Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood

PDSS2 is a gene that encodes one of the two subunits of trans-prenyl diphosphate synthase that is essential for ubiquinone biosynthesis. It is known that mutations in PDSS2 can cause primary ubiquinone deficiency in humans and a similar disease in mice. Cerebellum is the most often affected organ in ubiquinone deficiency, and cerebellar atrophy has been diagnosed in many infants with this disease. In this study, two Pdss2 conditional knockout mouse lines directed by Pax2-cre and Pcp2-cre were generated to investigate the effect of ubiquinone deficiency on cerebellum during embryonic development and in adulthood, respectively. The Pdss2 f/-; Pax2-cre mouse recapitulates some symptoms of ubiquinone deficiency in infants, including severe cerebellum hypoplasia and lipid accumulation in skeletal muscles at birth. During early cerebellum development (E12.5-14.5), Pdss2 knockout initially causes the delay of radial glial cell growth and neuron progenitor migration, so the growth of mutant cerebellum is retarded. During later development (E15.5-P0), increased ectopic apoptosis of neuroblasts and impaired cell proliferation result in the progression of cerebellum hypoplasia in the mutant. Thus, the mutant cerebellum contains fewer neurons at birth, and the cells are disorganized. The developmental defect of mutant cerebellum does not result from reduced Fgf8 expression before E12.5. Electron microscopy reveals mitochondrial defects and increased autophagic-like vacuolization that may arise in response to abnormal mitochondria in the mutant cerebellum. Nevertheless, the mutant mice die soon after birth probably due to cleft palate and micrognathia, which may result from Pdss2 knockout caused by ectopic Pax2-cre expression in the first branchial arch. On the other hand, the Pdss2 f/-; Pcp2-cre mouse is healthy at birth but gradually loses cerebellar Purkinje cells and develops ataxia-like symptoms at 9.5months; thus this conditional knockout mouse may serve as a model for ubiquinone deficiency in adult patients. In conclusion, this study provides two mouse models of Pdss2 based ubiquinone deficiency. During cerebellum development, Pdss2 knockout results in severe cerebellum hypoplasia by impairing cell migration and eliciting ectopic apoptosis, whereas Pdss2 knockout in Purkinje cells at postnatal stages leads to the development of cerebellar ataxia. © 2011 Elsevier Inc.postprin

Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion

Background: Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. It is difficult to detect early, has a high recurrence rate and is refractory to chemotherapies. Amplification of 1q21 is one of the most frequent genetic alterations in HCC. CHD1L is a newly identified oncogene responsible for 1q21 amplification. This study aims to investigate the role of CHD1L in predicting prognosis and chemotherapy response of patients with HCC, its chemoresistant mechanism and whether virus-mediated CHD1L silencing has therapeutic potentials for HCC treatment. Methods: The clinical significance of CHD1L in a cohort of 109 HCC cases including 50 cases who received transarterial chemoembolisation treatment was assessed by clinical correlation and Kaplan-Meier analyses. A CHD1L-overexpressing cell model was generated and the mechanism of chemoresistance involving CHD1L was investigated. An adenovirus-mediated silencing method was used to knockdown CHD1L, and its effects on tumorigenicity and chemoresistance were investigated in vivo and in vitro. Results: Overexpression of CHD1L was significantly associated with tumour microsatellite formation (p=0.045), advanced tumour stage (p=0.018), overall survival time (p=0.002), overall survival time of patients who received transarterial chemoembolisation treatment (p=0.028) and chemoresistance (p=0.020) in HCC. Interestingly, CHD1L could inhibit apoptosis induced by 5-fluorourail (5-FU) but not doxorubicin. The mechanistic study revealed that the involvement of the Nur77-mediated pathway in chemotherapeutic agent-induced apoptosis can dictate if CHD1L could confer resistance to chemotherapy. Furthermore, an adenoviral vector containing short hairpin RNAs against CHD1L (CHD1L-shRNAs) could suppress cell growth, clonogenicity and chemoresistance to 5-FU. An in vivo study found that CHD1L-shRNAs could inhibit xenograft tumour growth and increase the sensitivity of tumour cells to 5-FU in nude mice. Conclusions: This study highlighted for the first time the prognostic value of CHD1L in HCC and the potential application of virus-mediated CHD1L silencing in HCC treatment.published_or_final_versio

Preparation and analysis of a new bioorganic metallic material

Biofouling on metal surfaces is one of the main reasons for increased ship drag. Many methods have already been used to reduce or remove it with moderate success. In this study, a synthetic peptide has been utilized to react with 304 stainless steel aiming to generate a bioorganic stainless steel using a facile technique. After the reaction, white matter was found on the surface of the treated stainless steel via SEM, whilst the nontreated stainless steel had none. Elemental analysis confirmed that excessive N existed on the surface of the treated samples using an integrated SEM-EDS instrument, implying the presence of peptides binding on the surface of the bioorganic stainless steel. The FTIR spectra showed amide A and II peaks on the surface of the bioorganic stainless steel suggesting that either the peptides grafted onto the steel surface or the polypeptide composition accumulated on the steel samples. XPS analysis of the treated steel demonstrated that there was nitrogen bonding on the surface and it was a chemical bond via a previously unreported chemical interaction. The treated steel has a markedly increased contact angle (water contact angle of 65.7 ± 4.7° for nontreated steel in comparison to treated, 96.4 ± 2.1°), which supported the observation of the wettability change of the surface, i.e. the decrease of the surface energy value after peptide treatment. The changes of the surface parameters (such as, Sa, Sq, Ssk and Sku) of the treated steel by surface analysis were observed

On the Computational Precision of Finite Element Algorithms in Slope Stability Problems

Although the finite element method (FEM) has been used extensively to analyse the slope stability problems, the computational precision and definition of failure are still two main key concepts of finite element algorithms that attract the attention of researchers. In this paper, the modified Euler algorithm and the explicit modified Euler algorithm with stress corrections are used to analyse two dimensional (2D) slope stability problems with the associated flow rule, based on the shear strength reduction method. The rounded hyperbolic Mohr-Coulomb (M-C) yield surface is applied. Effects of the element type and various definitions of failure on the computational precision of 2D slope stability problems are evaluated. Conclusions can be drawn that the modified Euler scheme is applicable when the factor of safety (FOS) is small; however, the explicit modified Euler algorithm with stress corrections is more precise if the factor of safety is relatively large. The fully integrated quadrilateral isoparametric element is better than the triangular element in terms of the precision. With respect to the definition of failure, the displacement mutation of the characteristic point combining with the continuums of the plastic zone can be regarded as a reliable definition of failure and can be widely used to perform and analyse numerical simulations of slope stability problems

Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133

Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive treatment. We have previously identified a CSC population derived from HCC that is characterized by CD133. Despite our growing knowledge of the importance of this subset of cells in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. Here, we report the epigenetic regulation of CD133 by miR-142-3p. The interaction between CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in HCC clinical samples as well as in cell lines. Importantly, lower miR-142-3p expression in HCC was significantly associated with worst survival. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce angiogenesis and resist chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these features. Thus, miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC.published_or_final_versio

AMS Radiocarbon Dating of Tianma-Qucun Site in Shanxi, China

Tianma-Qucun is the biggest site of Western Zhou Dynasty discovered in Shanxi Province, China. It has been recognized as the early capital of Jin, a vassal state of Western Zhou. The territories were granted to the first Marquis of Jin with the title in the early days of Western Zhou. Bone sample series from the site were radiocarbon-dated by accelerator mass spectrometry (AMS) and calibrated with the Oxford calibration program OxCal 3.5. Bayesian analysis of the calibrated ages shows that the earliest residents of the Western Zhou came to Tianma-Qucun area in 1020-940 BC and the lower boundary of the Western Zhou is 796-754 BC, which corresponds well to the historical record 770 BC.Geochemistry & GeophysicsSCI(E)CPCI-S(ISTP)

Two diterpenes and three diterpene glucosides from Phlogacanthus curviflorus

Two new diterpene lactones, phlogacantholides B (1) and C (2), and three new diterpene lactone glucosides, phlogacanthosides A (3), B (4), and C (5), together with lupeol, beta-sitosterol, betulin, P-daucosterol, (+)syringaresinol, and (+)-syringaresinol-4-O-beta-D-glucopyranoside, were isolated from the roots of Phlogacanthus curviflorus. Their structures were elucidated by chemical and spectroscopic evidence. The structure, including the relative configuration of phlogacantholide B (1), was confirmed by X-ray crystallographic analysis of its diacetate (6)