Different esterase activities of exponential and plateau phases of EMT6 cells monitored by flow cytofluorimetry.

The reaction rates of enzymes hydrolysing fluorescein diacetate have been studied in populations of intact tissue-culture EMT6, cells using flow cytofluorimetric techniques. It was found that the activity of these enzymes increased in plateau phases and that this correlated inversely with plating efficiency. Highly abnormal substrate-dependent reaction velocity kinetics were found in 14-, 21-, 28- and 35-day cultures

Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours.

Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its O-demethylated metabolite, Ro-05-9963, for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour. Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS, this apparent advantage was offset by peak tumour levels 50% or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-05-9963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization produced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives. Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0.5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified

Evaluation of the gn-->pi-p differential cross sections in the Delta-isobar region

Differential cross sections for the process gn-->pi-p have been extracted from MAMI-B measurements of gd-->pi-pp, accounting for final-state interaction effects, using a diagrammatic technique taking into account the NN and piN final-state interaction amplitudes. Results are compared to previous measurements of the inverse process, pi-p--> ng, and recent multipole analyses.Comment: 6 pages, 4 figures. v2: Further clarifications and minor changes. A new figure inserte

Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology.

Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ

Sex differences in cognition, emotional reactivity, and motor ability in gonadally-intact middle-aged marmosets (Callithrix jacchus)

Sex differences in cognition are well documented. Women outperform men on measures of perceptual speed and verbal abilities, while men outperform women on tests of spatial processing. Robust sex differences also exist in stress responses. However, it is unclear how these sex differences change over time and whether males and females follow different trajectories of age-related cognitive decline. Studies in nonhuman primate models can help resolve this issue. The common marmoset (Callithrix jacchus) is a New World primate with a short lifespan that can perform complex cognitive tasks in computerized settings that are comparable to those used with humans. The present study is part of a longitudinal project aimed at determining whether males and females follow different trajectories of cognitive aging. This report focuses on sex differences at study entry. Thirteen marmosets (7 females), aged 4-6 years were tested on a comprehensive battery of tasks assessing cognitive function, motor skills and emotional reactivity. For cognition, monkeys were initially trained on a simple visual discrimination problem, followed by reversal learning using the Cambridge Neuropsychological Test Automated Battery (CANTAB). They also performed the Hill-and-Valley task as a measure of fine motor skills. To assess emotional reactivity, each marmoset was separated from their colony for 7 hours. Behavioral assessments, which involved recording the occurrence of approximately 25 behaviors, occurred a total of 6 times: immediately before separation, 3 times during separation, immediately after separation, and 24-hr later. No sex difference was found for simple discrimination, but males tended to perform better than females on the reversal learning task. No sex difference was observed in motor skills. During separation from the colony, females were more reactive than males, as indicated by more agitated locomotion, and vocalizations. Together, these findings expand upon previous studies and demonstrate sex differences in reversal learning and emotional reactivity in gonadally-intact middle-aged marmosets. As the study progresses, we should be able to determine the neural correlates of these sex differences and how they may change with aging. Supported by NIH grant AG04626

Extended Partial-Wave Analysis of piN Scattering Data

We present results from a comprehensive partial-wave analysis of pi+-p elastic scattering and charge-exchange data, covering the region from threshold to 2.6 GeV in the lab pion kinetic energy, employing a coupled-channel formalism to simultaneously fit pi-p-->eta n data to 0.8 GeV. Our main result, solution SP06, utilizes a complete set of forward and fixed-t dispersion relation constraints applied to the piN elastic amplitude. The results of these analyses are compared with previous solutions in terms of their resonance spectra and preferred values for couplings and low-energy parameters.Comment: 21 pages, 11 figure

A new model of the human atrial myocyte with variable T-tubule organization for the study of atrial fibrillation

Atrial fibrillation is the most common arrhythmia, yet treatment strategies are sub-optimal due to incomplete understanding of the underlying mechanisms. Spatiotemporal sub-cellular calcium cycling may play a critical role in the development of alternans and spontaneous activity, which may underlie arrhythmia in the human atria. In this study, we construct a novel electrophysiological model of the human atrial myocyte which incorporates new data on atrial intracellular structure and explicitly accounts for variations in T-tubule organization. The model reproduces spatio-temporal calcium dynamics associated with normal cardiac excitation. In preliminary simulations, the model demonstrates that a loss of T-tubules can promote both alternans and spontaneous calcium waves. The model produced in this study provides novel insight into arrhythmia mechanisms in the human atria and provides a platform for future investigation of proarrhythmic calcium dynamics