Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.

Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one kinase domain induces an active conformation in the other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3-5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a approximately 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition

STUDY ON THE ACCIDENTAL RUPTURE OF HOT LEG OR SURGE LINE IN SBO ACCIDENT

ABSTRACT The postulated total station blackout accident (SBO) of PWR NPP with 600 MWe in China is analyzed as the base case using SCDAP/RELAP5 code. Then the hot leg or surge line are assumed to rupture before the lower head of Reactor Pressure Vessel (RPV) ruptures, and the progressions are analyzed in detail comparing with the base case. The results sho

Classification between normal and tumor tissues based on the pair-wise gene expression ratio

BACKGROUND: Precise classification of cancer types is critically important for early cancer diagnosis and treatment. Numerous efforts have been made to use gene expression profiles to improve precision of tumor classification. However, reliable cancer-related signals are generally lacking. METHOD: Using recent datasets on colon and prostate cancer, a data transformation procedure from single gene expression to pair-wise gene expression ratio is proposed. Making use of the internal consistency of each expression profiling dataset this transformation improves the signal to noise ratio of the dataset and uncovers new relevant cancer-related signals (features). The efficiency in using the transformed dataset to perform normal/tumor classification was investigated using feature partitioning with informative features (gene annotation) as discriminating axes (single gene expression or pair-wise gene expression ratio). Classification results were compared to the original datasets for up to 10-feature model classifiers. RESULTS: 82 and 262 genes that have high correlation to tissue phenotype were selected from the colon and prostate datasets respectively. Remarkably, data transformation of the highly noisy expression data successfully led to lower the coefficient of variation (CV) for the within-class samples as well as improved the correlation with tissue phenotypes. The transformed dataset exhibited lower CV when compared to that of single gene expression. In the colon cancer set, the minimum CV decreased from 45.3% to 16.5%. In prostate cancer, comparable CV was achieved with and without transformation. This improvement in CV, coupled with the improved correlation between the pair-wise gene expression ratio and tissue phenotypes, yielded higher classification efficiency, especially with the colon dataset – from 87.1% to 93.5%. Over 90% of the top ten discriminating axes in both datasets showed significant improvement after data transformation. The high classification efficiency achieved suggested that there exist some cancer-related signals in the form of pair-wise gene expression ratio. CONCLUSION: The results from this study indicated that: 1) in the case when the pair-wise expression ratio transformation achieves lower CV and higher correlation to tissue phenotypes, a better classification of tissue type will follow. 2) the comparable classification accuracy achieved after data transformation suggested that pair-wise gene expression ratio between some pairs of genes can identify reliable markers for cancer

Assessing Air–Surface Exchange and Fate of Mercury in a Subtropical Forest Using a Novel Passive Exchange-Meter Device

Embargo until 01 April 2020acceptedVersio

Antioksidacijski kapacitet jetrenih proteina odojka i njihovih hidrolizata, te njihov učinak in vitro na inhibiciju steatoze

Non-alcoholic steatohepatitis is a potentially progressive hepatic disorder that can lead to end-stage liver disease and hepatocellular carcinoma. The inhibitory effects of proteins and hydrolysates from the liver of newborn piglets on hepatic steatosis in oleic acid-induced hepatocellular carcinoma (HepG2) cells were investigated in vitro. The extracted proteins from the liver of newborn piglets were hydrolysed with papain, pepsin, trypsin and Alcalase. Based on the comparison of different enzyme digestion conditions, a protein hydrolysis protocol was established to obtain hydrolysates with lipid-lowering effect. Trypsin-digested liver protein hydrolysate from newborn piglets exhibited strong antioxidant activity and good inhibitory effects against lipogenesis and cholesterol accumulation in HepG2 cells at the concentration of 150 μg/mL, with a triglyceride decrease of (43±3) % and cholesterol decrease of (31±5) %, compared with model group induced with 0.75 mM oleic acid. The addition of trypsin-digested liver protein hydrolysate from newborn piglets (300 μg/mL) decreased alanine aminotransferase and aspartate aminotransferase activities and increased superoxide dismutase activity. This study demonstrated that the trypsin-digested liver protein hydrolysate from newborn piglets has a potential preventive effect against non-alcoholic fatty liver disease in its early stage, and a potential use as the modulator of lipid overaccumulation in form of food supplements.Pozadina istraživanja. Nealkoholni steatohepatitis je progresivna bolest jetre koja može dovesti do terminalnog stadija bolesti i pojave hepatocelularnog karcinoma. Provedeno je ispitivanje in vitro učinka jetrenih proteina odojka i njihovih hidrolizata na inhibiciju steatoze u stanicama hepatocelularnog karcinoma induciranog oleinskom kiselinom (HepG2). Eksperimentalni pristup. Proteini su izdvojeni iz jetre odojaka i hidrolizirani pomoću papaina, pepsina, tripsina i alkalaze. Usporedbom različitih uvjeta enzimske razgradnje stvoren je protokol hidrolize proteina za dobivanje hidrolizata koji smanjuju količinu masnoća u krvi. Rezultati i zaključci. Hidrolizati jetrenih proteina odojka dobiveni pomoću 150 μg/mL tripsina imali su izražen antioksidacijski učinak i dobro svojstvo inhibicije lipogeneze i nakupljanja kolesterola u HepG2 stanicama, te su smanjili udjel triglicerida za (43±3) % i kolesterola za (31±5) %, u usporedbi s kontrolnom skupinom stanica karcinoma induciranog pomoću 0,75 mM oleinske kiseline. Dodatkom 300 μg/mL hidrolizata proteina dobivenog pomoću tripsina smanjila se aktivnost alanin aminotransferaze i aspartat aminotransferaze, a povećala aktivnost superoksid dismutaze. Novina i znanstveni doprinos. U radu je dokazano da hidrolizat jetrenih proteina odojka dobiven pomoću tripsina može u ranoj fazi prevenirati nealkoholnu bolest masne jetre, te se primijeniti kao dodatak hrani za regulaciju prekomjernog nakupljanja lipida

In vitro assessment of anti-diabetic potential of 4 kinds of dark tea (Camellia sinensis L.) protein hydrolysates

The contributions of four kinds of dark tea (Camellia sinensis L.) proteins and their hydrolysates to hypoglycemic activity were investigated in vitro. Four kinds of water-extracted dark tea proteins were hydrolyzed with trypsin and Alcalase, respectively. The complete proteins had α-amylase inhibitory activity with half maximal inhibitory concentration (IC50) values ranging from 1.27 to 2.78 mg/mL. Most of the dark tea proteins and hydrolysates significantly inhibited α-glucosidase and dipeptidyl peptidase (DPP-IV), with IC50 values in the range of 0.0103-1.3114 mg/mL and 0.1000-1.3364 mg/mL, respectively. In general, Heimaojian (HMJ) and Qianliang (QL) hydrolysates displayed high α-glucosidase inhibitory activity, while HMJ, Fuzhuan (FZ), and Heizhuan (HZ) hydrolysates exhibited a strong ability to inhibit DPP-IV. This study demonstrates the potential of dark tea proteins and their hydrolysates as a source of functional food and medicine for the control of type 2 diabetes

Neural Membrane Mutual Coupling Characterisation Using Entropy-Based Iterative Learning Identification

This paper investigates the interaction phenomena of the coupled axons while the mutual coupling factor is presented as a pairwise description. Based on the Hodgkin-Huxley model and the coupling factor matrix, the membrane potentials of the coupled myelinated/unmyelinated axons are quantified which implies that the neural coupling can be characterised by the presented coupling factor. Meanwhile the equivalent electric circuit is supplied to illustrate the physical meaning of this extended model. In order to estimate the coupling factor, a data-based iterative learning identification algorithm is presented where the Rényi entropy of the estimation error has been minimised. The convergence of the presented algorithm is analysed and the learning rate is designed. To verified the presented model and the algorithm, the numerical simulation results indicate the correctness and the effectiveness. Furthermore, the statistical description of the neural coupling, the approximation using ordinary differential equation, the measurement and the conduction of the nerve signals are discussed respectively as advanced topics. The novelties can be summarised as follows: 1) the Hodgkin-Huxley model has been extended considering the mutual interaction between the neural axon membranes, 2) the iterative learning approach has been developed for factor identification using entropy criterion, and 3) the theoretical framework has been established for this class of system identification problems with convergence analysis

Plasma lipid profiles and homocysteine levels in anti-N-methyl-D-aspartate receptor encephalitis

IntroductionWe aimed to investigate whether lipid profiles and homocysteine levels in patients with anti-N-methyl-D-aspartate receptor encephalitis are related to clinical presentation and prognosis, which may contribute to further research on the pathogenesis and treatment of this disease.MethodsThis study included a total of 43 patients with anti-N-methyl-D-aspartate receptor encephalitis and 43 sex–age-matched healthy controls. Baseline demography, clinical data, patient outcomes, and ancillary examination results were recorded. Patients were followed up every 2–3 months during the first year. The modified Rankin Scale score was used to evaluate the therapeutic effect and clinical outcome.ResultsAmong the 43 patients included in this study, 55.81% were male, the mean age of onset was 27 years old, and the median modified Rankin Scale score on admission was 3.0. Apolipoprotein A-1 was significantly lower in patients with anti-N-methyl-D-aspartate receptor encephalitis compared with healthy controls (p = 0.004). Compared with healthy controls, homocysteine (p = 0.002), apolipoprotein B (p = 0.004), Lpa (p = 0.045), and apolipoprotein B/apolipoprotein A-1 (p = 0.001) were significantly increased in patients with anti-N-methyl-D-aspartate receptor encephalitis. According to the modified Rankin Scale scores, 6 months after discharge, 72.09% of patients had a good prognosis and 27.91% had a poor prognosis. In the good prognosis group, age (p = 0.031), lipoprotein a (p = 0.023), apolipoprotein A-1 (p = 0.027) at baseline, and the modified Rankin Scale score on admission (p = 0.019) were significantly higher than those in the poor prognosis group.ConclusionThis study suggests the possibility that serum lipid profile and homocysteine play an important role in the pathogenesis of anti-N-methyl-D-aspartate receptor encephalitis, providing support for lipid-lowering treatment of anti-N-methyl-D-aspartate receptor encephalitis patients