Novel roles of human desmoglein 3 in the regulation of E-cadherin-mediated adherens junctions and the reorganisation of actin cytoskeleton.

PhDDesmosomes and adherens junctions are intercellular junctions crucial for epithelial cell-cell adhesion and maintenance of normal tissue architecture. Desmoglein 3 (Dsg3), a member of the desmoglein sub-family, serves as an adhesion molecule in desmosomes. Its importance in cell-cell adhesion has been highlighted by the autoimmune blistering disease pemphigus vulgaris, where autoimmune antibodies directed against Dsg3 trigger a cascade of intracellular events, resulting in structural defects and blister formation in the skin and oral mucosa. In addition to its adhesive function, Dsg3 is also acknowledged to have other important roles in the regulation of cell proliferation and differentiation. Our group suggested that Dsg3 is involved in the regulation of keratinocyte stem cell differentiation, but the underlying mechanism(s) were unclear (Wan et al, 2003; Wan et al, 2007). We hypothesise that Dsg3 may be involved in the regulation of the E-cadherin-mediated cell adhesion and the reorganisation of actin cytoskeleton, which in turn contributes to differentiation programs and tissue morphogenesis. Thus, the aim of this study was to examine the interactions between Dsg3, E-cadherin and actin and to explore the underlying signalling pathways that are associated with these intercellular junctions. Using both a gain and loss of Dsg3 functional approaches, I demonstrate that Dsg3 is capable of interacting with E-cadherin and involved in the regulation of calcium-induced E-cadherin junction assembly and the activation of Src signalling pathway. Overexpression of Dsg3 increased E-cadherin/Src signalling with enhanced levels of Src and pSrc co-purified with E-cadherin. Knockdown of Dsg3 inhibited this pathway with reversed effect, suggesting that Dsg3 acts as an upstream regulator of Src signalling in the regulation of E-cadherin-mediated adherens junction formation. In addition, I show another novel function of Dsg3 in promoting actin dynamics through regulating Rac1 and Cdc42-GTPase activities, resulting in pronounced membrane protrusions and enhanced rate of actin turnover. Taken together, my work suggests that Dsg3 play an important signalling role in the assembly of E-cadherin-mediated cell adhesion and the dynamic of actin cytoskeleton.Medical Research Council-funded studentship to Barts and The London School of Medicine and Dentistr

Role of Social Networks in the help seeking experiences among Chinese suffering from severe mental illness in England: a qualitative study

© The Author 2012. Published by Oxford University Press on behalf of The British Association of Social Workers. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/bjsw/bcr199The onset of mental illness can have a significant impact on individuals' lives and on the people who they come into contact with in their social networks. This paper presents the findings of the exploratory stage of a larger study that aims to examine the role of social networks in the help-seeking process of Chinese people suffering from severe mental illness in England. The study used a qualitative phenomenological approach in which in-depth interviews were conducted with three Chinese people suffering from severe mental illness and four network ties who were involved in the help-seeking process. The results of the study showed that family may not be involved in every stage of help-seeking. The size of social networks of Chinese people suffering from mental illness became bigger and the composition of social networks became more diverse after their first contact with mental health services. The implications of the study encourage social workers and mental health professionals to explore resources in the wider social networks to ensure that Chinese people suffering from mental illness receive ad- equate support to meet their mental health needs.Peer reviewedFinal Accepted Versio

Desmoglein 3 acting as an upstream regulator of Rho GTPases, Rac-1/Cdc42 in the regulation of actin organisation and dynamics

Desmoglein 3 (Dsg3), a member of the desmoglein sub-family, serves as an adhesion molecule in desmosomes. Our previous study showed that overexpression of human Dsg3 in several epithelial lines induces formation of membrane protrusions, a phenotype suggestive of Rho GTPase activation. Here we examined the interaction between Dsg3 and actin in detail and showed that endogenous Dsg3 colocalises and interacts with actin, particularly the junctional actin in a Rac1-dependent manner. Ablation of Rac1 activity by dominant negative Rac1 mutant (N17Rac1) or the Rac1 specific inhibitor (NSC23766) directly disrupts the interaction between Dsg3 and actin. Assembly of the junctional actin at the cell borders is accompanied with enhanced levels of Dsg3, while inhibition of Dsg3 by RNAi results in profound changes in the organisation of actin cytoskeleton. In accordance, overexpression of Dsg3 results in a remarkable increase of Rac1 and Cdc42 activities and to a lesser extent, RhoA. The enhancements in Rho GTPases are accompanied by the pronounced actin-based membrane structures such as lamellipodia and filopodia, enhanced rate of actin turnover and cell polarisation. Together, our results reveal an important novel function for Dsg3 in promoting actin dynamics through regulating Rac1 and Cdc42 activation in epithelial cells

An Epstein-Barr virus–encoded microRNA targets PUMA to promote host cell survival

Epstein-Barr virus (EBV) is a herpesvirus associated with nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and other malignancies. EBV is the first human virus found to express microRNAs (miRNAs), the functions of which remain largely unknown. We report on the regulation of a cellular protein named p53 up-regulated modulator of apoptosis (PUMA) by an EBV miRNA known as miR-BART5, which is abundantly expressed in NPC and EBV-GC cells. Modulation of PUMA expression by miR-BART5 and anti–miR-BART5 oligonucleotide was demonstrated in EBV-positive cells. In addition, PUMA was found to be significantly underexpressed in ∼60% of human NPC tissues. Although expression of miR-BART5 rendered NPC and EBV-GC cells less sensitive to proapoptotic agents, apoptosis can be triggered by depleting miR-BART5 or inducing the expression of PUMA. Collectively, our findings suggest that EBV encodes an miRNA to facilitate the establishment of latent infection by promoting host cell survival

Desmoglein 3, via an Interaction with E-cadherin, Is Associated with Activation of Src

Desmoglein 3 (Dsg3), a desmosomal adhesion protein, is expressed in basal and immediate suprabasal layers of skin and across the entire stratified squamous epithelium of oral mucosa. However, increasing evidence suggests that the role of Dsg3 may involve more than just cell-cell adhesion.To determine possible additional roles of Dsg3 during epithelial cell adhesion we used overexpression of full-length human Dsg3 cDNA, and RNAi-mediated knockdown of this molecule in various epithelial cell types. Overexpression of Dsg3 resulted in a reduced level of E-cadherin but a colocalisation with the E-cadherin-catenin complex of the adherens junctions. Concomitantly these transfected cells exhibited marked migratory capacity and the formation of filopodial protrusions. These latter events are consistent with Src activation and, indeed, Src-specific inhibition reversed these phenotypes. Moreover Dsg3 knockdown, which also reversed the decreased level of E-cadherin, partially blocked Src phosphorylation.Our data are consistent with the possibility that Dsg3, as an up-stream regulator of Src activity, helps regulate adherens junction formation

Uber and the sharing economy in Hong Kong : stakeholder action and regulatory responses

published_or_final_versionPolitics and Public AdministrationMasterMaster of Public Administratio

Sox11 regulates mammary tumour-initiating and metastatic capacity in Brca1-deficient mouse mammary tumour cells

Little is known about the role of Sox11 in the regulation of mammary progenitor cells. Sox11 is expressed by mammary bud epithelial cells during embryonic mammary gland development and is not detected in mammary epithelial cells after birth. As Sox11 is an oncofetal gene, we investigated the effects of reducing Sox11 levels in embryonic mammary progenitor cells and found that Sox11 regulates proliferative state, stem cell activity and lineage marker expression. We also investigated the effect of reducing Sox11 levels in two transplantable Brca1-deficient oestrogen receptor-negative mouse mammary tumour cell lines, to assess whether Sox11 regulates similar functions in tumour progenitor cells. When Sox11 levels were reduced in one Brca1-deficient mammary tumour cell line that expressed both epithelial and mesenchymal markers, similar effects on proliferation, stem cell activity and expression of lineage markers to those seen in the embryonic mammary progenitor cells were observed. Orthotopic grafting of mammary tumour cells with reduced Sox11 levels led to alterations in tumour-initiating capacity, latency, expression of lineage markers and metastatic burden. Our results support a model in which tumours expressing higher levels of Sox11 have more stem and tumour-initiating cells, and are less proliferative, whereas tumours expressing lower levels of Sox11 become more proliferative and capable of morphogenetic/metastatic growth, similar to what occurs during embryonic mammary developmental progression

The Opportunities and Challenges of the First Three Years of Open Up, an Online Text-Based Counselling Service for Youth and Young Adults

We present the opportunities and challenges of Open Up, a free, 24/7 online text-based counselling service to support youth in Hong Kong. The number of youths served more than doubled within the first three years since its inception in 2018 in response to increasing youth suicidality and mental health needs. Good practice models are being developed in order to sustain and further scale up the service. We discuss the structure of the operation, usage pattern and its effectiveness, the use of AI to improve users experience, and the role of volunteer in the operation. We also present the challenges in further enhancing the operation, calling for more research, especially on the identification of the optimal number of users that can be concurrently served by a counsellor, the effective approach to respond to a small percentage of repeated users who has taken up a disproportional volume of service, and the way to optimize the use of big data analytics and AI technology to enhance the service. These advancements will benefit not only Open Up but also similar services across the globe