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Biomedical subjects

C E Stevenson

Publications and source records attributed to C E Stevenson.

11 recordsLinked to original sources
PubMed2001

Two crystal structures of the cytoplasmic molybdate-binding protein ModG suggest a novel cooperative binding mechanism and provide insights into ligand-binding specificity.

The X-ray structures of the cytoplasmic molybdate-binding protein ModG from Azotobacter vinelandii in two different crystal forms have been determined. For such a small protein it is remarkably complex. Each 14.3 kDa subunit contains two small beta-barrel domains, which display an OB-fold motif, also seen in the related structure of ModE, a molybdenum-dependent transcriptional regulator, and very recently in the Mop protein that, like ModG, has been implicated in molybdenum homeostasis within the cell. In contrast to earlier speculation, the functional unit of ModG is actually not a dimer (as in ModE), but a trimer capable of binding a total of eight molybdate molecules that are distributed between two disparate types of site. All the binding sites are located at subunit interfaces, with one type lying on a crystallographic 3-fold axis, whilst the other lies between pairs of subunits. The two types of site are linked by short hydrogen bond networks that may suggest a cooperative binding mechanism. A superposition of two subunits of the ModG trimer on the apo-ModE dimer allows the probable locations of the molybdate-binding sites of the latter to be assigned. Through structural comparisons with other oxyanion-binding proteins, including Mop and ModE, it is possible to speculate about ligand-binding affinities, selectivity and evolution.

Aldehyde Oxidoreductases↗
PubMed2001

The burden of disease and injury in Australia.

An overview of the results of the Australian Burden of Disease (ABD) study is presented. The ABD study was the first to use methodology developed for the Global Burden of Disease study to measure the burden of disease and injury in a developed country. In 1996, mental disorders were the main causes of disability burden, responsible for nearly 30% of total years of life lost to disability (YLD), with depression accounting for 8% of the total YLD. Ischaemic heart disease and stroke were the main contributors to the disease burden disability-adjusted life years (DALYs), together causing nearly 18% of the total disease burden. Risk factors such as smoking, alcohol consumption, physical inactivity, hypertension, high blood cholesterol, obesity and inadequate fruit and vegetable consumption were responsible for much of the overall disease burden in Australia. The lessons learnt from the ABD study are discussed, together with methodological issues that require further attention.

Australia↗
PubMed2000

Crystal structure of the molybdenum cofactor biosynthesis protein MobA from Escherichia coli at near-atomic resolution.

BACKGROUND: All mononuclear molybdoenzymes bind molybdenum in a complex with an organic cofactor termed molybdopterin (MPT). In many bacteria, including Escherichia coli, molybdopterin can be further modified by attachment of a GMP group to the terminal phosphate of molybdopterin to form molybdopterin guanine dinucleotide (MGD). This modification reaction is required for the functioning of many bacterial molybdoenzymes, including the nitrate reductases, dimethylsulfoxide (DMSO) and trimethylamine-N-oxide (TMAO) reductases, and formate dehydrogenases. The GMP attachment step is catalyzed by the cellular enzyme MobA. RESULTS: The crystal structure of the 21.6 kDa E. coli MobA has been determined by MAD phasing with selenomethionine-substituted protein and subsequently refined at 1. 35 A resolution against native data. The structure consists of a central, predominantly parallel beta sheet sandwiched between two layers of alpha helices and resembles the dinucleotide binding Rossmann fold. One face of the molecule bears a wide depression that is lined by a number of strictly conserved residues, and this feature suggests that this is where substrate binding and catalysis take place. CONCLUSIONS: Through comparisons with a number of structural homologs, we have assigned plausible functions to several of the residues that line the substrate binding pocket. The enzymatic mechanism probably proceeds via a nucleophilic attack by MPT on the GMP donor, most likely GTP, to produce MGD and pyrophosphate. By analogy with related enzymes, this process is likely to require magnesium ions.

Amino Acid Sequence↗
PubMed2000

Unprecedented proximal binding of nitric oxide to heme: implications for guanylate cyclase.

Microbial cytochromes c' contain a 5-coordinate His-ligated heme that forms stable adducts with nitric oxide (NO) and carbon monoxide (CO), but not with dioxygen. We report the 1.95 and 1.35 A resolution crystal structures of the CO- and NO-bound forms of the reduced protein from Alcaligenes xylosoxidans. NO disrupts the His-Fe bond and binds in a novel mode to the proximal face of the heme, giving a 5-coordinate species. In contrast, CO binds 6-coordinate on the distal side. A second CO molecule, not bound to the heme, is located in the proximal pocket. Since the unusual spectroscopic properties of cytochromes c' are shared by soluble guanylate cyclase (sGC), our findings have potential implications for the activation of sGC induced by the binding of NO or CO to the heme domain.

Alcaligenes↗
PubMed2000

The Australian Burden of Disease Study: measuring the loss of health from diseases, injuries and risk factors.

This is an overview of the first burden of disease and injury studies carried out in Australia. Methods developed for the World Bank and World Health Organization Global Burden of Disease Study were adapted and applied to Australian population health data. Depression was found to be the top-ranking cause of non-fatal disease burden in Australia, causing 8% of the total years lost due to disability in 1996. Mental disorders overall were responsible for nearly 30% of the non-fatal disease burden. The leading causes of total disease burden (disability-adjusted life years [DALYs]) were ischaemic heart disease and stroke, together causing nearly 18% of the total disease burden. Depression was the fourth leading cause of disease burden, accounting for 3.7% of the total burden. Of the 10 major risk factors to which the disease burden can be attributed, tobacco smoking causes an estimated 10% of the total disease burden in Australia, followed by physical inactivity (7%).

Australia↗
PubMed1995

Statistical models for cancer screening.

This paper reviews the application of statistical models to planning and evaluating cancer screening programmes. Models used to analyse screening strategies can be classified as either surface models, which consider only those events which can be directly observed such as disease incidence, prevalence or mortality, or deep models, which incorporate hypotheses about the disease process that generates the observed events. This paper focuses on the latter type. These can be further classified as analytic models, which use a model of the disease to derive direct estimates of characteristics of the screening procedure and its consequent benefits, and simulation models, which use the disease model to simulate the course of the disease in a hypothetical population with and without screening and derive measures of the benefit of screening from the simulation outcomes. The main approaches to each type of model are described and an overview given of their historical development and strengths and weaknesses. A brief review of fitting and validating such models is given and finally a discussion of the current state of, and likely future trends in, cancer screening models is presented.

Computer Simulation↗
PubMed1983

Interstitial deletion 2q31 leads to q33.

We present an 8-month-old female with severe retardation of growth and development, multiple congenital anomalies, and an interstitial deletion del(2)(q31 leads to q33) including results of cytogenetic and gene marker studies. The manifestations of this infant are compared with those of four other known patients with a partial del(2q).

Abnormalities, Multiple↗
PubMed1978

Hypertensive reactions to phenylephrine eyedrops in patients with sympathetic denervation.

We studied the effects of topical phenylephrine eyedrops on systemic blood pressure in 298 patients about to undergo ocular surgical procedures by comparing their blood pressure on admission to the hospital with that measured immediately before surgery. The patients were divided into three groups. Group 1 consisted of 230 patients who had neither history of insulin-dependent diabetes nor prior teatment with reserpine or guanethidine. Group 2 included 41 insulin-dependent diabetic patients. Group 3 contained 27 hypertensive patients who had been taking reserpine or guanethidine. Patients in each group were divided into two subgroups (A and B). The 202 patients in the three A subgroups received preoperative phenylephrine eyedrops, whereas the 96 patients in the three B subgroups did not. All three B subgroups and Group 1A (176 patients) did not show significant increases in blood pressure. There was a statistically significant increase in both systolic and diastolic pressures in Group 2A (14 patients) and in Group 3A (12 patients). From this study, we concluded that administration of preoperative phenylephrine eyedrops can be hazardous in patients with long-standing insulin-dependent diabetes or in hypertensive patients receiving reserpine or guanethidine.

Aged↗