Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 ...upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when cocultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness. Pharmacologic inhibition of netrin-1 with a netrin-1-mAb (Net1-mAb) abrogated the CAF-mediated increase of cancer stemness both in coculture experiments and in mice. Net-1-mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as IL6. Together these data demonstrate that netrin-1 is upregulated not only in cancer cells but also in cancer-associated stromal cells. In addition to its direct activity on cancer cells, inhibition of netrin-1 may reduce proneoplastic CAF-cancer cell cross-talk, thus inhibiting cancer plasticity. SIGNIFICANCE: Netrin-1, a navigation cue during embryonic development, is upregulated in cancer-associated fibroblasts and regulates cancer cell stemness.
This study tested the hypothesis that intra-coronary transfusion of circulation-derived autologous CD34+ cells can improve ischemia-related left ventricular dysfunction in patients with severe ...diffuse coronary artery disease refractory to medication and unsuitable for coronary intervention.
A prospective, randomized, double-blinded phase I clinical trial.
Tertiary care center.
Thirty-eight patients with severe diffuse coronary artery disease were randomized into group 1 and group 2 receiving CD34+ cell infusion with dosages of 1.0 x 107 and 3.0 x 107 cells/vessel, respectively, after subcutaneous G-CSF injection (5 μg/kg twice a day for 4 d).
Cardiac catheterization and intra-coronary administration of CD34+ cells.
This clinical trial was to test effectiveness and safety of these two different dosages of CD34+ cells in the setting of severe diffuse coronary artery disease. Blood samples were collected for endothelial progenitor cell culture before and after granulocyte colony-stimulating factor injection for matrigel-assay and comparison of levels of soluble angiogenesis factors (vascular endothelial growth factor, epithelial growth factor, hepatocyte growth factor, angiopoietin-1, and transforming growth factor-β). Procedural safety was 100% with all patients uneventfully discharged. The numbers of endothelial progenitor cells in blood samples from coronary sinus after transfusion were higher than those in circulation, and the circulatory level was higher after granulocyte colony-stimulating factor treatment (all p < 0.001). Cardiac MRI and three-dimensional echocardiography at 6 month and angiographic follow-up at 9 month showed improvement in left ventricular ejection fraction (p < 0.001) and consistent increase in neovascularization (p < 0.001), respectively, in both groups. Despite good correlation in angiogenesis between 9-month angiography and matrigel-assay (p < 0.001), no significant correlation was noted in of soluble angiogenesis factor levels. Angina and heart failure were improved in both groups at 12-month follow-up (all p < 0.001). The survival rate at 18.5-month follow-up was 94.7% (n = 36).
CD34+ cell therapy was safe and efficacious in improving heart function for patients with severe diffuse coronary artery disease unsuitable for coronary intervention and with poor response to pharmacotherapy.
This paper proposes an optimal ensemble method for one-day-ahead hourly wind power forecasting. The ensemble forecasting method is the most common method of meteorological forecasting. Several ...different forecasting models are combined to increase forecasting accuracy. The proposed optimal ensemble method has three stages. The first stage uses the k-means method to classify wind power generation data into five distinct categories. In the second stage, five single prediction models, including a K-nearest neighbors (KNN) model, a recurrent neural network (RNN) model, a long short-term memory (LSTM) model, a support vector regression (SVR) model, and a random forest regression (RFR) model, are used to determine five categories of wind power data to generate a preliminary forecast. The final stage uses an optimal ensemble forecasting method for one-day-ahead hourly forecasting. This stage uses swarm-based intelligence (SBI) algorithms, including the particle swarm optimization (PSO), the salp swarm algorithm (SSA) and the whale optimization algorithm (WOA) to optimize the weight distribution for each single model. The final predicted value is the weighted sum of the integral for each individual model. The proposed method is applied to a 3.6 MW wind power generation system that is located in Changhua, Taiwan. The results show that the proposed optimal ensemble model gives more accurate forecasts than the single prediction models. When comparing to the other ensemble methods such as the least absolute shrinkage and selection operator (LASSO) and ridge regression methods, the proposed SBI algorithm also allows more accurate prediction.
This study presents a parameter estimation method that uses an enhanced gray wolf optimizer (EGWO) to optimize the parameters for a two-diode photovoltaic (PV) power generation system. The proposed ...method consists of three stages. The first stage converts seven parameters for the two-diode model into 17 parameters for different environmental conditions, which provides more precise parameter estimation for the PV model. A PV power generation model is then established to represent the nonlinear relationship between inputs and outputs. The second stage involves a parameter sensitivity analysis and uses the overall effect method to remove the parameters that have smaller effect on the output. The final stage uses an enhanced GWO that is associated with measurement data to optimally estimate the parameters that are selected in the second stage. When the parameters are estimated, the predicted value for the PV power output is calculated for specific values of solar irradiation and module temperature. The proposed method is verified on a 200 kWp PV power generation system. To confirm the feasibility of the proposed method, the parameter estimation before and after optimization are compared, and these results are compared with other optimization algorithms, as well as those for a single-diode PV model.
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•The risk of HBV reactivation for patients with lymphoma and resolved HBV infection varied.•High anti-HBc and low anti-HBs at baseline predicted high risk of HBV ...reactivation.•Quantification of baseline anti-HBc/anti-HBs may optimize preventive strategies.
Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation.
We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab–cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation.
HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio HR 8.48 and 4.52, respectively; p <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92–76.30; p <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15–5.05; p = 0.02).
Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients.
In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources.
Clinical trial number: NCT 00931229.
In this article, a new non-isolated interleaved DC–DC converter is proposed to provide a high voltage conversion ratio in renewable energy systems. The converter configuration is composed of a ...two-phase interleaved boost converter integrating a voltage-lift capacitor and three-winding coupled inductor-based voltage multiplier modules to achieve high step-up voltage conversion and reduce voltage stresses on the semiconductors (switches and diodes). The converter can achieve a high voltage conversion ratio when working at a proper duty ratio. The voltage stresses on the switches are significantly lower than the output voltage, which enables engineers to adopt low-voltage-rating MOSFETs with low on-state resistance. The switches can turn on under zero-current switching (ZCS) conditions because of the leakage inductor series reducing switching losses. Some diodes can naturally turn off under ZCS conditions to alleviate the reverse–recovery issue and to reduce reverse–recovery losses. The input current has small ripples due to the interleaved operation. The leakage inductor energy is recycled and voltage spikes on the switches are avoided. The proposed converter is suitable for applications in which high voltage gain, high efficiency and high power are required. The principle of operation, steady-state analysis and design considerations of the proposed converter are described in detail. In addition, a closed-loop controller is designed to reduce the effect of input voltage fluctuation and load change on the output voltage. Finally, a 1000 W laboratory prototype is built and tested. The theoretical analysis and the performance of the proposed converter were validated by the experimental results.
Abstract
Background
Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory ...distress syndrome (ARDS). Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Methods
We incubated SARS-CoV-2 with neutrophils in the presence or absence of platelets to observe NET formation. We further isolated extracellular vesicles from COVID-19 patients' sera (COVID-19-EVs) to examine their ability to induce NET formation.
Results
We demonstrated that antagonistic mAbs against anti-CLEC5A mAb and anti-TLR2 mAb can inhibit COVID-19-EVs-induced NET formation, and generated
clec5a
−/−
/tlr2
−/−
mice to confirm the critical roles of CLEC5A and TLR2 in SARS-CoV-2-induced lung inflammation in vivo. We found that virus-free extracellular COVID-19 EVs induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A) and TLR2. Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation was attenuated dramatically in
clec5a
−/−
/tlr2
−/−
mice.
Conclusions
This study demonstrates that SARS-CoV-2-activated platelets produce EVs to enhance thromboinflammation via CLEC5A and TLR2, and highlight the importance of CLEC5A and TLR2 as therapeutic targets to reduce the risk of ARDS in COVID-19 patients.
This article proposes a novel method to estimate the optimal parameters and power outputs for photovoltaic (PV) power generation. Accurate estimation for PV power generation allows efficient ...scheduling to meet the load demand and reduces the effect of uncertainty for a microgrid. The parameters that are provided by the PV manufacturer have a nonlinear relationship with power output and may vary with the aging of the PV cells. To allow finer and more accurate estimation for PV power output, the parameters of the single-diode <inline-formula><tex-math notation="LaTeX">R_{p}</tex-math></inline-formula> model are transformed into 13 parameters under various weather conditions. The principal component analysis (PCA) and an assessment index are used to delete the parameters that have little effect on the output. Using the actual input/output data, a hybrid charged system search (HCSS) algorithm is then used to estimate the optimal parameters. When the parameters are optimized, the estimation for PV power output can be produced as long as the inputs are given. The proposed method is tested on two different PV power generation systems. To verify the performance of the proposed method, the results are compared with the results for the application of the traditional differential evolution (DE) and particle swarm optimization (PSO) methods.
•Developed CMFs to address the safety effects of roadway lighting photometric measures.•Addressed the correlation between the mean and standard deviation of illuminance.•Included ratio-based ...illuminance uniformity in the model.•Overcame the issue of underestimating the safety effects of average lighting level.•Developed CMFs that can be implemented in standard nighttime safety management.
Roadway lighting is used to ensure nighttime safety and security for multimodal road users. However, the absence of reliable quantitative analyses of the safety effects of roadway lighting photometric characteristics prevents accurate assessment of street lighting maintenance and retrofitting projects. This study aimed to investigate the relationship between nighttime crash risk and two critical photometric criteria, i.e., average lighting level and uniformity. To achieve this goal, high-resolution horizontal illuminance data were collected in Florida for 300 + center-miles from 2011 to 2014. Based on the data, a matched case-control study was conducted to address two major issues existing in previous studies: (1) the confounding effects of illuminance standard deviation on illuminance mean and (2) spatially-unrelated extreme values for ratio-based uniformity. By eliminating the confounding effects through a random matching strategy (one case, a segment with nighttime crashes, to one control, a segment without nighttime crashes at 1,046 strata), this study successfully isolated the negative effects of the standard deviation and developed more significant crash modification factors (CMFs) for average lighting levels: 0.679 for increasing the average lighting level from 0 fc, 0.5 fc to (0.5 fc, 1.0 fc and 0.581 for increasing the average lighting from 0 fc, 0.5 fc to higher than 1.0 fc. Additionally, a CMF of 1.391 for a max-min ratio greater than 10 was identified by controlling the segment length at a short uniform unit (1,200 ft). The developed CMFs overcame the underestimation issue in previous studies and are implementable in current street lighting design and safety management.
This study tested the hypothesis that therapy with double overexpression of miR‐19a‐3p and miR‐20a‐5p (miRDOE) to human inducible pluripotent stem cell–derived mesenchymal stem cells (iPS‐MSCs) was ...superior to iPS‐MSCs alone for preserving renal function in rat with pre‐existing chronic kidney disease (CKD), followed by ischaemia‐reperfusion (IR) injury. In vitro study demonstrated that the protein expressions of oxidative stress (NOX‐1/NOX‐2/NOX4/oxidized protein/p22phox), inflammatory downstream signalling (TLR2&4/MyD88/TRAF6/IKK‐ß/p‐NFκB/IL‐1ß/IL‐6/MMP‐9) and cell apoptosis/death signalling (cleaved caspase‐3/mitochondrial Bax/p‐ERKs/p‐JNK/p‐p38) at time‐points of 24‐hour/48‐hour cell cultures were significantly increased in p‐Cresol‐treated NRK‐52E cells than in the control that was significantly reversed by miR‐19a‐3p‐transfected iPS‐MSC (all P < .001). Animals were categorized into group 1 (sham‐operated control), group 2 (CKD‐IR), group 3 (CKD‐IR + oligo‐miRDOE of iPS‐MSCs/6.0 ×105/intra‐renal artery transfusion/3 hours after IR procedure), group 4 (CKD‐IR + iPS‐MSCs) and group 5 (CKD‐IR + miRDOE of iPS‐MSCs/6.0 ×105/intra‐renal artery transfusion/3 hour after IR procedure). By day 35, the creatinine/BUN levels were lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3 and 4 (all P < .0001) but they showed no difference between the latter two groups. The protein expressions of oxidative stress, inflammatory downstream signalling and cell apoptosis/death signalling exhibited an identical pattern of creatinine level among the five groups (all P < .00001). Also, the microscopic findings demonstrated that the kidney injury score/fibrotic area/number of inflammatory cells (CD14+/CD68+) exhibited an identical pattern of creatine level (all P < .0001). The miRDOE of iPS‐MSCs was superior to iPS‐MSCs for preserving the residual kidney function and architecture in CKD‐IR rat.
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