The contrast between north and south in England, 1918-1939 : a study of economic, social and political problems with particular reference to the experience of Burnley, Halifax, Ipswich and Luton

The thesis begins with a discussion of present views on the nature of the contrast between North and South in England. It proceeds to test those views against the experience of four English towns - Burnley, Halifax, Ipswich and-Luton - between 1918 and 1939. Chapter Two examines the causes and extent of economic growth in the four towns, and devotes special attention to employment and factory construction. A discussion of industrial change in the four towns as individual entities comprises a major section of this chapter. Chapter Three discusses incomes. An attempt is made to establish the proportion of the population in each of the towns living in poverty. Account is taken of the impact of rent and union activities on incomes. Chapters Four, Five and Six analyse social conditions in the four towns. Chapter Four looks at changes in population, the role played by migration, compares the health of the towns, and concludes with a discussion of the development of the public health services. Chapter Five takes for its subject the provision of housing and the demolition of slums, and incorporates a note on town planning. In Chapter Six, the educational services are compared and special attention is given to the impact the depression had on their development. Chapter Seven reviews the financing of local government and compares the contributions made by the rates and by Central Government grants. Year-to-year management of local authority finance is surveyed, and the varying roles played by the Chairmen of the Finance Committees are considered. Chapter Eight examines local government, and isolates for special consideration movements in party support; the contrasting fortunes of the parties, and especially the rise of Labour and the decline of the Liberals; changes in the social composition of councils; the role of clubs, societies and religious organisations; and the contribution these factors made to the quality of local government, and to the interest the public showed in municipal elections. Chapter Nine looks into the relationship between councils and the business organisations they controlled, with special reference to the transport systems, which underwent a crisis in this period. The chapter concludes with a discussion of the relations between chairmen and local government officials. Chapter Ten presents the main findings of the thesis, and sums up the factors responsible for these conclusions

Reduction of Stabilin-2 Contributes to a Protection Against AtherosclerosisStabilin

We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 (Aath5), on mouse chromosome 10 by three-way QTL analyses between Apoe−/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 (Stab2), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe−/− mice carrying Aath5 covering the Stab2DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5, we generated Stab2−/−Apoe−/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2−/−Apoe−/− males developed approximately 30% smaller plaques than Stab2+/+Apoe−/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2−/−Apoe−/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5, although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2129 or STAB2DBA proteins, as well as STAB2129 proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing 125I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele

Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis

We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 (Aath5), on mouse chromosome 10 by three-way QTL analyses between Apoe−/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 (Stab2), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe−/− mice carrying Aath5 covering the Stab2DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5, we generated Stab2−/−Apoe−/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2−/−Apoe−/− males developed approximately 30% smaller plaques than Stab2+/+Apoe−/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2−/−Apoe−/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5, although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2129 or STAB2DBA proteins, as well as STAB2129 proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing 125I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele

Rapid Publication Direct Evidence for the Importance of Endothelium-derived Nitric Oxide in Vascular Remodeling

The vascular endothelium mediates the ability of blood vessels to alter their architecture in response to hemodynamic changes; however, the specific endothelial-derived factors that are responsible for vascular remodeling are poorly understood. Here we show that endothelial-derived nitric oxide (NO) is a major endothelial-derived mediator controlling vascular remodeling. In response to external carotid artery ligation, mice with targeted disruption of the endothelial nitric oxide synthase gene (eNOS) did not remodel their ipsilateral common carotid arteries whereas wild-type mice did. Rather, the eNOS mutant mice displayed a paradoxical increase in wall thickness accompanied by a hyperplastic response of the arterial wall. These findings demonstrate a critical role for endogenous NO as a negative regulator of vascular smooth muscle proliferation in response to a remodeling stimulus. Furthermore, our data suggests that a primary defect in the NOS/NO pathway can promote abnormal remodeling and may facilitate pathological changes in vessel wall morphology associated with complex diseases such as hypertension and atherosclerosis. (J. Clin. Invest. 1998. 101:731–736.) Key words: nitric oxide • eNOS knockout mice • proliferation • hyperplasty • carotid artery • atherosclerosi

Circular permutation of the native enzyme-mediated cyclization position in cyclotides

Cyclotides are a class of cyclic disulfide-rich peptides found in plants that have been adopted as a molecular scaffold for pharmaceutical applications due to their inherent stability and ability to penetrate cell membranes. For research purposes, they are usually produced and cyclized synthetically, but there are concerns around the cost and environmental impact of large-scale chemical synthesis. One strategy to improve this is to combine a recombinant production system with native enzyme-mediated cyclization. Asparaginyl endopeptidases (AEPs) are enzymes that can act as peptide ligases in certain plants to facilitate cyclotide maturation. One of these ligases, OaAEP1b, originates from the cyclotide-producing plant, , and can be produced recombinantly for use as an alternative to chemical cyclization of recombinant substrates. However, not all engineered cyclotides are compatible with AEP-mediated cyclization because new pharmaceutical epitopes often replace the most flexible region of the peptide, where the native cyclization site is located. Here we redesign a popular cyclotide grafting scaffold, MCoTI-II, to incorporate an AEP cyclization site located away from the usual grafting region. We demonstrate the incorporation of a bioactive peptide sequence in the most flexible region of MCoTI-II while maintaining AEP compatibility, where the two were previously mutually exclusive. We anticipate that our AEP-compatible scaffold, based on the most popular cyclotide for pharmaceutical applications, will be useful in designing bioactive cyclotides that are compatible with AEP-mediated cyclization and will therefore open up the possibility of larger scale enzyme-mediated production of recombinant or synthetic cyclotides alike