Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016632 (Fox)
 1,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection by hepatitis C viruses (HCVs) is a serious medical problem with no broadly effective treatment available for the progression of chronic hepatitis. The catalytic activity of a viral serine protease located in the N-terminal one-third of nonstructural protein 3 (NS3) is required for polyprotein processing at four site-specific junctions. The three-dimensional crystal structure of the NS3-NS4A co-complex [Kim, J. L., Morgenstern, K. A., Lin, C., Fox, T., Dwyer, M. D., Landro, J. A., Chambers, S. P., Markland, W., Lepre, C. A., O'Malley, E. T., Harbeson, S. L., Rice, C. M., Murcko, M. A., Caron, P. R., & Thomson, J. A. (1996) Cell 87, 343-355] delineates a small hydrophobic region within the 54-residue NS4A protein that intercalates with and makes extensive contacts to the core of the protease. The current investigation addresses the mechanism of NS3 protease catalytic activation by NS4A utilizing a small synthetic NS4A peptide (residues 1678-1691 of the virus polyprotein sequence) and the recombinantly expressed protease domain of NS3. The addition of NS4A dramatically increased NS3 kcat and kcat/Km catalytic parameters when measured against small peptide substrates representing the different site-specific junctions of the polyprotein. The catalytic effect of natural and non-natural amino acid substitutions at the P1 position in a 5A/5B peptide substrate was investigated. NS3-NS4A demonstrated a marked catalytic preference for the cysteine residue commonly found in authentic substrates. The pH dependence of the NS3 hydrolysis reaction is not affected by the presence of NS4A. This result suggests that NS4A does not change the pKa values of the active site residues of NS3 protease. A steady state kinetic analysis was performed and indicated that the binding of NS4A and the peptide substrate occurs in an ordered fashion during the catalytic cycle, with NS4A binding first. Two distinct kinetic classes of peptidyl inhibitors based upon the 5A/5B cleavage site were identified. An NS4A-independent class is devoid of prime residues. A second class of inhibitors is NS4A-dependent and contains a natural or non-natural cyclic amino acid substituted for the commonly found P1' residue serine. These inhibitors display an up to 80-fold increase in affinity for NS3 protease in the presence of NS4A. Sequential truncation of prime and P residues from this inhibitor class demonstrated the fact that the P4' and P1' residues are crucial for potent inhibition. The selectivity of this NS4A effect is interpreted using a model of the 5A/5B decapeptide substrate bound to the active site of the NS3-NS4A structure.
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PMID:Mechanistic role of an NS4A peptide cofactor with the truncated NS3 protease of hepatitis C virus: elucidation of the NS4A stimulatory effect via kinetic analysis and inhibitor mapping. 923 76

Infection with gastrointestinal nematodes, particularly Ostertagia species in domestic ruminants, continues to represent an important cause of impaired productivity in temperate parts of the world. The mechanisms responsible for such losses include changes in feed intake, gastrointestinal function, protein, energy and mineral metabolism, and body composition, and were described in detail at the last Ostertagia Workshop (Fox, M.T. 1993. Pathophysiology of infection with Ostertagia ostertagi in cattle. Vet. Parasitol. 46, 143-158). Since then, research into the pathophysiology of infection has focused on three main areas: mechanisms of appetite depression; changes in gastrointestinal function; and alterations in protein metabolism. Studies on the mechanisms responsible for appetite depression in Ostertagia-infected cattle have continued to support a close association between impaired feed intake and elevated blood gastrin concentrations. Alternative explanations will have to be sought, however, to account for the drop in feed intake associated with intestinal parasitism in which blood gastrin levels normally remain unaltered. Such work in sheep, and more recently in laboratory animals, has shown that central satiety signals are associated with inappetance accompanying intestinal infections, rather than changes in peripheral peptide levels. Changes in gastrointestinal function have also attracted attention, particularly the mechanisms responsible for increases in certain gut secretions, notably pepsinogen and gastrin. Elegant experimental studies have established that the gradient in pepsinogen concentration between abomasal mucosa and local capillaries could alone account for the increase in blood concentrations seen in Type 1 ostertagiosis. Additional factors, such as increases in capillary permeability and in surface area, probably contribute to such responses in cases of Type 2 disease. The increase in blood gastrin concentrations that accompanies Ostertagia infections in cattle is associated with the concurrent rise in abomasal pH. However, in sheep, additional factors appear to contribute to the hypergastrinaemia which may occur independent of parasite-induced changes in gastric pH. Alterations in protein metabolism have been well documented in ruminants harbouring monospecific infections with either abomasal or intestinal nematodes. More recently, however, the effects of dual abomasal and intestinal infections have been investigated and demonstrated that the host is able to compensate for impaired abomasal digestion provided that the intestinal parasite burden does not occupy the main site of digestion and absorption in the latter organ. An alternative method of improving the host's protein balance, dietary supplementation, has been shown not only to improve productivity, but also to enhance the innate resistance of susceptible breeds of sheep to Haemonchus and to accelerate the development of immunity to Ostertagia in lambs.
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PMID:Pathophysiology of infection with gastrointestinal nematodes in domestic ruminants: recent developments. 946 Feb 3

Infectious diseases are often transmitted through local interactions. Yet, both surveillance and control measures are implemented within administrative units. Capturing local transmission processes and spatial coupling between regions from aggregate level data is therefore a technical challenge that can shed light on both theoretical questions and practical decisions. Fox rabies has been eliminated from much of Europe through oral rabies vaccination (ORV) programmes. The European Union (EU) co-finances ORV to maintain rabies freedom in EU member and border states via a cordon sanitaire. Models to capture local transmission dynamics and spatial coupling have immediate application to the planning of these ORV campaigns and to other parts of the world considering oral vaccination. We fitted a hierarchical Bayesian state-space model to data on three decades of fox rabies cases and ORV campaigns from Eastern Germany. Specifically, we find that (i) combining regional spatial coupling and heterogeneous local transmission allows us to capture regional rabies dynamics; (ii) incursions from other regions account for less than 1% of cases, but allow for re-emergence of disease; (iii) herd immunity achieved through bi-annual vaccination campaigns is short-lived due to population turnover. Together, these findings highlight the need for regular and sustained vaccination efforts and our modelling approach can be used to provide strategic guidance for ORV delivery. Moreover, we show that biological understanding can be gained from inference from partially observed data on wildlife disease.
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PMID:Local rabies transmission and regional spatial coupling in European foxes. 3246 61