Hyperosmosis enhances radiation and hydroxyurea resistance of Schizosaccharomyces pombe checkpoint mutants through the spindle checkpoint and delayed cytokinesis

The DNA damage and stress response pathways interact to regulate cellular responses to genotoxins and environmental stresses. How these pathways interact in Schizosaccharomyces pombe is not well understood. We demonstrate that osmotic stress suppresses the DNA damage sensitivity of checkpoint mutants, and that this occurs through three distinct cell cycle delays. A delay in G2/M is dependent on Srk1. Progression through mitosis is halted by the Mad2‐dependent spindle checkpoint. Finally, cytokinesis is impaired by modulating Cdc25 expression. These three delays, imposed by osmotic stress, together compensate for the loss of checkpoint signalling.     

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.     

Adaptation of Natural Microbial Communities to Degradation of Xenobiotic Compounds: Effects of Concentration, Exposure Time, Inoculum, and Chemical Structure

Adaptation of microbial communities to faster degradation of xenobiotic compounds after exposure to the compound was studied in ecocores. Radiolabeled test compounds were added to cores that contained natural water and sediment. Adaptation was detected by comparing mineralization rates or disappearance of a parent compound in preexposed and unexposed cores. Microbial communities in preexposed cores from a number of freshwater sampling sites adapted to degrade p-nitrophenol faster; communities from estuarine or marine sites did not show any increase in rates of degradation as a result of preexposure. Adaptation was maximal after 2 weeks and was not detectable after 6 weeks. A threshold concentration of 10 ppb (10 ng/ml) was observed; below this concentration no adaptation was detected. With concentrations of 20 to 100 ppb (20 to 100 ng/ml), the biodegradation rates in preexposed cores were much higher than the rates in control cores and were proportional to the concentration of the test compound. In addition, trifluralin, 2,4-dichlorophenoxyacetic acid, and p-cresol were tested to determine whether preexposure affected subsequent biodegradation. Microbial communities did not adapt to trifluralin. Adaptation to 2,4-dichlorophenoxyacetic acid was similar to adaptation to nitrophenol. p-Cresol was mineralized rapidly in both preexposed and unexposed communities.     

Detecting non-neutral heterogeneity across a region of DNA sequence in the ratio of polymorphism to divergence

Natural selection, in the form of balancing selection or selective sweeps, can result in a decoupling of the amounts of molecular polymorphism and divergence. Thus natural selection can cause some areas of DNA sequence to have greater silent polymorphism, relative to divergence between species, than other areas. It would be useful to have a statistical test for heterogeneity in the polymorphism to divergence ratio across a region of DNA sequence, one that could identify heterogeneity greater than that expected from the neutral processes of mutation, drift, and recombination. The only currently available test requires that a region be arbitrarily divided into sections that are compared with each other, and the subjectivity of this division could be problematic. Here a test is proposed in which runs of polymorphic and fixed sites are counted, where a "run" is a set of one or more sites of one type preceded and followed by the other type. The number of runs is smaller than otherwise expected if polymorphisms are clumped together. By simulating neutral evolution and comparing the observed number of runs to the simulations, a statistical test is possible which does not require any a priori decisions about subdivision.      

Pindolol acts as beta-adrenoceptor agonist in orthostatic hypotension: therapeutic implications.

Three bedridden patients with severe orthostatic hypotension due to chronic autonomic failure were treated with pindolol (15 mg/day), a beta-adrenoceptor antagonist with partial agonist activity. While taking this drug the patients were free of orthostatic symptoms: they could walk, and standing blood pressure was maintained above 90/50 mm Hg. Supine heart rate rose during treatment by 12-21 beats/minute, and stroke volume and cardiac output by 12-24 ml and 1.5-3.1 l/min respectively. Supine blood pressure rose by 21-68 mm Hg systolic and 14-49 mm Hg diastolic. Pindolol 15 mg/day was therapeutically effective in these three patients with severe orthostatic hypotension due to chronic autonomic failure. Further studies in a larger series of patients are needed to confirm this result.     

Book reviews

Book reviewed in this article: Sweet Potato Pest Management : A Global Perspective. Edited by R.K. Jansson and K.V. Raman. E. Wajnberg, S. B. Vinson (eds.) Trichogramma and other egg parasitoids . Coll. Les Colloques de l'INRA, N° 56, 1991. Morphogenetic hormones of arthropods . Vol. III. Roles in histogenesis, organogenesis and morphogenesis. Edited by A.P. Gupta.