Six Top Messages of New Physics at the LHC

Six top signatures provide a novel probe of new physics. We discuss production of six top quarks as the decay products of a pair of top partners in the setting of a composite Higgs model, and argue that the six top signal may generically provide one of the first final states to show a discrepancy. We construct an analysis based on quantities such as $H_T$ and the numbers of jets which are tagged as boosted tops, $W$s, or containing $b$-tags, and show that the LHC with 3~ab$^{-1}$ can discover top partners with masses up to around 2.5 TeV in the six top signature.Comment: 15 pages, 6 figures, and 2 table

Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

A UHPLC-Q-Exactive-Orbitrap-MS method for simultaneous determination of three flavonoids from Parasitic loranthus and their pharmacokinetics in rat plasma

Purpose: To develop and validate a chromatographic method for the simultaneous determination of plasma levels of rutin, avicularin and quercitrin using UHPLC-Q-Exactive-Orbitrap-MS. Methods: A sensitive, selective, and reliable UHPLC-Q-Exactive-Orbitrap-MS method was developed and validated for simultaneous determination of the three flavonoids, with puerarin as internal standard (IS). Plasma samples were first treated with methanol, and then acidified using hydrochloric acid (HCl) prior to liquid-liquid extraction with ethyl acetate. The flavonoids were separated on a Syncronis C18 column (100×2.1mm, 1.7 µm) using an elution gradient of acetonitrile and 0.1 % formic acid at a flow rate of 0.3 mL/min. Results: A linear correlation was obtained for the three flavonoids over the investigated concentration range, with correlation coefficients > 0.9954. The values of validated lower limit of quantification (LLOQ) were 0.68, 1.42 and 2.54 ng/mL for rutin, avicularin and quercitrin, respectively. Intra- and inter-day precision (RSD) were < 10 %, while accuracy (RE) ranged from −3.76 to 4.04 %. Conclusion: The proposed method has been successfully validated and is suitable for studying the pharmacokinetics of the three analytes in rats treated with parasitic loranthus extract (PLE)

Effect of total flavones of buckwheat flowers and leaves on protein tyrosine phosphatase 1B expression in type 2 diabetic rats

The total flavone content was obtained from flowers and leaf of buckwheat (Fagopyrum esculentum Moench) by heating reflux method. The effects of the total flavone extract on the protein tyrosine phosphatase 1B (PTP1B) expression in type 2 diabetic rats were evaluated by immunofluorescence, western blotting and real-time quantitative PCR. The results suggested that the total flavone fraction from buckwheat flowers and leaves can significantly decrease the PTP1B expression in liver.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Superparamagnetic iron oxide nanoparticles mediated 131I-hVEGF siRNA inhibits hepatocellular carcinoma tumor growth in nude mice

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary liver tumor and is the most difficult human malignancy to treat. In this study, we sought to develop an integrative approach in which real-time tumor monitoring, gene therapy, and internal radiotherapy can be performed simultaneously. This was achieved through targeting HCC with superparamagnetic iron oxide nanoparticles (SPIOs) carrying small interfering RNA with radiolabled iodine 131 ((131)I) against the human vascular endothelial growth factor (hVEGF). METHODS: hVEGF siRNA was labeled with (131)I by the Bolton-Hunter method and conjugated to SilenceMag, a type of SPIOs. (131)I-hVEGF siRNA/SilenceMag was then subcutaneously injected into nude mice with HCC tumors exposed to an external magnetic field (EMF). The biodistribution and cytotoxicity of (131)I-hVEGF siRNA/SilenceMag was assessed by SPECT (Single-Photon Emission Computed Tomography) and MRI (Magnetic Resonance Imaging) studies and blood kinetics analysis. The body weight and tumor size of nude mice bearing HCC were measured daily for the 4-week duration of the experiment. RESULTS: (131)I-hVEGF siRNA/SilenceMag was successfully labeled; with a satisfactory radiochemical purity (>80%) and biological activity in vitro. External application of an EMF successfully attracted and retained more (131)I-hVEGF siRNA/SilenceMag in HCC tumors as shown by SPECT, MRI and biodistribution studies. The tumors treated with (131)I-hVEGF siRNA/SilenceMag grew nearly 50% slower in the presence of EMF than those without EMF and the control. Immunohistochemical assay confirmed that the tumor targeted by (131)I-hVEGF siRNA/SilenceMag guided by an EMF had a lower VEGF protein level compared to that without EMF exposure and the control. CONCLUSIONS: EMF-guided (131)I-hVEGF siRNA/SilenceMag exhibited an antitumor effect. The synergic therapy of (131)I-hVEGF siRNA/SilenceMag might be a promising future treatment option against HCC with the dual functional properties of tumor therapy and imaging