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Abstract MUC1 is a highly glycosylated transmembrane protein with a high molecular weight. It plays a role in lubricating and protecting mucosal epithelium, participates in epithelial cell renewal and differentiation, and regulates cell adhesion, signal transduction, and immune response. MUC1 is expressed in both normal and malignant epithelial cells, and plays an important role in the diagnosis, prognosis prediction and clinical monitoring of a variety of tumors and is expected to be a new therapeutic target. This article reviews the structural features, expression regulation mechanism, and research progress of MUC1 in the development of genitourinary cancers and its clinical applications.

Abstract Background Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive. Methods By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays. Results Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth. Conclusion Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.

Abstract Objective Our aim was to comprehensively investigate the relationship between blood volatile organic compounds (VOCs) and kidney stone prevalence for U.S. adults. Methods In this cross-sectional study, 10,052 participants from the 2007–2020 National Health and Nutrition Examination Survey (NHANES) were included. Multivariate logistic regression model was employed to investigate the association between 9 blood VOCs and kidney stones. We explored the dose–response relationship between blood VOCs and kidney stones using restricted cubic spline (RCS) analysis. Additionally, weighted quantile sum (WQS) regression model was performed to assess the overall association of 9 blood VOCs with kidney stones. Finally, subgroup analyses were conducted to identify the findings in different populations at high prevalence. Results Logistic regression analysis and dose–response risk curves revealed that blood benzene (aOR = 1.308, 95% CI: 1.118–1.530, P = 0.001), blood ethylbenzene (aOR = 1.280, 95% CI: 1.054–1.554, P = 0.013), blood m-/p-xylene (aOR = 1.187, 95% CI: 1.008–1.398, P = 0.040), blood 2,5-dimethylfuran (aOR = 1.319, 95% CI: 1.135–1.533, P

ABSTRACT Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies, we determined that a heat-killed, Cryptococcus neoformans fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2+ monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2+ cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c+ cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against Cryptococcus infection.IMPORTANCEThe number of patients susceptible to invasive fungal infections across the world continues to rise at an alarming pace yet current antifungal drugs are often inadequate. Immune-based interventions and novel antifungal vaccines hold the promise of significantly improving patient outcomes. In previous studies, we identified a Cryptococcus neoformans mutant strain (Fbp1-deficient) as a potent, heat-inactivated vaccine candidate capable of inducing homologous and heterologous antifungal protection. In this study, we used a combination of methods together with a cohort of conditional knockout mouse strains to interrogate the roles of innate cells in the orchestration of vaccine-induced antifungal protection. We uncovered novel roles for neutrophils and monocytes as coordinators of a STAT1-dependent cascade of responses that mediate vaccine-induced protection against invasive cryptococcosis. This new knowledge will help guide the future development of much-needed antifungal vaccines.

BackgroundThe immunogenicity of allogeneic mesenchymal stem cells (MSCs) is significantly enhanced after transplantation or differentiation, and these cells can be recognized and cleared by recipient immune cells. Graft rejection has become a major obstacle to improving the therapeutic effect of allogeneic MSCs or, after their differentiation, transplantation in the treatment of diabetes and other diseases. Solving this problem is helpful for prolonging the time that cells play a role in the recipient body and for significantly improving the clinical therapeutic effect.MethodsIn this study, canine adipose-derived mesenchymal stem cells (ADSCs) were used as seed cells, and gene editing technology was used to knock out the B2M gene in these cells and cooperate with the overexpression of the PD-L1 gene. Gene-edited ADSCs (GeADSCs), whose biological characteristics and safety are not different from those of normal canine ADSCs, have been obtained.ResultsThe immunogenicity of GeADSCs is reduced, the immune escape ability of GeADSCs is enhanced, and GeADSCs can remain in the body for a longer time. Using the optimized induction program, the efficiency of the differentiation of GeADSCs into new islet β-cells was increased, and the maturity of the new islet β-cells was increased. The immunogenicity of new islet β-cells decreased, and their immune escape ability was enhanced after the cells were transplanted into diabetic dogs (the graft site was prevascularized by the implantation of a scaffold to form a vascularized pouch). The number of infiltrating immune cells and the content of immune factors were decreased at the graft site.ConclusionsNew islet β-cell transplantation, which has low immunogenicity, can reverse diabetes in dogs, and the therapeutic effect of cell transplantation is significantly enhanced. This study provides a new method for prolonging the survival and functional time of cells in transplant recipients and significantly improving the clinical therapeutic effect.

Patients diagnosed with papillary renal cell carcinoma (pRCC) exhibit a high rate of clinical metastasis; however, the underlying molecular mechanism is unclear. In this study, KH-type splicing regulatory protein (KHSRP) participated in pRCC progression and was associated with metastasis. It was positively correlated with the hallmark of epithelial-mesenchymal transition. KHSRP inhibition effectively alleviated the cellular function of migration and invasion. Additionally, KHSRP knockdown inhibited the proliferative ability of pRCC cells. A pharmaceutical screening was based on the KHSRP protein structure. Gemcitabine (Gem) decreased KHSRP expression. UIO-66@Gem@si-KHSRP (UGS) nanoparticles (NPs) were prepared for targeted delivery and applied in both in vitro and in vivo experiments to explore the clinical transition of KHSRP. UGS NPs exhibited better performance in inhibiting cellular proliferation, migration, and invasion than Gem. Additionally, the in vivo experiment results confirmed their therapeutic effects in inhibiting tumor metastasis with excellent biosafety. The silico analysis indicated that KHSRP knockdown increased cytotoxic cell infiltration in the tumor microenvironment to potentiate anti-tumor effects. Thus, KHSRP can promote pRCC progression as an oncogene and serve as a target in clinical transition through UGS NP-based therapy.

Abstract The long non-coding RNA X-inactive specific transcript (lncRNA XIST) and MUC1 gene are dysregulated in chronic inflammation and cancer; however, there is no known interaction of their functions. The present studies demonstrate that MUC1-C regulates XIST lncRNA levels by suppressing the RBM15/B, WTAP and METTL3/14 components of the m6A methylation complex that associate with XIST A repeats. MUC1-C also suppresses the YTHDF2-CNOT1 deadenylase complex that recognizes m6A sites and contributes to XIST decay with increases in XIST stability and expression. In support of an auto-regulatory pathway, we show that XIST regulates MUC1-C expression by promoting NF-κB-mediated activation of the MUC1 gene. Of significance, MUC1-C and XIST regulate common genes associated with inflammation and stemness, including (i) miR-21 which is upregulated across pan-cancers, and (ii) TDP-43 which associates with the XIST E repeats. Our results further demonstrate that the MUC1-C/XIST pathway (i) is regulated by TDP-43, (ii) drives stemness-associated genes, and (iii) is necessary for self-renewal capacity. These findings indicate that the MUC1-C/XIST auto-regulatory axis is of importance in cancer progression.

Aims: Radiotherapy is a well-known local treatment for spinal metastases. However, in the presence of postoperative systemic therapy, the efficacy of radiotherapy on local control (LC) and overall survival (OS) in patients with spinal metastases remains unknown. This study aimed to evaluate the clinical outcomes of post-surgical radiotherapy for spinal metastatic non-small-cell lung cancer (NSCLC) patients, and to identify factors correlated with LC and OS. Methods: A retrospective, single-centre review was conducted of patients with spinal metastases from NSCLC who underwent surgery followed by systemic therapy at our institution from January 2018 to September 2022. Kaplan-Meier analysis and log-rank tests were used to compare the LC and OS between groups. Associated factors for LC and OS were assessed using Cox proportional hazards regression analysis. Results: Overall, 123 patients with 127 spinal metastases from NSCLC who underwent decompression surgery followed by postoperative systemic therapy were included. A total of 43 lesions were treated with stereotactic body radiotherapy (SBRT) after surgery and 84 lesions were not. Survival rate at one, two, and three years was 83.4%, 58.9%, and 48.2%, respectively, and LC rate was 87.8%, 78.8%, and 78.8%, respectively. Histological type was the only significant associated factor for both LC (p = 0.007) and OS (p < 0.001). Treatment with targeted therapy was significantly associated with longer survival (p = 0.039). The risk factors associated with worse survival were abnormal laboratory data (p = 0.021), lesions located in the thoracic spine (p = 0.047), and lumbar spine (p = 0.044). This study also revealed that postoperative radiotherapy had little effect in improving OS or LC. Conclusion: Tumour histological type was significantly associated with the prognosis in spinal NSCLC metastasis patients. In the presence of post-surgical systemic therapy, radiotherapy appeared to be less effective in improving LC, OS, or quality of life in spinal NSCLC metastasis patients. Cite this article: Bone Jt Open 2024;5(4):350–360.

Feline chronic gingivostomatitis (FCGS) is an ulcerative and/or proliferative disease that typically affects the palatoglossal folds. Because of its unknown pathogenesis and long disease course, it is difficult to treat and has a high recurrence rate. Most of the bacteria in the oral microbiota exist in the mouth symbiotically and maintain a dynamic balance, and when the balance is disrupted, they may cause disease. Disturbance of the oral microbiota may play an important role in the development of FCGS. In this study, the medical records of 3109 cats in three general pet hospitals in Xi ‘an were collected. Sixty-one cats with FCGS were investigated via questionnaires, routine oral examinations and laboratory examinations. Oral microbiota samples were collected from 16 FCGS-affected cats, and microbial species were identified by 16S rDNA sequencing. The results showed that the incidence of FCGS had no significant correlation with age, sex or breed. However, the incidence of FCGS was associated with immunization, a history of homelessness and multicat rearing environments. The number of neutrophils and the serum amyloid A concentration were increased, and the percentage of cells positive for calicivirus antigen was high in all cases. All the cats had different degrees of dental calculus, and there were problems such as loss of alveolar bone or tooth resorption. Compared with those in healthy cats, the bacterial diversity and the abundance of anaerobic bacteria were significantly increased in cats with FCGS. Porphyromonas, Treponemas and Fusobacterium were abundant in the mouths of the affected cats and may be potential pathogens of FCGS. After tooth extraction, a shift could be seen in the composition of the oral microbiota in cats with FCGS. An isolated bacteria obtained from the mouths of the affected cats was homologous to P. gulae. Both the identified oral microbiota and the isolated strain of the cats with FCGS had high sensitivity to enrofloxacin and low sensitivity to metronidazole. This study provides support to current clinical criteria in diagnosing FCGS and proposes a more suitable antibiotic therapy.

Abstract The oncogenic MUC1-C transmembrane protein is a critical effector of the cancer stem cell (CSC) state. Addiction to MUC1-C for self-renewal in the progression of human cancers has emphasized the need for development of anti-MUC1-C agents. However, there are presently no approved small molecules for targeting MUC1-C-dependent CSCs. In screening for small molecules, we identified salinomycin (SAL), an inducer of ferroptosis, as a potent inhibitor of MUC1-C signaling. We demonstrate that SAL suppresses MUC1-C expression by disrupting a NF-κB/MUC1-C auto-inductive circuit that is necessary for ferroptosis resistance. Our results show that SAL-induced MUC1-C suppression downregulates a MUC1-C→MYC pathway that activates genes encoding (i) glutathione-disulfide reductase (GSR), and (ii) the LDL receptor related protein 8 (LRP8), which inhibit ferroptosis by generating GSH and regulating selenium levels, respectively. GSR and LRP8 contribute to the function of glutathione peroxidase 4 (GPX4), an essential negative regulator of ferroptotic cell death. We demonstrate that targeting MUC1-C genetically or with the GO-203 peptide inhibitor suppresses GPX4 expression and GPX activity in association with the induction of ferroptosis. Studies of CSCs enriched by serial passage as tumorspheres further demonstrate that the effects of SAL are mediated by downregulation of MUC1-C and thereby overcoming resistance to ferroptosis. As confirmation of these results, rescue of MUC1-C downregulation with the MUC1-C cytoplasmic domain (i) reversed the suppression of GSR, LRP8 and GPX4 expression, and (ii) attenuated the induction of ferroptosis. These findings identify SAL as a unique small molecule inhibitor of MUC1-C signaling and demonstrate that MUC1-C is an important effector of resistance to ferroptosis.

Abstract Background Topical photodynamic therapy (PDT) has demonstrated encouraging results in the treatment of oral leukoplakia (OLK). However, data on the clinical efficacy of PDT in Chinese patients with OLK are still limited. Methods Fifty patients diagnosed with OLK were enrolled, including patients with various dysplastic tissues. All patients received topical PDT with 5-aminolevulinic acid (5-ALA) as a photosensitizer. Clinical efficacy was evaluated 4 weeks after treatment. Follow-up was performed every 3 months during the first year and every 6 months during the second year. Results The overall response rate was 68% (34/50): 12% (n = 6) complete and 56% (n = 28) partial responses. Aneuploidy was reduced in the patients with dysplastic lesions. Oral pain and local ulcers developed in 52% of the patients (n = 26). Patients with a long history of OLK including hyperplasia and dysplastic lesions, as well as those with non-homogenous lesions, were more likely to develop pain and ulcer. During follow-up, the recurrence rate of hyperplasia and dysplastic lesions was 32% (n = 16) and the malignant transformation rate of dysplastic lesions was 4% (n = 2). Lesions on the buccal mucosa were associated with recurrence (P = 0.044; OR: 0.108, 95% CI: 0.013–0.915). Conclusion Topical 5-ALA-mediated PDT is an effective treatment for OLK, particularly for homogenous leukoplakia, with few side effects. The buccal mucosa may be a protective factor that can reduce recurrence.

Abstract Background In a multi‐institutional clinical study, we assessed the prognostic significance of a novel indicator preoperative peripheral blood immune (PBIS) scores that combined ratios of preoperative lymphocyte, monocyte, and neutrophil of renal cell carcinoma (RCC) patients undergoing laparoscopic nephrectomy. Methods Between January 2014 and December 2019, 438 patients with RCC were retrospectively analyzed in three centers. We used X‐tile software to obtain the optimum cut‐off values for neutrophils, monocytes, and lymphocytes to classify the patients. To assess the relationship between PBIS score and overall survival (OS), and cancer‐specific survival (CSS) in patients with RCC by Kaplan–Meier survival curves and Cox regression analyses. In addition, predictive OS and CSS nomograms were constructed. The discriminative ability of nomogram and predictive performance accuracy were verified with consistency index (C‐index), calibration curves, receiver operating curve (ROC) curves, decision curve analysis (DCA) curves, and time‐dependent ROC curves. Results The optimum cutoff values for monocytes, lymphocytes, and neutrophils were 0.46, 1.01, and 4.50, respectively. We divided patients into four subgroups according to PBIS scores, which were significantly associated with M‐stage (p = 0.008), T‐stage (p

Background: Metamycoplasma orale (M.orale), a symbiotic bacterium observed in the human oral cavity, is generally regarded as non-pathogenic to humans. Although infrequent, symptomatic infections caused by M.orale may occur in individuals with compromised humoral immunity. Accurate identification and early diagnosis of M.orale still present significant challenges due the limitations associated with conventional detection methods. Although metagenomic next-generation sequencing (mNGS) is currently widely utilized in clinical practices and exhibits a remarkable specificity and sensitivity for detecting various pathogens, its application in the diagnosis of M.orale-induced osteomyelitis remains largely unexplored. Case description: In this report, we present a case study of osteonecrosis caused by M.orale in a 20-year-old female patient with nephrotic syndrome and other comorbidities. She was administered long-term hormone therapy and immunosuppressants, leading to her admission to the hospital due to recurrent fever, hip abscess and left thigh pain. Imaging examination revealed bilateral mid-femoral lesions, with the extensive nature of the left femoral lesion suggesting a potential secondary infection. Although no pathogen was detected in pus culture, mNGS analysis identified M.orale in the sample. Following treatment with doxycycline and levofloxacin, the patient's symotoms improved and she was discharged with favorable outcomes. Conclusion: mNGS enables rapid identification of etiology in patients with osteomyelitis caused by the rare pathogen M.orale. This case accentuate the strength of mNGS for early detection and targeted clinical treatment of infectious diseases caused by uncommon pathogens.

Abstract Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 methyltransferases. We find that MUC1-C regulates (i) bulk H3K4 methylation levels, and (ii) the COMPASS SET1A/SETD1A and WDR5 genes by an NF-κB-mediated mechanism. The importance of MUC1-C in regulating the SET1A COMPASS complex is supported by the demonstration that MUC1-C and WDR5 drive expression of FOS, ATF3 and other AP-1 family members. In a feedforward loop, MUC1-C, WDR5 and AP-1 contribute to activation of genes encoding TRAF1, RELB and other effectors in the chronic NF-κB inflammatory response. We also show that MUC1-C, NF-κB, WDR5 and AP-1 are necessary for expression of the (i) KLF4 master regulator of the pluripotency network and (ii) NOTCH1 effector of stemness. In this way, MUC1-C/NF-κB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in the KLF4 and NOTCH1 genes with increases in H3K4me3 levels, chromatin accessibility and transcription. These findings indicate that MUC1-C regulates the SET1A COMPASS complex and the induction of genes that integrate NF-κB-mediated chronic inflammation with cancer progression.

Monkeypox virus (MPXV) is a cross-kingdom pathogen infecting both humans and wildlife, which poses a significant health risk to the public. Although MPXV attracts broad attention, there is a lack of adequate studies to elucidate pathogenic mechanisms associated with viral infections. In this study, a high-throughput RNA sequencing (RNA-seq) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach was used to explore the transcriptional and metabolic responses of MPXV A23 protein to HEK293T cells. The protein–protein interactions and signaling pathways were conducted by GO and KEGG analyses. The localization of A23 protein in HEK293T cells was detected by immunofluorescence. A total of 648 differentially expressed genes (DEGs) were identified in cells by RNA-Seq, including 314 upregulated genes and 334 downregulated genes. Additionally, liquid chromatography–tandem mass spectrometry (LC-MS/MS) detected 115 cellular proteins that interact with the A23 proteins. Transcriptomic sequencing analysis revealed that transfection of MPXV A23 protein modulated genes primarily associated with cellular apoptosis and DNA damage repair. Proteomic analysis indicated that this protein primarily interacted with host ribosomal proteins and histones. Following the identification of the nuclear localization sequence RKKR within the A23 protein, a truncated mutant A23ΔRKKR was constructed to investigate the subcellular localization of A23 protein. The wild-type A23 protein exhibits a significantly higher nuclear-to-cytoplasmic ratio, exceeding 1.5, in contrast to the mutant A23ΔRKKR, which has a ratio of approximately 1. Immunofluorescence assays showed that the A23 protein was mainly localized in the nucleus. The integration of transcriptomics and proteomics analysis provides a comprehensive understanding of the interaction between MPXV A23 protein and the host. Our findings highlight the potential role of this enzyme in suppressing host antiviral immune responses and modulating host gene expression.

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.

Cuproptosis is a newly identified specific form of programmed cell death. Our study aimed to identify cuproptosis-related genes (CRGs) in patients with kidney renal clear cell carcinoma (KIRC) from the The Cancer Genome Atlas database and to evaluate CRG biological functions. Using lasso regression, we identified four KIRC prognosis-associated CRGs and constructed an associated prognostic risk signature. Kaplan-Meier curves showed that patients with high-risk scores had significantly lower survival times than patients with low-risk scores. Multivariate Cox analysis identified MTF1 and FDX1 as two independent overall survival CRGs. Moreover, qRT-PCR showed that MTF1 and FDX1 expression was downregulated in KIRC and knockdown of MTF1 and FDX1 significantly promoted KIRC cell proliferation and migration ability. In addition, the MTF1 level was positively correlated with immune cell infiltration and knockdown of MTF1 promoted tumor growth in vivo . We developed a signature of prognostic risk-associated CRGs that accurately predicted the prognostic status of KIRC patients. MTF1 and FDX1 were shown to be key CRGs. MTF1 acts as a tumor suppressor, and may be involved in the progression of KIRC by inhibiting proliferation and regulating immune cell infiltration.

Abstract Accumulating studies have confirmed that PIWI-interacting RNAs (piRNAs) are considered epigenetic effectors in cancer. We performed piRNA microarray expression analysis on renal cell carcinoma (RCC) tumor tissues and paired normal tissues and performed a series of in vivo and in vitro experiments to explore piRNAs associated with RCC progression and investigate their functional mechanisms. We found that piR-1742 was highly expressed in RCC tumors and that patients with high piR-1742 expression had a poor prognosis. Inhibition of piR-1742 significantly reduced tumor growth in RCC xenograft and organoid models. Mechanistically, piRNA-1742 regulates the stability of USP8 mRNA by binding directly to hnRNPU, which acts as a deubiquitinating enzyme that inhibits the ubiquitination of MUC12 and promotes the development of malignant RCC. Subsequently, nanotherapeutic systems loaded with piRNA-1742 inhibitors were found to effectively inhibit the metastasis and growth of RCC in vivo. Therefore, this study highlights the functional importance of piRNA-related ubiquitination in RCC and demonstrates the development of a related nanotherapeutic system, possibly contributing to the development of therapeutic approaches for RCC.

Abstract N 6-methyladenosine (m6A) is a form of posttranscriptional modification that plays important roles in cancer including oral squamous cell carcinoma (OSCC). Most studies to date have focused on a limited number of regulators and oncogenic pathways, thus failing to provide comprehensive insight into the dynamic effects of m6A modification. In addition, the role of m6A modification in shaping immune cell infiltration in OSCC has yet to be clarified. This study was designed to assess m6A modification dynamics in OSCC and to understand how such modifications influence clinical immunotherapeutic treatment outcomes. m6A modification patterns linked with 23 m6A regulators were analyzed in 437 OSCC patients from TCGA and GEO cohorts. These patterns were then quantified through m6A score based on algorithms derived from a principal component analysis (PCA) approach. The m6A modification patterns of OSCC samples were grouped into two clusters based on the m6A regulators expression, and immune cell infiltration was linked with the 5-year survival outcomes of patients in these clusters. 1575 genes associated with OSCC patient prognosis were identified and used to re-cluster these samples into two groups. Patients in clusters exhibiting higher levels of m6A regulator expression exhibited poorer overall survival (OS), whereas patients with high m6A scores survived for longer (p

Abstract The transformation of nonmuscle‐invasive bladder cancer (BLCa) to muscle‐invasive type and distant metastasis are the two major threats to patients after surgery. Thus, it is important to identify the key genes of BLCa cell invasion and metastasis. Long noncoding RNA (lncRNA) is a potential clinical tool for cancer diagnosis and treatment. Herein, we verified that lncRNA SNHG3 is upregulated in human BLCa specimens and is proportional to poor clinical prognosis via a combination of bioinformatic analyses and wet bench experiments. Then, we constructed SNHG3 knockdown and overexpression cell models via lentiviral packaging and CRISPR‐Cas9 technique. Fluorescence in situ hybridization assay showed that SNHG3 is distributed in both the nucleus and cytoplasm of BLCa cell lines. In vitro assays including CCK‐8, EdU, colony formation, wound healing, transwell, and tube formation demonstrated that SNHG3 knockdown and overexpression potently inhibited and enhanced BLCa cell proliferation, migration, invasion, and angiogenesis. In addition, IVIS imaging revealed that SNHG3 knockdown could significantly inhibit M‐NSG mice xenograft tumor growth. Next, RNA sequencing, bioinformatics analyses and western blots indicated that SNHG3 could promote c‐MYC expression. RNA immunoprecipitation, actinomycin D assay and western blot assays suggested that SNHG3 could also bind c‐MYC protein which subsequently facilitate the stabilization of BMI1 mRNA, thus enhancing BMI1 protein level. However, SNHG3 knockdown had a slightly weaker inhibitory effect on BMI1 expression than c‐MYC knockdown. Further, in vitro assays demonstrated that BMI1 knockdown could suppress the SNHG3 activation‐induced tumor promoting effect in BLCa cells. Overall, this study has provided new insights into the potential implication of lncRNA SNHG3 in the pathogenesis of BLCa. Importantly, SNHG3/c‐MYC/BMI1 axis may be a novel target for regulating tumor growth and metastasis in BLCa patients.

Applying microbial fertilizer to assist phytoremediation using high production energy crops is a promising method to improve the removal efficiency of metals contaminated soils. The study was conducted to evaluate the effects of Earth Total Support (ETS, a complex microbial agent) in enhancing the phytoremediation of Arsenic (As) in soils using Arundo donax L, which were grown in mesocosms with As at 20 mg kg-1. The results showed that the addition of ETS significantly increase the biomass of A. donax L by 27.27 %–37.04 %. Additionally, ETS was found to mitigate the adverse effects of As stress on A. donax L by enhancing net photosynthetic rate and transpiration, increasing the activities of superoxide dismutases and peroxidases, and decreased malondialdehyde content. Moreover, the addition of ETS led to a 99.25 % increase in As content in roots and a 7.10 % increase in stems. These findings suggest that ETS agents hold promise in improving the remediation efficiency of low concentration As contaminated soil by significantly increasing the biomass of A. donax and facilitating As extraction.

Purpose: To examine the relationship between the muscle-fat ratio (MFR) and kidney stone disease (KSD) in the adult population of the United States between 2011 and 2018, and whether it can be used as a predictor of KSD prognosis. Materials and methods: We conducted a cross-sectional study analysing 9326 patients from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. We analyzed all participants by sex, age, race, level of education, marital status, household income-to-poverty ratio, hypertension, diabetes, vigorous physical activity, moderate physical activity, blood urea nitrogen, creatinine, uric acid, cotinine, and MFR. Dose-response curves with a restricted cubic spline function, univariate and multifactorial logistic regression were used for the analysis of the correlation between MFR and KSD. Finally, we created predictive models based on age, race, hypertension, diabetes mellitus, cotinine and MFR. The prediction model was evaluated using calibration curves, receiver operating characteristic curves and clinical decision curves from the training and test sets. Results: Of the 9326 participants, 8582 (92%) self-reported that they did not have KSD and 744 (8%) self-reported that they had KSD. Univariate and multifactorial logistic regression showed that MFR was negatively associated with the prevalence of KSD (odds ratio [OR]: 0.770, 95% CI: 0.703–0.843; OR: 0.815, 95% CI: 0.738–0.897). Similarly, the risk of developing KSD decreased with increasing MFR as shown by the dose curves in the restricted cubic bar graphs. Furthermore, there is some accuracy (AUC = 0.652) and clinical applicability to the model we constructed based on the results of multifactorial logistic regression. Conclusion: The MFR is protective factor against the developing KSD in adults in the USA.

Background Melanotic schwannoma is a rare tumor when it occurs in the sacrum. Though it is mostly classified as benign, the prognosis is unpredictable due to the possibility of recurrence and metastasis. Here, we reported a case of intraosseous of sacrum with good results and reviewed the literature. Case Presentation A 33‐year‐old male patient complained of low back pain and was discovered to have an obstruction at S2. Following the necessary imaging diagnosis, we treated the patient with piecemeal excision in conjunction with extended curettage, and the frozen biopsy revealed that the tumor was melanotic schwannoma. The intraosseous portion of the lesion was curettaged using high‐speed drill to enlarge the edge of curettage, and piecemeal excision for lesion within the sacral canal. After surgery, the patient received total 56Gy radiotherapy and frequent follow‐up. After 15 months follow‐up, there was no evidence of recurrence, and the nerve function was normal. Conclusion Melanotic schwannoma that occurs intraosseous of the sacrum is extremely rare and lacks typical clinical manifestations; however it can be identified through careful pathological and imaging diagnosis. Intralesional extended curettage combined with radiotherapy can achieve a good local control with a satisfactory clinical effect in this rare disease.

Tongue diagnosis is one of the four diagnostic methods of traditional Chinese medicine (TCM), which has important value in clinical disease diagnosis and efficacy evaluation. The change in tongue coating is a comprehensive cause of multi-dimensional changes such as color, texture, and substance. However, the color tongue image contains less spectral information, which may lead to the lack of key information in tongue diagnosis. Hyperspectral images can obtain reflection information of tongue images in hundreds of spectral bands. Unlike traditional color images, the rich spectral information can more accurately and sensitively describe and classify tongue coating, and has been widely applied in biomedical images. In this paper, we conducted feature extraction and analysis on hyperspectral images of different tongue coatings, and proposed a spectral-spatial feature deep learning framework to classification and quantitative recognition the tongue coating based on hyperspectral image features. Firstly, 360 hyperspectral images of tongue body were collected, and clinicians were identify all tongue coatings and divided them into 6 different grades. The hyperspectral features of each tongue coating area were extracted respectively. In order to reduce noise interference, singular spectrum analysis was used to preprocess the hyperspectral curve features. Considering the actual situation of tongue coating, a depth learning model was established to analyze the spectral and spatial feature of the hyperspectral tongue image to identified the grading of tongue coating. The experimental results showed that tongue coating with different quantization levels had different hyperspectral features, and the recognition rate of tongue coating quantization level can reach 87.21% using the spatial-spectral features.

The pathogenic yeast Cryptococcus neoformans forms large, so-called ‘titan cells’ during infection. Here, Cao et al. show that a ubiquitin ligase inhibits this process by targeting for degradation a CDK-related kinase that stimulates titan cell formation.

Elastic metamaterials are recently emerging structural–functional materials, which provide a new way for the control of elastic waves. However, the current low-frequency broadband performance is yet to be further improved. Herein, a novel large-linear negative stiffness mechanism is first proposed, which is capable of generating constant negative stiffness; the influences of the relevant structural parameters are discussed, and a design method for this mechanism is also given. Subsequently, a new type of elastic metamaterial is designed by combining the inerter and the proposed negative stiffness mechanism; a parametric programming method with general characteristics is proposed to guide the selection of unit-cell parameters, and it is revealed that only at most one negative stiffness spring is allowed to exist in the system. Finally, the low-frequency broadband characteristics of the metamaterial are investigated. It is found that the proposed metamaterial can produce a basin-like attenuation band, i.e., the attenuation curve at the bottom of the attenuation band is a stable flat line; in a given frequency range, the introduction of negative stiffness can further increase the attenuation strength of the metamaterial basin-like band.

To improve understanding of rainfall-runoff processes and the fundamental hydrological mechanisms, rainfall and runoff data during six hydrological years (2007/06–2012/06) were collected in a small headwater catchment at the Kadoorie Agricultural Research Centre (KARC) in Shek Kong, Yuen Long District, New Territories, Hong Kong. Totally, 28 storms were selected; using the one parameter filter method, the direct and baseflow hydrographs were obtained. Their runoff coefficients (which are the ratios of direct runoff volumes to the total rainfall volumes) were computed and the values were very low (mean value is less than 2%). At the event scale, the results revealed that the runoff coefficient which represents the catchment response was highly correlated with rainfall depth, maximum 15-min rainfall intensity and initial discharge. Linear relationships were found and two variables (rainfall depth and initial discharge) gave a better result to predict runoff coefficient indicating that hydrological response depended both on rainfall depth and initial discharge. The principal component analysis and cluster method were used to discriminate types of hydrological responses. Three types of characteristics of hydrological behavior were identified. The different types of hydrological responses show similar characteristics such as the quick rise and the prolonged recession. This study highlights the importance of interflow in the rainfall-runoff process and provides insight into the relationship between rainfall and runoff. The findings have significant implications for water resources management and will help inform decision-making processes.

Abstract Background The accumulating evidence confirms that long non-coding RNAs (lncRNAs) play a critical regulatory role in the progression of renal cell carcinoma (RCC). But, the application of lncRNAs in gene therapy remains scarce. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA-SLERCC (SLERCC) in RCC cells. Methods We performed lncRNAs expression profiling in paired cancer and normal tissues through microarray and validated in our clinical data and TCGA dataset. The Plasmid-SLERCC@PDA@MUC12 nanoparticles (PSPM-NPs) were tested in vivo and in vitro, including cellular uptake, entry, CCK-8 assay, tumor growth inhibition, histological assessment, and safety evaluations. Furthermore, experiments with nude mice xenografts model were performed to evaluate the therapeutic effect of PSPM-NPs nanotherapeutic system specific to the SLERCC. Results We found that the expression of SLERCC was downregulated in RCC tissues, and exogenous upregulation of SLERCC could suppress metastasis of RCC cells. Furthermore, high expression DNMT3A was recruited at the SLERCC promoter, which induced aberrant hypermethylation, eventually leading to downregulation of SLERCC expression in RCC. Mechanistically, SLERCC could directly bind to UPF1 and exert tumor-suppressive effects through the Wnt/β-catenin signaling pathway, thereby inhibiting progression and metastasis in RCC. Subsequently, the PSPM-NPs nanotherapeutic system can effectively inhibit the growth of RCC metastases in vivo. Conclusions Our findings suggested that SLERCC is a promising therapeutic target and that plasmid-encapsulated nanomaterials targeting transmembrane metastasis markers may open a new avenue for the treatment in RCC.

IntroductionIn wheat, kernel weight (KW) is a key determinant of grain yield (GY). However, it is often overlooked when improving wheat productivity under climate warming. Moreover, little is known about the complex effects of genetic and climatic factors on KW. Here, we explored the responses of wheat KW to diverse allelic combinations under projected climate warming conditions.MethodsTo focus on KW, we selected a subset of 81 out of 209 wheat varieties with similar GY, biomass, and kernel number (KN) and focused on their thousand-kernel weight (TKW). We genotyped them at eight kompetitive allele-specific polymerase chain reaction markers closely associated with TKW. Subsequently, we calibrated and evaluated the process-based model known as Agricultural Production Systems Simulator (APSIM-Wheat) based on a unique dataset including phenotyping, genotyping, climate, soil physicochemistry, and on-farm management information. We then used the calibrated APSIM-Wheat model to estimate TKW under eight allelic combinations (81 wheat varieties), seven sowing dates, and the shared socioeconomic pathways (SSPs) designated SSP2-4.5 and SSP5-8.5, driven by climate projections from five General Circulation Models (GCMs) BCC-CSM2-MR, CanESM5, EC-Earth3-Veg, MIROC-ES2L, and UKESM1-0-LL.ResultsThe APSIM-Wheat model reliably simulated wheat TKW with a root mean square error (RMSE) of < 3.076 g TK-1 and R2 of > 0.575 (P < 0.001). The analysis of variance based on the simulation output showed that allelic combination, climate scenario, and sowing date extremely significantly affected TKW (P < 0.001). The impact of the interaction allelic combination × climate scenario on TKW was also significant (P < 0.05). Meanwhile, the variety parameters and their relative importance in the APSIM-Wheat model accorded with the expression of the allelic combinations. Under the projected climate scenarios, the favorable allelic combinations (TaCKX-D1b + Hap-7A-1 + Hap-T + Hap-6A-G + Hap-6B-1 + H1g + A1b for SSP2-4.5 and SSP5-8.5) mitigated the negative effects of climate change on TKW.DiscussionThe present study demonstrated that optimizing favorable allelic combinations can help achieve high wheat TKW. The findings of this study clarify the responses of wheat KW to diverse allelic combinations under projected climate change conditions. Additionally, the present study provides theoretical and practical reference for marker-assisted selection of high TKW in wheat breeding.

PurposeTo investigate the relationship between kidney stones and sarcopenia in United States adult population between 2011 and 2018.Materials and methodsWe conducted a cross-section study based on the National Health and Nutrition Examination Survey (NHANES) including 39,156 individuals. Sarcopenia was assessed by the sarcopenia index. Association between kidney stones and sarcopenia verified by multiple logistic regression analysis and dose–response curves analysis using restricted cubic spline (RCS) regression. Meanwhile, propensity score matching (PSM) was performed to exclude the effect of confounding variables.ResultsThere were 9,472 participants in the study by our accurate enrollment screening process. The odds of kidney stones decreased significantly with the increase of sarcopenia index. Logistic regression analysis showed that sarcopenia expressed significant differences in the participants which suffered kidney stone before PSM (p

The normal coefficient of restitution (Rn) is the most critical input parameter in the prediction and analysis of rockfall disasters. Because of its many controlling factors, how to determine an accurate and reasonable value of Rn is still a difficult problem. In order to explore the law and mechanism of the joint influence of multiple factors on Rn, the response surface methodology-central composite design method is used to investigate the combined effect of seven factors on Rn for the first time. Through regression and variance analysis of the test results, the seven selected factors have the significant effects on Rn, and the order of significance is the impact angle (θ) > block hardness (H1) > rotational speed (ω) > shape factor (η) > incident velocity (V) > slope hardness (H2) > size (d). Many interaction parameters also show the significant effects on Rn, in the order of d−θ > H1−d > V−η > H1−ω > d−η > η−ω > H1−η. For a single factor parameter, Rn increases with the decrease of d, V, η, θ and the increase of H1, H2, ω; for interaction parameters, d and ω have a weak effect on Rn, only when H1 is small, and the effect gradually increases with the increase of H1; η has a significant effect on Rn when H1 is small, and the effect significantly decreases with the increase of H1; when η is small, Rn increases significantly with the decrease of V or d, and this effect is not significant when η is large; when θ is small, Rn decreases rapidly with the increase of θ, and the decreasing trend slows down when θ is large. Compared with block with small η, the ω of block with larger η has a more significant effect on Rn. These conclusions can provide an important reference for the construction of the Rn calculation model of rockfall, and provide a basis for the accurate prediction and prevention of rockfall disasters.

In this study, a biomimetic artificial muscle electroactive actuator was fabricated using environmentally friendly sodium alginate extract. Ultrasonic agitation was employed to embed ultrafine copper powder within a mesh-like structure formed by multi-walled carbon nanotubes (MWCNTs), aimed at reducing the internal resistance of the composite electrode membrane and enhancing its output force performance. Focused gallium ion beam-scanning electron microscopy observations, energy-dispersive X-ray spectroscopy (EDS) analysis, and surface morphology imaging confirmed the successful incorporation of the ultrafine copper powder into the MWCNT network. Additionally, we designed and constructed an output force measurement apparatus to assess the output performance of biomimetic artificial muscles (BMAMs) doped with varying quantities of ultrafine copper powder. Electrochemical testing results demonstrated that the artificial muscles exhibited optimal performance when doped with a mass of 1.5 g, yielding a maximum output force of 6.96 mN, an output force density of 30.64 mN/g, and a peak average rate of 0.059 mN/s. These values represented improvements of 224%, 189%, and 222% compared to the electrode membrane without the addition of ultrafine copper powder, respectively.

Head and neck squamous cell carcinoma (HNSCC) has become a prevalent malignancy, and its incidence and mortality rate are increasing worldwide. Accumulating evidence has indicated that lipid metabolism-related genes (LMRGs) are involved in the occurrence and development of HNSCC. This study investigated the latent association of lipid metabolism with HNSCC and established a prognostic signature based on LMRGs. A prognostic risk model composed of eight differentially expressed LMRGs (PHYH, CYP4F8, INMT, ELOVL6, PLPP3, BCHE, TPTE, and STAR) was constructed through The Cancer Genome Atlas database. Then, ELOVL6 expression was validated in oral squamous cell carcinoma (OSCC), which is a common type of HNSCC, by immunohistochemical analysis. ELOVL6 expression in the OSCC II/III group was significantly higher than that in the other three groups (normal, dysplasia, and OSCC I), and OSCC patients with high ELOVL6 expression had poorer survival than those with low ELOVL6 expression. In summary, the LMRG-based prognostic feature had prognostic predictive capacity. ELOVL6 may be a potential prognostic factor for HNSCC patients.

Abstract Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR, CCK-8, wound healing, transwell, colony formation, Edu, tumor xenograft and lung metastasis in NSG mice. RNA pull-down, dual luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the therapeutic effect of the nanocomplexes on tumor in vivo. ciRS-7 was highly expressed in RCC tumor tissues and cell lines, and high ciRS-7 expression correlated with tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion, tumor growth and metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC tumor progression and metastasis in vivo. ciRS-7 acts as a tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and metastasis. Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.

Abstract Kidney cancer is a common urological tumour. Owing to its high prevalence and mortality rate, it is the third most malignant tumour of the urinary system, followed by prostate and bladder cancers. It exerts a high degree of malignancy, and most of the distant metastasis occurs at an early stage; it is insensitive to chemoradiotherapy and easily develops drug resistance. The current treatment for kidney cancer mainly includes surgery, interventional embolization and targeted therapy; however, the treatment efficacy is poor. In recent years, the role of exosomes as mediators of intercellular communication and information exchange in the tumour microenvironment in tumour pathogenesis has attracted much attention. Exosomes are rich in bioactive substances such as nucleic acids, proteins and lipids and are involved in angiogenesis, immune regulation, drug resistance, formation of pre-metastatic niche, invasion and metastasis. This article reviews the ongoing research and applications of exosomes for the diagnosis and treatment of kidney cancer.

BackgroundThis study aimed to identify the prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in patients with malignant adrenal tumors and establish a predictive nomogram for patient survival.MethodsThe clinical characteristics of patients diagnosed with malignant adrenal tumors between 1988 and 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. As the external validation set, we included 110 real-world patients from our medical centers. Univariate and multivariate Cox regressions were implemented to determine the prognostic factors of patients. The results from Cox regression were applied to establish the nomogram.ResultsA total of 2,206 eligible patients were included in our study. Patients were randomly assigned to the training set (1,544; 70%) and the validation set (662; 30%). It was determined that gender, age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy were prognostic factors that affected patient survival. The OS prediction nomogram contained all the risk factors, while gender was excluded in the CSS prediction nomogram. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) indicated that the nomogram had a better predictive performance than SEER stage. Moreover, the clinical impact curve (CIC) showed that the nomograms functioned as effective predictive models in clinical application. The C-index of nomogram for OS and CSS prediction was 0.773 (95% confidence interval [CI]: 0.761–0.785) and 0.689 (95% CI: 0.675–0.703) in the training set. The calibration curves exhibited significant agreement between the nomogram and actual observation. Additionally, the results from the external validation set also presented that established nomograms functioned well in predicting the survival of patients with malignant adrenal tumors.ConclusionsThe following clinical variables were identified as prognostic factors: age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy. The nomogram for patients with malignant adrenal tumors contained the accurate predictive performance of OS and CSS, contributing to optimizing individualized clinical treatments.

BackgroundWe evaluated the prognostic value of preoperative blood glucose to lymphocyte ratio (GLR) in renal cell carcinoma (RCC) patients who underwent laparoscopic nephrectomy through a multi-institutional clinical study.MethodsA total of 420 patients with RCC from three medical centers from 2014 to 2019 were included in this study. The effect of GLR on overall survival (OS) and cancer-specific survival (CSS) in RCC patients was assessed by Kaplan-Meier survival curves, univariate and multivariate Cox regression analysis. Moreover, a 1:1 propensity score matching (PSM) analysis of different GLR groups was utilized to further confirm the prognostic ability of GLR.ResultsThe optimal cut-off value for GLR was 6.8. Patients were divided into high GLR and low GLR groups according to the optimal cut-off value. GLR was significant association with diabetes, cardiovascular disease and AJCC stage. High GLR predicted adverse OS (P = 0.002) and CSS (P

Using a naturally extracted polymer sodium alginate extracted from natural seaweed as the primary raw material, we have successfully developed an electroactive actuator known as biomimetic artificial muscle (BMAM). In comparison to conventional synthetic materials, this BMAM aligns more coherently with the prevailing principles of environmentally friendly development. During the preparation of the BMAM electrode membrane, we employed ultrasonic oscillation to adsorb varying quantities of MoS2 onto a reticulated structure formed by multi-walled carbon nanotubes (MWCNTs), thus enhancing the mechanical and electrochemical performance of the BMAM. Scanning electron microscopy and energy-dispersive X-ray spectroscopy (EDS) confirmed the successful encapsulation of MoS2 by the MWCNTs network in the composite. To measure the output force of the BMAM fabricated with different masses of MoS2 doping, we established a self-built experimental platform and conducted tests on the electrode membranes doped with varying quantities of MoS2 using an electrochemical workstation. The results revealed that the BMAM exhibited optimal mechanical performance when doped with 1.5 g of MoS2, with a maximum output force of 7.81 mN, an output force density of 34.36 mN/g, and a response rate of 0.09 mN/s. These performances were improved by 309%, 276%, and 175%, respectively, compared to the samples without MoS2 doping, with a mass-specific capacitance enhancement of 151%.

BackgroundCellular prion protein (PRPC) exerts brain-protective effects. We determined the relationship between plasma PRPC levels and disease severity plus clinical outcome after acute intracerebral hemorrhage (ICH).MethodsA total of 138 ICH patients and 138 healthy controls were included in this prospective, observational study. Hematoma volume and Glasgow coma scale (GCS) score were used to assess disease severity. Glasgow outcome scale (GOS) scores of 1–3 and 4–5 at 90 days after stroke were defined as a poor outcome and good outcome, respectively. Using multivariate analysis, we discerned the relation of plasma PRPC levels to disease severity and poor outcome. The receiver operating characteristic (ROC) curve was built to evaluate the prognostic predictive capability.ResultsPlasma PRPC levels in ICH patients were significantly higher than those in healthy controls (median, 4.20 vs. 2.02 ng/ml; P < 0.001), and were independently correlated with GCS score (r = −0.645, P < 0.001) and hematoma volume (r = 0.627, P < 0.001). Plasma PRPC levels were highly correlated with GOS score (r = −0.762, P < 0.001), and were substantially higher in patients with poor outcomes than in those with the good outcomes. Using maximum Youden index, plasma PRPC levels >3.893 ng/ml distinguished the risk of poor outcome at 90 days, with a sensitivity of 86.4% and a specificity of 65.8% (area under the curve, 0.809; 95% confidence interval (CI), 0.737–0.881, P < 0.001). Plasma PRPC levels >3.893 ng/ml were independently associated with a poor 90-day outcome with an odds ratio of 12.278 (95% CI, 5.101–29.554).ConclusionElevated plasma PRPC levels are significantly associated with disease severity and poor 90-day outcome in ICH patients, indicating that plasma PRPC may be used as a potential prognostic biomarker after ICH.

ObjectiveThe complement cascade is activated early following intracerebral hemorrhage (ICH) and causes acute brain injury. We intended to explore the effects of plasma complement component 1q (C1q) levels on hemorrhagic severity and functional outcome in ICH patients.MethodsIn this prospective cohort study, we measured the plasma C1q levels of 101 ICH patients and 101 healthy controls. The Glasgow Coma Scale (GCS) score and hematoma volume were used to assess the ICH severity. Poor prognosis was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at three months following a stroke. A multivariate logistic regression model was configured to determine the independent relation of plasma C1q levels to severity and poor prognosis. Under receiver operating characteristic (ROC) curve, prognostic capability of plasma C1q levels was evaluated.ResultsThere was a significant elevation of plasma C1q levels in patients, as compared to controls [median (percentiles 25th-75th), 225.04 mg/l (156.10-280.15 mg/l) versus 88.18 mg/l (70.12-117.69 mg/l); P 270.11 mg/l distinguished patients at risk of poor prognosis at 3 months with 56.52% sensitivity and 94.55% specificity. Meanwhile, the prognostic predictive ability of plasma C1q levels was equivalent to those of GCS score and hematoma volume (both P>0.05). Moreover, plasma C1q levels > 270.11 mg/l independently predicted a poor prognosis at 3 months (odds ratio, 4.821; 95% confidence interval, 1.211-19.200; P=0.026).ConclusionPlasma C1q levels are closely related to the illness severity and poor prognosis of ICH at 3 months. Hence, complement C1q may play an important role in acute brain injury after ICH and plasma C1q may represent a promising prognostic predictor of ICH.

Extrachromosomal circular DNA (eccDNA) is independent of the chromosome and exists in many eukaryotes. However, the nature and origin of eccDNA in plants remains unclear. In this study, we sequenced 12 samples from four tissues (leaf, flower, stem and root) with three biological replicates. In total, we found 743 eccDNAs found in at least two samples. Most of eccDNA have inverted repeats ranging from 4 to 12 bp in the boundaries. Interestingly, eccDNA is not only related to transposon activity, but also hosts tRNA genes, suggesting that the eccDNAs may be associated with tRNA abundance which controls protein synthesis under conditions of stress. Our results provide an unprecedented view of eccDNA, which is still naïve in scope.

Macrophages are key cellular components of innate immunity, acting as the first line of defense against pathogens to modulate homeostatic and inflammatory responses. They help clear pathogens and shape the T-cell response through the production of cytokines and chemokines. The facultative intracellular fungal pathogen Cryptococcus neoformans has developed a unique ability to interact with and manipulate host macrophages. These interactions dictate how Cryptococcus infection can remain latent or how dissemination within the host is achieved. In addition, differences in the activities of macrophages have been correlated with differential susceptibilities of hosts to Cryptococcus infection, highlighting the importance of macrophages in determining disease outcomes. There is now abundant information on the interaction between Cryptococcus and macrophages. In this review we discuss recent advances regarding macrophage origin, polarization, activation, and effector functions during Cryptococcus infection. The importance of these strategies in pathogenesis and the potential of immunotherapy for cryptococcosis treatment is also discussed.

Since its outbreak in December 2019, a series of clinical trials on coronavirus disease 2019 (COVID-19) have been registered or carried out. However, the significant heterogeneity and less critical outcomes of such trials may be leading to a waste of research resources. This study aimed to develop a core outcome set (COS) for clinical trials on COVID-19 in order to tackle the outcome issues. The study was conducted according to the Core Outcome Measures in Effectiveness Trials (COMET) Handbook: Version 1.0, a guideline for COS development. A research group was set up that included experts in respiratory and critical medicine, traditional Chinese medicine (TCM), evidence-based medicine, clinical pharmacology, and statistics, in addition to medical journal editors. Clinical trial registry websites (www.chictr.org.cn and clinicaltrials.gov) were searched to retrieve clinical trial protocols and outcomes in order to form an outcome pool. A total of 78 clinical trial protocols on COVID-19 were included and 259 outcomes were collected. After standardization, 132 outcomes were identified within seven different categories, of which 58 were selected to develop a preliminary outcome list for further consensus. After two rounds of Delphi survey and one consensus meeting, the most important outcomes for the different clinical classifications of COVID-19 were identified and determined to constitute the COS for clinical trials on COVID-19 (COS-COVID). The COS-COVID includes one outcome for the mild type (time to 2019 novel coronavirus (2019-nCoV) reverse transcription-polymerase chain reaction (RT-PCR) negativity), four outcomes for the ordinary type (length of hospital stay, composite events, score of clinical symptoms, and time to 2019-nCoV RT-PCR negativity), five outcomes for the severe type (composite events, length of hospital stay, arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2), duration of mechanical ventilation, and time to 2019-nCoV RT-PCR negativity), one outcome for critical type (all-cause mortality), and one outcome for rehabilitation period (pulmonary function). The COS-COVID is currently the most valuable and practical clinical outcome set for the evaluation of intervention effect, and is useful for evidence assessment and decision-making. With a deepening understanding of COVID-19 and application feedback, the COS-COVID should be continuously updated.

This paper proposes a novel 24-slot/10-pole dual three-phase (DTP) fractional-slot overlapped winding, which can simultaneously achieve the goals of low non-working space harmonics and stator modularization. Moreover, the proposed winding inherits the majority of the merits of conventional fractional-slot concentrated winding (FSCW), such as low cogging torque, low torque ripple and short end-windings. The winding configuration of the proposal is described first, and then its magnetomotive force (MMF) analysis is conducted to calculate the winding factors by using the star of slots. According to the theoretical analysis, the harmonic reduction mechanism of the proposal is expounded in depth. In addition, a specific case of a permanent magnet synchronous machine (PMSM) equipped with the proposal is analyzed and compared with two PMSMs equipped with DTP-FSCW and two-slot-pitch fractional-slot winding (TSP-FSW) respectively by finite element method (FEM) in terms of no-load back electromotive force (EMF), cogging torque, armature reaction field, on-load torque, efficiency, and fault tolerance. A prototype with the proposed winding is built and tested to verify the theoretical analysis and numerical simulations.

In order to study the relationship between wind speed and such combustion characteristics as pool fire flame length, tilt angle, combustion mass loss rate and heat release rate, a small round diesel pool fire with wind-blown experimental platform was built. The wind speed was 0–1 m/s and the oil pan diameters were 0.218 m, 0.175 m and 0.13 m, respectively. A new dimensionless parameter Hr is defined to describe the effects of buoyancy, initial momentum and horizontal wind force on flame length and tilt angle. The results show that when 0

Self-similarity and plane-filling are intrinsic structure properties of natural river networks. Statistical data indicates that most natural river networks are Tokunaga trees. Researchers have explored to use iterative binary tree networks (IBTNs) to simulate natural river networks. However, the characteristics of natural rivers such as Tokunaga self-similarity and plane-filling cannot be easily guaranteed by the configuration of the IBTN. In this paper, the generator series and a quasi-uniform iteration rule are specified for the generation of nonstochastic quasi-uniform iterative binary tree networks (QU-IBTNs). First, we demonstrate that QU-IBTNs definitely satisfy self-similarity. Second, we show that the constraint for a QU-IBTN to be a Tokunaga tree is that the exterior links must be replaced in the generator series with a neighboring generator that is larger than the interior links during the iterative process. Moreover, two natural river networks are examined to reveal the inherent consistency with QU-IBTN at low Horton-Strahler orders.

BackgroundWe conducted a multi-institutional clinical study to assess the prognostic value of the advanced lung cancer inflammatory index (ALI) and modified ALI (mALI) in patients with renal cell carcinoma (RCC).MethodsWe collected 440 patients who underwent laparoscopic nephrectomy at three centers from 2014 to 2019. ALI was defined as body mass index (BMI) × serum albumin (ALB)/neutrophil-to-lymphocyte ratio (NLR) and mALI as L3 muscle index × ALB/NLR. Kaplan-Meier curves, receiver operating characteristic (ROC) curves and Cox survival analysis were used to assess the effect of ALI and mALI on overall survival (OS). In addition, we performed 1:1 propensity score matching (PSM) for the high mALI and low mALI groups to further explore the impact of mALI on survival in RCC patients.ResultsThe optimal cut-off values for ALI and mALI were 40.6 and 83.0, respectively. Based on the cut-off values, we divided the patients into high ALI and low ALI groups, high mALI and low mALI groups. ALI and mALI were significantly associated with the AJCC stage, Fuhrman grade, T stage, and M stage. Low ALI (p = 0.002) or low mALI (p < 0.001) was associated with poorer prognosis. ROC curves showed that mALI was a better predictor of OS than ALI. Multivariate Cox regression analysis showed that low mALI (aHR = 2.22; 95% CI 1.19–4.13, p = 0.012) was an independent risk factor for OS in RCC patients who underwent nephrectomy, while ALI (aHR = 1.40; 95% CI 0.73–2.66, p = 0.309) was not significantly associated. Furthermore, after PSM analysis, we found that mALI remained an independent risk factor for OS (aHR = 2.88; 95% CI 1.33–6.26, p = 0.007) in patients with RCC.ConclusionsFor RCC patients undergoing laparoscopic nephrectomy, low ALI and low mALI were associated with poor prognosis, and preoperative mALI can be used as a potential independent prognostic indicator for RCC patients.

Recent studies offer more evidence that the rate of warming is amplified with elevation, indicating thereby that high-elevation ecosystems tend to be exposed to more accelerated changes in temperature than ecosystems at lower elevations. The phenomenon of elevation-dependent warming (EDW), as one of the regional climate-change impacts, has been observed across the Tibetan Plateau. Studies have often found large-scale greening trends, but the drivers of vegetation dynamics are still not fully understood in this region, such that the local implications of vegetation change have been infrequently discussed. This study was designed to quantify and characterize the seasonal changes in vegetation across the Three Rivers Headwaters Region (TRHR), where the land cradles the headwaters of the Yangtze, the Yellow, and the Lancang (Mekong). By mapping the normalized difference vegetation index (NDVI) over the growing season from 1982 to 2015, we were able to evaluate seasonal changes in vegetation cover over time. The results show a slightly increased tendency in green vegetation cover, which could possibly be attributed to sustained warming in this region over the past three decades, whereas a decline in the green-up rate with elevation was found, indicating an inconsistent trend of vegetation greening with EDW. The cause of the green-up rate decline at high elevations could be linked to the reduced soil water availability induced by the fast increase in warming rates associated with EDW. The findings of this study have important implications for devising adaptation strategies for alpine ecosystems in a changing climate.

Background: Serum cystatin C (CysC) is still becoming used as a marker of renal function but is far from being commonly used worldwide. The purpose of this study was to characterize the ureteral calculi patients with hydronephrosis-caused CysC changes in renal function. Methods: To better reflect the changes of renal function, we constructed models of ureteral obstruction in rats to mimic the hydronephrosis caused by human ureteral calculi. Moreover, our study included 200 patients diagnosed with ureteral calculi in our hospital between June 2017 and 2018. We compared the estimated glomerular filtration rate using different equations based on CysC and/or serum creatinine (SCr). Results: We found that the expression of CysC and SCr increased with the prolonged obstruction time by enzyme linked immunosorbent assay. Moreover, quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry further demonstrated that the expression of CysC increases with the degree of hydronephrosis. Among 200 patients with ureteral calculi, 40 (20.0%) had no hydronephrosis, 110 (55.0%) had mild hydronephrosis, 32 (16.0%) had moderate hydronephrosis and 18 (9.0%) had severe hydronephrosis. As the degree of hydronephrosis increased, the expression of neutrophil percentage, CysC, blood urea nitrogen, SCr and serum uric acid also increased. Multivariate analyses demonstrated that only CysC was an independent risk factor for hydronephrosis (p = 0.003). In addition, CysC and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) CysC equation showed the highest veracity in renal function estimation of patients with hydronephrosis caused by ureteral calculus. Conclusion: For patients with hydronephrosis caused by ureteral calculi, CysC better reflects the changes in renal function, and the CKD-EPI CysC equation has the highest accuracy.