A Transmission/Disequilibrium Test That Allows for Genotyping Errors in the Analysis of Single-Nucleotide Polymorphism Data

The present study assesses the effects of genotyping errors on the type I error rate of a particular transmission/disequilibrium test (TDT(std)), which assumes that data are errorless, and introduces a new transmission/disequilibrium test (TDT(ae)) that allows for random genotyping errors. We evaluate the type I error rate and power of the TDT(ae) under a variety of simulations and perform a power comparison between the TDT(std) and the TDT(ae), for errorless data. Both the TDT(std) and the TDT(ae) statistics are computed as two times a log-likelihood difference, and both are asymptotically distributed as chi(2) with 1 df. Genotype data for trios are simulated under a null hypothesis and under an alternative (power) hypothesis. For each simulation, errors are introduced randomly via a computer algorithm with different probabilities (called "allelic error rates"). The TDT(std) statistic is computed on all trios that show Mendelian consistency, whereas the TDT(ae) statistic is computed on all trios. The results indicate that TDT(std) shows a significant increase in type I error when applied to data in which inconsistent trios are removed. This type I error increases both with an increase in sample size and with an increase in the allelic error rates. TDT(ae) always maintains correct type I error rates for the simulations considered. Factors affecting the power of the TDT(ae) are discussed. Finally, the power of TDT(std) is at least that of TDT(ae) for simulations with errorless data. Because data are rarely error free, we recommend that researchers use methods, such as the TDT(ae), that allow for errors in genotype data.     

Variation among early North American crania

The limited morphometric work on early American crania to date has treated them as a single, temporally defined group. This paper addresses the question of whether there is significant variability among ancient American crania. A sample of 11 crania (Spirit Cave, Wizards Beach, Browns Valley, Pelican Rapids, Prospect, Wet Gravel male, Wet Gravel female, Medicine Crow, Turin, Lime Creek, and Swanson Lake) dating from the early to mid Holocene was available. Some have recent accelerator mass spectrometry (AMS) dates, while others are dated geologically or archaeologically. All are in excess of 4500 BP, and most are 7000 BP or older. Measurements follow the definitions of Howells [(1973) Cranial variation in man, Cambridge: Harvard University). Some crania are incomplete, but 22 measurements were common to all fossils. Cranial variation was examined by calculating the Mahalanobis distance between each pair of fossils, using a pooled within sample covariance matrix estimated from the data of Howells. The distance relationships among crania suggest the presence of at least three distinct groups: 1) a middle Archaic Plains group (Turin and Medicine Crow), 2) a Paleo/Early Archaic Great Lakes/Plains group (Browns Valley, Pelican Rapids, Lime Creek), and 3) a spatially and temporally heterogeneous group that includes the Great Basin/Pacific Coast (Spirit Cave, Wizards Beach, Prospect) and Nebraska (Wet Gravel specimens and Swanson Lake). These crania were also compared to Howells' worldwide recent sample, which was expanded by including six additional American Indian samples. None of the fossils, except for the Wet Gravel male, shows any particular affinity to recent Native Americans; their greatest similarities are with Europe, Polynesia, or East Asia. Several crania would be atypical in any recent population for which we have data. Browns Valley, Pelican Rapids, and Lime Creek are the most distinctive. They provide evidence for the presence of an early population that bears no similarity to the morphometric pattern of recent American Indians or even to crania of comparable date in other regions of the continent. The heterogeneity among early American crania makes it inadvisable to pool them for purposes of morphometric analysis. Whether this heterogeneity results from different early migrations or one highly differentiated population cannot be established from our data. Our results are inconsistent with hypotheses of an ancestor-descendent relationship between early and late Holocene American populations. They suggest that the pattern of cranial variation is of recent origin, at least in the Plains region.     

The genome sequence of the gram-positive sugarcane pathogen Leifsonia xyli subsp. xyli

The genome sequence of Leifsonia xyli subsp. xyli, which causes ratoon stunting disease and affects sugarcane worldwide, was determined. The single circular chromosome of Leifsonia xyli subsp. xyli CTCB07 was 2.6 Mb in length with a GC content of 68% and 2,044 predicted open reading frames. The analysis also revealed 307 predicted pseudogenes, which is more than any bacterial plant pathogen sequenced to date. Many of these pseudogenes, if functional, would likely be involved in the degradation of plant heteropolysaccharides, uptake of free sugars, and synthesis of amino acids. Although L. xyli subsp. xyli has only been identified colonizing the xylem vessels of sugarcane, the numbers of predicted regulatory genes and sugar transporters are similar to those in free-living organisms. Some of the predicted pathogenicity genes appear to have been acquired by lateral transfer and include genes for cellulase, pectinase, wilt-inducing protein, lysozyme, and desaturase. The presence of the latter may contribute to stunting, since it is likely involved in the synthesis of abscisic acid, a hormone that arrests growth. Our findings are consistent with the nutritionally fastidious behavior exhibited by L. xyli subsp. xyli and suggest an ongoing adaptation to the restricted ecological niche it inhabits.     

FcgammaRIIb-mediated negative regulation of BCR signalling is associated with the recruitment of the MAPkinase-phosphatase, Pac-1, and the 3'-inositol phosphatase, PTEN

The low-affinity receptor for IgG, FcgammaRIIb, negatively regulates B cell antigen receptor (BCR)-mediated proliferative signalling. FcgammaRIIb has been reported to mediate this inhibition by uncoupling the BCR from the RasMAPkinase pathway. We now show that FcgammaRIIb-mediated negative feedback inhibition also correlates with induction of an Erk-associated phosphatase activity that reflects the rapid association of Erk and the MAPkinase phosphatase, Pac-1, and dephosphorylation and inactivation of ErkMAPkinase. This mechanism of abrogating ongoing ErkMAPkinase signalling therefore provides a rationale for rapid immune-complex-mediated feedback inhibition of active antigen-driven B cell responses. In addition, FcgammaRIIb signalling also induces the recruitment and activation of the 3'-inositol phosphatase, PTEN, which by antagonising PI 3kinase activity and inhibiting BCR-coupling to the anti-apoptotic kinase, Akt, provides an additional mechanism for FcgammaRIIb-mediated negative regulation of BCR-coupling to ErkMAPkinase, cell survival and proliferation.     

Folate, homocysteine, endothelial function and cardiovascular disease

Evidence reported from numerous clinical studies over the past decade has revealed an association between increased plasma total homocysteine (tHcy) concentrations and cardiovascular disease (CVD). In addition, epidemiological studies have identified an inverse association between blood folate concentrations, folate intake and cardiovascular endpoints, that are independent of homocysteine. Folic acid supplementation can lower plasma tHcy concentrations safely and inexpensively. Furthermore, folic acid can reverse endothelial dysfunction observed in patients with CVD. This reversal in endothelial dysfunction with folic acid has been shown to be independent of plasma tHcy lowering, suggesting that folate has pleiotropic effects on the vasculature other than homocysteine lowering. In vitro evidence demonstrates that 5-methyltetrahydrofolate (5MeTHF) the main circulating metabolite of folate, can increase nitric oxide production and can directly scavenge superoxide radicals. The potential beneficial role of folic acid supplements on vascular disease are currently being tested in randomized placebo controlled studies.     

Preconditioning protects by inhibiting the mitochondrial permeability transition

Mitochondrial permeability transition (mPT) is a crucial event in the progression to cell death in the setting of ischemia-reperfusion. We have used a model system in which mPT can be reliably and reproducibly induced to test the hypothesis that the profound protection associated with the phenomenon of myocardial preconditioning is mediated by suppression of the mPT. Adult rat myocytes were loaded with the fluorescent probe tetramethylrhodamine methyl ester, which generates oxidative stress on laser illumination, thus inducing the mPT (indicated by collapse of the mitochondrial membrane potential) and ATP depletion, seen as rigor contracture. The known inhibitors of the mPT, cyclosporin A (0.2 microM) and N-methyl-4-valine-cyclosporin A (0.4 microM), increased the time taken to induce the mPT by 1.8- and 2.9-fold, respectively, compared with control (P < 0.001) and rigor contracture by 1.5-fold compared with control (P < 0.001). Hypoxic preconditioning (HP) and pharmacological preconditioning, using diazoxide (30 microM) or nicorandil (100 microM), also increased the time taken to induce the mPT by 2.0-, 2.1-, and 1.5-fold, respectively (P < 0.001), and rigor contracture by 1.9-, 1.7-, and 1.5-fold, respectively, compared with control (P < 0.001). Effects of HP, diazoxide, and nicorandil were abolished in the presence of mitochondrial ATP-sensitive K(+) (K(ATP)) channel blockers glibenclamide (10 microM) and 5-hydroxydecanoate (100 microM) but were maintained in the presence of the sarcolemmal K(ATP) channel blocker HMR-1098 (10 microM). In conclusion, preconditioning protects the myocardium by reducing the probability of the mPT, which normally occurs during ischemia-reperfusion in response to oxidative stress.     

Buffering capacity of whole corn mash alters concentrations of organic acids required to inhibit growth of Saccharomyces cerevisiae and ethanol production

Growth of Saccharomyces cerevisiae and fermentative ethanol production in the presence of acetic and lactic acids was measured in whole corn mash. In this industrial medium, as compared to glucose minimal medium, the yeast had increased tolerance to organic acid stress. It was concluded that the increased buffering capacity of whole corn mash, resulting in decreased concentration of undissociated acid, was responsible for this phenomenon.