Superbroadband near-infrared emission and energy transfer in Pr³⁺-Er³⁺ codoped fluorotellurite glasses

Author name used in this publication: Yuen H. Tsang2011-2012 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Superbroadband near-IR photoluminescence from Pr³⁺-doped fluorotellurite glasses

Author name used in this publication: Yuen H. Tsang2011-2012 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

ER stress mediates homocysteine-induced endothelial dysfunction: Modulation of IKCa and SKCa channels

AbstractObjectiveIt remains incompletely understood how homocysteine impairs endothelial function. Whether mechanisms such as calcium-activated potassium (KCa) channels are involved is uncertain and the significance of endoplasmic reticulum (ER) stress in KCa channel-dependent endothelial function in hyperhomocysteinemia remains unexplored. We investigated the effect of homocysteine on endothelial KCa channels in coronary vasculature with further exploration of the role of ER stress.MethodsVasorelaxation mediated by intermediate- and small-conductance KCa (IKCa and SKCa) channels was studied in porcine coronary arteries in a myograph. IKCa and SKCa channel currents were recorded by whole-cell patch-clamp in coronary endothelial cells. Protein levels of endothelial IKCa and SKCa channels were determined for both whole-cell and surface expressions.ResultsHomocysteine impaired bradykinin-induced IKCa and SKCa-dependent EDHF-type relaxation and attenuated the vasorelaxant response to the channel activator. IKCa and SKCa currents were suppressed by homocysteine. Inhibition of ER stress during homocysteine exposure enhanced IKCa and SKCa currents, associated with improved EDHF-type response and channel activator-induced relaxation. Homocysteine did not alter whole-cell protein levels of IKCa and SKCa whereas lowered surface expressions of these channels, which were restored by ER stress inhibition.ConclusionsHomocysteine induces endothelial dysfunction through a mechanism involving ER stress-mediated suppression of IKCa and SKCa channels. Inhibition of cell surface expression of these channels by ER stress is, at least partially, responsible for the suppressive effect of homocysteine on the channel function. This study provides new mechanistic insights into homocysteine-induced endothelial dysfunction and advances our knowledge of the significance of ER stress in vascular disorders

Expression of Foxp3 in colorectal cancer but not in Treg cells correlates with disease progression in patients with colorectal cancer

Background: Regulatory T cells (Treg) expressing the transcription factor forkhead-box protein P3 (Foxp3) have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC) the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC). Methods and Findings: Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival. Conclusions: Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy

The effect of the C. elegans transcription factor CES-2 on mammalian apoptosis

The basic region leucine zipper (bZIP) transcription factor CES-2 (cell death specification) controls the apoptotic fate of a subset of neurones in the pharynx of the nematode C.elegans. Conserved components of the cell death pathway have previously been shown to function across species. The aim of the work described in this thesis was to use ces-2 to identify critical genes involved in apoptotic control in mammalian cells. Preliminary experiments were performed to ascertain whether mammalian cells contained endogenous CES-2 like proteins, and whether the C.elegans protein, when expressed in mammalian cells, is correctly localised. The former was confirmed in HeLa nuclear extracts utilising the specific DNA binding sequence of CES-2 in an electrophoretic mobility shift assay; and the latter by immunofluorescence studies established that expression of CES-2 in several mammalian cell types was confined to the nucleus, consistent with its role as a nuclear transcription factor. The bZIP family of proteins function as specific homo- and hetero-dimers. The strategy used, therefore, to identify CES-2-like or CES-2-interacting proteins was by two-hybrid screening of a HeLa cDNA library. Two mammalian bZIP transcription factors were identified which interacted specifically with CES-2, CHOP (C/EBP homologous protein) and ATF4/CREB-2 (activating transcription factor 4 / cAMP response element binding protein-2). The bZIP domain of CES-2 was sufficient for these interactions and this was confirmed by co-immunoprecipitation studies. Since CHOP is upregulated in response to ER-stress and apoptosis induced by the N-linked glycosylation inhibitor tunicamycin, the effect of expressing CES-2 on the response of HeLa cells to tunicamycin was investigated. In contrast to its pro-apoptotic role in the C.elegans neurones, overexpression of CES-2 in HeLa cells, in both transient and stable transfectants, increased the resistance of the cells to apoptosis induced by tunicamycin. Experiments using thapsigargin, calcium ionophore and taxol suggested that CES-2 protection depended on the upregulation of CHOP. Results obtained from expressing the CES-2 bZIP domain alone point to protection being by a dominant negative mechanism to down-regulate CHOP activity. Analysis of the second CES-2 interacting protein showed that ATF4 is also upregulated by agents that induce ER-stress, with a time course similar to CHOP. In the light of recent published data that ATF4 activates CHOP by binding its promoter element, CES-2 binding to ATF4 may also affect the regulation of ATF4-dependent chop transcription. Thus CES-2 is able to bind proteins positioned at different levels of the ER-stress pathway to influence apoptosis. The results presented in this thesis demonstrate that CES-2 can function in mammalian cells and suggest that CES-2-like proteins exist as conserved elements of the apoptotic program

第十七屆 MCS 年度研討會 = The 17th Annual MCS Symposium

這是一個跨境、跨界、跨體驗的時代。以三篇MCSian的文章為引子，梁文道先生作嘉賓、潘毅教授為主持一起探討「文化與日常政治 : 電影、音樂、戲劇」。 This is an era where borders, lines and experiences cross and intersect with each other. We will begin with the presentation of three papers by MCSians. Prof. Pun Ngai will serve as moderator while Mr. Leung Man-tao as guest speaker. They will hold a dialogue with the three MCSians and participants about Culture and Everyday Politics: Film, Music, Drama

A Variable-Volume Heart Model for Galvanic Coupling-Based Conductive Intracardiac Communication

Conductive intracardiac communication (CIC) has become one of the most promising technologies in multisite leadless pacemakers for cardiac resynchronization therapy. Existing studies have shown that cardiac pulsation has a significant impact on the attenuation of intracardiac communication channels. In this study, a novel variable-volume circuit-coupled electrical field heart model, which contains blood and myocardium, is proposed to verify the phenomenon. The influence of measurements was combined with the model as the equivalent circuit. Dynamic intracardiac channel characteristics were obtained by simulating models with varying volumes of the four chambers according to the actual cardiac cycle. Subsequently, in vitro experiments were carried out to verify the model’s correctness. Among the dependences of intracardiac communication channels, the distance between pacemakers exerted the most substantial influence on attenuation. In the simulation and measurement, the relationship between channel attenuation and pulsation was found through the variable-volume heart model and a porcine heart. The CIC channel attenuation had a variation of less than 3 dB

Integrins as a drug target in liver fibrosis

As the worldwide prevalence of Chronic Liver Diseases is high and continuing to increase, there is an urgent need for treatment to prevent cirrhosis-related morbidity and mortality. Integrins are heterodimeric cell-surface proteins that are promising targets for therapeutic intervention. αv integrins are central in the development of fibrosis as they activate latent TGFβ, a known profibrogenic cytokine. The αv subunit can form heterodimers with β1, β3, β5, β6 or β8 subunits and one or more of these integrins are central to the development of liver fibrosis, however, their relative importance is not understood. This review summarises the current knowledge of αv integrins and their respective β subunits in different organs, with a focus on liver fibrosis and the emerging preclinical and clinical data with regards to αv integrin inhibitors