•Recent advances towards infectious pathogens diagnostics are introduced.•Integrated microfluidic devices for infectious disease diagnostics are summarized.•Current challenges and future perspectives ...for POC diagnostics are discussed.
Rapid and timely diagnosis of infectious diseases is a critical determinant of clinical outcomes and general public health. For the detection of various pathogens, microfluidics-based platforms offer many advantages, including speed, cost, portability, high throughput, and automation. This review provides an overview of the recent advances in microfluidic technologies for point-of-care (POC) diagnostics for infectious diseases. The key aspects of such technologies for the development of a fully integrated POC platform are introduced, including sample preparation, on-chip nucleic acid analysis and immunoassay, and system integration/automation. The current challenges to practical implementation of this technology are discussed together with future perspectives.
Organ-on-a-chip technology can simulate the physiological and pathological microenvironment of tissues and organs in vitro, thus offering the potential of dispensing with animal models to predict the ...toxicity and efficacy of therapies. In this study, taking the alveolar microenvironment as a model, we developed a lung-on-a-chip with a poly(lactic-co-glycolic acid) (PLGA) electrospinning nanofiber membrane as the chip substrate and cell scaffold. The PLGA nanofiber membrane, with a controlled thickness of ∼3 μm, is porous and permeable to molecules, has good biocompatibility, and offers a means to simulate the alveolar respiratory membrane. On the chip, we carried out cell culture and co-culture of human non-small cell lung cancer cells (A549) and human fetal lung fibroblasts (HFL1), and evaluated gefitinib, an epidermal growth factor receptor (EGFR)-targeted anti-tumor drug. We further probed the possible sources of A549 cell drug resistance in the presence of HFL1 cells. In addition, we co-cultured A549, HFL1, and human umbilical vein endothelial cells (HUVECs), and found that A549 cells could lead to endothelial cell apoptosis or death, and then the occurrence of tumor invasion. This established lung-on-a-chip is simple, effective, and easy to operate. It is expected to have important applications in personalized treatment of lung tumors and to play a potential role in other clinical treatments and tissue engineering.
A proposed model illustrating the therapeutic effect of QCT on AKI. QCT inhibits the expression of ATF3. While ATF3 blocks the system Xc-, and then suppresses GPX4, inducing ferroptosis. In another ...side, ferroptotic cells secrete chemokines like CCL2, CCL7, induce the recruitment of macrophages, and then cause the inflammation in AKI. In summary, QCT ameliorates AKI through the inhibition on ferroptosis and the following inflammation.
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•Quercetin (QCT) inhibits ferroptosis but not apoptosis, necrosis or autophagy of renal proximal tubular epithelial cells, and ameliorates AKI induced by ischemia–reperfusion (I/R) or folic acid (FA).•Activation transcription factor 3 (ATF3) plays an important role in cell ferroptosis, while QCT significantly inhibits the expression of ATF3 and further blocks the downstream signaling pathway of ferroptosis.•Ferroptotic cells induce the recruitment and chemotaxis of macrophages through CCL2, triggering inflammation and enhancing tissue injury.
Ferroptosis is an iron-dependent regulated necrosis and has been proven to contribute to the progress of acute kidney injury (AKI). Quercetin (QCT), a natural flavonoid which is commonly found in numerous fruits and vegetables, has extensive pharmacological effects, such as anti-oxidant, anti-inflammatory and anti-senescence effects.
This study aims to explain whether ferroptosis is a therapeutic strategy to AKI, and to explore the effect of QCT on AKI ferroptosis.
NRK-52E cells and HK-2 cells were used for in vitro ferroptosis studies. Morphology of cells was detected by transmission electron microscopy. Lipid ROS was assayed using flow cytometry. In vivo, AKI was induced by ischemia–reperfusion (I/R) or folic acid (FA). To explore the molecular mechanisms, RNA-sequence analysis was performed. Transwell was used to detect macrophage migration.
We discovered that quercetin (QCT), a natural flavonoid, inhibited ferroptosis in renal proximal tubular epithelial cells. QCT blocked the typical morphologic changes of ferroptotic cells by reducing the levels of malondialdehyde (MDA) and lipid ROS and increasing the levels of glutathione (GSH). Moreover, QCT ameliorated AKI induced by I/R or FA. RNA-sequence analysis highlighted activation transcription factor 3 (ATF3), as it was the dominant one among all the 299 down-regulated genes by QCT. Knockdown of ATF3 could significantly increase the levels of SLC7A11, GPX4 and increased the cell viability. In addition, ferroptotic cells were found to be extremely pro-inflammatory by recruiting macrophages through CCL2, while QCT inhibited the chemotaxis of macrophages induced by ferroptosis in AKI.
Collectively, these results identify QCT as a ferroptosis inhibitor and provide new therapeutic strategies for diseases related to ferroptosis.
Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium ...(DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6−/− mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.
The term ferroptosis coined in 2012 causes acute kidney injury (AKI). However, its pathway mechanism in AKI is poorly understood. In this study, we conducted an RNA-sequence analysis of kidneys in ...AKI and normal mice to explore the pathway mechanism of ferroptosis. Consequently, differentially expressed genes highlighted Acyl-CoA synthetase long-chain family (ACSL4), a known promotor for ferroptosis. Besides, RT-PCR, Western blot, and immunohistochemical analyses confirmed its upregulation. HIF-1α was downregulated in I/R-AKI mice, and in vitro studies confirmed a negative regulation of HIF-1α on ACSL4. To explore the role of ACSL4 in AKI, we constructed ACSL4 knockout in kidney tubules of mice-as Cdh16Cre-ACSL4F/F mice. Results revealed that ACSL4 knockout significantly reduced ferroptosis and inhibited the functional and pathological injury of AKI mice. Meanwhile, the kidneys of Cdh16Cre-ACSL4F/F mice demonstrated a significantly decreased inflammation and macrophage infiltration. Further, additional explorations were explored to decipher a more thorough understanding of ferroptotic immunogenicity. As a result, neutrophils were not directly recruited by ferroptotic cells, but by ferroptotic cell-induced macrophages. Further, ACSL4 inhibitor rosiglitazone significantly inhibited AKI. Collectively, these data provide novel insights into the AKI pathogenesis, and defined ACSL4 as an effective target in AKI.
Proposed effects of ACSL4 in AKI. Low HIF-1α induces a high expression of ACSL4 and leads to the ferroptosis and inflammation during the occurrence of AKI. Ferroptotic cells recruit macrophages, then induce the neutrophils recruitment to the kidney injury site, producing several inflammatory cytokines and inducing an inflammatory cascade. Therefore, ACSL4 could be a potential target for the prevention and treatment of AKI. Display omitted
Despite the agency perspective of corporate tax avoidance, there is little empirical evidence that managers do extract rents derived from aggressive tax practices. This study investigates the ...association between tax aggressiveness and managerial rent extraction by focusing on informed insider trading, a self-serving action with an unambiguous impact on insiders’ personal wealth and representing the most direct channel through which managers expropriate outside shareholders. We find that insiders at firms more aggressive in tax avoidance gain significantly higher returns from insider purchases than insiders in less aggressive firms and this outperformance results from trading on future earnings news. We also find that insiders under the cover of aggressive tax practices more likely trade on bad news through insider sales and gain more from these trades. The overall evidence is consistent with aggressive tax planning serving managerial interests through gainfully exploiting private information and extracting rents from uninformed shareholders.
The lung is the primary respiratory organ of the human body and has a complicated and precise tissue structure. It comprises conductive airways formed by the trachea, bronchi and bronchioles, and ...many alveoli, the smallest functional units where gas-exchange occurs via the unique gas-liquid exchange interface known as the respiratory membrane. In vitro bionic simulation of the lung or its microenvironment, therefore, presents a great challenge, which requires the joint efforts of anatomy, physics, material science, cell biology, tissue engineering, and other disciplines. With the development of micromachining and miniaturization technology, the concept of a microfluidics-based organ-on-a-chip has received great attention. An organ-on-a-chip is a small cell-culture device that can accurately simulate tissue and organ functions in vitro and has the potential to replace animal models in evaluations of drug toxicity and efficacy. A lung-on-a-chip, as one of the first proposed and developed organs-on-a-chip, provides new strategies for designing a bionic lung cell microenvironment and for in vitro construction of lung disease models, and it is expected to promote the development of basic research and translational medicine in drug evaluation, toxicological detection, and disease model-building for the lung. This review summarizes current lungs-on-a-chip models based on the lung-related cellular microenvironment, including the latest advances described in studies of lung injury, inflammation, lung cancer, and pulmonary fibrosis. This model should see effective use in clinical medicine to promote the development of precision medicine and individualized diagnosis and treatment.
The application of superamphiphobic coatings improves the surface’s ability to repel fluids, thereby greatly enhancing its various functions, including anti-fouling, anti-corrosion, anti-icing, ...anti-bacterial, and self-cleaning properties. This maximizes the material’s potential for industrial applications. This work utilized the agglomeration phenomenon exhibited by nano-spherical titanium dioxide (TiO2) particles to fabricate 1H,1H,2H,2H-perfluorodecyltriethoxysilane (PFDTES) modified TiO2 (TiO2@fluoroPOS) fillers with low surface energy. This was achieved through the in-situ formation of protective armor on the surface of the agglomerates using the sol-gel method and fluorination modification. Polyvinylidene fluoride-tetrafluoropropylene (PVDF-HFP) and TiO2@fluoroPOS fillers were combined using a spraying technique to prepare P/TiO2@fluoroPOS coatings with superamphiphobicity. Relying on the abundance of papillae, micropores, and other tiny spaces on the surface, the coating can capture a stable air film and reject a variety of liquids. When the coatings were immersed in solutions of 2 mol/L HCl, NaCl, and NaOH for a duration of 12 h, they retained their exceptional superamphiphobic properties. Owing to the combined influence of the armor structure and the organic binder, the coating exhibited good liquid repellency during water jetting and sandpaper abrasion tests. Furthermore, the coating has shown exceptional efficacy in terms of its ability to be anti-icing, anti-waxing, and self-cleaning.
In this paper, we consider a fast algorithm to calculate a two-dimensional nonlinear time distributed-order and space fractional diffusion equation, which is called the time two-mesh (TT-M) finite ...element (FE) method. In time, the TT-M algorithm combined with both the implicit second-order σ backward difference formula and Crank–Nicolson scheme for computing the numerical solution at time t1 is used to speed up the calculation. At the same time, the spatial direction is approximated by the FE method. The detailed analyses of stability and error are also given, and the second-order time convergence accuracy can be arrived at. Finally, some numerical examples are shown to illustrate the effectiveness of our numerical method.
Management earnings forecasts (MEFs) may reduce information risk by corroborating the inferences that lenders draw from their private communication with borrowers. Consistent with this idea, we find ...that among firms with a general policy of issuing MEFs, those providing MEFs in the 6 months before loan origination with a forecast horizon beyond the origination date enjoy lower loan spreads. The frequency and precision of MEFs are also negatively associated with loan spreads. The associations are stronger when lenders’ need for corroboration of their private information is expected to be greater. The associations are not driven by a firm’s general information environment, signaling of managerial ability, opportunistic disclosure, or competition between public and private debt markets. Moreover, the issuance, frequency, and precision of MEFs are associated with loan amounts more spread out among participating lenders, suggesting that MEFs also reduce information asymmetry within a loan syndicate. Our study provides insight into the corroboration role of publicly disseminated MEFs in private loan markets.
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