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Biomedical subjects

M McAlister

Publications and source records attributed to M McAlister.

6 recordsLinked to original sources
PubMed2004

Use of bacteriophages as surrogates for mammalian viruses.

The threat of viral contamination is common to all processes using biological products of animal or human origin. Therefore, demonstration of virus clearance (i.e. validation of virus removal and/or inactivation steps) is of utmost importance to the biopharmaceutical industries. Ultimately, virus clearance studies should show that any virus removal/inactivation stage incorporated into the manufacturing process not only removes or inactivates known viruses that may be conceivably present (e.g. from cell banks and source materials), but also other viruses that may be introduced adventitiously (e.g. by addition of supplements downstream of the manufacturing process). In this paper, we outline the shared properties of mammalian viruses and similar sized bacteriophages, and factors that may influence the virus clearance process. We also present test data from filtration studies, showing similar titre reductions for both types of virus. We propose that well-characterised bacteriophage, such as PP7 and PR772 can be used as models for mammalian viruses if the virus removal mechanism is based on size exclusion.

Animals↗
PubMed2001

Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase.

Nitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 3.5.3.18). Levels of asymmetric NG,NG-dimethylarginine (ADMA) are known to correlate with certain disease states. Here, the first structure of a DDAH shows an unexpected similarity to arginine:glycine amidinotransferase (EC 2.1.4.1) and arginine deiminase (EC 3.5.3.6), thus defining a superfamily of arginine-modifying enzymes. The identification of a Cys-His-Glu catalytic triad and the structures of a Cys to Ser point mutant bound to both substrate and product suggest a reaction mechanism. Comparison of the ADMA-DDAH and arginine-amidinotransferase complexes reveals a dramatic rotation of the substrate that effectively maintains the orientation of the scissile bond of the substrate with respect to the catalytic residues. The DDAH structure will form a basis for the rational design of selective inhibitors, which are of potential use in modulating NO synthase activity in pathological settings.

Amidohydrolases↗
PubMed1982

Interactions between neutral phospholipid bilayer membranes.

We have obtained force vs. separation relations between bilayers in 10 different phospholipid preparations: dilauroyl-dimyristoyl-, dipalmitoyl-, distearoyl-, or dioleoylphosphatidylcholine (PC); egg phosphatidylethanolamine; cholesterol-containing bilayers of dipalmitoyl PC and of egg PC. The chemical potential of water in the multilamellar lattice is determined at all water contents and changes continuously with bilayer separation; no discrete classes of water are observed. The interbilayer van der Waals force is estimated from the balance of forces at the bilayer separation where the multilayer lattice is in equilibrium with pure water. Although quantitative differences are evident for different phospholipids, all force curves but one show a clear, exponentially decaying "hydration "repulsion" whose decay distance is 2-3 A . Estimates of forces between bilayer vesicles show great sensitivity to the identity of the phospholipid polar group and to the packing of the hydrocarbon acyl chains. On major implication of this is the likelihood of local structural changes and lipid segregation in the area of closest approach of interacting vesicles of mixed phospholipids.

Chemical Phenomena↗
PubMed1982

Measurement of the lateral compressibility of several phospholipid bilayers.

Lateral compressibilities of bilayers in multilayer lattices are given for 10 phospholipid preparation:dilauryl-, dimyristoyl-, dipalmitoyl-, distearoyl-, and dioleoylphosphatidylcholine (PC); egg phosphatidylethanolamine (PE); as well as cholesterol-containing bilayers of dipalmitoyl PC or of egg PC. Bilayer deformability is highly nonlinear and does not permit description in terms of a simple modulus. The presence of cholesterol or C=C bonds (dioleoyl PC) increases deformability, but freezing of acyl chains does not cause dramatic stiffening of the bilayer. Lateral compression of dilauryl PC an dimyristoyl PC causes a transition from "melted" to "frozen" acyl chains above the normal transition temperatures. Our measurements do not correspond in any obvious way to lateral compressibilities in monolayers at the air-water interface.

Cholesterol↗
PubMed1980

The effect of cholesterol on measured interaction and compressibility of dipalmitoylphosphatidylcholine bilayers.

We have examined the phase diagram of dipalmitoylphosphatidylcholine (DPPC)--cholesterol-water mixtures at low cholesterol content, and report phase separation between 3 and 10 mol% cholesterol. The two lamellar phases at equilibrium in this region appear to be pure DPPC and 11 mol% cholesterol in DPPC. For these two lamellar phases, which are made up of alternating layers of water and bimolecular lipid leaflets, we have measured the forces of interaction between leaflets and the lateral pressure and compressibility of the leaflets. Both bilayers experience a strong repulsive force when forced together only a few ångströms (1 A = 0.1 nm) closer than their maximum separation in excess water. However, the presence of 11 mol% cholesterol causes the bilayers to move apart of 35-A separation from the 19-A characteristic of pure DPPC in excess water. This swelling may result from a decrease in van der Waals attraction between bilayers or from an increase in bilayer repulsion. Differences in bilayer interaction can be a cause for phase separation. More importantly these differences can cause changes in the composition of regions of membranes approaching contact. At 11 mol%, cholesterol substantially increases the lateral compressibility of DPPC bilayers leading to higher lateral density fluctuations and potentially higher bilayer permeability.

Chemical Phenomena↗