Effect of acute global ischemia on the upper limit of vulnerability: a simulation study

The goal of this modeling research is to provide mechanistic insight into the effect of altered membrane kinetics associated with 5-12 min of acute global ischemia on the upper limit of cardiac vulnerability (ULV) to electric shocks. We simulate electrical activity in a finite-element bidomain model of a 4-mm-thick slice through the canine ventricles that incorporates realistic geometry and fiber architecture. Global acute ischemia is represented by changes in membrane dynamics due to hyperkalemia, acidosis, and hypoxia. Two stages of acute ischemia are simulated corresponding to 5-7 min (stage 1) and 10-12 min (stage 2) after the onset of ischemia. Monophasic shocks are delivered in normoxia and ischemia over a range of coupling intervals, and their outcomes are examined to determine the highest shock strength that resulted in induction of reentrant arrhythmia. Our results demonstrate that acute ischemia stage 1 results in ULV reduction to 0.8A from its normoxic value of 1.4A. In contrast, no arrhythmia is induced regardless of shock strength in acute ischemia stage 2. An investigation of mechanisms underlying this behavior revealed that decreased postshock refractoriness resulting mainly from 1) ischemic electrophysiological substrate and 2) decrease in the extent of areas positively-polarized by the shock is responsible for the change in ULV during stage 1. In contrast, conduction failure is the main cause for the lack of vulnerability in acute ischemia stage 2. The insight provided by this study furthers our understanding of mechanisms by which acute ischemia-induced changes at the ionic level modulate cardiac vulnerability to electric shocks.     

The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress

The budding yeast S phase checkpoint responds to hydroxyurea-induced nucleotide depletion by preventing replication fork collapse and the segregation of unreplicated chromosomes. Although the block to chromosome segregation has been thought to occur by inhibiting anaphase, we show checkpoint-defective rad53 mutants undergo cycles of spindle extension and collapse after hydroxyurea treatment that are distinct from anaphase cells. Furthermore, chromatid cohesion, whose dissolution triggers anaphase, is dispensable for S phase checkpoint arrest. Kinetochore-spindle attachments are required to prevent spindle extension during replication blocks, and chromosomes with two centromeres or an origin of replication juxtaposed to a centromere rescue the rad53 checkpoint defect. These observations suggest that checkpoint signaling is required to generate an inward force involved in maintaining preanaphase spindle integrity during DNA replication distress. We propose that by promoting replication fork integrity under these conditions Rad53 ensures centromere duplication. Replicating chromosomes can then bi-orient in a cohesin-independent manner to restrain untimely spindle extension.     

Contact dermatitis associated with the use of Always sanitary napkins.

OBJECTIVE: To report a clinical association between vulvar irritation or contact dermatitis and the use of Always sanitary napkins. DESIGN: Case series. SETTING: A gynecology practice in Montreal. PATIENTS: Women presenting between September 1991 and September 1994 with itching or burning of areas that would be in contact with a sanitary napkin (mons pubis, external surfaces of the vulva and perineum) beginning at least 1 day after the use of the napkins was started and less than 5 days after the use was stopped. RESULTS: Twenty-eight women experienced vulvar itching and burning, often associated with eruptions resembling contact dermatitis, of the vulvar and perineal surfaces after using Always sanitary napkins. Twenty-six reported that symptoms disappeared after they stopped using that brand of sanitary napkin. Seven women who later used the same brand again reported a recurrence of the vulvar irritation. CONCLUSION: The findings of this case series reveal Always sanitary napkins as a potentially important cause of recurrent vulvitis. Physician awareness of the association will enable effective advice and relief for a large number of women suffering "chronic vaginitis".     

The efficiency of folding of some proteins is increased by controlled rates of translation in vivo. A hypothesis

We propose that the way in which some proteins fold is affected by the rates at which regions of their polypeptide chains are translated in vivo. Furthermore, we suggest that their gene sequences have evolved to control the rate of translational elongation such that the synthesis of defined portions of their polypeptide chains is separated temporally. We stress that many proteins are capable of folding efficiently into their native conformations without the help of differential translation rates. For these proteins the amino acid sequence does indeed contain all the information needed for the polypeptide chain to fold correctly (even in vitro, after denaturation). However, other proteins clearly do not fold efficiently into their native conformation in vitro. We argue that the efficiency of folding of these problematic proteins in vivo may be improved by controlled synthesis of the nascent polypeptide.     

Electron microscopy and structural model of human fibronectin receptor.

Highly-purified human fibronectin receptor (a heterodimer of two distinct subunits, alpha and beta) was studied using electron microscopy and a variety of preparative procedures. It was found that the receptor consists of a globular head approximately 80 by 120 A and two tails about 20 A thick and 180-200 A long. The whole complex is approximately 280 A long. At low concentrations of detergent the receptor forms doublets, triplets or rosettes associated with the tails which possess the transmembrane portion of the molecule. Computer-assisted structure prediction using the published amino acid sequence of both subunits showed differences in the secondary structure of the tails, the alpha-tail being rich in beta-strands, the beta-tail having five cysteine-rich repeats analogous to the EGF-like repeats of laminin. Estimates of the length of the tails from the predicted structure conformed well with the dimensions obtained from electron micrographs.     

Effects of landmarks on territorial establishment

The period of territorial settlement is critical for territorial species, and the initial disputes to fix the boundaries can be energetically expensive. Territorial residents may be able to reduce defensive costs during settlement by selecting territories with landmarks at the sites of potential boundaries. We examined the effects of landmarks on defensive costs in a laboratory study of a cichlid fish, the blockhead, Steatocranus casuarius. In the landmark treatment, we placed a row of flat rocks across the centre of the aquaria; trials in the control treatment were identical but lacked landmarks. When landmarks were present, blockheads spent significantly less time in territorial defence, as they had fewer and shorter aggressive interactions with their neighbours. In addition, fights in landmark trials tended to be of lower intensity than fights in control trials: most fights in landmark trials included only low-level displays but most fights in control trials included physical contact. Both of these measures thus indicated that defensive costs were lowered by landmarks. In addition, in landmark trials typically both pairs of fish successfully established territories; in contrast, in control trials generally only one pair was able to establish a territory, with the other pair being evicted. The presence of landmarks appeared to make possible the division of the area available for settlement, with pairs establishing smaller territories than when there were no landmarks. Copyright 2003 Published by Elsevier Science Ltd on behalf of The Association for the Study of Animal Behaviour.      

Intensity of Land Use in the Catchment Influences Ecosystem Functioning Along a Freshwater-Marine Continuum

Intensification of catchment land use often adversely affects ecosystem health in rivers and estuaries via changes to physicochemistry and ecosystem functioning, but whether such land-use effects differ along a freshwater-marine continuum has not been studied. We investigated relationships between intensity of land use and two measures of ecosystem function in freshwater, estuarine and near-marine habitats. Standardized bioassays to determine cellulose breakdown (cotton and canvas strips) and algal accrual rates (ceramic tiles) were deployed in 10 river-to-marine continua whose catchment areas ranged from 2.6 to 99.6% developed. Using general linear models and an information-theoretic approach to select the best predictive models for our response variables, we found that higher dissolved phosphorus concentrations, linked with highly developed catchments, were associated with greater rates of cellulose decomposition (both tensile strength loss and mass loss). Furthermore, after controlling for the contribution of phosphorus or salinity, decomposition rates in freshwater and near-marine habitats generally responded curvilinearly to catchment development, indicating the involvement of additional unmeasured, land-use-related physicochemical or biological variables. The strength and shape of relationships between percentage developed land area and algal biomass accrual rates also contrasted among freshwater (strongest, curvilinear), mid-estuary (intermediate, positive), and near-marine sites (weakest, no obvious shape). Because land-use intensity can influence ecosystem functioning along the entire continuum from streams and rivers to estuaries and coasts, resource managers should adopt an integrated approach to decisions affecting catchment land use.