Scombroid fish poisoning caused by histamine intoxication is one of the most prevalent allergies associated with seafood consumption in the United States. Typical symptoms range from mild itching up ...to fatal cardiovascular collapse seen in anaphylaxis. In this paper, we demonstrate rapid, sensitive, and quantitative detection of histamine in both artificially spoiled tuna solution and real spoiled tuna samples using thin layer chromatography in tandem with surface-enhanced Raman scattering (TLC-SERS) sensing methods, enabled by machine learning analysis based on support vector regression (SVR) after feature extraction with principal component analysis (PCA). The TLC plates used herein, which were made from commercial food-grade diatomaceous earth, served simultaneously as the stationary phase to separate histamine from the blended tuna meat and as ultra-sensitive SERS substrates to enhance the detection limit. Using a simple drop cast method to dispense gold colloidal nanoparticles onto the diatomaceous earth plate, we were able to directly detect histamine concentration in artificially spoiled tuna solution down to 10 ppm. Based on the TLC-SERS spectral data of real tuna samples spoiled at room temperature for 0–48 h, we used the PCA-SVR quantitative model to achieve superior predictive performance exceling traditional partial least squares regression (PLSR) method. This work proves that diatomaceous earth based TLC-SERS technique combined with machine-learning analysis is a cost-effective, reliable, and accurate approach for on-site detection and quantification of seafood allergen to enhance food safety.
•SVR-based machine learning analysis for TLC-SERS with better quantification accuracy•Ultra-sensitive detection of histamine in spoiled tuna down to 10 ppm•Quantitative PCA-SVR model to evaluate the spoilage time of tuna•Demonstration of TLC-SERS sensing with a portable Raman spectrometer
Parallel optical interconnects at the extreme scale hold the key to resolve the grand challenge of moving enormous amount of data between on-chip cores and within multi-chip modules. Silicon photonic ...modulators, as one of the most pivotal devices conducting electronic to photonic signal conversion, must excel in energy efficiency and bandwidth density in order to meet the stringent requirement of extreme scale photonic interconnects. In this manuscript, the energy efficiency and bandwidth limit of ultra-compact resonator-based silicon photonic modulators are analyzed from three fundamental perspectives: free carrier dispersion strength of the active materials, Purcell factors of the resonators, and electrical configuration of the capacitors. Our simulation results reveal convincing advantages of photonic crystal nanocavity over micro-ring and micro-disk resonators in terms of energy efficiency and device footprint. While for the electro-optic modulation region, metal-oxide-semiconductor (MOS) capacitors truly outperform reversed PN junctions due to the large capacitance density. However, all resonator-based silicon photonic modulators suffer the intrinsic trade-off between energy efficiency and resistance-capacitance-delay limited bandwidth. The general model developed herein lays the theoretical foundation and identify possible routes to achieve atto-joule per bit energy efficiency and how to approach the bandwidth limit of silicon photonic modulators.
Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma ...cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.
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•PTEN deficiency in GBM drives macrophage infiltration via upregulation of LOX•LOX is directly regulated by YAP1 in PTEN-deficient GBM•LOX recruits macrophages into GBM via the β1 integrin-PYK2 pathway•LOX inhibition impairs PTEN-deficient GBM progression by decreasing TAM-derived SPP1
Chen et al. find that PTEN deficiency in glioblastoma (GBM) increases macrophage infiltration via a YAP1-LOX-β1 integrin-PYK2 axis, the infiltrated macrophages in turn secrete SPP1 to support GBM survival. In PTEN-null GBM xenograft mouse models, inhibition of LOX reduces macrophage infiltration and tumor growth.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to treat. It is refractory to most existing therapies, including immunotherapies, due to the presence of an excessive ...desmoplastic stroma, which restricts penetration of drugs and cytotoxic CD8+ T cells. Stromal modulation has shown promising results in the enhancement of immune checkpoint blockade treatment in PDAC. We demonstrate here effective stromal modulation by a polymeric micelle-based nanoformulation to codeliver a sonic hedgehog inhibitor (cyclopamine, abbreviated as CPA) and a cytotoxic chemotherapy drug (paclitaxel, abbreviated as PTX). The formulation, M-CPA/PTX, modulated the PDAC stroma by increasing the intratumoral vasculature density, which then promoted the tumor infiltration by cytotoxic CD8+ T cells without depletion of tumor-restraining α-smooth muscle action-positive fibroblasts and type I collage in the stroma. The combination of M-CPA/PTX and the PD-1 checkpoint blockade significantly prolonged animal survival in an orthotopic murine PDAC model as well as a genetically engineered mouse model of PDAC. The superior antitumor efficacy was mediated by enhanced tumor infiltration of CD8+ T cells without concomitant infiltration of suppressive regulatory T cells or myeloid-derived suppressor cells and by the coordinated action of PTX and interferon-gamma. Our results demonstrate that stroma-modulating nanoformulations are a promising approach to potentiate immune checkpoint blockade therapy of pancreatic cancer.
With increasing knowledge demands and limited availability of expertise and resources within organizations, professionals often rely on external sources when seeking knowledge. Online knowledge ...communities are Internet based virtual communities that specialize in knowledge seeking and sharing. They provide a virtual media environment where individuals with common interests seek and share knowledge across time and space. A large online community may have millions of participants who have accrued a large knowledge repository with millions of text documents. However, due to the low information quality of user-generated content, it is very challenging to develop an effective knowledge management system for facilitating knowledge seeking and sharing in online communities. Knowledge management literature suggests that effective knowledge management should make accessible not only written knowledge but also experts who are a source of information and can perform a given organizational or social function. Existing expert finding systems evaluate one's expertise based on either the contents of authored documents or one's social status within his or her knowledge community. However, very few studies consider both indicators collectively. In addition, very few studies focus on virtual communities where information quality is often poorer than that in organizational knowledge repositories. In this study we propose a novel expert finding algorithm, ExpertRank, that evaluates expertise based on both document-based relevance and one's authority in his or her knowledge community. We modify the PageRank algorithm to evaluate one's authority so that it reduces the effect of certain biasing communication behavior in online communities. We explore three different expert ranking strategies that combine document-based relevance and authority: linear combination, cascade ranking, and multiplication scaling. We evaluate ExpertRank using a popular online knowledge community. Experiments show that the proposed algorithm achieves the best performance when both document-based relevance and authority are considered.
► We propose ExpertRank, an expert finding technique in online knowledge communities. ► It evaluates experts on both knowledge relevance and authority in the community. ► PageRank is modified to reduce the bias of small-interconnected groups. ► ExpertRank outperforms both document-centric and hybrid expert finding techniques.
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant ...prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b
Gr1
) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.
Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a ...crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin αvβ5 (ITGαvβ5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target.
The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of ...Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP-TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5-CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer.
We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo-YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5-CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival.
This article examines whether competition in the deposit and loan markets results in a more stable or fragile banking industry. Following the assumption that deposit and loan competitions are not ...separable, a simple equilibrium model is developed. Then, using the aggregate time-series data of Federal Deposit Insurance Corporation (FDIC)-insured financial institutions, we estimate the generalized VAR model of deposit rate (DR), interest margin between the loan and DRs, and non-performing loan ratio. Our results support the competition-fragility hypothesis.
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