Influences of point defects on electron transport of two-dimensional gep semiconductor device.

The quantum transport properties of defective two-dimensional (2D) GeP semiconductor nanodevice consisting of typical point defects, such as antisite defect, substitutional defect, and Schottky defect, have been studied by using density functional theory combined with non-equilibrium Green's function calculation. The antisite defect has indistinctive influences on electron transport. However, both substitutional and Schottky defect have introduced promising defect state at the Fermi level, indicating the possibility of improvement on the carrier transport. Our quantitative quantum transport calculations ofI-Vbbehavior have revealed that the electrical characters are enhanced. Moreover, the P atom vacancy could induce significant negative differential resistance phenomenon, and the physical mechanism is unveiled by detailed analysis. The transfer characteristic properties could be prominently improved by substitutional defect and vacancy defect. Most importantly, we have proposed a computational design of GeP-based electronic device with improved electrical performance by introducing vacancy defect. Our findings could be helpful to the practical application of novel 2D GeP semiconductor nanodevice in future.

Simulation of the nonlinear Kerr and Raman effect with a parallel local time-stepping DGTD solver.

In this paper, an efficient discontinuous Galerkin time-domain (DGTD) method is proposed to solve Maxwell's equations for nonlinear Kerr or Raman media. Based on our previous work, an arbitrary high-order derivatives DGTD method with a local time-stepping scheme is introduced for simulating dynamic optical responses in nonlinear dispersive media such that the nonlinear effects do not impose constraints on the stability conditions for linear subdomains. Therefore, the scheme enables the simulations in the nonlinear and linear media regions with independent time-stepping increments, which greatly improves the efficiency of the time-domain analysis. Moreover, by applying an iteration solution scheme, the proposed method preserves the intrinsic local features, which is favorable for the realization of highly parallelized algorithms. Numerical examples demonstrate the accuracy and the efficiency of our proposed method. We believe the proposed method provides an effective tool for numerical analysis of nonlinear optical phenomena.

Design and Analysis of a Hybrid-Type RF MEMS Phase Detector in X-Band.

In this paper, we have designed, analyzed, and characterized a hybrid-type MEMS device for X-band phase shift measurement. The signal related to a phase shift of the inputs is fractionally in-line coupled by a MEMS beam and delivered to a thermoelectric power sensor, where the phase is ultimately converted into DC voltage output. With the hybrid of the MEMS beam and the thermoelectric power sensor, both in-line detection process and phase-DC voltage conversion is reserved, which is a benefit for large power capacity, good linearity property, and high-level integration density. In order to get a deep insight into the physical mechanisms involved in the phase detection process, a comprehensive analysis model is presented. The beam is modeled as a precise RLC circuit component, where the capacitance is related to the input power. The fabrication is compatible with GaAs monolithic microwave integrated circuit (MMIC) technology. Experimental results show that return loss is smaller than -11.3 dB and isolation is better than -9.3 dB over X-band. Phase shift detection from 0 to 180 degrees is verified for a large power range of 200-1600 mW (23-32 dBm). The perfect linearity property of the phase-detection sensitivity is demonstrated in the same power range. Low intermodulation distortion is also confirmed through measurement. It is revealed from the comparison between this work and other published results in the literature that this presented hybrid-type structure shows superiorities in both power handling ability and phase-detection linearity. It can be adopted in medium power signal applications with a high level of integration.

Efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitor versus chemotherapy for advanced lung cancer: A meta-analysis.

BACKGROUND: This meta-analysis was performed to compare efficacy and tolerability between antiprogrammed cell death (PD-1)/programmed cell death-ligand-1 (PD-L1) + anticytotoxic T-lymphocyte-associated protein-4 (CTLA-4) treatment and chemotherapy in advanced lung cancer. METHODS: Cochrane Library, Embase, and PubMed databases were searched for potential articles. The fixed-effect model or random-effect model was adopted for pooled analysis based on the I2 and P-value. RESULTS: Six articles with 1338 patients were identified and subjected to meta-analysis. Compared with chemotherapy, anti-PD-1/PD-L1 + anti-CTLA-4 treatment could significantly improve the overall survival (hazard ratio [HR] = 0.78, 95%confidence interval [CI]: 0.71-0.84, P = .21) and progression-free survival (HR = 0.77, 95%CI: 0.71-0.83, P = .30) of advanced lung cancer patients. Moreover, there was no obvious difference in the incidence of 3 to 4 adverse events (AEs) serious adverse reactions (HR = 1.35, 95%CI: 0.66-2.74, P < .00001) between the 2 treatment groups, but the incidence rates of AEs leading to discontinuation (HR = 2.56, 95%CI: 1.53-4.30, P < .00001) and AEs leading to death (HR = 2.10, 95%CI: 1.21-3.63, P = .20) were higher. Furthermore, no remarkable differences in objective response rate (HR = 1.31, 95%CI: 0.97-1.77, P = .02) were observed between the 2 groups. CONCLUSION: Our meta-analysis revealed that PD-1/PD-L1 inhibitors plus CTLA-4 inhibitor could markedly improve the endpoint outcomes of patients compared with chemotherapy alone, and did not significantly increase the serious adverse reactions. Thus, it can serve as a new treatment strategy for advanced lung cancer.

Runt-related transcription factor 2 influences cell adhesion-mediated drug resistance and cell proliferation in B-cell non-Hodgkin's lymphoma and multiple myeloma.

Several lines of evidence show that RUNX2 as a transcription factor is closely involved in carcinogenesis in a variety of human cancers. Cell adhesion-mediated drug resistance (CAM-DR) is an important part of the mechanism underlying drug resistance in hematological tumors. In this study, we investigated the biological function of RUNX2 in B-cell Non-Hodgkin's lymphoma (B-NHL) and multiple myeloma (MM). We assessed the expression of RUNX2 in suspension and adhesion model by western blot in B-NHL and MM. Adhesion assay, flow cytometry and CCK-8 were utilized to examine the role and mechanism of RUNX2 in CAM-DR and proliferation in B-NHL and MM. RUNX2 was highly expressed in adherent B-NHL and MM cells compared to suspension cells, and knockdown the expression of RUNX2 could reverse CAM-DR. Besides, RUNX2 could promote the proliferation of B-NHL and MM cells. Furthermore, RUNX2 participated the process of CAM-DR and proliferation by regulating the AKT/GSK-3ß pathway. Developing RUNX2 inhibitor may be a possible strategy for drug resistance.

C­type natriuretic peptide prevents angiotensin II­induced atrial connexin 40 and 43 dysregulation by activating AMP­activated kinase signaling.

C­type natriuretic peptide (CNP), from the family of natriuretic peptides (NPs), has been shown to induce antihypertrophic and antifibrotic effects in cardiomyocytes. However, the roles of CNP in the atrial dysregulation of connexin (Cx)40 and Cx43 remain to be elucidated. The present study aimed to investigate the effects of CNP on angiotensin (Ang) II­induced Cx40 and Cx43 dysregulation in isolated perfused beating rat left atria. A rat isolated perfused beating atrial model was used and the protein levels were determined via western blotting. Ang II significantly upregulated NF­κB, activator protein­1, transforming growth factor­ß1 (TGF­ß1), collagen I and matrix metalloproteinase 2, leading to atrial fibrosis, and downregulated expression of Cx40 and Cx43. The changes in Cx40 and Cx43 induced by Ang II were abolished by CNP through upregulation of phosphorylated AMP­activated kinase a1 (AMPK) and downregulation of TGF­ß1. The effects of CNP on AMPK and TGF­ß1 levels were inhibited by KT5823 and pertussis toxin, inhibitors of protein kinase G (PKG) and NP receptor type C (NPR­C), respectively. Thus, CNP can prevent Ang II­induced dysregulation of Cx40 and Cx43 through activation of AMPK via the CNP­PKG and CNP­NPR­C pathways in isolated beating rat atria. The present findings suggested that CNP may be therapeutically useful for clinical conditions involving cardiac dysregulation of Cx expression­related diseases.

Correction to: Sam68 Promotes Invasion, Migration, and Proliferation of Fibroblast-like Synoviocytes by Enhancing the NF-κB/P65 Pathway in Rheumatoid Arthritis.

Unfortunately the author name, Rongqing Qin, was wrongly spelt as Rongqin Qin in the original version. It has been updated and the complete corrected author group is given below.

Runx2 was Correlated with Neurite Outgrowth and Schwann Cell Differentiation, Migration After Sciatic Nerve Crush.

Runx2, also known as Cbfa1, is a multifunctional transcription factor essential for osteoblast differentiation. It also plays major roles in chondrocyte maturation, mesenchymal stem cell differentiation, cleidocranial dysplasia, and the growth and metastasis of tumors. The present study was performed to investigate the functions of Runx2 in the differentiation and migration of Schwann cells and outgrowth of neurites after peripheral nervous system injury. In a model of sciatic nerve crush (SNC) injury, we found a gradual increase in the expression of Runx2, which reached a peak after 1 week. Immunofluorescence revealed increased expression of Runx2 in Schwann cells and axons after SNC injury. Runx2 and Oct-6 expression trends were consistent with each other in western blotting, and colocalization of Runx2 and Oct-6 was observed in immunofluorescence. In vitro, Runx2 promoted Schwann cell differentiation by activation of the Akt-GSK3ß signaling pathway. In addition, Runx2 promoted the migration of Schwann cells and outgrowth of neurites. These findings suggest that Runx2 may be involved in neurite outgrowth and Schwann cell differentiation and migration after sciatic nerve injury.

Sam68 Promotes Invasion, Migration, and Proliferation of Fibroblast-like Synoviocytes by Enhancing the NF-κB/P65 Pathway in Rheumatoid Arthritis.

Src-associated substrate during mitosis of 68 KDa (Sam68), also known as KH domain containing, RNA binding, signal transduction associated 1 (KHDRBS1), is the prototypic member of the signal transduction activator of RNA (STAR) family of RNA-binding proteins. Previous studies have indicated that Sam68 regulates nuclear transcription factor kappa B (NF-κB) to mediate inflammation. In this study, we analyzed the effect and possible mechanisms of Sam68 in rheumatoid arthritis (RA). By western blot analysis and immunohistochemistry, we found that the expression of Sam68 in synovial tissue of RA patients was increased compared with the control group. Immunoflourescent staining demonstrated that Sam68 co-localized with fibroblast-like synoviocytes (FLS) of RA patients. Additionally, the expression of Sam68 in FLS was increased by tumor necrosis factor (TNF)-α stimulation, in a time-dependent manner. Upon TNF-α treatment, Sam68 translocated from the cytoplasm to the nucleus where it interacted with the p65 subunit of NF-κB, as examined by immunoprecipitation and immunofluorescent staining assay. Furthermore, inhibiting the expression of Sam68 by siRNA significantly suppressed the TNF-α-induced expression of interleukin (IL)-6, and matrix metalloproteinase (MMP)-1, reduced the proliferation, migration, and invasion, and markedly decreased the phosphorylation of P65 and IκBα in FLS. Collectively, our findings suggested that Sam68 contributed to the production of inflammatory cytokines, proliferation, migration, and invasion of RA FLS through the NF-κB P65 signal transduction pathway and underscored the importance of Sam68 in the inflammation process of RA.

Up-Regulation of Cdc37 Contributes to Schwann Cell Proliferation and Migration After Sciatic Nerve Crush.

Cell division cycle protein 37 (Cdc37), a molecular chaperone takes part in a series of cellular processes including cell signal transduction, cell cycle progression, cell proliferation, cell motility, oncogenesis and malignant progression. It can not only recruit immature protein kinases to HSP90 but also work alone. Cdc37 was reported to be associated with neurogenesis, neurite outgrowth, axon guidance and myelination. However, the roles of Cdc37 on Schwann cells (SC) after peripheral nerve injury (PNI) remain unknown. In this study, we found that the expression of Cdc37 increased and reached the peak at 1 week after sciatic nerve crush (SNC), which was consistent with that of proliferation cell nuclear antigen. Immunofluorescence verified that Cdc37 co-localized with SC in vivo and in vitro. Intriguingly, Cdc37 protein level was potentiated in the model of TNF-α-induced SC proliferation. Moreover, we found that Cdc37 silencing impaired proliferation of SC in vitro. Moreover, Cdc37 suppression attenuated kinase signaling pathways of Raf-ERK and PI3K/AKT which are crucial cell signaling for SC proliferation. Finally, we found that Cdc37 silencing inhibited SC migration in vitro. In conclusion, we demonstrated that the way Cdc37 contributed to SC proliferation is likely via activating kinase signaling pathways of Raf-ERK and PI3K/AKT, and CDC37 was also involved in SC migration after SNC.

Expression of TRIM28 correlates with proliferation and Bortezomib-induced apoptosis in B-cell non-Hodgkin lymphoma.

Tripartite motif containing 28 (TRIM28) as a transcriptional co-repressor has been reported playing a role in regulating DNA damage response (DDR), cell differentiation, immune response, and tumorigenesis. The present study was performed to explore the biological function and clinical significance of TRIM28 in B-cell non-Hodgkin lymphoma (B-NHL). Results of the study displayed that high expression of TRIM28 was positively associated with the poorer survival of B-NHL patients as an independent prognostic factor. In addition, TRIM28 could promote the B-NHL cells proliferation through modulating cell cycle progression. The change of cyclinA, P21, and PCNA expression after TRIM28 expression modified further illustrated the mechanism in which TRIM28 participated in cell proliferation progression. Moreover, inhibition TRIM28 expression in B-NHL cells enhanced the sensibility to Bortezomib by regulating p53-mediated apoptosis pathway. Taken together, the present study showed that TRIM28 functions as a tumor promoter in B-NHL and may be a novel target for drug resistance to Bortezomib.

Increased Circulating Cathepsin K in Patients with Chronic Heart Failure.

Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the "lowLVEF" group) and the 90 patients showing LVEF values ≥ 40% (the "highLVEF" group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = -0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84-0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF.

MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria.

Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways are pivotal and intensively studied signaling pathways in hypoxic conditions. However, the roles of MAPK and PI3K in the regulation of hypoxia-induced atrial natriuretic peptide (ANP) secretion are not well understood. The purpose of the present study was to investigate the mechanism by which the MAPK/ERK (extracellular signal-regulated kinase) and PI3K signaling pathways regulate the acute hypoxia-induced ANP secretion in isolated beating rabbit atria. An acute hypoxic perfused beating rabbit atrial model was used. The ANP levels in the atrial perfusates were measured by radioimmunoassay, and the hypoxia-inducible factor-1α (HIF-1α) mRNA and protein levels in the atrial tissue were determined by RT-PCR and Western blot. Acute hypoxia significantly increased ANP secretion and HIF-1α mRNA and protein levels. Hypoxia-induced ANP secretion was markedly attenuated by the HIF-1α inhibitors, rotenone (0.5µmol/L) and CAY10585 (10µmol/L), concomitantly with downregulation of the hypoxia-induced HIF-1α mRNA and protein levels. PD098059 (30µmol/L) and LY294002 (30µmol/L), inhibitors of MAPK and PI3K, markedly abolished the hypoxia-induced ANP secretion and atrial HIF-1α mRNA and protein levels. The hypoxia-suppressed atrial dynamics were significantly attenuated by PD098059 and LY294002. Acute hypoxia in isolated perfused beating rabbit atria, markedly increased ANP secretion through HIF-1α upregulation, which was regulated by the MAPK/ERK and PI3K pathways. ANP appears to be part of the protective program regulated by HIF-1α in the response to acute hypoxic conditions.

Ouabain stimulates atrial natriuretic peptide secretion via the endothelin-1/ET(B) receptor-mediated pathway in beating rabbit atria.

AIMS: Ouabain has been reported to increase the secretion of atrial natriuretic peptide (ANP) in vitro. However, the mechanism by which ouabain increases ANP secretion is not well known. Therefore, the purpose of the present study was to investigate the underlying mechanism of ouabain-stimulated ANP secretion. MAIN METHODS: A perfused beating rabbit atrial model was used. The ANP and ET-1 levels in the atrial perfusates were measured by radioimmunoassays. KEY FINDINGS: Ouabain (1.0, 3.0 and 6.0 µmol/L) significantly increased atrial ANP secretion in a dose-dependent manner, while the endothelin (ET)-1 levels were increased by the higher doses (3.0 and 6.0 µmol/L) of ouabain. Ouabain-increased atrial ET-1 release was blocked by PD98059 (30.0 µmol/L), an inhibitor of mitogen-activated protein kinase (MAPK). Nifedipine (1.0 µmol/L), an inhibitor of L-type Ca(2+) channels, completely abolished ouabain-increased ANP secretion without changing the ouabain-induced atrial dynamics. KB-R7943 (3.0 µmol/L), an inhibitor of Na(+)-Ca(2+) exchangers, completely blocked the effects of ouabain-increased atrial dynamics, but did not modulate ouabain-increased ANP secretion. ET-1 significantly stimulated atrial ANP release in a dose-dependent manner. The effects of ET-1 and ouabain on ANP secretion were completely blocked by BQ788 (0.3 µmol/L), an inhibitor of ET-1 type B (ET(B)) receptors, but not by BQ123 (0.3 µM), an inhibitor of ET-1 type A receptors. Ouabain-increased atrial ANP secretion was blocked by PD98059 and indomethacin (30.0 µmol/L), an inhibitor of cyclooxygenase. SIGNIFICANCE: Ouabain significantly stimulated atrial ANP secretion via an ET-1-ET(B) receptor-mediated pathway involving MAPK signaling pathway activation and prostaglandin formation.

The ethical Kampo formulation Sho-seiryu-to (TJ-19) prevents bleomycin-induced pulmonary fibrosis in rats.

The effects of Sho-seiryu-to (TJ-19), an ethical Kampo formulation, on bleomycin (BLM)-induced pulmonary fibrosis in rats was examined. Pulmonary fibrosis was induced by intratracheal instillation of a single dose of BLM (5 mg/kg). The TJ-19 used consisted of at least 21 constituents, as determined by three-dimensional HPLC analysis, and was administered orally twice a day at a dose of 1.5 g/kg until the end of the study period. Changes in general appearance and body weight were monitored. Twenty-eight days after BLM instillation, the animals were sacrificed and the study parameters were measured. TJ-19 attenuated the loss in body weight, increase in lung/body weight ratio and concentration of hydroxyproline and malondialdehyde in the lung tissues induced by BLM administration. TJ-19 also prevented BLM-induced fibrotic changes in the lung histology. These protective effects of TJ-19 were observed when administration was started 1 week before and simultaneously with the instillation of BLM. These results suggest that TJ-19 has prophylactic potential against BLM-induced pulmonary fibrosis, and may therefore be a promising drug candidate and medicinal resource for preventing BLM-induced and idiopathic pulmonary fibrosis.