Immunological studies of the connective tissue diseases using New Zealand mice as a laboratory model

Systemic lupus erythematosus (SLE) is primarily a disease affecting the connective tissues of the many organs of the body. It is associated with the production of a wide spectrum of autoantibodies, which, with one exception, have no defined pathogenetic role. The one exception is antibody to deoxyribonucleic acid (DNA), which complexes with DNA in the circulating blood, and the resultant complexes are deposited in the renal glomeruli, where they are responsible for the induction of glomerulonephritis. For many years research on SLE was hampered by lack of a suitable laboratory model. The discovery that New Zealand Black (NZB) and the FI hybrid progeny (NZB x NZW F1; BWF1) resulting from crossing NZB with New Zealand White (NZW) mice develop an autoimmune disease closely mimicking SLE, has since stimulated considerable research into the pathogenesis of the disease. Numerous immunological peculiarities have been shown to be present in these mice, yet nocompletely statisfactory explanation for their occurrence has been proposed. Phagocytosis and the processing of antigen by macrophages have been shown to be important events in the initiation of immune responses. In this thesis I describe studies of the early events of the immune response in NZ mice in order to evaluate their importance, if any, in the production of the immunological peculiarities known to occur in these strains of mice. An initial study of the development of the time of onset of autoimmune disease in our mouse colonies was undertaken in order to compare our mice with those previously reported from other centres. The results showed that although minor differences could be detected, the mice in the main behaved very similarly to those previously reported. Studies of the in vivo phagocytosis of colloidal carbon by the fixed macrophages of the liver and spleen and the peritoneal macrophages were undertaken. Carbon was removed from the blood more slowly by NZB than other mice, but when correction was made for liver and spleen weight in relation to total body weight, phagocytosis was found to be normal. Peritoneal cellular responses to carbon, and its phagocytosis and subsequent tissue localisation, were normal. The phagocytosis and subsequent intracellular killing of Staphylococcus aureus by the peritoneal macrophages of NZ mice was measured and found to be normal in a supravital system. Serum factors did not appear to affect the rate of phagocytosis or killing of bacteria. As NZB and BWF1 mice have been shown to produce heightened immune responses to the soluble protein antigens, bovine gamma globulin (BGG) and bovine serum albumin (BSA), and have also been shown to be relatively resistant to the induction of both high and low zone tolerance to these antigens, it was decided to study the rates of non-immune elimination of these antigens. New Zealand mice were found to have faster rates of catabolism than control strains of mice, but a study of the antibody responses in these mice showed that there was no relationship between antigen elimination rate and the tit re or affinity of the antibody subsequently produced, However, it was found that the time of onset of immune elimination, indicating production of antibody, was earlier in those mice having rapid rates of antigen non-immune elimination. A new method of studying thyroxine secretion rates in mice (based on ''the Occupancy Principle") was devised, and a study of endogenous thyroxine secretion rates was undertaken in order to investigate the possible role of thyroxine metabolism in relation to BGG elimination rates. No correlation was demonstrated in the strains of mice studied, Thus interstrain variations in non-immune antigen elimination probably result from differences in macrophage function, although the action of naturally occurring adjuvants cannot be excluded, as adjuvants have also been shown to accelerate non-immune antigen elimination. Finally using E. coli DNA labelled with phosphorus-32 (32P), a study of DNA catabolism in New Zealand mice was undertaken to investigate the possibility that abnormalities of DNA catabolism might be responsible for the production of DNA antibodies, which are known to occur spontaneously in these mice. NZB mice removed DNA more slowly from the blood than other strains of mice, but unlike the slow clearance of colloidal carbon, the slow rate of DNA clearance was not found to be due to the small size of liver and spleen. It was found that phagocytosis rather than nuclease activity was responsible for the removal of DNA from the blood, as injected DNA was mainly localised in the liver and spleen, and its removal from the blood could be slowed by the administration of ethyl stearate, which is known to produce reticuloendothelial blockade. Apart from the relatively low rates of elimination, no peculiarities likely to be responsible for the proneness of NZ mice to produce antibodies to DNA could be demonstrated

3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1,600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×106 PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment

The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005

Background Recent studies of the Hiroshima and Nagasaki A-bomb survivors, together with some (but not all) cohorts exposed occupationally or medically to ionizing radiation, have found an increasing trend in mortality from non-malignant disease with increasing radiation dose. The aim of this study was to establish whether such a trend could be found in a large cohort of employees in the UK nuclear industry

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

An Approach To Resource Allocation on Wildlands

This report presents the results of a project conducted for the Rocky Mountain Forest and Range Experiment Station, U.S. Forest Service. This study entitled Natural Resource valuation - the conceptual and operational basis for economic analysis in a mUltiple use context had two objectives: 1) To develop concepts and procedures for determining comparable values of natural resources used in production of goods and services that move through markets. Comparability must be in terms of (a) theoretical framework and (b) stage of production and distribution process. 2) To develop concepts and procedures for determining comparable values of natural resources used in production of goods and services that do not move through markets. Comparability must be in terms of (a) theoretical framework and (b) stage of production and distribution process