The TET (ten-eleven translocation) family of α-ketoglutarate (α-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), ...5-formylcytosine and 5-carboxylcytosine, leading to eventual DNA demethylation. The TET2 gene is a bona fide tumor suppressor frequently mutated in leukemia, and TET enzyme activity is inhibited in IDH1/2-mutated tumors by the oncometabolite 2-hydroxyglutarate, an antagonist of α-KG, linking 5mC oxidation to cancer development. We report here that the levels of 5hmC are dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers when compared with the matched surrounding normal tissues. Associated with the 5hmC decrease is the substantial reduction of the expression of all three TET genes, revealing a possible mechanism for the reduced 5hmC in cancer cells. The decrease of 5hmC was also observed during tumor development in different genetically engineered mouse models. Together, our results identify 5hmC as a biomarker whose decrease is broadly and tightly associated with tumor development.
The Nonlinear Output Frequency Response Functions (NOFRFs) are an extension of the well-known Frequency Response Function (FRF) of linear systems to the nonlinear case and have recently been applied ...by many researchers to resolve different engineering problems. However, there exist several issues with current methods that can be used for the evaluation of the NOFRFs of practical systems. These include the difficulty and lack of an effective approach of accurately evaluating the NOFRFs for a general class of nonlinear systems. In the present study, a new concept known as the Generalized Associated Linear Equations (GALEs) is introduced to develop a novel approach to systematically address these problems. By using the GALEs, the NOFRFs of the NARX (Nonlinear Auto Regressive with eXegenous input) model or NDE (Nonlinear Differential Equation) model of nonlinear systems can be accurately evaluated by simply dealing with the solutions to a series of linear difference or differential equations. This can significantly facilitate the NOFRFs based nonlinear system analyses and associated practical applications. Two experimental studies including monitoring fatigue damage of train wheels and inspecting wearing conditions of cutting tools, respectively, demonstrate the significance and potential applications of the new GALEs based NOFRFs evaluation in railway and manufacturing systems’ condition monitoring.
The aim of this study is to determine whether PAQR3, a protein specifically localized in the Golgi apparatus, is associated with tumor progression, metastasis and survival of human patients with ...gastric cancer.
PAQR3 expression status was investigated in a large panel of gastric cancer (n = 300) and their corresponding para-cancerous histological normal tissues (PCHNT) at both mRNA and protein levels. The correlation of PAQR3 expression levels with clinical features such as metastasis and prognosis was analyzed. The effect of PAQR3 on the growth and migration of gastric cancer cells was also determined.
PAQR3 was frequently down-regulated in gastric cancer samples compared with PCHNT at both mRNA and protein levels (both P < 0.0001). The expression level of PAQR3 was negatively correlated with Helicobacter pylori infection (P < 0.0001), tumor size (P < 0.0001), tumor stage (P < 0.0001), venous and lymphatic invasion (P < 0.0001), distant and nodal metastasis (P < 0.0001), and patient survival (P < 0.0001). Down-regulation of PAQR3 was highly correlated with increased epithelial–mesenchymal transition (EMT) in gastric cancer samples. In addition, PAQR3 overexpression was able to negatively modulate cell proliferation, migration and EMT of gastric cancer cells.
PAQR3 is markedly down-regulated in human gastric cancers. PAQR3 expression level is closely associated with the progression and metastasis of gastric cancers. PAQR3 is also a new genetic signature that can predict the prognosis of the patients with gastric cancer.
In this article, we propose a novel switching-table-based direct torque control (ST-DTC) method to eliminate the current harmonics in dual-three-phase permanent-magnet synchronous machines due to the ...back electromotive force (back EMF) harmonics and voltage vector selection. By employing a novel space voltage vector selection strategy and the optimal action time for different groups of vectors, a novel ST-DTC method is developed. Furthermore, in order to implement standard pulsewidth modulation (PWM) switching sequence, a centralization PWM method for 36 voltage vectors is introduced. The proposed method can effectively reduce the phase current harmonics caused by both back EMF distortion and voltage vector selection, and still reserve the advantages of the conventional ST-DTC, such as fast torque response and simple structure. Its effectiveness is verified by simulations and experiments.
This article investigates the torque characteristics of a switched flux hybrid magnet memory machine (SF-HMMM) by employing a coupled solution combining a quasi-linear hysteresis model (QLHM) of low ...coercive force (LCF) magnet and frozen-permeability method (FPM). This provides an in-depth understanding of the torque production of SF-HMMM. The QLHM is utilized to characterize the repetitive remagnetizing/demagnetizing behaviors of LCF permanent magnets (PMs), while the FPM is employed to separate and quantify the torque contributions due to two sets of PMs and armature windings. The machine topology and analysis methodology are described, respectively. The torque segregation results accounting for magnetization state variation are analyzed by the proposed coupled solution. The influence of the LCF PM property on the torque segregation result is investigated to facilitate the establishment of general design guidelines. Finally, the prototype is tested to experimentally validate the theoretical analysis.
Objective
Multiple trials have demonstrated the metabolic effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors in patients regardless of diabetes status, and recent trials have been conducted ...on the combined sodium/glucose cotransporter 1 and sodium/glucose cotransporter 2 (SGLT1/SGLT2) inhibitors. Therefore, a meta‐analysis was conducted to investigate the weight reduction effects and dose‐response relationship of SGLT inhibitors and to assess the relative efficacy of SGLT1/SGLT2 inhibitors.
Methods
Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched on November 21, 2020, for articles published from January 1, 2000, up to November 21, 2020.
Results
In total, 116 randomized‐controlled trials were included, with a combined cohort of 98,497 patients. Overall, patients had a mean weight reduction of −1.79 kg (95% CI: −1.93 to −1.66, p < 0.001) compared with placebo. This effect was observed across diabetes status, duration of follow‐up, various comorbidities, and all SGLT drug types. Mean BMI changes were −0.71 kg/m2 (95% CI: −0.94 to −0.47, p < 0.001) compared with placebo. Canagliflozin, empagliflozin, sotagliflozin, and licogliflozin showed a dose‐response relationship for mean weight change. Compared with SGLT2 inhibitors, SGLT1/SGLT2 inhibitors had a significantly larger reduction in weight.
Conclusions
SGLT inhibitors demonstrated weight reduction benefits in this meta‐analysis. Further studies are needed to clarify their role in weight management.
The switching-table-based direct torque control (ST-DTC) has the merits of simple structure, easy implementation, and fast response, but suffers from large torque ripples. Previous literature, i.e. ...the classical DTC, can achieve torque ripple reduction in the high-speed region but has a limited capability for torque ripple reduction in the low-speed region. In this paper, the issue of torque ripple reduction in the full-speed region, i.e. both the low-speed and high-speed regions, is addressed. The effects of each group in all possible six groups of virtual voltage vectors (VVs) on torque variation are firstly investigated. Then, a multiple VV DTC based on only three groups of VVs is proposed and the corresponding optimal selections of three VV groups and level of torque regulator are presented. The proposed DTC not only can effectively reduce torque ripples in the full speed region, but also is simple and easy to implement. The superiority of the proposed DTC with optimal selections of VVs and level of torque regulator are verified by experimental results.
Summary
E‐cadherin is a 120‐KD transmembrane calcium‐dependent cell adhesion protein that has been demonstrated drownregulated in a large amount of invasive tumors. However, its effect on the ...prognosis of esophageal cancer (EC) remains controversial. All the relevant English articles that reported survival data or clinicopathological parameters were enrolled in this meta‐analysis. A total of 24 studies, including 2691 cases, were included in this study. Twelve studies containing 1669 cases were enrolled to synthesize with hazard ratio (HR) and its 95% confidence interval (CI). The pooled HR for all 12 studies enrolled in this meta‐analysis was 1.33 (95% CI 1.16–1.52; z = 3.99, P = 0.00). When the study measured by enzyme‐linked immunosorbent assay is excluded, the pooled HR‐evaluated E‐cadherin to reduce the expression in EC, and in esophageal squamous cell carcinoma was 1.39 (95% CI 1.22–1.58; z = 5.08, P = 0.00) and 1.38 (95% CI 1.21–1.56; z = 4.87, P = 0.00), respectively. The risk of reduced E‐cadherin expression on poor differentiation degree was 1.636 (95% CI 1.33–2.02). The pooled odds ratio of reduced E‐cadherin expression on deeper tumor invasion, lymph node metastasis, and higher clinical stage were 2.63 (95% CI 1.75–3.94), 1.77 (95% CI 1.06 −2.97), and 3.39 (95% CI 1.85–6.23). Reduced E‐cadherin expression detected by immunohistochemistry could be a valid prognostic marker in patients with EC, especially in patients with esophageal squamous cell carcinoma. Reduced E‐cadherin expression is significantly associated with poorer differentiation degree.
Transplant recipients have a higher risk of SARS-CoV-2 infection owing to the use of immunosuppressive drugs like tacrolimus (FK506). FK506 and nirmatrelvir (NMV) (an anti-SARS-CoV-2 drug) are ...metabolized by cytochrome P450 3A4 and may have potential drug-drug interactions. It is important to determine the effect of NMV on FK506 concentrations.
Following protein precipitation from blood, FK506 and its internal standard (FK506-13C,2d4) were detected by ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). Total 22 blood samples (valley concentrations) from two coronavirus disease 2019 (COVID-19) patients were collected and analyzed for FK506 concentrations.
Blood levels of FK506 (0.5-100 ng/mL) showed good linearity. The UHPLC-MS/MS method was validated with intra- and inter-batch accuracies of 104.55-107.85%, and 99.52-108.01%, respectively, and precisions of < 15%. Mean blood FK506 concentration was 12.01 ng/mL (range, 3.15-33.1 ng/mL). Five-day co-administration with NMV increased the FK506 concentrations from 3.15 ng/mL to 33.1 ng/mL, returning to 3.36 ng/mL after a 9-day-washout.
We developed a simple quantification method for therapeutic drug monitoring of FK506 in patients with COVID-19 using UHPLC-MS/MS with protein precipitation. We found that NMV increased FK506 blood concentration 10-fold. Therefore, it is necessary to re-consider co-administration of FK506 with NMV.
In this paper, the problem of non-negative edge consensus of undirected networked linear time-invariant systems is addressed by associating each edge of the network with a state variable, for which a ...distributed algorithm is constructed. Sufficient conditions referring only to the number of edges are derived for non-negative edge consensus of the networked systems. Subsequently, the linear programming method and a low-gain feedback technique are introduced to simplify the design of the feedback gain matrix for achieving the non-negative edge consensus. It is found that the low-gain feedback technique has a good effect on the non-negative edge consensus of the networked systems subject to input saturation. Numerical simulations are presented to verify the effectiveness of the theoretical results.
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