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In this paper, a two-grid alternating direction implicit (ADI) finite element (FE) method based on the weighted and shifted Grünwald difference (WSGD) operator is proposed for solving a two-dimensional nonlinear time distributed-order fractional sub-diffusion equation. The stability and optimal error estimates with second-order convergence rate in spatial direction are obtained. The storage space can be reduced and computing efficiency can be improved in this method. Two numerical examples are provided to verify the theoretical results.

We carried out whole transcriptome sequencing (WTS) on the tumor and the matching adjacent normal tissues from five patients having Xp11 translocation renal cell carcinoma (RCC). This was performed in terms of obtaining more understanding of the genomic panorama and molecular basis of this cancer. To examine gene-regulatory networks in XP11 translocation RCC, variance expression analysis was carried out, followed by functional enrichment analysis. Gene Expression Omnibus (GEO) of Xp11 translocation RCC data was used to validate the results. As per inclusion criteria, a total of 1886 differentially expressed mRNAs (DEmRNAs), 56 differentially expressed miRNAs (DEmiRNAs), 223 differentially expressed lncRNAs (DElncRNAs), and 1764 differentially expressed circRNAs (DEcircRNAs) were found. KEGG enrichment study of DEmiRNA, DElncRNA, and DEcircRNA target genes identified the function of protein processing in the endoplasmic reticulum, lysosome, and neutrophil-mediated immunity. Three subnetwork modules integrated from the PPI network also revealed the genes involved in protein processing in the endoplasmic reticulum, lysosome, and protein degradation processes, which may regulate the Xp11 translocation RCC process. The ceRNA complex network was created by Cytoscape, which included three upregulated circRNAs, five upregulated lncRNAs, 24 upregulated mRNAs, and two downregulated miRNAs (hsa-let-7d-5p and hsa-miR-433-3p). The genes as a prominent component of the complex ceRNA network may be key factors in the pathogenesis of Xp11 translocation RCC. Our findings clarified the genomic and transcriptional complexity of Xp11 translocation RCC while also pointing to possible new targets for Xp11 translocation RCC characterization.

Mitophagy is involved in the development of various cardiovascular diseases, such as atherosclerosis, heart failure, myocardial ischemia/reperfusion injury, and hypertension. Mitophagy is essential for maintaining intracellular homeostasis and physiological function in most cardiovascular origin cells, such as cardiomyocytes, endothelial cells, and vascular smooth muscle cells. Mitophagy is crucial to ensuring energy supply by selectively removing dysfunctional mitochondria, maintaining a balance in the number of mitochondria in cells, ensuring the integrity of mitochondrial structure and function, maintaining homeostasis, and promoting cell survival. Substantial research has indicated a "dual" effect of mitophagy on cardiac function, with inadequate and increased mitochondrial degradation both likely to influence the progression of cardiovascular disease. This review summarizes the main regulatory pathways of mitophagy and emphasizes that an appropriate amount of mitophagy can prevent endothelial cell injury, vascular smooth muscle cell proliferation, macrophage polarization, and cardiomyocyte apoptosis, avoiding further progression of cardiovascular diseases.

Breast cancer is the most commonly occurring cancer worldwide. The ultrasound reflectivity imaging technique can be used to obtain breast ultrasound (BUS) images, which can be used to classify benign and malignant tumors. However, the classification is subjective and dependent on the experience and skill of operators and doctors. The automatic classification method can assist doctors and improve the objectivity, but current convolution neural network (CNN) is not good at learning global features and vision transformer (ViT) is not good at extraction local features. In this study, we proposed a visual geometry group attention ViT (VGGA-ViT) network to overcome their disadvantages.In the proposed method, we used a CNN module to extract the local features and employed a ViT module to learn the global relationship among different regions and enhance the relevant local features. The CNN module was named the VGGA module. It was composed of a VGG backbone, a feature extraction fully connected layer, and a squeeze-and-excitation block. Both the VGG backbone and the ViT module were pretrained on the ImageNet dataset and retrained using BUS samples in this study. Two BUS datasets were employed for validation.Cross-validation was conducted on two BUS datasets. For the Dataset A, the proposed VGGA-ViT network achieved high accuracy (88.71In this study, we proposed the VGGA-ViT for the BUS classification, which was good at learning both local and global features. The proposed network achieved higher accuracy than the compared previous methods.

Current endocrine therapy for prostate cancer (PCa) mainly inhibits androgen/androgen receptor (AR) signaling. However, due to increased intratumoural androgen synthesis and AR variation, PCa progresses to castration-resistant prostate cancer (CRPC), which ultimately becomes resistant to endocrine therapy. A search for new therapeutic perspectives is urgently needed. Methods: By screening lipid metabolism-related gene sets and bioinformatics analysis in prostate cancer database, we identified the key lipid metabolism-related genes in PCa. Bisulfite genomic Sequence Polymerase Chain Reaction (PCR) (BSP) and Methylation-Specific Polymerase Chain Reaction (PCR) (MSP) were preformed to detect the promoter methylation of ACSS3. Gene expression was analyzed by qRT-PCR, Western blotting, IHC and co-IP. The function of ACSS3 in PCa was measured by CCK-8, Transwell assays. LC/MS, Oil Red O assays and TG and cholesterol measurement assays were to detect the levels of TG and cholesterol in cells. Resistance to Enzalutamide in C4-2 ENZR cells was examined in a xenograft tumorigenesis model in vivo. Results: We found that acyl-CoA synthetase short chain family member 3 (ACSS3) was downregulated and predicted a poor prognosis in PCa. Loss of ACSS3 expression was due to gene promoter methylation. Restoration of ACSS3 expression in PCa cells significantly reduced LD deposits, thus promoting apoptosis by increasing endoplasmic reticulum (ER) stress, and decreasing de novo intratumoral androgen synthesis, inhibiting CRPC progression and reversing Enzalutamide resistance. Mechanistic investigations demonstrated that ACSS3 reduced LD deposits by regulating the stability of the LD coat protein perilipin 3 (PLIN3). Conclusions: Our study demonstrated that ACSS3 represses prostate cancer progression through downregulating lipid droplet-associated protein PLIN3.

Designing highly efficient and low-cost catalysts for conversion of renewable biomass into high value-added chemicals and biofuels is important and challenging. Herein, a non-noble Ni-Mn bifunctional catalyst supported on activated carbon (Ni-Mn/AC) was developed by an incipient wetness impregnation method. The catalyst was found to be economic and efficient for the selective hydrodeoxygenation of biomass-derived 5-hydroxymethylfurfural (5-HMF) to 2,5-dimethylfuran (2,5-DMF). The optimal Ni-Mn/AC (Ni/Mn=3) catalyst achieved 98.5 % 2,5-DMF yield with 100 % conversion of 5-HMF under mild reaction conditions of 180 °C, 2.0 MPa H

In this article, a numerical algorithm is presented to solve a two-dimensional nonlinear time fractional coupled sub-diffusion problem, where the second-order Crank–Nicolson scheme with a second-order WSGD formula is used in the time direction, and a mixed element method is applied in the space direction. The existence and uniqueness of the mixed element solution and the stability for fully discrete scheme are proven. In addition, the optimal a priori error estimates for unknown scalar function u and v in $$L^2$$ and $$H^1$$ -norms and a priori error estimates for their fluxes $$\sigma$$ and $$\lambda$$ in $$(L^2)^2$$ -norm are obtained. Finally, some numerical calculations are presented to illustrate the validity for the proposed numerical algorithm.

Nanozymes are a kind of nanomaterials with enzyme-like activities. Since Chinese scientists first found that Fe3O4 nanoparticles have intrinsic peroxidase-like activity in 2007, the researches of nanozymes have been gradually developed. So far, 540 kinds of nanomaterials with different composition and structure have been found to possess enzyme-like activities. Compared with natural enzymes, nanozymes are more stable, more economical, and have diverse and adjustable functions. By now, nanozymes have been widely used in molecular detection, disease diagnosis, environmental management and other fields related to catalysis. Recently, a variety of nanozymes were found to be capable of regulating reactive oxygen species (ROS) in organisms, which indicates its potential as prooxidants/antioxidants in the field of ROS-related disease treatment. In this review, we summarized the latest research progress of nanozymes in the treatment of diseases. The challenges for the future development of nanozymes in biomedicine were discussed for inspiring researchers to carry out further in-depth studies.

Simple Summary The overexpression of Carboxypeptidase A4 (CPA4) has been observed in plenty of types of cancer and has been elucidated to promote tumor growth and invasion; however, its role in bladder urothelial carcinoma (BLCA) is still unclear. Therefore, we aimed to show the prognostic role of CPA4 and its relationship with immune infiltrates in BLCA. We confirmed that the overexpression of CPA4 is associated with shorter overall survival, disease-specific survival, progress-free intervals, and higher dead events. Moreover, we found that several infiltrating immune cells (Th1cell, Th2 cell, T cell exhaustion, and Tumor-associated macrophage) were correlated with the expression of CPA4 in bladder cancer using TIMER2 and GEPIA2. In conclusion, CPA4 may be a novel and great prognostic biomarker based on bioinformation analysis in BLCA. Abstract Carboxypeptidase A4 (CPA4) has shown the potential to be a biomarker in the early diagnosis of certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via the TIMER2, STRING, and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA + GETx database. The connection between CPA4 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan–Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared with matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that the overexpression of CPA4 is linked with shorter OS, DSF(Disease-specific survival), PFI(Progression-free interval), and increased diagnostic potential using Kaplan–Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.

Single-cell sequencing technologies have noteworthily improved our understanding of the genetic map and molecular characteristics of bladder cancer (BC). Here we identify CD39 as a potential therapeutic target for BC via single-cell transcriptome analysis. In a subcutaneous tumor model and orthotopic bladder cancer model, inhibition of CD39 (CD39i) by sodium polyoxotungstate is able to limit the growth of BC and improve the overall survival of tumor-bearing mice. Via single cell RNA sequencing, we find that CD39i increase the intratumor NK cells, conventional type 1 dendritic cells (cDC1) and CD8 + T cells and decrease the Treg abundance. The antitumor effect and reprogramming of the tumor microenvironment are blockaded in both the NK cells depletion model and the cDC1-deficient Batf3−/− model. In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.

Background Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration‐resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. Methods We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. Results We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta‐analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1‐knockout (Ces−/−) mice verified the important role of endogenous Ces1 in PCa. Conclusions Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa., MLT regulated epigenetic modification of CES1 through SIRT1‐mediated DNMT1 deacetylation. MLT‐mediated CES1 expression induced lipid depletion, leading to ER stress‐related apoptosis and blocking the intratumoral androgen synthesis that results in the inhibition of PCa progression and reversal of the enzalutamide resistance

Graphene as a novel additive in low density polyethylene (LDPE), high density polyethylene–low density polyethylene blend (10%HDPE–LDPE) and polypropylene–low density polyethylene blend (10%PP–LDPE), is investigated for promising eco-friendly insulating materials in high voltage cables. The composites with graphene amounts of 0, 0.002 wt%, 0.02 wt%, and 0.2 wt% are prepared by the solution mixing method. With attempt to disclose the structure–property relationships, the composites are extensively characterized by physical techniques including Fourier transform infrared spectroscopy, X-ray diffraction, atomic force microscopy, transmission electron microscopy, scanning electron microscopy, thermogravimetric analysis and differential scanning calorimetry, and electrical measurements including electrical treeing, direct current conductivity and space charge distributions. Results show that graphene can significantly enhances the thermal stability of LDPE and 10%PP–LDPE, slightly decrease the degree of crystallinity, change the size of the crystal diameters, and improve the phase distribution of the polymer blends. Consequently, graphene can prolong the electrical tree initiation time and block the extension of electrical tree. Besides, it can modulate the trap distributions, which will further change the conductivity and ability to suppress space charge accumulations. This excellent performance of graphene could be attributed to its good exfoliation, uniform dispersion and outstretched morphology in the polymer matrix, as well as its strong ability to capture electrons.

This paper presents investigations on a usage of graphene as a voltage stabilizer for polyethylene blends in the potential recyclable high voltage direct current (HVDC) cable insulation. Thermal and electrical properties of the blends with/without graphene were evaluated by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), electrical treeing tests, DC conductivity and space charge measurements. Trap energy distributions in the blends were estimated using the measured space charge decay data. The obtained results show that additive-like amounts of graphene can improve the thermal stability of the polyethylene blends. The influence of the graphene on the tree inception voltage (TIV) of the polyethylene blends is not significant, whereas the low density polyethylene/high density polyethylene (LDPE/HDPE) with/without graphene demonstrates the highest TIV comparing to the LDPE, LDPE/polypropylene, and their corresponding graphene added materials. It is found that the DC conductivity of the polyethylene blends with/without graphene increases consistently with the increase of the temperature. The conductivity of the LDPE/HDPE decreases apparently with the inclusion of graphene. It has been shown that space charge accumulations can be suppressed by the addition of graphene in the polyethylene blends. It is postulated that the high trap level and trap energy density of the polyethylene blends with graphene are closely connected to the suppression of the space charge accumulation in the blends.

In the present work, a series of Pt-based catalysts, alloyed with a second metal, i.e., Re, Sn, Er, La, and Y, and supported on activated carbon, ordered mesoporous carbon, N-doped mesoporous carbon or reduced graphene oxide (rGO), have been developed for selective hydrogenation of cinnamaldehyde to cinnamylalcohol. Re and rGO were proved to be the most favorable metal dopant and catalyst support, respectively. Pt50Re50/rGO showed the highest cinnamylalcohol selectivity of 89% with 94% conversion of cinnamaldehyde at the reaction conditions of 120 °C, 2.0 MPa H2 and 4 h.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. The mortality of advanced RCC remains high despite advances in systemic therapy of RCC. Considering the misdiagnosis of early-stage RCC, the identification of effective biomarkers is of great importance. Tissue inhibitor matrix metalloproteinase 1 (TIMP1), which belongs to TIMP gene family, is a natural inhibitor of the matrix metalloproteinases (MMPs). In this study, we found TIMP1 was significantly up-regulated in cell lines and RCC tissues. Kaplan-Meier analysis revealed that high expression of TIMP1 indicated a poor prognosis. Multivariate analysis further indicated that TIMP1 overexpression was an independent prognostic factor of RCC patients. Furthermore, knockdown of TIMP1

(1) Background: Increasing evidence indicates that lipid metabolism may influence the concentration of prostate-specific antigen (PSA). However, the association between triglycerides and PSA remains unclear and complicated. Hence, we evaluated the correlation between triglycerides and PSA based on the U.S. National Health and Nutrition Examination Survey (NHANES) database. (2) Methods: A total of 2910 participants out of 41,156 participants fit into our study after conducting the screening from the 2003 to 2010 NHANES survey. Serum triglycerides were the independent variable of our study, and PSA was the dependent variable; (3) Results: In our study, the average age of chosen participants was 59.7 years (±12.7). After adjusting for covariates, the result indicated that for each additional unit of serum triglyceride (mg/dL), the PSA concentrations were reduced by 0.0043 ng/mL (−0.0082, −0.0005) with a statistical difference. Furthermore, we used machine learning of the XGBoost model to determine the relative importance of selected variables as well as constructed a smooth curve based on the fully adjusted model to investigate the possible linear relationship between the triglyceride and PSA concentrations. (4) Conclusions: The serum triglyceride is independently and negatively correlated with PSA among American males, which may make it hard to detect asymptomatic prostate cancer and diagnose at an advance stage with higher triglycerides due to detection bias.

Osthole (Ost) is an active constituent of Cnidium monnieri (L.) Cusson which possesses anti-inflammatory and anti-oxidative properties. It also has estrogen-like activity and can stimulate corticosterone secretion. The present study was aimed to check the role of Ost on progesterone (P4) secretion in cultured granulosa cells obtained from hen preovulatory follicles. Different concentrations (5, 2.5, and 1.25 &micro, g/mL) of Ost was added to granulosa cells for 6, 12, 18, and 24 h to investigate the level of progesterone secretions using enzyme linked immunosorbent assay (ELISA). The results showed that progesterone secretion was significantly increased in cells treated with Ost at 2.5 &mu, g/mL. Also, qRT-PCR showed that mRNA expression of steroidogenic acute regulatory protein (StAR) was significantly up-regulated by Ost at 2.5 &mu, g/mL concentration. Cytochrome P450 side-chain cleavage (P450scc) and 3&beta, hydroxysteroid dehydrogenase (3&beta, HSD) was significantly up-regulated by Ost. However, no significant differences were observed for the expression of proliferating cell nuclear antigen (PCNA). The protein expression of StAR, P450scc and 3&beta, HSD were significantly up-regulated by Ost treatment. The concentration of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in cell lysates showed no change with Ost treatment at 2.5 &mu, g/mL by ELISA. An ROS kit showed non-significant difference in the level of reactive oxygen species (ROS). In conclusion, Ost treatment at a concentration of 2.5 &mu, g/mL for 24 h had significantly up-regulated P4 secretion by elevating P450scc, 3&beta, HSD and StAR at both gene and protein level in granulosa cells obtained from hen preovulatory follicles.

Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future., Bladder urothelial carcinoma is one of the most prevalent urogenital cancer types with limited therapeutic options. Here, the authors characterize the tumor immune microenvironment of bladder cancer using single cell RNA sequencing and suggest a role for inflammatory cancer-associated fibroblasts in tumor progression.

Clear-cell renal cell carcinoma (ccRCC) is the most common histological type of RCC. To investigate the intratumoral heterogeneity of ccRCC, we analyzed single-cell RNA-sequencing data and identified 15 major cell types, along with 39 subgroups of cells derived from tumor or non-malignant tissues, and confirmed their presence by immunofluorescence staining in tissue chips. In this study, we verified that T cell exhaustion was the key factor responsible for the immunosuppressive property of ccRCC tissues, which was significantly related to poor prognosis. We also found that abnormal metabolic patterns occurred not only in cancer cells, but also in tumor-infiltrating stromal cells. Based on the fraction of each cell cluster detected by CIBERSORTx, 533 patients from The Cancer Genome Atlas (TCGA) KIRC dataset were divided into three groups. One group, which showed a lesser proportion of activated CD8(+) cells and greater proportion of exhausted CD8(+) cells, was associated with a poor prognosis. Hence, the blockade of immunosuppressive checkpoints, not only PD-1, but also LAG3, TIM-3, and other inhibitory checkpoints, could serve as a potential target for ccRCC immunotherapy. Our work will further the understanding of the heterogeneity among ccRCC tissues and provide novel strategies for treating ccRCC.

PURPOSE Breast cancer is the most common cancer among women worldwide. Medical ultrasound imaging is one of the widely applied breast imaging methods for breast tumors. Automatic breast ultrasound (BUS) image segmentation can measure the size of tumors objectively. However, various ultrasound artifacts hinder segmentation. We proposed an attention-supervised full-resolution residual network (ASFRRN) to segment tumors from BUS images. METHODS In the proposed method, Global Attention Upsample (GAU) and deep supervision were introduced into a full-resolution residual network (FRRN), where GAU learns to merge features at different levels with attention for deep supervision. Two datasets were employed for evaluation. One (Dataset A) consisted of 163 BUS images with tumors (53 malignant and 110 benign) from UDIAT Centre Diagnostic, and the other (Dataset B) included 980 BUS images with tumors (595 malignant and 385 benign) from the Sun Yat-sen University Cancer Center. The tumors from both datasets were manually segmented by medical doctors. For evaluation, the Dice coefficient (Dice), Jaccard similarity coefficient (JSC), and F1 score were calculated. RESULTS For Dataset A, the proposed method achieved higher Dice (84.3 ± 10.0%), JSC (75.2 ± 10.7%), and F1 score (84.3 ± 10.0%) than the previous best method: FRRN. For Dataset B, the proposed method also achieved higher Dice (90.7 ± 13.0%), JSC (83.7 ± 14.8%), and F1 score (90.7 ± 13.0%) than the previous best methods: DeepLabv3 and dual attention network (DANet). For Dataset A + B, the proposed method achieved higher Dice (90.5 ± 13.1%), JSC (83.3 ± 14.8%), and F1 score (90.5 ± 13.1%) than the previous best method: DeepLabv3. Additionally, the parameter number of ASFRRN was only 10.6 M, which is less than those of DANet (71.4 M) and DeepLabv3 (41.3 M). CONCLUSIONS We proposed ASFRRN, which combined with FRRN, attention mechanism, and deep supervision to segment tumors from BUS images. It achieved high segmentation accuracy with a reduced parameter number.

In this paper, we consider the wave equation of variable coefficients with Balakrishnan–Taylor damping, time-varying delay and source term. By establishing some Lyapunov functionals which are equivalent to the energy of the system and using the potential well method to deal with the source term, we prove a general stability result.