The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein–coupled receptors

Communication between different signaling pathways enables cells to coordinate the responses to diverse environmental signals. Activation of the transmembrane growth factor precursors plays a critical role in this communication and often involves metalloprotease-mediated proteolysis. Stimulation of G protein–coupled receptors (GPCR) transactivates the EGF receptors (EGFRs), which occurs via a metalloprotease-dependent cleavage of heparin-binding EGF (HB-EGF). However, the metalloprotease mediating the transactivation remains elusive. We show that the integral membrane metalloprotease Kuzbanian (KUZ; ADAM10), which controls Notch signaling in Drosophila, stimulates GPCR transactivation of EGFR. Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors Src homology 2 domain–containing protein and Gab1 on the EGFR, and activation of Ras and Erk. In contrast, transfection of a protease domain–deleted KUZ, or blocking endogenous KUZ by morpholino antisense oligonucleotides, suppresses the transactivation. The effect of KUZ on shedding of HB-EGF and consequent transactivation of the EGFR depends on its metalloprotease activity. GPCR activation enhances the association of KUZ and its substrate HB-EGF with tetraspanin CD9. Thus, KUZ regulates the relay between the GPCR and EGFR signaling pathways

Deformable Object Tracking with Gated Fusion

The tracking-by-detection framework receives growing attentions through the integration with the Convolutional Neural Networks (CNNs). Existing tracking-by-detection based methods, however, fail to track objects with severe appearance variations. This is because the traditional convolutional operation is performed on fixed grids, and thus may not be able to find the correct response while the object is changing pose or under varying environmental conditions. In this paper, we propose a deformable convolution layer to enrich the target appearance representations in the tracking-by-detection framework. We aim to capture the target appearance variations via deformable convolution, which adaptively enhances its original features. In addition, we also propose a gated fusion scheme to control how the variations captured by the deformable convolution affect the original appearance. The enriched feature representation through deformable convolution facilitates the discrimination of the CNN classifier on the target object and background. Extensive experiments on the standard benchmarks show that the proposed tracker performs favorably against state-of-the-art methods

Pharmacokinetic Comparison of 20(R)- and 20(S)-Ginsenoside Rh1 and 20(R)- and 20(S)-Ginsenoside Rg3 in Rat Plasma following Oral Administration of Radix Ginseng Rubra and Sheng-Mai-San Extracts

Ginsenosides Rh1 and Rg3, as the main bioactive components from Ginseng, are effective for prevention and treatment of cardiovascular diseases. Sheng-Mai-San (SMS), a classical complex prescription of traditional Chinese medicines, is composed of Radix Ginseng Rubra, Fructus Schisandrae, and Radix Ophiopogonis. In this research, a sensitive and specific liquid chromatography-mass spectrometric method was developed and validated for stereoselective determination and pharmacokinetic studies of 20(R)- and 20(S)-ginsenoside Rh1 and 20(R)- and 20(S)-ginsenoside Rg3 epimers in rat plasma after oral administration of Radix Ginseng Rubra or SMS extracts. The main pharmacokinetic parameters including Tmax, Cmax, t1/2, and AUC were calculated by noncompartment model. Compared with Radix Ginseng Rubra, SMS could significantly increase the content of ginsenosides Rh1 and Rg3 in the decocting process. Ginsenosides Rh1 and Rg3 following SMS treatment displayed higher Cmax, AUC(0–t), and AUC0–∞ and longer t1/2 and tmax except for 20(R)-Rh1 in rat plasma. The results indicated SMS compound compatibility could influence the dissolution in vitro and the pharmacokinetic behaviors in vivo of ginsenosides Rh1 and Rg3, suggesting pharmacokinetic drug-drug interactions between ginsenosides Rh1 and Rg3 and other ingredients from Fructus Schisandrae and Radix Ophiopogonis. This study would provide valuable information for drug development and clinical application of SMS

Clinical study on the effect of remifentanil patient-controlled intravenous labor analgesia compared to patient-controlled epidural labor analgesia

Objectives: This study aims to investigate the safety and efficacy of remifentanil for patient-controlled intravenous labor analgesia as an alternative to the patient-controlled epidural labor analgesia. Material and methods: Out of 453 parturients who volunteered for labor analgesia and were selected as research objects, 407 completed the trial. They were divided into the research group (n = 148) and the control group (n = 259; patient-controlled epidural analgesia). In the research group, the first dose of remifentanil, the background dose and the patient-controlled analgesia (PCA) dose were 0.4 μg/kg, 0.04 μg/min and 0.4 μg/kg, respectively, with a lockout interval of 3 min. The control group was given epidural analgesia. The first dose and background dose were 6–8 mL, and PCA dose and the locking time of analgesia pump were 5 mL and 20 min, respectively. The following indexes of the two groups were observed and recorded: the analgesic and sedative effects on parturient, labor process, forceps delivery, cesarean section rate and adverse reactions, and maternal and neonatal conditions. Results:1. The onset time of analgesia in the research group was (0.97 ± 0.08) min, which was noticeably shorter than that in the control group ([15.74 ± 1.91] min), with a statistically significant difference (t = –93.979, p = 0.000).2. There was no significant difference in the labor process, forceps delivery, cesarean section rate and neonatal condition between the two groups (p > 0.05). Conclusions: Remifentanil patient-controlled intravenous labor analgesia has the advantage of rapid onset of labor analgesia. Although its analgesic effect is not as accurate and stable as epidural patient-controlled labor analgesia, it shows a high level of maternal and family satisfaction

Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.

BackgroundThis pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib.MethodsThe data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.ResultsGreater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.ConclusionsGreater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses

Experimental investigation on electrostatic monitoring technology for civil turbofan engine

This study analyzes the necessity, development, and principles of aero-engine electrostatic monitoring technology. An electrostatic sensor with specific size is assembled in the exhaust nozzle of an RB-211 turbofan engine located near the low-pressure turbine outlet, a stress checking procedure for safety is conducted. Two test program cycles are included in the whole experimental process. Electrostatic signal processing flow is presented, and feature parameters used for analysis are root-mean-square (RMS), activity level (AL), negative event rate (NER), positive event rate (PER), kurtosis, impulse factor, and absolute mean value. Thrust is used to parameterize the working conditions of the turbofan engine. Moreover, data fitting is conducted to determine the relations between feature and performance parameters. Accordingly, lubrication oil leakage fault and fuel-rich combustion condition are detected in two test run cycles, which result in the appearance of abnormal signals. The AL, RMS, and absolute mean values exhibit similar trends with the change in thrust. A positive linear correlation is also observed between the AL and the thrust in the varying thrust test period. The method of blade-casing rubbing fault recognition is discussed. Experiment results show that the electrostatic sensor is very sensitive to large-sized charged particles in the exhaust emissions

Generation and characterization of β1,2-gluco-oligosaccharide probes fromBrucella abortuscyclic β-glucan and their recognition by C-type lectins of the immune system

The β1,2-glucans produced by bacteria are important in invasion, survival and immunomodulation in infected hosts be they mammals or plants. However, there has been a lack of information on proteins which recognize these molecules. This is partly due to the extremely limited availability of the sequence-defined oligosaccharides and derived probes for use in the study of their interactions. Here we have used the cyclic β1,2-glucan (CβG) of the bacterial pathogen Brucella abortus, after removal of succinyl side chains, to prepare linearized oligosaccharides which were used to generate microarrays. We describe optimized conditions for partial depolymerization of the cyclic glucan by acid hydrolysis and conversion of the β1,2-gluco-oligosaccharides, with degrees of polymerization 2-13, to neoglycolipids for the purpose of generating microarrays. By microarray analyses we show that the C-type lectin receptor DC-SIGNR, like the closely related DC-SIGN we investigated earlier, binds to the β1,2-gluco-oligosaccharides, as does the soluble immune effector serum mannose-binding protein. Exploratory studies with DC-SIGN are suggestive of the recognition also of the intact CβG by this receptor. These findings open the way to unravelling mechanisms of immunomodulation mediated by β1,2-glucans in mammalian systems

The correlation of retinal neurodegeneration and brain degeneration in patients with Alzheimer’s disease using optical coherence tomography angiography and MRI

IntroductionPathological changes in Alzheimer’s disease can cause retina and optic nerve degeneration. The retinal changes are correlated with cognitive function. This study aimed to explore the relationship of retinal differences with neuroimaging in patients with Alzheimer’s disease, analyze the association of cognitive function with retinal structure and vascular density, and identify potential additional biomarkers for early diagnosis of Alzheimer’s disease.MethodWe performed magnetic resonance imaging (MRI) scans and neuropsychological assessments in 28 patients with mild Alzheimer’s disease and 28 healthy controls. Retinal structure and vascular density were evaluated by optical coherence tomography angiography (OCTA). Furthermore, we analyzed the correlation between neuroimaging and OCTA parameters in patients with mild Alzheimer’s disease with adjustment for age, gender, years of education, and hypertension.ResultsIn patients with mild Alzheimer’s disease, OCTA-detected retinal parameters were not significantly correlated with MRI-detected neuroimaging parameters after Bonferroni correction for multiple testing. Under multivariable analysis controlled for age, gender, years of education, and hypertension, the S-Hemi (0–3) sector of macular thickness was significantly associated with Mini-cog (β = 0.583, P = 0.002) with Bonferroni-corrected threshold at P < 0.003.ConclusionOur findings suggested decreased macular thickness might be associated with cognitive function in mild AD patients. However, the differences in retinal parameters didn’t correspond to MRI-detected parameters in this study. Whether OCTA can be used as a new detection method mirroring MRI for evaluating the effect of neuronal degeneration in patients with mild Alzheimer’s disease still needs to be investigated by more rigorous and larger studies in the future

Engineering of betabellin-15d: A 64 residue beta sheet protein that forms long narrow multimeric fibrils

The betabellin target structure is a beta-sandwich protein consisting of two 32 residue beta-sheets packed against one another by interaction of their hydrophobic faces. The 32 residue chain of betabellin-15S (HSLTAKIpkLTFSIAphTYTCAV pkYTAKVSH, where p=DPro, k=DLys, and h=DHis) did not fold in water at pH 6.5. Air oxidation of betabellin-15S provided betabellin-15D, the 64 residue disulfide bridged two-chain molecule, which also remained unfolded in water at pH 6.5. By circular dichroic spectropolarimetry, the extent of beta structure observed for betabellin-15D increased with the pH and ionic strength of the solution and the betabellin-15D concentration. By electron microscopy, in 5.0 mM MOPS and 0.25 M NaCl at pH 6.9, betabellin-15D formed long narrow multimeric fibrils. A molecular model was constructed to show that the dimensions of these betabellin-15D fibrils are consistent with a single row of beta-sandwich molecules joined by multiple intersheet H-bonds

Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer

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