Positional identification and functional analysis of genes regulating autoimmune arthritis

The major histocompatibility complex (MHC) is the most gene-dense and polymorphic region in the human genome with strong associations to many autoimmune disorders, including rheumatoid arthritis (RA). However, even the genetic association between MHC and RA was known more than 40 years ago, we still have not fully explained the functional roles of the MHC genes and identified the underlying specific polymorphisms. This thesis describes some of our research aimed for a better understanding of this topic, which can largely be divided into three parts as follows. First, we made use of a panel of MHC class II (MHC-II) congenic strains to evaluate the functional roles of MHC-II polymorphisms in arthritis. By performing an extensive genetic and functional analysis, we showed that MHC-II RT1-B (the rat orthologs of HLA-DQ) determines the onset and severity of experimental arthritis, possibly due to the amino acid variations in the P1 pocket of RT1-B. In addition, we showed that natural allelic variants in Tap2, another gene in the MHC-II region, regulates the thymic selection of CD8+ T cells. Second, in order to investigate whether other MHC genes also contribute to arthritis susceptibility, we assessed arthritis development in congenic strains mapped to other parts of the MHC region. We identified a second arthritis-regulatory QTL in the MHC class III region, that regulates not only the onset and severity, but also chronicity of arthritis. We subsequently mapped this effect to a conserved, 33-kb large haplotype Ltab-Ncr3 comprising five polymorphic genes. Interestingly, unlike other positionally-identified arthritis genes in rats, Ltab-Ncr3 regulates only adjuvant arthritis models but not autoimmunity triggered by specific tissue antigens, such as type II collagen. Furthermore, we found that gene expression and alternative splicing of the Ltab-Ncr3 genes correlate remarkably with arthritis severity and some of the gene expression differences were reproduced in a cohort of RA patients and healthy controls. Third, the MHC-II gene expression is regulated by class II transactivator (CIITA or C2TA), and in humans, genetic variation in CIITA has been associated with differential expression of MHC-II and susceptibility to autoimmune diseases. Using a congenic mouse strain with an allelic variant in the type I promoter of C2ta, we demonstrate that whereas genetic polymorphisms in C2ta promoter result in differential MHC-II expression and antigen presentation, these do not necessarily have a strong impact on autoimmune diseases such as arthritis. In summary, these studies demonstrate how the congenic approach remains powerful to conclusively identify and characterise genes regulating a complex disease like arthriti

Creative Destruction and Firm-Specific Performance Heterogeneity

Traditional U.S. industries with higher firm-specific stock return and fundamentals performance heterogeneity use information technology (IT) more intensively and post faster productivity growth in the late 20th century. We argue that elevated firm performance heterogeneity mechanically reflects a wave of Schumpeter's (1912) creative destruction disrupting a wide swath of U.S. industries, with newly successful IT adopters unpredictably undermining established firms. This evidence validates endogenous growth theory models of creative destruction, such as Aghion and Howitt (1992); and suggests that recent findings of more elevated firm-specific performance variation in richer, faster growing countries with more transparent accounting, better financial systems, and more secure property rights might partly reflect more intensive creative destruction in those economies.

Gap Theorem on Riemannian manifolds using Ricci flow

In this work, we consider complete non-compact manifolds with non-negative complex sectional curvature and small average curvature decay. By developing the Ricci flow existence theory, we show that complete non-compact manifolds with non-negative complex sectional curvature and sufficiently small average curvature decay are necessarily flat. We also prove a gap Theorem in the Euclidean volume case. In the compact case, we use the Ricci flow to generalise the celebrated Gromov-Ruh Theorem in this direction.Comment: 29 page

Exquisite jade carving: figures, animals, ornaments

Exhibition held at the University Museum and Art Gallery, University of Hong Kong on Dec. 6, 1995-Feb. 6, 1996.published_or_final_versionFurther comments on flying deity/winged figure 17Foreword Lau, Michael W.M. Lau, Michael W.M. 4List of lenders 18借出展品的藏家和機構 18Chronology 19年表 19Works cited in the descriptions 20Plates 25Introduction Yeung, Chun-tong Yeung, Chun-tong 10展品圖版 25序言 楊春棠 楊春棠 12On Hongshan jade pendants So, Jenny F. So, Jenny F. 14Preface Fung, Sydney Fung, Sydney

Arp2/3 complex activity in filopodia of spreading cells

Background Cells use filopodia to explore their environment and to form new adhesion contacts for motility and spreading. The Arp2/3 complex has been implicated in lamellipodial actin assembly as a major nucleator of new actin filaments in branched networks. The interplay between filopodial and lamellipodial protrusions is an area of much interest as it is thought to be a key determinant of how cells make motility choices. Results We find that Arp2/3 complex localises to dynamic puncta in filopodia as well as lamellipodia of spreading cells. Arp2/3 complex spots do not appear to depend on local adhesion or on microtubules for their localisation but their inclusion in filopodia or lamellipodia depends on the activity of the small GTPase Rac1. Arp2/3 complex spots in filopodia are capable of incorporating monomeric actin, suggesting the presence of available filament barbed ends for polymerisation. Arp2/3 complex in filopodia co-localises with lamellipodial proteins such as capping protein and cortactin. The dynamics of Arp2/3 complex puncta suggests that they are moving bi-directionally along the length of filopodia and that they may be regions of lamellipodial activity within the filopodia. Conclusion We suggest that filopodia of spreading cells have regions of lamellipodial activity and that this activity affects the morphology and movement of filopodia. Our work has implications for how we understand the interplay between lamellipodia and filopodia and for how actin networks are generated spatially in cells