Stacking interactions of ApA analogues with modified backbones

CD spectra have been measured as a function of temperature for a number of ApA analogues with modified backbones. Oligonucleotides with these modified backbones are being used as antisense agents having potential as viral therapeutics. Results of these studies show that when a carbonyl is substituted for the phosphate to produce an uncharged backbone, the analogues that have either sugar or morpholino substitution do not stack. In contrast, when a morpholino group is substituted for the sugar and the phosphate is modified so as to be uncharged, there is strong base stacking. Stacking interactions in the phosphorus-linked morpholino analogues are at least as strong as those found in d(ApA). The stacking interactions in ApA are weak by comparison. Singular value decomposition demonstrates that the stacking is two state, and Taylor series decomposition yields a coefficient that measures base stacking interactions. The van't Hoff equation is applied to the base stacking coefficient from the Taylor series fitting to give thermodynamic parameters.     

Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest

The anti-tumour alkaloid taxol shows strong cytotoxic and antiproliferative activity in two human malignant glioma cell lines, T98G and LN-229. CD95 (Fas/APO-1) ligand is a novel cytotoxic cytokine of the tumour necrosis factor (TNF) family that exerts prominent antiglioma activity. At clinically relevant taxol concentrations of 5-100 nM, taxol and CD95 ligand showed significant synergistic cytotoxicity and growth inhibition. High concentrations of taxol induced G/M cell cycle arrest in both cell lines. The synergy of taxol and CD95 ligand was independent of cell cycle effects of taxol as synergy was achieved at much lower taxol concentrations than G2/M arrest and as cell cycle effects of taxol were unaffected by co-exposure to CD95 ligand. Similarly, high concentrations of taxol were required to induce p53 activity in the p53 wild-type cell line LN-229. This effect was not modulated by CD95 ligand, suggesting that synergy is also independent of p53 activation. However, taxol induced a mobility shift of the bcl-2 protein on immunoblot analysis, indicative of bcl-2 phosphorylation. Bcl-2 phosphorylation on serine was confirmed by immunoprecipitation and phosphoserine immunoblot analysis. Considering (1) that phosphorylation of bcl-2 interferes with its heterodimerization with bax and (2) the inhibition of CD95-mediated apoptosis by bcl-2, we propose that taxol sensitizes malignant glioma cells to CD95 ligand by increasing the functional bax/bcl-2 rheostat in favour of bax and thus cell death.     

Dermatomyositis and nasopharyngeal carcinoma

Four novel series of 4(3 H)-quinazolinone derivatives have been synthesized by cyclization of the intermediate 3-aryl-2-(6-aryl-2-cyclohexen-1-on-5-yl)-4(3 H)-quinazolinones 3a-f with hydrazine, phenylhydrazine, hydroxylamine and thiourea. The products are 3-aryl-2-(6-aryl-3-methyl-1 H-4,5-dihydrobenzo[d]pyrazol-4-yl)-4(3 H)-quinazolinones 4a-f; 3-aryl-2-(6-aryl-3-methyl-1-phenyl-1 H-4,5-dihydrobenzo[d]pyrazol-4-yl)-4(3 H)-quinazolinones 4g-1; 3-aryl-2-(6-aryl-3-methyl-4,5-dihydrobenzo[d]-1,2-oxazol-4-yl)-4(3 H)-quinazolinones 5a-f, and 3-aryl-2-(7-aryl-4-methyl-5,6-dihydro-2(1 H)thioxoquinazolin-5-yl)-4(3 H)-quinazolinones 6a-f. Some of these compounds showed anti-inflammatory activity comparable to or higher than that of the reference compound proquazone.     

Effects of days open on annualized milk yields in current and following lactations

Length of open period affected annualized yield [(total lactation yield/calving interval) 365]. Yield was maximum with more days open for low, as opposed to high, peak production and for primiparous, as opposed to multiparous, cows. Interactions with days open were not found for mean herd production or cow production relative to the herd mean. Number of days open for maximum yield was similar for milk, fat, and economically fat-corrected milk [.67 kg milk + 10 kg fat]. Correction factors were derived by smoothed least square means of days open classes. Additive adjustment factors were more appropriate than multiplicative adjustment factors. Records adjusted for days open were not able to predict the following lactation yield significantly better than unadjusted records. Cumulative yield of current and following annualized lactations, including the contribution of the calf expressed in units of milk production, was greatest at 117 and 98 days open for primiparous and multiparous cows. For cows with high peak production maximum yield was with 12 to 14 fewer days open than for cows with moderate peak. Conception prior to 2 mo postpartum had an adverse effect on cumulative yield.     

Robert Koch and the modern investigator

Combining a habituation-recovery paradigm with procedures to minimize brightness cues, we evaluated 1-3-month-olds' ability to discriminate among broadband mid- and long-wavelength stimuli. One-month olds showed evidence of discriminating a red (dominant lambda = 650 nm) from green (dominant lambda = 545 nm) but failed to discriminate either of these from a yellow (dominant lambda = 585 nm). At 2 months, infants showed evidence of discriminating 545-nm green from 585-nm yellow, but only at 3 months do they appear to discriminate 650-nm red from the yellow. Consistent with previous work, these data imply that chromatic discrimination emerges slowly over the first three postnatal months. Moreover, the developmental pattern is consistent with the notion that early human vision is limited by general rather than selective immaturities within the requisite retinal and neural mechanisms.     

A model for the unfoamed skin on microcellular foams

In microcellular plastics, an unfoamed skin that is integral with the foamed core can be created by allowing the nucleating gas to diffuse from the surfaces of a gas saturated specimen prior to foaming. In this paper, a semi-empirical model is proposed that predicts the skin thickness variation in microcellular foams as a function of gas desorption time. The model shows good agreement with experimental results on the polycarbonate–carbon dioxide system.