Vaginal involvement in a woman with Darier's disease: a case report

BACKGROUND: Involvement of the female genital tract by Darier's disease, an unusual genodermatosis, is uncommon, and the manifestation of the disease in a cervicovaginal smear is exceptionally rare. CASE: A 39-year-old woman had an abnormal Pap smear caused by involvement of the female genital tract by Darier's disease. Cytologic examination showed features consistent with a low grade squamous intraepithelial lesion, but during a biopsy it was found to be vaginal involvement by Darier's disease. CONCLUSION: The correct interpretation of cytologic findings is not possible when the diagnosis of Darier's disease is not known since a low grade squamous intraepithelial lesion cannot be ruled out. This case underlines the importance of knowing the patient's medical histoiy in any moment of medical attention.     

Correctly estimating how environmental stochasticity influences fitness and population growth

Increased temporal variance in life-history traits is generally predicted to decrease individual fitness and population growth. We show that a widely used result of stochastic sensitivity analysis that bolsters this generality is flawed because it ignores the effects of correlations between vital rates. Considering the effects of these correlations (although ignoring autocorrelations), we show that the apparently simple relationship between vital rate variance and fitness can be considerably more complex than previously thought. In particular, the previously estimated negative sensitivities of fitness or population growth to variance in a vital rate can be either enhanced by positive correlations between rates or reversed by negative correlations, even to the point that variability in a rate can increase fitness or population growth. We apply this new sensitivity calculation to data from the desert tortoise and discuss its interpretation in light of the factors generating vital rate correlations.     

Proton uptake upon anaerobic reduction of the Paracoccus denitrificans cytochrome c oxidase: a kinetic investigation of the K354M and D124N mutants

The kinetics and stoichiometry of the redox-linked protonation of the soluble Paracoccus denitrificans cytochrome c oxidase were investigated at pH = 7.2-7.5 by multiwavelength stopped-flow spectroscopy, using the pH indicator phenol red. We compared the wild-type enzyme with the K354M and the D124N subunit I mutants, in which the K- and D-proton-conducting pathways are impaired, respectively. Upon anaerobic reduction by Ru-II hexamine, the wild-type enzyme binds 3.3 +/- 0.6 H(+)/aa(3), i.e., approximately 1 H(+) in excess over beef heart oxidase under similar conditions and the D124N mutant 3.2 +/- 0.5 H(+)/aa(3). In contrast, in the K354M mutant, in which the reduction of heme a(3)-Cu(B) is severely impaired, approximately 0.8 H(+) is promptly bound synchronously with the reduction of heme a, followed by a much slower protonation associated with the retarded reduction of the heme a(3)-Cu(B) site. These results indicate that complete reduction of heme a (and Cu(A)) is coupled to the uptake of approximately 0.8 H(+), which is independent of both H(+)-pathways, whereas the subsequent reduction of the heme a(3)-Cu(B) site is associated with the uptake of approximately 2.5 H(+) transferred (at least partially) through the K-pathway. On the basis of these results, the possible involvement of the D-pathway in the redox-linked protonation of cytochrome c oxidase is discussed.     

The methylerythritol phosphate pathway is functionally active in all intraerythrocytic stages of Plasmodium falciparum

Two genes encoding the enzymes 1-deoxy-D-xylulose-5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase have been recently identified, suggesting that isoprenoid biosynthesis in Plasmodium falciparum depends on the methylerythritol phosphate (MEP) pathway, and that fosmidomycin could inhibit the activity of 1-deoxy-D-xylulose-5-phosphate reductoisomerase. The metabolite 1-deoxy-D-xylulose-5-phosphate is not only an intermediate of the MEP pathway for the biosynthesis of isopentenyl diphosphate but is also involved in the biosynthesis of thiamin (vitamin B1) and pyridoxal (vitamin B6) in plants and many microorganisms. Herein we report the first isolation and characterization of most downstream intermediates of the MEP pathway in the three intraerythrocytic stages of P. falciparum. These include, 1-deoxy-D-xylulose-5-phosphate, 2-C-methyl-D-erythritol-4-phosphate, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol-2-phosphate, and 2-C-methyl-D-erythritol-2,4-cyclodiphosphate. These intermediates were purified by HPLC and structurally characterized via biochemical and electrospray mass spectrometric analyses. We have also investigated the effect of fosmidomycin on the biosynthesis of each intermediate of this pathway and isoprenoid biosynthesis (dolichols and ubiquinones). For the first time, therefore, it is demonstrated that the MEP pathway is functionally active in all intraerythrocytic forms of P. falciparum, and de novo biosynthesis of pyridoxal in a protozoan is reported. Its absence in the human host makes both pathways very attractive as potential new targets for antimalarial drug development.     

Osmotic response in Lactobacillus casei ATCC 393: biochemical and biophysical characteristics of membrane

The biochemical and biophysical properties of the membrane and some general characteristics of the response of Lactobacillus casei ATCC 393 (reclassified Lactobacillus zeae) to hyperosmotic conditions were studied. Under hypertonic conditions, the hydrophobicity and the bile salt sensitivity of the cultures were increased. The glycolipid AcylH3DG is only present in membranes of NaCl containing medium, whereas, H4DG undergoes a significant increment and H2DG a significant decrease. The fluidity of both the purified membranes and the total lipid vesicles, as determined with the fluorescent probe DPH, did not change in conditions of high salinity. This was coincident with changes in the fatty acid (FA) composition where an increase in the saturated/unsaturated FA ratio was compensated by a rise in the fluidifying 11,12-methyleneoctadecanoic FA (cyc 19:0). Under osmotic stress conditions, Laurdan and acridine orange in total lipid vesicles showed increased lateral lipid packing and proton permeability, respectively.     

Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein Ialpha

Peptidoglycan recognition proteins (PGRPs) are pattern recognition receptors of the innate immune system that bind, and in some cases hydrolyze, peptidoglycans (PGNs) on bacterial cell walls. These molecules, which are highly conserved from insects to mammals, participate in host defense against both Gram-positive and Gram-negative bacteria. We report the crystal structure of the C-terminal PGN-binding domain of human PGRP-Ialpha in two oligomeric states, monomer and dimer, to resolutions of 2.80 and 1.65 A, respectively. In contrast to PGRPs with PGN-lytic amidase activity, no zinc ion is present in the PGN-binding site of human PGRP-Ialpha. The structure reveals that PGRPs exhibit extensive topological variability in a large hydrophobic groove, located opposite the PGN-binding site, which may recognize host effector proteins or microbial ligands other than PGN. We also show that full-length PGRP-Ialpha comprises two tandem PGN-binding domains. These domains differ at most potential PGN-contacting positions, implying different fine specificities. Dimerization of PGRP-Ialpha, which occurs through three-dimensional domain swapping, is mediated by specific binding of sodium ions to a flexible hinge loop, stabilizing the conformation found in the dimer. We further demonstrate sodium-dependent dimerization of PGRP-Ialpha in solution, suggesting a possible mechanism for modulating PGRP activity through the formation of multivalent adducts.     

The non-polar solvent potential of mean force for the dimerization of alanine dipeptide: the role of solute-solvent van der Waals interactions

The non-polar component of the potential of mean force of dimerization of alanine dipeptide has been calculated in explicit solvent by free energy perturbation. We observe that the calculated PMF is inconsistent with a non-polar hydration free energy model based solely on the solute surface area. The non-linear behavior of the solute-solvent van der Waals energy is primarily responsible for the non-linear dependence of the potential of mean force with respect to the surface area. The calculated potential of mean force is reproduced by an implicit solvent model based on a solvent continuum model for the solute-solvent van der Waals interaction energy and the surface area for the work of forming the solute cavity.