Testing the association between residential fungus and health using ergosterol measures and cough recordings

Questionnaire surveys in several countries have consistently detected an association between symptoms and residential mould growth. Confirmation by objective measures would strengthen the argument for causality. To address this issue, quantitative and qualitative fungal measures (airborne ergosterol and viable fungi in dust) were compared to respiratory symptoms (n = 403) and nocturnal cough recordings (n = 145) in Canadian elementary schoolchildren during the winter of 1993–1994. There was a 25 percent to 50 percent relative increase in symptom prevalence when mould was reported to be present (p < 0.05). However, neither symptoms nor recorded cough was related to objective measures of mould. In conclusion, the inability to find an association between objective measures of fungus and health suggest that either these objective measures, or the traditionally used questionnaire data are inaccurate. This discrepancy limits the acceptance of a causal relation between indoor fungal growth and illness.This revised version was published online in October 2005 with corrections to the Cover Date.     

What a tangled web we weave: discriminating between malingering and anosmia

Two groups of normosmic subjects were instructed to feign a total olfactory loss when tested with the Olfactory Confusion Matrix (OCM). One of the groups was given specific instructions as to the number of odorants and trials in the test, as well as the number of items that might be expected to be correctly identified by chance. The responses of both groups of malingerers were compared with responses gathered from a group of anosmic patients. The groups did not differ in terms of performance level (percent correct). In spite of the similarity in terms of accuracy level, an analysis of the pattern of OCM responses to an irritant allowed the anosmic patients to be distinguished from subjects attempting to feign a loss. Subjects were given explicit details about the test performed at the same level as those simply told to feign a loss. These results suggest that the OCM is an effective tool in separating malingering from anosmia.     

Effects of ethanol on lipid bilayers with and without cholesterol: the distearoylphosphatidylcholine system

Differential scanning calorimetry (DSC) and fluorescence spectroscopy are useful techniques for investigating the phase transitions of phospholipid bilayers. In this study, these methods have been extended to determine the effects of ethanol on DSPC and DSPC/2 mol.% cholesterol bilayers. The biphasic effect of the main transition was observed on the DSC heating scans above 0.60 M ethanol. In addition, the concentration at which the biphasic effect occurs is not significantly changed in the presence of 2 mol.% cholesterol. For the fluorescence studies, 1,6-diphenyl-1,3,5-hexatriene (DPH) has been incorporated into the bilayer to monitor the phase transitions through the displacement of DPH. This fluorescent probe is used to directly determine the onset of interdigitation in the bilayer systems as indicated by a large decrease in the DPH fluorescence intensity. The addition of cholesterol lowered and broadened the transition temperatures of the phosphatidylcholine (PC) system. However, 2 mol.% cholesterol did not have a significant effect on the induction of the interdigitated phase in DSPC as observed from the small difference in ethanol threshold concentration for the two systems. This suggests that DSPC forms a more stable interdigitated gel phase than other PCs with shorter acyl chains.     

Perceptual dominance time distributions in multistable visual perception

Perceptual multistability, alternative perceptions of an unchanging stimulus, gives important clues to neural dynamics. The present study examined 56 perceptual dominance time series for a Necker cube stimulus, for ambiguous motion, and for binocular rivalry. We made histograms of the perceptual dominance times, based on from 307 to 2478 responses per time series (median=612), and compared these histograms to gamma, lognormal and Weibull fitted distributions using the Kolmogorov–Smirnov goodness-of-fit test. In 40 of the 56 tested cases a lognormal distribution provided an acceptable fit to the histogram (in 24 cases it was the only fit). In 16 cases a gamma distribution, and in 11 cases a Weibull distribution, were acceptable but never as the only fit in either case. Any of the three distributions were acceptable in three cases and none provided acceptable fits in 12 cases. Considering only the 16 cases in which a lognormal distribution was rejected (p<0.05) revealed that minor adjustments to the fourth-moment term of the lognormal characteristic function restored good fits. These findings suggest that random fractal theory might provide insight into the underlying mechanisms of multistable perceptions.     

Potentiation of cytotoxic drug activity in human tumour cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1 inhibitors

The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line.     

A new 2-carbamoyl pteridine that inhibits mycobacterial FtsZ

The preparation of a new 2-carbamoyl pteridine, its activity data against FtsZ from M. tuberculosis (Mtb), and in vitro antibacterial data against Mtb strain H37Ra are presented.     

Partial characterisation of high-molecular weight glycoconjugates in the trail mucus of the freshwater pond snail Lymnaea stagnalis

We have studied the glycoconjugates in trail mucus of the pond snail Lymnaea stagnalis. The mucus was dissolved with 6 M guanidinium hydrochloride (GuHCl) and the major component was comprised of very high-M_r glycoconjugates that were eluted in the void volume of a Sepharose CL-4B gel-filtration column. This high-M_r material was pooled and thereafter subjected to density gradient centrifugation first in 4 M GuHCl/CsCl and subsequently 0.2 M GuHCl/CsCl to further remove non-glycosylated proteins and DNA. The harvested glycoconjugate pool chromatographed in the void volume of Sepharose CL-2B. However, reduction of disulfide bonds lowered the molecular size of approximately 80% of the void material yielding a major fragment and some minor smaller fragments in gel chromatography. The reduced glycoconjugates were digested with papain and yielded high molecular weight, proteinase-resistant glycopeptides. This fragmentation pattern is similar to that found for oligomeric gel-forming mucins in mammals and the amino acid composition (60% Ser/Thr) and sugar analysis of the glycopeptides is consistent with mucin-like molecules, there being no significant amounts of xylose or uronic acids. The residual 20% of the preparation, which apparently resisted reduction and protease digestion, had a similar amino acid composition to the bulk, but was somewhat different in sugar composition, containing some xylose and a significant amount of glucuronic acid. The two groups of molecules had very different morphologies in the electron microscope. Taken together, these data suggest that trail mucus is a complex mixture of at least two families of protein-glycoconjugate molecules based upon the gel-forming mucin and proteoglycan families, though we cannot rule out that polysaccharides may also be present.     

Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover

Notch signaling releases the Notch receptor intracellular domain (ICD), which complexes with CBF1 and Mastermind (MAM) to activate responsive genes. We previously reported that MAM interacts with CBP/p300 and promotes hyperphosphorylation and degradation of the Notch ICD in vivo. Here we show that CycC:CDK8 and CycT1:CDK9/P-TEFb are recruited with Notch and associated coactivators (MAM, SKIP) to the HES1 promoter in signaling cells. MAM interacts directly with CDK8 and can cause it to localize to subnuclear foci. Purified recombinant CycC:CDK8 phosphorylates the Notch ICD within the TAD and PEST domains, and expression of CycC:CDK8 strongly enhances Notch ICD hyperphosphorylation and PEST-dependent degradation by the Fbw7/Sel10 ubiquitin ligase in vivo. Point mutations affecting conserved Ser residues within the ICD PEST motif prevent hyperphosphorylation by CycC:CDK8 and stabilize the ICD in vivo. These findings suggest a role for MAM and CycC:CDK8 in the turnover of the Notch enhancer complex at target genes.