Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance

Infections caused by the yeast Candida albicans represent an increasing threat to debilitated and immunosuppressed patients, and neutropenia is an important risk factor. Monoclonal antibody depletion of neutrophils in mice was used to study the role of these cells in host resistance. Ablation of neutrophils increased susceptibility to both systemic and vaginal challenge. The fungal burden in the kidney increased threefold on day 1, and 100-fold on day 4, and infection was associated with extensive tissue destruction. However, a striking feature of the disseminated disease in neutrophil-depleted animals was the altered pattern of organ involvement. The brain, which is one of the primary target organs in normal mice, was little affected. There was a threefold increase in the number of organisms recovered from the brains of neutrophil-depleted mice on day 4 after infection, but detectable abscesses were rare. In contrast, the heart, which in normal mice shows only minor lesions, developed severe tissue damage following neutrophil depletion. Mice deficient in C5 demonstrated both qualitative and quantitative increases in the severity of infection after neutrophil depletion when compared with C5-sufficient strains. The results are interpreted as reflecting organ-specific differences in the mechanisms of host resistance.

Evidence that two independent host genes influence the severity of tissue damage and susceptibility to acute pyelonephritis in murine systemic candidiasis

Tissue damage in the kidney and brain after systemic infection with Candida albicans was examined in recombinant inbred strains (AKXL) derived from AKR and C57/L progenitors. Nine of the 15 strains showed mild (C57/L-like) tissue damage. Of the remainder, two strains developed lesions comparable to the AKR parental strain, whereas four exhibited a much move severe pattern of tissue damage. This was characterized by pronounced mycelial growth in the brain, and gross oedema of the kidney, with extensive fungal colonization and marked tissue destruction. The presence of the null allele of the haemolytic complement gene (Hc) may be necessary but not sufficient, for the expression of the very severe lesions. The results were interpreted as reflecting the actions of two independent genes, which have been designated Carg1 and Carg2 (Candida albicans resistance genes 1 and 2). (C) 1997 Academic Press Limited.

Structure optimization combining soft-core interaction functions, the diffusion equation method, and molecular dynamics

Smoothing the potential energy surface for structure optimization is a general and commonly applied strategy. We propose a combination of soft-core potential energy functions and a variation of the diffusion equation method to smooth potential energy surfaces, which is applicable to complex systems such as protein structures; The performance of the method was demonstrated by comparison with simulated annealing using the refinement of the undecapeptide Cyclosporin A as a test case. Simulations were repeated many times using different initial conditions and structures since the methods are heuristic and results are only meaningful in a statistical sense.

Proposal for the interaction of non-conventional partial agonists and catecholamines with the 'putative beta(4)-adrenoceptor' in mammalian heart

1. Evidence for a 'putative beta(4)-adrenoceptor' originated over 20 years ago when cardiostimulant effects were observed to nonconventional partial agonists, These agonists were originally described as beta(1)- and beta(2)-adrenoceptor antagonists; however, they cause cardiostimulant effects at much higher concentrations than those required to block beta(1)- and beta(2)-adrenoceptors. Cardiostimulant effects of non-conventional partial agonists have been observed in mouse, rat, guinea-pig, cat, ferret and human heart tissues, 2. The receptor is expressed in several heart regions, including the sinoatrial node, atrium and ventricle, 3. The receptor is resistant to blockade by most antagonists that possess high affinity for beta(1)- and beta(2)- adrenoceptors, but is blocked with moderate affinity by (-)-bupranolol and CGP 20712A. 4. The receptor is pharmacologically distinct from the beta(3)-adrenoceptor. Micromolar concentrations of beta(3)-adrenoceptor agonists have no agonist or blocking activity, The receptor is also resistant to blockade by a beta(3)-adrenoceptor-selective antagonist. 5. The receptor mediates increases in cAMP levels and cAMP-dependent protein kinase (PK) A activity in cardiac tissues. Phosphodiesterase inhibition potentiates the positive chronotropic and inotropic effects of non-conventional partial agonists. 6. The receptor mediates hastening of atrial and ventricular relaxation, which is consistent with involvement of a cAMP-dependent pathway. 7. The non-conventional partial agonist (-)-[H-3]-CGP 12177A labels the cardiac putative beta(4)-adrenoceptor, Non-conventional partial agonists compete for binding with affinities that are closely similar to their agonist potencies, Catecholamines compete for binding in a stereoselective manner with a rank order of affinity of (-)-R0363 > (-)-isoprenaline > (-)-noradrenaline greater than or equal to (-)-adrenaline much greater than (-)-isoprenaline, suggesting that catecholamines can interact with the receptor. 8. The putative beta(4)-adrenoceptor appears to be coupled to the G(s)-adenylyl cyclase system, which could serve as a guide to its future cloning, Activation of the receptor may plausibly improve diastolic function but could also mediate arrhythmias.