The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Discovery of novel glucosinolates inhibiting advanced glycation end products: Virtual screening and molecular dynamic simulation.

Protein glycation can result in the formation of advanced glycation end products (AGEs), which pose a potential health risk due to their association with diabetic complications. Natural products are a source of drugs discovery and the search for potential natural inhibitors of AGEs is of great significance. Glucosinolates (GSLs) mainly from cruciferous plants have potential antioxidant, anti-inflammatory, and anti-glycation activities. In this study, the inhibitory activity of GSLs on bovine serum albumin (BSA) along with its mechanism was investigated by virtual screening and various computational simulation techniques. Virtual screening revealed that 174 GSLs were screened using Maestro based on the glide score and 89% of the compounds were found to have potential anti-glycation ability with the docking scores less than -5 kcal/mol. Molecular docking showed that the top 10 GSLs were bound to the IIA structural domain of BSA. Among them, glucohesperin (1) and 2-hydroxyethyl glucosinolate (2) had the lowest docking scores of -9.428 and -9.333 kcal/mol, respectively, reflecting their good binding affinity. Molecular dynamics simulations of 1 (ΔG = -43.46 kcal/mol) and 2 (ΔG = -43.71 kcal/mol) revealed that the complexes of these two compounds with proteins had good stability. Further binding site analysis suggested that the mechanism of inhibition of protein glycation by these two active ingredients might be through competitive hydrogen bonding to maintain the structural integrity of the protein, thus inhibiting glycation reaction. Moreover, the ADMET values and CYP450 metabolism prediction data were within the recommended values. Therefore, it can be concluded that 1 and 2 may act as potential anti-glycation agents.

Prevalence of tumour-infiltrating CD103+ cells identifies therapeutic-sensitive prostate cancer with poor clinical outcome.

BACKGROUND: The clinical significance and immune correlation of CD103+ cells in prostate cancer (PCa) remain explored. METHODS: In total, 1080 patients with PCa underwent radical prostatectomy from three cohorts were enrolled for retrospective analysis. Tumour microarrays were constructed and fresh tumour samples were analysed by flow cytometry. RESULTS: High CD103+ cell infiltration correlated with reduced biochemical recurrence (BCR)-free survival in PCa. Adjuvant hormone therapy (HT) prolonged the BCR-free survival for high-risk node-negative diseases with CD103+ cell abundance. CD103+ cell infiltration correlated with less cytotoxic expression and increased infiltration of CD8+ and CD4+ T cells, M1 macrophages and mast cells in PCa. Intratumoral CD8+ T cell was the predominant source of CD103, and the CD103+ subset of CD8+ T cells was featured with high IL-10, PD-1 and CTLA-4 expression. Tumour-infiltrating CD103+ CD8+ T cells exerted anti-tumour function when treated with HT ex vivo. DISCUSSION: CD103+ cell infiltration predicted BCR-free survival and response to adjuvant HT in PCa. CD103+ cell infiltration correlated with an enriched but immune-evasive immune landscape. The study supported a model that CD103 expression conferred negative prognostic impact and immunosuppressive function to tumour-infiltrating CD8+ T cells, while the CD103+ CD8+ T cells exhibited a powerful anti-tumour immunity with response to HT.

Exosome-derived circTRPS1 promotes malignant phenotype and CD8+ T cell exhaustion in bladder cancer microenvironments.

Circular RNAs (circRNAs) play critical roles in different diseases. Exosomes are important intermediates of intercellular communication. While both have been widely reported in cancers, exosome-derived circRNAs are rarely studied. In this work, we identified the differently expressed circRNAs in bladder cancer (BCa) tissue and exosomes through high-throughput sequencing. RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays were used to investigate the interactions between specific circRNAs, microRNAs (miRNAs), and mRNAs. Wound-healing, Transwell, Cell Counting Kit-8 (CCK8), and colony-formation assays were used to study the biological roles in vitro. Metabolomics were used to explore the mechanism of how specific circRNAs influenced BCa cell behavior. Flow cytometry was used to study how specific circRNAs affected the function of CD8+ T cells in tumor microenvironments. We identified that exosome-derived hsa_circ_0085361 (circTRPS1) was correlated with aggressive phenotypes of BCa cells via sponging miR-141-3p. Metabolomics and RNA sequencing (RNA-seq) identified GLS1-mediated glutamine metabolism was involved in circTRPS1-mediated alterations. Exosomes derived from circTRPS1 knocked down BCa cells, prevented CD8+ T cells from exhaustion, and repressed the malignant phenotype of BCa cells. In conclusion, exosome-derived circTRPS1 from BCa cells can modulate the intracellular reactive oxygen species (ROS) balance and CD8+ T cell exhaustion via the circTRPS1/miR141-3p/GLS1 axis. Our work may provide a potential biomarker and therapeutic target for BCa.

Identification and validation of a poor clinical outcome subtype of primary prostate cancer with Midkine abundance.

Recent studies identified Midkine (MDK) as playing a key role in immune regulation. In this study, we aimed to discover the clinical significance and translational relevance in prostate cancer (PCa). We retrospectively analyzed 759 PCa patients who underwent radical prostatectomy from Huashan Hospital, Fudan University (training cohort, n = 369) and Chinese Prostate Cancer Consortium (validation cohort, n = 390). A total of 325 PCa patients from The Cancer Genome Atlas (TCGA) database (external cohort) were analyzed for exploration. Immune landscape and antitumor immunity were assessed through immunohistochemistry and flow cytometry. Patient-derived explant culture system was applied for evaluating the targeting potential of MDK. We found that intratumoral MDK expression correlated with PCa progression, which indicated an unfavorable biochemical recurrence (BCR)-free survival for postoperative PCa patients. Addition of MDK expression to the postoperative risk assessment tool CAPRA-S could improve its prognostic value. Tumors with MDK abundance characterized the tumor-infiltrating CD8+ T cells with less cytotoxicity production and increased immune checkpoint expression, which were accompanied by enriched immunosuppressive contexture. Moreover, MDK inhibition could reactivate CD8+ T cell antitumor immunity. MDK mRNA expression negatively correlated with androgen receptor activity signature and positively associated with radiotherapy-related signature. In conclusion, intratumoral MDK expression could serve as an independent prognosticator for BCR in postoperative PCa patients. MDK expression impaired the antitumor function of CD8+ T cells through orchestrating an immunoevasive microenvironment, which could be reversed by MDK inhibition. Moreover, tumors with MDK enrichment possessed potential sensitivity to postoperative radiotherapy while resistance to adjuvant hormonal therapy of PCa. MDK could be considered as a potential therapeutic target for PCa.

Multi-Stage Attentive Network for Motion Deblurring via Binary Cross-Entropy Loss.

In this paper, we present the multi-stage attentive network (MSAN), an efficient and good generalization performance convolutional neural network (CNN) architecture for motion deblurring. We build a multi-stage encoder-decoder network with self-attention and use the binary cross-entropy loss to train our model. In MSAN, there are two core designs. First, we introduce a new attention-based end-to-end method on top of multi-stage networks, which applies group convolution to the self-attention module, effectively reducing the computing cost and improving the model's adaptability to different blurred images. Secondly, we propose using binary cross-entropy loss instead of pixel loss to optimize our model to minimize the over-smoothing impact of pixel loss while maintaining a good deblurring effect. We conduct extensive experiments on several deblurring datasets to evaluate the performance of our solution for deblurring. Our MSAN achieves superior performance while also generalizing and compares well with state-of-the-art methods.

Hsa_circ_0068307 mediates bladder cancer stem cell-like properties via miR-147/c-Myc axis regulation.

BACKGROUND: Circular RNAs (circRNAs) play an essential role in the regulation of gene expression. However, the underlying mechanisms remain unknown. This study aimed to evaluate the role of hsa_circ_0068307 in bladder cancer (BCa). METHODS: Rt-qPCR was used to detect hsa_circ_0068307 expression in BCa cell lines. The CCK8, colony formation, and Transwell assays were used to evaluate the effect of hsa_circ_0068307 on BCa cell migration and proliferation. Bioinformatics and luciferase reporter experiments were used to study the regulatory mechanism. Nude mouse xenografts were generated to examine the effect of hsa_circ_0068307 on tumor growth. RESULTS: The results showed that hsa_circ_0068307 was upregulated in BCa cell lines. Downregulation of hsa_circ_0068307 suppressed cell migration and proliferation in T24 and UMUC3 cells. Hsa_circ_0068307 silencing suppressed cancer stem cell differentiation by upregulating miR-147 expression. Upregulation of miR-147 suppressed c-Myc expression, which is involved in cancer stem cell differentiation. Luciferase reporter assays confirmed that hsa_circ_0068307 upregulated c-Myc expression by targeting miR-147. In vivo studies showed that hsa_circ_0068307 knockdown suppressed T24 tumor growth. CONCLUSIONS: These data indicate that downregulation of hsa_circ_0068307 reversed the stem cell-like properties of human bladder cancer through the regulation of the miR-147/c-Myc axis.

Association between red blood cell distribution width and long-term mortality among patients undergoing percutaneous coronary intervention with previous history of cancer.

Background: The number of patients suffering from coronary heart disease with cancer is rising. There is scarce evidence concerning the biomarkers related to prognosis among patients undergoing percutaneous coronary intervention (PCI) with cancer. Thus, the aim of this study was to investigate the association between red blood cell distribution width (RDW) and prognosis in this population.Methods: A total of 172 patients undergoing PCI with previous history of cancer were enrolled in this retrospective study. The endpoint was long-term all-cause mortality. According to tertiles of RDW, the patients were classified into three groups: Tertile 1 (RDW <12.8%), Tertile 2 (RDW ≥12.8% and <13.5%) and Tertile 3 (RDW ≥13.5%).Results: During an average follow-up period of 33.3 months, 29 deaths occurred. Compared with Tertile 3, mortality of Tertile 1 and Tertile 2 was significantly lower in the Kaplan-Meier analysis. In multivariate Cox regression analysis, RDW remained an independent risk factor of mortality (HR: 1.938, 95% CI: 1.295-2.655, p < 0.001). The all-cause mortality in Tertile 3 was significantly higher than that in Tertile 1 (HR: 5.766; 95% CI: 1.426-23.310, p = 0.014).Conclusions: An elevated RDW level (≥13.5%) was associated with long-term all-cause mortality among patients undergoing PCI with previous history of cancer.

An Adaptive and Secure Holographic Image Watermarking Scheme.

A novel adaptive secure holographic image watermarking method in the sharp frequency localized contourlet transform (SFLCT) domain is presented. Based upon the sine logistic modulation map and the logistic map, we develop an encrypted binary computer-generated hologram technique to fabricate a hologram of a watermark first. Owing to the enormous key space of the encrypted hologram, the security of the image watermarking system is increased. Then the hologram watermark is embedded into the SFLCT coefficients with Schur decomposition. To obtain better imperceptibility and robustness, the entropy and the edge entropy are utilized to select the suitable watermark embedding positions adaptively. Compared with other watermarking schemes, the suggested method provides a better performance with respect to both imperceptibility and robustness. Experiments show that our watermarking scheme for images is not only is secure and invisible, but also has a stronger robustness against different kinds of attack.

A Semi-Supervised Approach to Bearing Fault Diagnosis under Variable Conditions towards Imbalanced Unlabeled Data.

Fault diagnosis of rolling element bearings is an effective technology to ensure the steadiness of rotating machineries. Most of the existing fault diagnosis algorithms are supervised methods and generally require sufficient labeled data for training. However, the acquisition of labeled samples is often laborious and costly in practice, whereas there are abundant unlabeled samples which also imply health information of bearings. Thus, it is worthwhile to develop semi-supervised methods of fault diagnosis to make effective use of the plentiful unlabeled samples. Nevertheless, considering the normal data are much more than the faulty ones, the problem of imbalanced data exists among unlabeled samples for fault diagnosis. Besides, in practice, bearings often work under uncertain and variable operation conditions, which would also have negative influence on fault diagnosis. To solve these issues, a novel hybrid method for bearing fault diagnosis is proposed in this paper: (1) Inspired by visibility graph, a novel fault feature extraction method named visibility graph feature (VGF) is proposed. The obtained features by VGF are natively insensitive to variable conditions, which has been validated by a simulation experiment in this paper; (2) On basis of VGF, to deal with imbalanced unlabeled data, graph-based rebalance semi-supervised learning (GRSSL) for fault diagnosis is proposed. In GRSSL, a graph based on a weighted sparse adjacency matrix is constructed by the k-nearest neighbors and Gaussian Kernel weighting algorithm by means of the samples. Then, a bivariate cost function over classification and normalized label variable is built up to rebalance the importance of labels. Finally, the proposed VGF-GRSSL method was verified by data collected from Case Western Reserve University Bearing Data Center. The experiment results show that the proposed method of bearing fault diagnosis performs effectively to deal with the imbalanced unlabeled data under variable conditions.

Adaptive Multiclass Mahalanobis Taguchi System for Bearing Fault Diagnosis under Variable Conditions.

Bearings are vital components in industrial machines. Diagnosing the fault of rolling element bearings and ensuring normal operation is essential. However, the faults of rolling element bearings under variable conditions and the adaptive feature selection has rarely been discussed until now. Thus, it is essential to develop a practicable method to put forward the disposal of the fault under variable conditions. Considering these issues, this paper uses the method based on the Mahalanobis Taguchi System (MTS), and overcomes two shortcomings of MTS: (1) MTS is an effective tool to classify faults and has strong robustness to operating conditions, but it can only handle binary classification problems, and this paper constructs the multiclass measurement scale to deal with multi-classification problems. (2) MTS can determine important features, but uses the hard threshold to select the features, and this paper selects the proper feature sequence instead of the threshold to overcome the lesser adaptivity of the threshold configuration for signal-to-noise gain. Hence, this method proposes a novel method named adaptive Multiclass Mahalanobis Taguchi system (aMMTS), in conjunction with variational mode decomposition (VMD) and singular value decomposition (SVD), and is employed to diagnose the faults under the variable conditions. Finally, this method is verified by using the signal data collected from Case Western Reserve University Bearing Data Center. The result shows that it is accurate for bearings fault diagnosis under variable conditions.

Unbalanced regularized optimal mass transport with applications to fluid flows in the brain.

As a generalization of the optimal mass transport (OMT) approach of Benamou and Brenier's, the regularized optimal mass transport (rOMT) formulates a transport problem from an initial mass configuration to another with the optimality defined by the total kinetic energy, but subject to an advection-diffusion constraint equation. Both rOMT and the Benamou and Brenier's formulation require the total initial and final masses to be equal; mass is preserved during the entire transport process. However, for many applications, e.g., in dynamic image tracking, this constraint is rarely if ever satisfied. Therefore, we propose to employ an unbalanced version of rOMT to remove this constraint together with a detailed numerical solution procedure and applications to analyzing fluid flows in the brain.

Toward morphologically relevant extracellular matrix: nanofiber-hydrogel composites for tumor cell culture.

The natural extracellular matrix (ECM) consists of a continuous integrated fibrin network and a negatively charged proteoglycan-based matrix. In this work, we report a novel three-dimensional nanofiber hydrogel composite that mimics the natural ECM structure, exhibiting both degradability and mechanical characteristics comparable to that of tumor tissue. The embedded nanofiber improves the hydrogel mechanical properties, and varying the fiber density can match the elastic modulus of different tumor tissues (1.51-10.77 kPa). The degradability of the scaffold gives sufficient space for tumor cells to secrete and remodel the ECM. The expression levels of cancer stem cell markers confirmed the development of aggressive and metastatic phenotypes of prostate cancer cells in the 3D scaffold. Similar results were obtained in terms of anticancer resistance of prostate cancer cells in 3D scaffolds showing stem cell-like properties, suggesting that the current bionic 3D scaffold tumor model has broad potential in the development of effective targeted agents.

Polyelectrolyte-coated liposomes microfluidically assembled in one-step for enhancing cell endocytosis and in-vivo immune responses.

To enhance the cellular uptake of liposomes, we prepared conventional liposomes with targeting molecules and surface-charged liposomes and evaluated their potential as nano-carriers and vaccine adjuvants by comparing their endocytosis efficiencies using immune cells. Surface-charged liposomes were synthesized via a one-step microfluidic method, which provided a novel, simple, fast, and highly reproducible method for preparing liposomes. Flow cytometry revealed that cationic polyelectrolyte-coated liposomes exhibited higher endocytosis efficiencies (of up to a factor of 100) in A774A.1 cells and JAWs II cells compared with uncoated liposomes or those coated with anionic polyelectrolytes. Positively charged liposomes exhibited some cytotoxicity at quaternary-chitosan coating concentrations higher than 6 mg/mL; however, significantly lower cytotoxicities (by a factor of almost ten) were obtained by protein mixing. Furthermore, BALB/c mice vaccinated with a mixture of Anthrax vaccine adsorbed (AVA) and quaternary chitosan-coated liposomes showed faster and stronger anti-PA IgG inductions compared to those vaccinated with AVA alone, with titers positively correlating with the amount of cationic liposome used. This finding clearly reveals that quaternary chitosan-coated liposomes act as both nano-carriers and vaccine adjuvants that significantly enhance in-vivo immune responses to vaccines with low immunogenicities.

Endoscopic Cryoablation Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Cryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. METHODS: We retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). KEY FINDINGS AND LIMITATIONS: At median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. CONCLUSIONS AND CLINICAL IMPLICATIONS: In comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. PATIENT SUMMARY: Our study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.

KNTC1 as a putative tumor oncogene in pancreatic cancer.

PURPOSE: Recent studies have demonstrated that kinetochore-associated protein 1 (KNTC1) plays a significant role in the carcinogenesis of numerous types of cancer. This study aimed to explore the role and possible mechanisms of KNTC1 in the development of pancreatic cancer. METHODS AND RESULTS: We analyzed differentially expressed genes by RNA sequencing in three paired pancreatic cancer and para-cancerous tissue samples and found that the expression of KNTC1 was significantly upregulated in pancreatic cancer. A Cancer and Tumor Gene Map pan-analysis showed that high expression of KNTC1 was related to poor prognosis in 9499 tumor samples. With immunohistochemical staining, we found that the high expression of KNTC1 in pancreatic cancer was related to pathological grade and clinical prognosis. Similarly, RT-PCR results indicated that the expression of KNTC1 was higher in three groups of pancreatic cancer cell lines (BxPC-3, PANC-1, and SW1990) than in normal pancreatic ductal cells. We introduced lentivirus-mediated shRNA targeting KNTC1 into PANC-1 and SW1990 cells and found that KNTC1 knockdown significantly decreased cell growth and increased cell apoptosis compared to the control group cells. Bioinformatic analysis of the cell expression profile revealed that differential genes were mainly enriched in the cell cycle, mitosis, and STAT3 signaling pathways, and co-immunoprecipitation confirmed an interaction between KNTC1 and cell division cycle associated 8. CONCLUSIONS: KNTC1 could be linked to the pathophysiology of pancreatic cancer and may be an early diagnostic marker of cervical precancerous lesions.

Visualizing Fluid Flows via Regularized Optimal Mass Transport with Applications to Neuroscience.

The regularized optimal mass transport (rOMT) problem adds a diffusion term to the continuity equation in the original dynamic formulation of the optimal mass transport (OMT) problem proposed by Benamou and Brenier. We show that the rOMT model serves as a powerful tool in computational fluid dynamics for visualizing fluid flows in the glymphatic system. In the present work, we describe how to modify the previous numerical method for efficient implementation, resulting in a significant reduction in computational runtime. Numerical results applied to synthetic and real-data are provided.

Design, synthesis and antibacterial evaluation of a novel class of tetrahydrobenzothiophene derivatives.

In this study, a new series of tetrahydrobenzothiophene derivatives have been designed. Newly designed molecules have been synthesized through a medicinal chemistry route, and their characterization was done by using NMR and HR-MS techniques. Biological evaluation of the synthesized compounds has been done on Gram-negative and Gram-positive bacteria. The marketed antibiotics such as ciprofloxacin and gentamicin were used as controls. The in vitro evaluation results have shown that most of the targeted compounds exhibit good potency in inhibiting the growth of bacteria, including E. coli (MIC: 0.64-19.92 µM), P. aeruginosa (MIC: 0.72-45.30 µM), Salmonella (MIC: 0.54-90.58 µM) and S. aureus (MIC: 1.11-99.92 µM). In particular, compound 3b showed excellent activity with an MIC value of 1.11 µM against E. coli, 1.00 µM against P. aeruginosa, 0.54 µM against Salmonella, and 1.11 µM against S. aureus. From the results, a promising lead compound was identified for future development.

Cryoablation inhibits the recurrence and progression of bladder cancer by enhancing tumour-specific immunity.

BACKGROUND: Recurrence and metastasis of bladder cancer are major factors affecting patient prognosis. Endoscopic cryoablation achieved a better clinical outcome among clinical patients and could be synergistic with ICIs. Thus, this study aimed to evaluate the immunological mechanism of cryoablation for bladder cancer to reveal the therapeutic mechanism. METHODS: We systematically reviewed the clinical prognosis of patients underwent cryoablation at Huashan Hospital in these first-in-human studies (ChiCTR-INR-17013060). Murine models were constructed to explore cryoablation-induced tumour-specific immunity, which was further confirmed by primary bladder tumour organoids and autologous lymphocytes cocultured system. RESULTS: Cryoablation improved progression-free survival and recurrence-free survival respectively. Assessment of murine models after cryoablation confirmed microenvironment remodelling and tumour-specific T cells expansion. Enhanced antitumour effects were found after coculture of organoids with autologous lymphocytes collected from post-cryoablation. We also demonstrated cryoablation-induced tumour elimination required IFNGR expression on tumour cells. In addition, a long-lasting antitumour memory response is achieved by cryoablation and could be enhanced after combination with ICIs. CONCLUSIONS: This study revealed endoscopic cryoablation is an efficient and safe therapy for bladder tumour treatment. The tumour-specific immune responses induced by cryoablation could reduce tumour recurrence and metastasis.