A pseudosymmetric cell adhesion regulatory domain in the β7 tail of the integrin α4β7 that interacts with focal adhesion kinase and src

The β7 integrins α4β7 and Eβ7 play key roles in forming the gut-associated lymphoid tissue, and contribute to chronic inflammation. The α4β7 integrin-mediated adhesion of activated lymphocytes is largely due to a transient increase in avidity from ligand-induced clustering of α4β7 at the cell-surface. Here, we report that L and D enantiomers of a cell-permeable peptide YDRREY encompassing residues 735-740 of the cytoplasmic tail of the β7 subunit inhibit the adhesion of T cells to β7 integrin ligands. The YDRREY peptide abrogated mucosal addressin cell adhesion molecule-1-induced clustering of α4β7 on the surface of activated T cells. A mutated form of the YDRREY peptide carrying either single or double conservative mutations at Tyr⁷³⁵Phe and Tyr⁷⁴⁰Phe was unable to inhibit T cell adhesion, suggesting that both tandem tyrosines are critical for activity. The YDRREY peptide was bound and phosphorylated by focal adhesion kinase and src, which may serve to sequester cytoskeletal proteins to the cytoplasmic domain of 4β7. The quasi-palindromic sequence YDRREY within the β7 cytoplasmic tail constitutes a cell adhesion regulatory domain that modulates the interaction of β7-expressing leukocytes with their endothelial and epithelial ligands. Cell-permeable peptidomimetics based on this motif have utility as anti-inflammatory reagents for the treatment of chronic inflammatory disease.

Control of the Australian life insurance industry: an example of regulatory externalities within the Australian financial sector 1870-1945

The regulatory environment in which the Australian life insurance industry operates has its antecedents in two major periods of legislative intervention. The first established the principle of ‘freedom with disclosure’ in the 1870s, which has since formed the basis of the regulatory approach. In the 1940s, the second refined the concept in the context of a general recognition of an interventionist approach to financial markets. It is suggested that regulation of the life insurance market in Australia came about not in response to problems associated with market failure but in reaction to external influences not directly related to conditions in the Australian life insurance industry. This was impacted not only on the timing of intervention but on the approach taken as well.

So far no good: the regulatory failure of criminal racial vilification laws in Australia

This article considers the efficacy of the two main legislative models in Australia which make racial vilification a crime. To this end, it considers whether the laws are compatible with the protection and promotion of freedom of speech; whether they sit comfortably within the existing criminal law frameworks; and whether the text of the offences is sufficiently clear and precise. It considers that the current models are fundamentally flawed and ought to be repealed, arguing, instead, for a particular kind of penalty enhancement statute.

Optimal provisioning theory and regulatory distortions

Firms must often invest in large-scale capacity expansions in order to service their expectation of future demand. This is known as provisioning. This paper introduces and examines issues and contributions in optimal provisioning theory. It discusses some regulatory distortions and suggests how an awareness of optimal provisioning can improve regulatory outcomes.

Regulatory Change v's volume of trade effects in HSIF and HSI volatility

In an earlier paper we adopted a BEKK-GARCH framework and employed a systematic approach to examine structural breaks in the HSIF and HSI volatility. Switching dummy variables were included and tested in the variance equations to check for any structural changes in the autoregressive volatility structure due to the events that have taken place in the Hong Kong market. A Bi-variate GARCH model with 3 switching points was found to be superior as it captured the potential structural changes in return volatilities. Abolishment of the uptick rule, increase of initial margins for the HSIF and electronic trading of HSIF were found to have significant impact on the volatility structure of HSIF and HSI. In this paper we include measures of daily trading volume from both markets in the estimation. Likelihood ratio tests indicate the switching dummy variables become insignificant and the GARCH effects diminish but remain significant.

The Australian advertising self-regulatory framework - Who`s complaining?

Complaints about advertising in Australia have been on the increase in recent years under the stewardship of the new industry self-regulatory body, the Advertising Standards Board. This study utilises clustering analyses based on geodemographic and psychographic data to present a concrete profile of complainants about advertising in Australia. The findings indicate that the advertising publics must shoulder responsibility and ensure that greater care is taken to include all members of Australian society in the current complaints
process and that this inclusivity will ensure that the highest possible standards are the norms of the industry.

Regulatory change, structural breaks, and transmission effects in HSIF and HSI volatility

A systematic BEKK-GARCH model with multiple switch points in the variance equations captures the structural changes that have taken place in the Hong Kong markets. Abolishment of the uptick rule in the Hong Kong stock market, increase of initial margins, and electronic trading of Hang Seng Index Futures are found to have significant impacts. These changes affect the volatility structure of the HSI and HSIF and hence their lead-lag relationship. The multivariate GARCH model with three specific switching points is found to be superior to any other combination of up to six separate switch points.

Identifying cis-regulatory elements by statistical analysis and phylogenetic footprinting and analyzing their coexistence and related gene ontology

Discovery of cis-regulatory elements in gene promoters is a highly challenging research issue in computational molecular biology. This paper presents a novel approach to searching putative cis-regulatory elements in human promoters by first finding 8-mer sequences of high statistical significance from gene promoters of humans, mice, and Drosophila melanogaster, respectively, and then identifying the most conserved ones across the three species (phylogenetic footprinting). In this study, a conservation analysis on both closely related species (humans and mice) and distantly related species (humans/mice and Drosophila) is conducted not only to examine more candidates but also to improve the prediction accuracy. We have found 124 putative cis-regulatory elements and grouped these into 20 clusters. The investigation on the coexistence of these clusters in human gene promoters reveals that SP1, EGR, and NRF-1 are the dominant clusters appearing in the combinatorial combination of up to five clusters. Gene Ontology (GO) analysis also shows that many GO categories of transcription factors binding to these cis-regulatory elements match the GO categories of genes whose promoters contain these elements. Compared with previous research, the contribution of this study lies not only in the finding of new cis-regulatory elements, but also in its pioneering exploration on the coexistence of discovered elements and the GO relationship between transcription factors and regulated genes. This exploration verifies the putative cis-regulatory elements that have been found from this study and also gives new insight on the regulation mechanisms of gene expression.

Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes

Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T_reg) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4⁺ T_reg that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4⁺CD25⁺ T_reg, CD4⁺ T_reg induced by proinsulin DNA were both CD25⁺ and CD25^– and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T_reg and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T_reg, but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity.

Survey commentaries and analysis on Singapore biotechnology venture capital, intellectual and property regulatory law

The article presents survey commentaries and analysis on biotechnology venture capital, intellectual and property regulatory law in Singapore as of April 2006. The survey revealed that the financial sector and venture capitalists lack the ability to evaluate and understand biotechnology. Some major concerns for stakeholders are the lack of experience in the litigation of cases by Singaporean law firms and the lack of strategic management of portfolios for biomedical and pharmaceutical companies and the government. Stakeholders cited the need for Singaporean laws to be amended to accommodate developments in medical devices, herbal medicine, some biological areas and pre-clinical and clinical trials.