The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q

We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.63 on 6q; P<.0001 and P=.0001, respectively, after a genomewide permutation procedure). The second-best BPAD interaction evidence was observed between chromosomes 2q22-q24 and 15q26. Here, we also observed a symmetrical interaction (NPL scores of 6.26 on 2q and 4.59 on 15q; P=.0057 and .0022, respectively). We covered the implicated regions by genotyping additional marker sets and performed a detailed interaction linkage analysis, which narrowed the susceptibility intervals. Although the heterogeneity analysis produced less impressive results (highest NPL score of 3.32) and a less consistent picture, we achieved evidence of locus heterogeneity at chromosomes 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. Our results provide systematic insights in the framework of BPAD epistasis and locus heterogeneity, which should facilitate gene identification by the use of more-comprehensive cloning strategies.     

Dynein participates in chromosome segregation in fission yeast

Background information. In eukaryotic cells, proper formation of the spindle is necessary for successful cell division. For faithful segregation of sister chromatids, each sister kinetochore must attach to microtubules that extend to opposite poles (chromosome bi‐orientation). At the metaphase—anaphase transition, cohesion between sister chromatids is removed, and each sister chromatid is pulled to opposite poles of the cell by microtubule‐dependent forces. Results. We have studied the role of the minus‐end‐directed motor protein dynein by analysing kinetochore dynamics in fission yeast cells deleted for the dynein heavy chain (Dhc1) or the light chain (Dlc1). In these mutants, we found an increased frequency of cells showing defects in chromosome segregation, which leads to the appearance of lagging chromosomes and an increased rate of chromosome loss. By following simultaneously kinetochore dynamics and localization of the checkpoint protein Mad2, we provide evidence that dynein function is not necessary for spindle‐assembly checkpoint inactivation. Instead, we have demonstrated that loss of dynein function alters chromosome segregation and activates the Mad2‐dependent spindle‐assembly checkpoint. Conclusions. These results show an unexpected role for dynein in the control of chromosome segregation in fission yeast, most probably operating during the process of bi‐orientation during early mitosis.     

Inhibition of mycobacterial arylamine N-acetyltransferase contributes to anti-mycobacterial activity of Warburgia salutaris

In this study, we show that extracts and a purified compound of Warburgia salutaris exhibit anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv and Mycobacterium bovis BCG Pasteur. The extracts did not inhibit growth of Escherichia coli and were not toxic to cultured mammalian macrophage cells at the concentrations at which anti-mycobacterial activity was observed. The extract and pure compound inhibited pure recombinant arylamine N-acetyltransferase (NAT), an enzyme involved in mycobacterial cell wall lipid synthesis. Moreover, neither extract nor pure compound inhibited growth of a strain of M. bovis BCG in which nat has been deleted suggesting that NAT may indeed be a target within the mycobacterial cell. The purified compound is a novel drimane sesquiterpenoid lactone, 11alpha-hydroxycinnamosmolide. These studies show that W. salutaris is a useful source of anti-tubercular compounds for further analysis and supports the hypothesis of a link between NAT inhibition and anti-mycobacterial activity.     

Feeding ecology of phocid seals and some walrus in the Alaskan and Canadian Arctic as determined by stomach contents and stable isotope analysis

Feeding habits of ringed (Phoca hispida), bearded (Erignathus barbatus), spotted (Phoca largha) and ribbon (Phoca fasciata) seals and walrus (Odobenus rosmarus) were studied using stomach contents and stable carbon and nitrogen isotopes. Bearded seals fed benthically, primarily crustaceans and mollusks. Both zooplankton and fish were significant prey for ringed seals, while fish was principal spotted seal prey. Few gastric contents were available from ribbon seals. δ¹⁵N was positively correlated with age in ribbon seals and δ¹³C was positively correlated with age in ringed and ribbon seals. δ¹⁵N was highest in spotted seals, in agreement with their fish-dominated diet. δ¹⁵N was not different between Alaskan-harvested ringed and bearded seals, while δ¹⁵N was lowest in ribbon seals and walrus. Carbon-13 was most enriched in bearded seals and walrus reflecting benthic ecosystem use. Canadian ringed seals were depleted in ¹³C compared to Alaskan pinnipeds, likely because of Beaufort Sea versus Chukchi and Bering seas influence.     

Chromosomal rearrangements in wheat: their types and distribution.

Four hundred and sixty polyploid wheat accessions and 39 triticale forms from 37 countries of Europe, Asia, and USA were scored by C-banding for the presence of translocations. Chromosomal rearrangements were detected in 70 of 208 accessions of tetraploid wheat, 69 of 252 accessions of hexaploid wheat, and 3 of 39 triticale forms. Altogether, 58 types of major chromosomal rearrangements were identified in the studied material; they are discussed relative to 11 additional translocation types described by other authors. Six chromosome modifications of unknown origin were also observed. Among all chromosomal aberrations identified in wheat, single translocations were the most frequent type (39), followed by multiple rearrangements (9 types), pericentric inversions (9 types), and paracentric inversions (3 types). According to C-banding analyses, the breakpoints were located at or near the centromere in 60 rearranged chromosomes, while in 52 cases they were in interstitial chromosome regions. In the latter case, translocation breakpoints were often located at the border of C-bands and the euchromatin region or between two adjacent C-bands; some of these regions seem to be translocation "hotspots". Our results and data published by other authors indicate that the B-genome chromosomes are involved in translocations most frequently, followed by the A- and D-genome chromosomes; individual chromosomes also differ in the frequencies of translocations. Most translocations were detected in 1 or 2 accessions, and only 11 variants showed relatively high frequencies or were detected in wheat varieties of different origins or from different species. High frequencies of some translocations with a very restricted distribution could be due to a "bottleneck effect". Other types seem to occur independently and their broad distribution can result from selective advantages of rearranged genotypes in diverse environmental conditions. We found significant geographic variation in the spectra and frequencies of translocation in wheat: the highest proportions of rearranged genotypes were found in Central Asia, the Middle East, Northern Africa, and France. A low proportion of aberrant genotypes was characteristic of tetraploid wheat from Transcaucasia and hexaploid wheat from Middle Asia and Eastern Europe.     

Selected anthropometric variables and aerobic fitness as predictors of cardiovascular disease risk in children

The aim of this study was to assess the suitability of body mass index, waist circumference, waist-to-height ratio and aerobic fitness as predictors of cardiovascular risk factor clustering in children. A cross-sectional study was conducted with 290 school boys and girls from 6 to 10 years old, randomly selected. Blood was collected after a 12-hour fasting period. Blood pressure, waist circumference (WC), height and weight were evaluated according to international standards. Aerobic fitness (AF) was assessed by the 20-metre shuttle-run test. Clustering was considered when three of these factors were present: high systolic or diastolic blood pressure, high low-density lipoprotein (LDL) cholesterol, high triglycerides, high plasma glucose, high insulin concentrations and low high-density lipoprotein (HDL) cholesterol. A ROC curve identified the cut-off points of body mass index (BMI), WC, waist-to-height ratio (WHtR) and AF as predictors of risk factor clustering. BMI, WC and WHR resulted in significant areas under the ROC curves, which was not observed for AF. The anthropometric variables were good predictors of cardiovascular risk factor clustering in both sexes, whereas aerobic fitness should not be used to identify cardiovascular risk factor clustering in these children.     

Switch-like Responses of Two Cholesterol Sensors Do Not Require Protein Oligomerization in Membranes

Many cellular processes are sensitive to levels of cholesterol in specific membranes and show a strongly sigmoidal dependence on membrane composition. The sigmoidal responses of the cholesterol sensors involved in these processes could arise from several mechanisms, including positive cooperativity (protein effects) and limited cholesterol accessibility (membrane effects). Here, we describe a sigmoidal response that arises primarily from membrane effects due to sharp changes in the chemical activity of cholesterol. Our models for eukaryotic membrane-bound cholesterol sensors are soluble bacterial toxins that show an identical switch-like specificity for endoplasmic reticulum membrane cholesterol. We show that truncated versions of these toxins fail to form oligomers but still show sigmoidal binding to cholesterol-containing membranes. The nonlinear response emerges because interactions between bilayer lipids control cholesterol accessibility to toxins in a threshold-like fashion. Around these thresholds, the affinity of toxins for membrane cholesterol varies by >100-fold, generating highly cooperative lipid-dependent responses independently of protein-protein interactions. Such lipid-driven cooperativity may control the sensitivity of many cholesterol-dependent processes.