It provides an essential tool for assessing and treating knee diseases early and monitoring and rehabilitation after knee surgery. Due to the potential bias in the selection of datasets in this study, different datasets should be examined in the future to optimize the model so that it can be reliably applied in clinical practice. TRIAL REGISTRATION: The study was registered at the Medical Research Registration and Filing Information System (medicalresearch.org.cn) MR-61-23-013065. Date of registration: May 04, 2023 (retrospectively registered).

Regulating the Solvation Structure in Polymer Electrolytes for High-Voltage Lithium Metal Batteries.

Solid polymer electrolytes are promising electrolytes for safe and high-energy-density lithium metal batteries. However, traditional ether-based polymer electrolytes are limited by their low lithium-ion conductivity and narrow electrochemical window because of the well-defined and intimated Li+-oxygen binding topologies in the solvation structure. Herein, we proposed a new strategy to reduce the Li+-polymer interaction and strengthen the anion-polymer interaction by combining strong Li+-O (ether) interactions, weak Li+-O (ester) interactions with steric hindrance in polymer electrolytes. In this way, a polymer electrolyte with a high lithium ion transference number (0.80) and anion-rich solvation structure is obtained. This polymer electrolyte possesses a wide electrochemical window (5.5 V versus Li/Li+) and compatibility with both Li metal anode and high-voltage NCM cathode. Li||LiNi0.5Co0.2Mn0.3O2 full cells with middle-high active material areal loading (~7.5 mg cm-2) can stably cycle at 4.5 V. This work provides new insight into the design of polymer electrolytes for high-energy-density lithium metal batteries through the regulation of ion-dipole interactions.

Exploring the Molecular Mechanisms of Huaier on Modulating Metabolic Reprogramming of Hepatocellular Carcinoma: A Study based on Network Pharmacology, Molecular Docking and Bioinformatics.

BACKGROUND: Huaier (Trametes robiniophila Murr), a traditional Chinese medicine, is widely used in China as a complementary and alternative therapy to treat hepatocellular carcinoma (HCC). Past studies have shown that Huaier can arrest the cell cycle, promote apoptosis and inhibit the proliferation of cancer cells. However, how it regulates the metabolism of HCC is still unclear. OBJECTIVE: This study explores the metabolic-related function of Huaier in treating HCC with an in-silico approach. METHODS: A network pharmacology and bioinformatics-based approach was employed to investigate the molecular pathogenesis of metabolic reprogramming in HCC with Huaier. The compounds of Huaier were obtained from public databases. Oral bioavailability and drug likeness were screened using the TCMSP platform. The differential gene expressions between HCC and non-tumor tissue were calculated and used to find the overlap from the targets of Huaier. The enrichment analysis of the overlapped targets by Metascape helped filter out the metabolism-related targets of Huaier in treating HCC. Protein-protein interaction (PPI) network construction and topological screening revealed the hub nodes. The prognosis and clinical correlation of these targets were validated from the cancer genome atlas (TCGA) database, and the interactions between the hub nodes and active ingredients were validated by molecular docking. RESULTS: The results showed that Peroxyergosterol, Daucosterol, and Kaempferol were the primary active compounds of Huaier involved in the metabolic reprogramming of HCC. The top 6 metabolic targets included AKR1C3, CYP1A1, CYP3A4, CYP1A2, CYP17A1, and HSD11B1. The decreased expression of CYP3A4 and increased expression of AKR1C3 were related to the poor overall survival of HCC patients. The molecular docking validated that Peroxyergosterol and Kaempferol exhibited the potential to modulate CYP3A4 and AKR1C3 from a computational perspective. CONCLUSION: This study provided a workflow for understanding the mechanism of Huaier in regulating the metabolic reprogramming of HCC.

Doped Porous Carbon Spheres with Controllable Vesicle Structure: Preparation and the Effects of Pore Size on Electromagnetic Wave Absorption Properties.

This work reports on the preparation of uniform vesicle-structural carbon spheres doped with heteroatoms of N, P, and S, with the pore sizes strictly controlled by the hard templates of monodisperse submicron SiO2 spheres. The uniformly doped vesicular carbon microspheres are obtained in three steps: Stöber hydrolysis for the SiO2; in situ polymerization for the immobilization; and alkaline etching after carbonization. The size of the vesicles can be easily adjusted by regulating the particle size of the submicron SiO2 spheres, which has a significant effect on its electromagnetic wave (EMW) absorption performance. Compared with microspheres with pore sizes of 180 and 480 nm, when the vesicle aperture is 327 nm, with only 5.5 wt.% filling load and 1.9 mm thickness, the material shows the best EMW absorption behavior with the effective absorption bandwidth (EAB) covers the entire Ku band (6.32 GHz) and the minimum reflection loss (RLmin) of -36.10 dB, suggesting the optimized pore size of the microspheres can significantly improve the overall impedance matching of the material and achieve broadband wave absorption. This work paves the way for the enhancement of EMW absorption properties of porous material by optimizing the pore size of uniform apertures while maintaining their composition.

Construction of 5-Fluorouracil and Gallium Corrole Conjugates for Enhanced Photodynamic Therapy.

Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy (PDT) efficiency, a series of novel 5-fluorouracil (5FU) gallium corrole conjugates (1-Ga-4-Ga) were designed and synthesized by hybridizing a chemotherapeutic drug and PSs. Their photodynamic antitumor activity was also evaluated. The most active complex (2-Ga) possesses a low IC50 value of 0.185 µM and a phototoxic index of 541 against HepG2 cells. Additionally, the 5FU-gallium corrole conjugate (2-Ga) exhibited a synergistic increase in cytotoxicity under irradiation. Excitedly, treatment of HepG2 tumor-bearing mice with 2-Ga under irradiation could completely ablate tumors without harming normal tissues. 2-Ga-mediated PDT could disrupt mitochondrial function, cause cell cycle arrest in the sub-G1 phase, and activate the cell apoptosis pathway by upregulating the cleaved PARP expression and the Bax/Bcl-2 ratios. This work provides a useful strategy for the design of new corrole-based chemo-photodynamic therapy drugs.

Chandipura viral glycoprotein (CNV-G) promotes Gectosome generation and enables delivery of intracellular therapeutics.

Overexpression of vesicular stomatitis virus G protein (VSV-G) elevates the secretion of EVs known as gectosomes, which contain VSV-G. Such vesicles can be engineered to deliver therapeutic macromolecules. We investigated viral glycoproteins from several viruses for their potential in gectosome production and intracellular cargo delivery. Expression of the viral glycoprotein (viral glycoprotein from the Chandipura virus [CNV-G]) from the human neurotropic pathogen Chandipura virus in 293T cells significantly augments the production of CNV-G-containing gectosomes. In comparison with VSV-G gectosomes, CNV-G gectosomes exhibit heightened selectivity toward specific cell types, including primary cells and tumor cell lines. Consistent with the differential tropism between CNV-G and VSV-G gectosomes, cellular entry of CNV-G gectosome is independent of the Low-density lipoprotein receptor, which is essential for VSV-G entry, and shows varying sensitivity to pharmacological modulators. CNV-G gectosomes efficiently deliver diverse intracellular cargos for genomic modification or responses to stimuli in vitro and in the brain of mice in vivo utilizing a split GFP and chemical-induced dimerization system. Pharmacokinetics and biodistribution analyses support CNV-G gectosomes as a versatile platform for delivering macromolecular therapeutics intracellularly.

Robot-assisted total knee arthroplasty system provides more precise control of the femoral rotation angle: A retrospective study.

BACKGROUND: Rotational alignment in total knee arthroplasty (TKA) is a crucial technical point that needs attention. We conducted a retrospective study to investigate whether a new robot-assisted TKA (RA-TKA) could improve the accuracy of rotational alignment and whether rotational alignment affects postoperative pain and functional evaluation of the knee. METHODS: A total of 136 consecutive patients who underwent TKA were included in this study. Half of the patients underwent RA-TKA and the other half underwent conventional TKA (CON-TKA) by the same group of surgeons. Collect the relevant parameters. RESULTS: The postoperative femoral rotation angle (FRA) was -0.72 ± 2.59° in the robot-assisted group and 1.13 ± 2.73° in the conventional group, and were statistically significantly different (p < 0.001). CONCLUSION: This study provides preliminary evidence that the RA-TKA provides more precise control of FRA than CON-TKA, and verifies that tibial rotation angle and combined rotation angle affect postoperative knee pain and functional evaluation.

Airway basal cell­derived exosomes suppress epithelial­mesenchymal transition of lung cells by inhibiting the expression of ANO1.

Disruption of the epithelial-mesenchymal transition (EMT) of activated lung cells is an important strategy to inhibit the progression of idiopathic pulmonary fibrosis (IPF). The present study investigated the role of exosomes derived from airway basal cells on EMT of lung cells and elucidate the underlying mechanism. Exosomes were characterized by nanoparticle tracking analysis, transmission electron microscopy imaging and markers detection. The role of exosome on the EMT of lung epithelial cells and lung fibroblasts induced by TGF-ß1 was detected. RNA sequencing screened dysregulated genes in exosome-treated group, followed by the bioinformatical analysis. One of the candidates, anoctamin-1 (ANO1), was selected for further gain-and-loss phenotype assays. A bleomycin-induced pulmonary fibrosis model was used to evaluate the treatment effect of exosomes. Exosomes were round-like and positively expressed CD63 and tumor susceptibility gene 101 protein. Treatment with exosomes inhibited the EMT of lung cells activated by TGF-ß1. 4158 dysregulated genes were identified in exosome-treated group under the threshold of |log2 fold-change| value >1 and they were involved in the metabolism of various molecules, as well as motility-related biological processes. A key gene, ANO1, was verified by reverse transcription-quantitative PCR, whose overexpression induced the EMT of lung cells. By contrast, ANO1 knockdown reversed the EMT induced by TGF-ß1. In vivo assay indicated that exosome treatment ameliorated pulmonary fibrosis and inhibited the upregulation of ANO1 induced by bleomycin. In conclusion, airway basal cell-derived exosomes suppressed the EMT of lung cells via the downregulation of ANO1. These exosomes represent a potential therapeutic option for patients with IPF.

Circulating tumor cells shielded with extracellular vesicle-derived CD45 evade T cell attack to enable metastasis.

Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45+ CTCs) that resisted T cell attack. A higher percentage of CD45+ CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45+ tumor cells orchestrated an immunosuppressive milieu and CD45+ CTCs exhibited remarkably stronger metastatic potential than CD45- CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

Latency-aware Unified Dynamic Networks for Efficient Image Recognition.

Dynamic computation has emerged as a promising strategy to improve the inference efficiency of deep networks. It allows selective activation of various computing units, such as layers or convolution channels, or adaptive allocation of computation to highly informative spatial regions in image features, thus significantly reducing unnecessary computations conditioned on each input sample. However, the practical efficiency of dynamic models does not always correspond to theoretical outcomes. This discrepancy stems from three key challenges: 1) The absence of a unified formulation for various dynamic inference paradigms, owing to the fragmented research landscape; 2) The undue emphasis on algorithm design while neglecting scheduling strategies, which are critical for optimizing computational performance and resource utilization in CUDA-enabled GPU settings; and 3) The cumbersome process of evaluating practical latency, as most existing libraries are tailored for static operators. To address these issues, we introduce Latency-Aware Unified Dynamic Networks (LAUDNet), a comprehensive framework that amalgamates three cornerstone dynamic paradigms-spatially-adaptive computation, dynamic layer skipping, and dynamic channel skipping-under a unified formulation. To reconcile theoretical and practical efficiency, LAUDNet integrates algorithmic design with scheduling optimization, assisted by a latency predictor that accurately and efficiently gauges the inference latency of dynamic operators. This latency predictor harmonizes considerations of algorithms, scheduling strategies, and hardware attributes. We empirically validate various dynamic paradigms within the LAUDNet framework across a range of vision tasks, including image classification, object detection, and instance segmentation. Our experiments confirm that LAUDNet effectively narrows the gap between theoretical and real-world efficiency. For example, LAUDNet can reduce the practical latency of its static counterpart, ResNet-101, by over 50% on hardware platforms such as V100, RTX3090, and TX2 GPUs. Furthermore, LAUDNet surpasses competing methods in the trade-off between accuracy and efficiency. Code is available at: https://www.github.com/LeapLabTHU/LAUDNet.

Unveiling the Mechanism of the ChaiShao Shugan Formula Against Triple-Negative Breast Cancer.

Background: The ChaiShao Shugan Formula (CSSGF) is a traditional Chinese medicine formula with recently identified therapeutic value in triple-negative breast cancer (TNBC). This study aimed to elucidate the underlying mechanism of CSSGF in TNBC treatment. Methods: TNBC targets were analyzed using R and data were from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The major ingredients and related protein targets of CSSGF were explored via the Traditional Chinese Medicine Systems Pharmacology database, and an ingredient-target network was constructed via Cytoscape to identify hub genes. The STRING database was used to construct the PPI network. GO and KEGG enrichment analyses were performed via R to obtain the main targets. The online tool Kaplan‒Meier plotter was used to identify the prognostic genes. Molecular docking was applied to the core target genes and active ingredients. MDA-MB-231 and MCF-7 cell lines were used to verify the efficacy of the various drugs. Results: A total of 4562 genes were screened as TNBC target genes. The PPI network consisted of 89 nodes and 845 edges. Our study indicated that quercetin, beta-sitosterol, luteolin and catechin might be the core ingredients of CSSGF, and EGFR and c-Myc might be the latent therapeutic targets of CSSGF in the treatment of TNBC. GO and KEGG analyses indicated that the anticancer effect of CSSGF on TNBC was mainly associated with DNA binding, transcription factor binding, and other biological processes. The related signaling pathways mainly involved the TNF-a, IL-17, and apoptosis pathways. The molecular docking data indicated that quercetin, beta-sitosterol, luteolin, and catechin had high affinity for EGFR, JUN, Caspase-3 and ESR1, respectively. In vitro, we found that CSSGF could suppress the expression of c-Myc or promote the expression of EGFR. In addition, we found that quercetin downregulates c-Myc expression in two BC cell lines. Conclusion: This study revealed the effective ingredients and latent molecular mechanism of action of CSSGF against TNBC and confirmed that quercetin could target c-Myc to induce anti-BC effects.

Emission and optical characteristics of brown carbon in size-segregated particles from three types of Chinese ships.

Brown carbon (BrC) is one of the important light absorption substances that have high light absorption ability under short wavelength light. However, limit studies have focused on the BrC emission from ships. In this study, size-segregated particulate matters (PM) were collected from three different types of ships, light absorption characteristics and size distribution of methanol-soluble BrC and water-soluble BrC in PM from ship exhausts were investigated. Results showed that four-stroke low-power diesel fishing boat (4-LDF) had the highest mass concentrations of methanol-soluble organic carbon (MSOC) and water-soluble organic carbon (WSOC), followed by 2-stroke high-power heavy-fuel-oil vessel (2-HHV), and four-stroke high-power marine-diesel vessel (4-HMV). While 2-HHV had obviously higher light absorption coefficients of methanol-soluble BrC (Abs365,M) and water-soluble BrC (Abs365,W) in unit weight of PM than the other two types of ships. The tested ships presented comparable or higher absorption efficiency of BrC in water extracts (MAE365,W) compared with other BrC emission sources. Majority of BrC was concentrated in fine particles, and the particle size distributions of both Abs365,M and Abs365,W showed bimodal patterns, peaking at 0.43-0.65 µm and 4.7-5.8 µm, respectively. However, different particle size distributions were found for MAE365,M between diesel and heavy fuel oil ships. Besides, different wavelength dependence in particles with different size were also detected. Ship exhaust could be confirmed as a non-ignorable BrC emission source, and complex influencing factor could affect the light absorption characteristics of ship emissions. Particle size should also be considered when light absorption ability of BrC was evaluated.

Impact of Off-Hour Admission on In-Hospital Outcomes for Patients With Stroke Receiving Reperfusion Therapy in China.

BACKGROUND: The structure and staffing of hospitals greatly impact patient outcomes, with frequent changes occurring during nights and weekends. This retrospective cohort study assessed the impact of admission timing on in-hospital management and outcomes for patients with stroke receiving reperfusion therapy in China using data from a nationwide registry. METHODS: Data from patients receiving reperfusion therapy were extracted from the Chinese Stroke Center Alliance. Hospital admission time was categorized according to day/evening versus night and weekday versus weekend. Primary outcomes were in-hospital death or discharge against medical advice, hemorrhage transformation, early neurological deterioration, and major adverse cardiovascular events. Logistic regression was performed to compare in-hospital management performance and outcomes based on admission time categories. RESULTS: Overall, 42 381 patients received recombinant tissue-type plasminogen activator (r-tPA) therapy, and 5224 underwent endovascular treatment (EVT). Patients admitted during nighttime had a higher probability of receiving r-tPA therapy within 4.5 hours from onset or undergoing EVT within 6 hours from onset compared with those admitted during day/evening hours (adjusted odds ratio, 1.04 [95% CI, 1.01-1.08]; P=0.021; adjusted odds ratio, 1.72 [95% CI, 1.59-1.86]; P<0.001, respectively). However, no significant difference was observed between weekend and weekday admissions for either treatment. No notable differences were noted between weekends and weekdays or nighttime and daytime periods in door-to-needle time for r-tPA or door-to-puncture time for EVT initiation. Furthermore, weekend or nighttime admission did not have a significant effect on the primary outcomes of r-tPA therapy or EVT. Nevertheless, in patients undergoing EVT, a higher incidence of pneumonia was observed among those admitted at night compared with those admitted during day/evening hours (adjusted odds ratio, 1.22 [95% CI, 1.05-1.42]; P=0.011). CONCLUSIONS: Patients admitted at nighttime were more likely to receive r-tPA therapy or EVT within the time window recommended in the guidelines. However, patients receiving EVT admitted at night had an increased risk of pneumonia.

Microstructural abnormality of white matter tracts in rheumatoid arthritis.

BACKGROUND: Structural and functional brain imaging studies have reported abnormalities of gray matter morphology and functional activities in patients with rheumatoid arthritis (RA). However, it is largely unknown whether patients with RA show alterations of white matter microstructural organization. OBJECTIVES: To automatically identify alteration of white matter microstructure in patients with RA and further examine how this alteration associates with clinical characteristics. METHODS: This single-institutional prospective study included 66 participants (33 patients with RA [52 ± 9 years, 29 women] and 33 sex/age-matched healthy controls [53 ± 12 years, 27 women]), who underwent diffusion MRI scan from January 2021 to December 2021. The white matter microstructure was assessed using fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Voxelwise analyses were conducted on white matter skeleton using an automated, observer-independent tract-based spatial statistics analysis. The relationship between white matter microstructural alterations and clinical and neuropsychological variables was evaluated using correlation analysis. RESULTS: Compared with healthy controls, patients with RA exhibited lower fractional anisotropy in several major white matter tracts (threshold-free cluster enhancement at P < 0.05 for multiple comparison correction, permutation test), involving the forceps minor, bilateral inferior fronto-occipital fasciculus, bilateral anterior thalamic radiation, and bilateral uncinate fasciculus. Lower fractional anisotropy values in the patients with RA were significantly associated with pain-related assessments, including tender joint count (r = -0.43, P = 0.015), Clinical Disease Activity Index score (r = -0.36, P = 0.049), pain severity rated through visual analogue scale (r = -0.45, P = 0.012), and Simplified Disease Activity Index score (r = -0.36, P = 0.045). No significant group difference was found in mean diffusivity, axial diffusivity, and radial diffusivity. CONCLUSIONS: We report the first anatomical evidence for aberrant microstructure organization of several major white matter tracts and its associations with pain processing in patients with rheumatoid arthritis.

Cloflucarban Illuminates Specificity and Context-Dependent Activation of the PINK1-Parkin Pathway by Mitochondrial Complex Inhibition.

The PTEN-induced kinase 1 (PINK1)-Parkin pathway plays a vital role in maintaining a healthy pool of mitochondria in higher eukaryotic cells. While the downstream components of this pathway are well understood, the upstream triggers remain less explored. In this study, we conducted an extensive analysis of inhibitors targeting various mitochondrial electron transport chain (ETC) complexes to investigate their potential as activators of the PINK1-Parkin pathway. We identified cloflucarban, an antibacterial compound, as a novel pathway activator that simultaneously inhibits mitochondrial complexes III and V, and V. RNA interference (RNAi) confirmed that the dual inhibition of these complexes activates the PINK1-Parkin pathway. Intriguingly, we discovered that albumin, specifically bovine serum albumin (BSA) and human serum albumin (HSA) commonly present in culture media, can hinder carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced pathway activation. However, cloflucarban's efficacy remains unaffected by albumin, highlighting its reliability for studying the PINK1-Parkin pathway. This study provides insights into the activation of the upstream PINK1-Parkin pathway and underscores the influence of culture conditions on research outcomes. Cloflucarban emerges as a promising tool for investigating mitochondrial quality control and neurodegenerative diseases.

Association between multiple sclerosis and cancer risk: A two-sample Mendelian randomization study.

Multiple Sclerosis (MS) is an immune-related disease and the relationship between MS and cancer has raised attention. Previous studies of the relationship between MS and cancer have reached conflicting conclusions. In this study, the two-sample MR method is used to investigate whether MS has a causal correlation with cancers and offer scientific evidence for cancer prevention. Single nucleotide polymorphisms (SNPs) related to MS were obtained from the genome-wide association study (GWAS) based on International Multiple Sclerosis Genetics Consortium (IMSGC) and SNPs related to 15 types of cancers were obtained from the GWASs based on UK Biobank. Inverse variance weighted (IVW) method was mainly used to assess causal effects. Sensitivity analyses were conducted with Cochran's Q-test, MR Egger intercept, leave-one-out test, and MR Steiger method. IVW analysis showed that MS was only associated with a marginal increased risk of cervical cancer (OR 1.0004, 95% CI 1.0002-1.0007, p = 0.0003). Sensitivity analyses showed that the results of MR analysis were robust and found no heterogeneity, no pleiotropy, and no reverse causation. In conclusion, this study finds no causal relationship between MS and 15 types of cancers except cervical cancer.

Small-molecule agents for cancer immunotherapy.

Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Effects of grazing exclusion on soil properties, fungal community structure, and diversity in different grassland types.

Soil fungi are involved in the decomposition of organic matter, and they alter soil structure and physicochemical properties and drive the material cycle and energy flow in terrestrial ecosystems. Fungal community assembly processes were dissimilar in different soil layers and significantly affected soil microbial community function and plant growth. Grazing exclusion is one of the most common measures used to restore degraded grasslands worldwide. However, changes in soil fungal community characteristics during grazing exclusion in different types of grasslands are unknown. Here, we investigated the effects of a 9-year grazing exclusion on soil properties, fungal community composition, and diversity in three grassland types (temperate desert, temperate steppe, and mountain meadow). The results showed that (1) in the 0-5 cm soil layer, grazing exclusion significantly increased the differences in SWC, SOC, KN, and N:P among the three grassland types, while the final pH, BD, TP, C:N, and C:P values were consistent with the results before exclusion. In the 5-10 cm soil layer, grazing exclusion significantly increased total phosphorus (TP) in temperate deserts by 34.1%, while significantly decreasing bulk density (BD) by 9.8% and the nitrogen: phosphorus ratio (N:P) by 47.1%. (2) The soil fungal community composition differed among the grassland types, For example, significant differences were found among the three grassland types for the Glomeromycota and Mucoromycota. (3) Under the influence of both grazing exclusion and grassland type, there was no significant change in soil fungal alpha diversity, but there were significant differences in fungal beta diversity. (4) Grassland type was the most important factor influencing changes in fungal community diversity, and vegetation cover and soil kjeldahl nitrogen were the main factors influencing fungal diversity. Our research provides a long-term perspective for better understanding and managing different grasslands, as well as a better scientific basis for future research on grass-soil-microbe interactions.

METTL3-mediated m6A modification enhances ZDHHC16 expression in nonsmall- cell lung cancer patients, attenuating ferroptosis by suppressing CREB ubiquitination.

At present, the early diagnosis and treatment of non-small cell lung cancer (NSCLC) is still an urgent problem to be solved worldwide, including in China. The present work investigated the possible protective effect of ZDHHC16 in cell proliferation and metastasis of NSCLC and explored its possible mechanisms. ZDHHC16 expression level in patients with Non-Small-Cell Lung Cancer was up-regulation. ZDHHC16 gene is stabilized by m6A methylation. ZDHHC16 gene reduced ferroptosis of NSCLC by the rehabilitation of the mitochondrial structure. ZDHHC16 promoted CREB expression through the inhibition of CREB Ubiquitination. Confocal microscopy showed that ZDHHC16 reduced the CREB expression of NSCLC. ZDHHC16 up-regulation reduced CREB Ubiquitination, and down-regulation of ZDHHC16 promoted CREB Ubiquitination of NSCLC. CREB Agonists reduced the effects of ZDHHC16 on ferroptosis, not affecting the Warburg effect of NSCLC. CREB inhibitor reduced the effects of si-ZDHHC16 on ferroptosis, not affecting the Warburg effect of NSCLC. METTL3-mediated m6A modification increases ZDHHC16 stability. Our study revealed that the m6A-forming enzyme METTL3 upregulates ZDHHC16 expression in NSCLC patients, leading to the reduction of ferroptosis by inhibiting CREB ubiquitination.

Care stressors and perceived stress among family caregivers of Chinese older adults with disabilities: The mediation effect of resilience.

OBJECTIVES: Guided by the Stress Process Model, this study examined the mediating effect of resilience on the relationship between care stressors and perceived caregiving stress. METHODS: Data were based on 234 older adults with disabilities and their caregivers from 6 urban districts and 6 rural counties from Jinan, China. Descriptive analysis, analysis of variance, ordinary least squares regression, and mediation analysis were performed. RESULTS: Perceived stress among family caregivers of Chinese older adults with disabilities was affected by the physical and mental health of both themselves and the care recipients, as well as care intensity and financial difficulties. Resilience played a partial mediating role in the associations among three stressors (i.e. older adults' disability levels, number of chronic diseases, and caregivers' self-reported mental) and perceived caregiving stress. CONCLUSIONS: Enhanced resilience aids caregivers' adaptation to their roles, suggesting the need for societal, spiritual, emotional, and behavioral resilience training.