36 research outputs found

    Machine learning–driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins

    Get PDF
    RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades

    in gastric carcinoma and lymph node metastasis

    No full text
    Detecting the amplification and expression of human epidermal growth factor receptor (HER2) is important for planning trastuzumab treatment for patients with gastric carcinoma. The present study aimed to analyse HER2 amplification and expression in primary gastric adenocarcinoma tumours and metastatic lymph nodes using microarray methods, and to assess the potential contribution of these methods to treatment planning. In total, 60 patients with lymph node metastasis were included in the present study. Microarray blocks were obtained from the tissue blocks of primary tumours and metastatic lymph nodes. HER2 expression and amplification were investigated using immunohistochemical and silver in situ hybridisation (SISH) methods, respectively. Following immunohistochemical evaluation of HER2 in primary tumours, the sensitivity and specificity of the microarray method relative to the single block method were 69 and 100%, respectively. For HER2 detection in microarray block sections from primary tumours, the sensitivity and specificity of the SISH method relative to immunohistochemistry were 56 and 100%, respectively. When using SISH in microarray blocked sections, there was a high degree of concordance (98% concordance rate) between HER2 amplification in the primary tumour and the metastatic lymph node. Furthermore, the sensitivity and specificity of metastatic lymph node results relative to those of the primary tumour were 100 and 98%, respectively. Overall, the single block method was more reliable compared with the microarray method for planning treatment. When microarray blocking was used, a large number of samples must be tested to ensure reliable results. The immunohistochemical method is recommended as the first step as SISH alone increases the risk of false-negative results. Assessing HER2 amplification for treatment planning would be beneficial for primary tumours, as well as metastatic lymph nodes.C1 [Gulten, Gulsun] Sanliurfa Training & Res Hosp, Dept Pathol, 1 Yenice St, TR-63250 Sanliurfa, Turkey.[Yilmaz, Bayram] Hitit Univ, Dept Pathol, Erol Olcok Training & Res Hosp, TR-19040 Corum, Turkey.[Demirkan, Nese Calli] Pamukkale Univ, Fac Med, Dept Pathol, TR-20160 Denizli, Turkey

    A Homozygous Synonymous Variant Likely Cause of Severe Ciliopathy Phenotype

    No full text
    Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive–compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G>A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C>T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G>A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C>T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome

    Influence of Nb and Ta on the corrosion and mechanical properties of CrYN coatings

    No full text
    Barrier coatings are applied to many machine components that are exposed to aggressive/harsh service conditions to prevent corrosion, oxidation, and wear at high temperatures. These coatings are widely used to protect structural components of gas/steam turbines in the energy and aerospace industries against aggressive operating conditions. In this study, Nb and Ta-doped CrYN films were deposited onto 316L stainless steel (SS) using the CFUBMS (Closed Field Unbalanced Magnetron Sputtering) technique. Then, the corrosion resistance, and structural and mechanical properties of the CrYN:Nb/Ta thin films were investigated. SEM, XPS, EDS, nanoindentation and potentiostat tester were used to determine the structural, mechanical and corrosion properties of the thin films, respectively. The highest hardness was found to be 21.4 GPa for CrYN:Nb films and 18.2 GPa for CrYN:Ta films. The results show that the coated specimens (lowest Icorr value 4 nA obtained in all tests) have higher corrosion resistance than the uncoated specimens (substrate Icorr value 1826 nA). In addition, it has been observed that the corrosion resistance of Ta-doped CrYN thin films is somewhat better than the niobium-doped thin films

    Effect of Nb and V doped elements on the mechanical and tribological properties of CrYN coatings

    No full text
    One of the most promising approaches to enhancing the tribological properties of engineering coatings is to add transition elements to the structure. In this study, Nb-doped CrYN and V-doped CrYN thin films were deposited by pulsed DC reactive sputtering in a closed-field unbalanced magnetron sputtering (CFUBMS) system. The deposition parameters examined were target current (1, 1.5 and 2 A), deposition pressure (0.15, 0.25 and 0.35 Pa), pulse frequency (100, 200 and 350 kHz) and duty cycle (85 %, 70 % and 50 %). A Taguchi L9 orthogonal design was used to define the deposition process parameters for each doped film. The Nb and V-doped CrYN thin films were characterized in terms of their microstructure, thickness, composition, hardness and tribological properties by X-ray diffraction (XRD), scanning electron microscopy (SEM), Energy dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), nanohardness and pin-on-disc testing, respectively. The bond strength between the substrate and the films (adhesion) was analyzed by scratch testing. For the Nb-doped thin films, a maximum hardness value of 21.4 GPa and the lowest friction coefficient of 0.36 were obtained. On the other hand, in the V-doped thin films, the maximum hardness value was 16.1 GPa, while the lowest friction coefficient obtained was 0.11. In addition, Nb-doped and V-doped CrYN thin films exhibited extraordinary adhesion properties. The effect of the selected deposition parameters (target current, pulse frequency, and duty cycle) in relation to the film thickness, hardness, and coefficient of friction properties of the Nb and V-doped CrYN thin films were investigated using the Taguchi approach and optimum operating conditions were identified and confirmed

    AST/ALT ratio is not useful in predicting the degree of fibrosis in chronic viral hepatitis patients

    No full text
    Conclusion In conclusion, our data suggest that four of the five noninvasive methods evaluated in this study can be used to predict advanced fibrosis in patients with hepatitis B and C. However, there was no significant relationship between the degree of hepatic fibrosis and the AAR score, indicating that AAR is not useful in estimating the fibrosis stage in hepatitis B and C patients. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved

    The crystal structure of 3-epicaryoptin and the reversal of the currently accepted absolute configuration of clerodin

    No full text
    Evidence, based on an X-ray assignmet of the chirality of 3-epicaryopti and a fresh X-ray study of clerodin bromolactone, is presented for the reversal of the long-held absolute configuration of clerodin, and new terminology is suggested to avoid confusion in future
    corecore