Altered Dihydropyrimidine Dehydrogenase Activity Associated with Mild Toxicity in Patients Treated with 5-Fluorouracil Containing Chemotherapy

Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5-fluorouracil (5FU). In patients treated with capecitabine or 5FU combined with other chemotherapeutic drugs, DPD activity in peripheral blood mononuclear cells was increased in patients experiencing grade I/II neutropenia. In contrast, decreased DPD activity proved to be associated with grade I/II dermatological toxicity, including hand-foot syndrome. Thus, patients with a low-normal or high-normal DPD activity proved to be at risk of developing mild toxicity upon treatment with 5FU-based chemotherapy, demonstrating the important role of DPD in the etiology of toxicity associated with 5FU and the catabolites of 5FU.     

Spatial Distributions of Early and Late Replicating Chromatin in Interphase Chromosome Territories

The surface area of chromosome territories has been suggested as a preferred site for genes, specific RNAs, and accumulations of splicing factors. Here, we investigated the localization of sites of replication within individual chromosome territories.In vivoreplication labeling with thymidine analogues IdUrd and CldUrd was combined with chromosome painting by fluorescentin situhybridization on three-dimensionally preserved human fibroblast nuclei. Spatial distributions of replication labels over the chromosome territory, as well as the territory volume and shape, were determined by 3D image analysis. During late S-phase a previously observed shape difference between the active and inactive X-chromosome in female cells was maintained, while the volumes of the two territories did not differ significantly. Domains containing early or mid to late replicating chromatin were distributed throughout territories of chromome 8 and the active X. In the inactive X-chromosome early replicating chromatin was observed preferentially near the territory surface. Most important, we established that the process of replication takes place in foci throughout the entire chromosome territory volume, in early as well as in late S-phase. This demonstrates that activity of macromolecular enzyme complexes takes place throughout chromosome territories and is not confined to the territory surface as suggested previously.     

Asymmetrical Effects of Prior Winning and Losing on Dominance in Sticklebacks (Gasterosteus aculeatus)

Reproductive male three-spined sticklebacks, Gasterosteus aculeatus L., without fighting experience, were given either an experience of dominance or an experience of inferiority. They were then tested for their ability to dominate an inexperienced male in a dyadic combat either a) immediately following the experience treatment, b) 3 h later or c) 6 h later. The effect of prior losing proved to be stronger and more prolonged than that of prior winning. The influence of non-experimental factors, and possible causes for this asymmetrical effect are discussed.     

Colorectal cancers choosing sides

In contrast to the majority of sporadic colorectal cancer which predominantly occur in the distal colon, most mismatch repair deficient tumours arise at the proximal side. At present, these regional preferences have not been explained properly. Recently, we have screened colorectal tumours for mutations in Wnt-related genes focusing specifically on colorectal location. Combining this analysis with published data, we propose a mechanism underlying the side-related preferences of colorectal cancers, based on the specific acquired genetic defects in β-catenin signalling.     

Kin discrimination in sticklebacks is mediated by social learning rather than innate recognition

Theory predicts several advantages for animals to recognize kin. These include inbreeding avoidance and an increase in inclusive fitness. In shoaling species, kin recognition may lead to an increased amount of altruism among shoal members. Adult, non‐reproductive three‐spined sticklebacks, Gasterosteus aculeatus, prefer to shoal with kin. This preference was shown for familiar as well as for unfamiliar individuals. However, whether it is based on learned cues of familiar individuals or on innate mechanisms like self‐referent phenotype matching or ‘true’ kin recognition through recognition alleles remains unknown. In our experiments, juvenile fish were given the choice between shoals that differed in relatedness and familiarity. The number of testfish who joined each group indicated that sticklebacks prefer to shoal with familiar kin when the alternative shoal was composed of unfamiliar non‐kin. When one shoal consisted of familiar kin while the second consisted of familiar non‐kin testfish did not show any preference. Kin recognition in sticklebacks is thus most likely mediated by social learning.     

Viral Load Levels Measured at Set-Point Have Risen Over the Last Decade of the HIV Epidemic in the Netherlands

Background

HIV-1 RNA plasma concentration at viral set-point is associated not only with disease outcome but also with the transmission dynamics of HIV-1. We investigated whether plasma HIV-1 RNA concentration and CD4 cell count at viral set-point have changed over time in the HIV epidemic in the Netherlands.

Methodology/Principal Findings

We selected 906 therapy-naïve patients with at least one plasma HIV-1 RNA concentration measured 9 to 27 months after estimated seroconversion. Changes in HIV-1 RNA and CD4 cell count at viral set-point over time were analysed using linear regression models. The ATHENA national observational cohort contributed all patients who seroconverted in or after 1996; the Amsterdam Cohort Studies (ACS) contributed seroconverters before 1996. The mean of the first HIV-1 RNA concentration measured 9–27 months after seroconversion was 4.30 log₁₀ copies/ml (95% CI 4.17–4.42) for seroconverters from 1984 through 1995 (n = 163); 4.27 (4.16–4.37) for seroconverters 1996–2002 (n = 232), and 4.59 (4.52–4.66) for seroconverters 2003–2007 (n = 511). Compared to patients seroconverting between 2003–2007, the adjusted mean HIV-1 RNA concentration at set-point was 0.28 log₁₀ copies/ml (95% CI 0.16–0.40; p<0.0001) and 0.26 (0.11–0.41; p = 0.0006) lower for those seroconverting between 1996–2002 and 1984–1995, respectively. Results were robust regardless of type of HIV-1 RNA assay, HIV-1 subtype, and interval between measurement and seroconversion. CD4 cell count at viral set-point declined over calendar time at approximately 5 cells/mm³/year.

Conclusion

The HIV-1 RNA plasma concentration at viral set-point has increased over the last decade of the HIV epidemic in the Netherlands. This is accompanied by a decreasing CD4 cell count over the period 1984–2007 and may have implications for both the course of the HIV infection and the epidemic.     

Change to alanine of one out of four selectivity filter glycines in KtrB causes a two orders of magnitude decrease in the affinities for both K and Na of the Na dependent K uptake system KtrAB from Vibrio alginolyticus

KtrAB from Vibrio alginolyticus is a recently described new type of high affinity bacterial K⁺ uptake system. Its activity assayed in an Escherichia coli K⁺ uptake negative mutant depended on Na⁺ ions (K_m of 40 μM). Subunit KtrB contains four putative P-loops. The selectivity filter from each P-loop contains a conserved glycine residue. Residue Gly-290 from the third P-loop selectivity filter in KtrB was exchanged for Ala, Ser or Asp. KtrB variants Ser-290 and Asp-290 were without activity. In contrast, KtrB variant Ala-290 was still active. This variant transported K⁺ with a two orders of magnitude decrease in apparent affinity for both K⁺ and Na⁺ with little effect on V_max.     

How predatory mites cope with the web of their tetranychid prey: a functional view on dorsal chaetotaxy in the Phytoseiidae

It has been proposed from behavioural observations that the ability of Phytoseiidae to penetrate the web is related to chaetotaxy. As phytoseiid species differ widely in chaetotaxy, as well as in their ability to cope with complex webs, this hypothesis was tested by studying relations between these two variables. In this paper we develop a simple method to quantify the degree to which the soma is protected from contact with the silk and apply it to phytoseiid species for which behavioural performance in the web is known from the literature. It is found that the better protected species experience less hinder from complex webs, such as produced byTetranychus spp. Moreover, they appear to be more successful in exterminating local populations ofTetranychus spp. Thus, setal patterns in the Phytoseiidae may well be a good indicator for selecting candidates for biological control ofTetranychus spp. Finally, we propose a parsimonious scenario for the evolution of dorsal chaetotaxy in the Phytoseiidae.