Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase

1. Download : Download high-res image (280KB)
2. Download : Download full-size image

     

On blocking rules for the bootstrap with dependent data

We address the issue of optimal block choice in applicationsof the block bootstrap to dependent data. It is shown that optimalblock size depends significantly on context, being equal ton^1/3, n^1/4 and n^1/5 in the cases of variance or bias estimation,estimation of a onesided distribution function, and estimationof a two-sided distribution function, respectively. A clearintuitive explanation of this phenomenon is given, togetherwith outlines of theoretical arguments in specific cases. Itis shown that these orders of magnitude of block sizes can beused to produce a simple, practical rule for selecting blocksize empirically. That technique is explored numerically.     

Comparison of basic peptides- and lipid-based strategies for the delivery of splice correcting oligonucleotides

Expression of alternatively spliced mRNA variants at specific stages of development or in specific cells and tissues contributes to the functional diversity of the human genome. Aberrations in alternative splicing were found as a cause or a contributing factor to the development, progression, or maintenance of numerous diseases. The use of antisense oligonucleotides (ON) to modify aberrant expression patterns of alternatively spliced mRNAs is a novel means of potentially controlling such diseases. Oligonucleotides can be designed to repair genetic mutations, to modify genomic sequences in order to compensate for gene deletions, or to modify RNA processing in order to improve the effects of the underlying gene mutation. Steric block ON approach have proven to be effective in experimental model for various diseases. Here, we describe our experience in investigating two strategies for ON delivery: ON conjugation with basic peptides and lipid-based particulate system (lipoplex). Basic peptides or Cell Penetrating Peptides (CPP) such as the TAT-derived peptide appear to circumvent many problems associated with ON and drug delivery. This strategy may represent the next paradigm in our ability to modulate cell function and offers a unique avenue for the treatment of disease. Lipoplexes result from the intimate interaction of ON with cationic lipids leading to ON carrying particles able to be taken up by cells and to release ON in the cytoplasm. We have used as an experimental model the correction of a splicing alteration of the mutated β-globin intron causing thalassemia. Data on cell penetration and efficacy of correction of specific steric block ON delivered either by basic peptides or lipoplex are described. A comparison of the properties of both delivery systems is made respective to the use of this new class of therapeutic molecules.     

Determination of field output correction factors of radiophotoluminescence glass dosimeter and CC01 ionization chamber and validation against IAEA-AAPM TRS-483 code of practice

PurposeTo determine the field output correction factors of the radiophotoluminescence glass dosimeter (RPLGD) in parallel and perpendicular orientations with reference to CC01, the ionization chamber.MethodsThe dose to a small water volume and the sensitive volume of the RPLGD and the IBA-CC01 were determined for 6-MV, 100-cm SAD, 10-cm depth using egs_chamber user-code. The RPLGD in perpendicular and parallel orientations to the beam axis were studied. The field output correction factors of each detector for 0.5 × 0.5 to 10 × 10 cm² field sizes were determined. These field output correction factors were validated by comparing field output factors against data determined from IAEA-AAPM TRS-483 code of practice.ResultsThe field output correction factors of all detectors were within 5% for field sizes down to 0.8 × 0.8 cm². For 0.5 × 0.5 cm², the field output correction factors of CC01, RPLGD in perpendicular and parallel orientations differed from unity by 14%, 19%, and 5%, respectively. The percentage difference between field output factors determined using RPLGD and CC01 data, corrected using the field output correction factors determined in this work and measurements with CC01 data corrected using TRS-483, was less than 3% for all field sizes, except for the smallest field size of RPLGD in perpendicular orientation and the CC01.ConclusionsThe field output correction factors of RPLGD and CC01 are reported. The validation proves that RPLGD in parallel orientation combined with the field output correction factors is the most suitable for determining the field output factors for the smallest field used in this study.     

Conditional Maximum Likelihood Estimation Following a Group Sequential Test

We consider estimation after a group sequential test. An estimator that is unbiased or has small bias may have substantial conditional bias (Troendle and Yu, 1999, Coburger and Wassmer, 2001). In this paper we derive the conditional maximum likelihood estimators of both the primary parameter and a secondary parameter, and investigate their properties within a conditional inference framework. The method applies to both the usual and adaptive group sequential test designs. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Bias of heritability estimates from twin data in presence of errors of zygosity determination

Simple heritability estimators of continuous as well as discrete traits from twin data are known to overestimate the degree of genetic determination of the measured traits for several reasons. Errors of zygosity determination will, however, underestimate the true heritability. The bias due to wrong assignment of dizygous twin pairs into monozygous type is evaluated here, and the results indicate that this negative bias has a compensatory effect on the estimate of the degree of genetic determination when other factors of similarity between twin pairs are taken into account. It is shown that when an estimate of zygosity error is available, the bias due to this factor can be evaluated quantitatively, and hence the adjustment for zygosity error can be incorporated in the estimation of the degree of genetic determination of a trait. Although this theory is explicitly developed here for twin studies, the general principle also applies for other types of errors of determining the degree of biological relationships for estimation of heritability, in which case this type of error may be more important than the simple zygosity error.     

The pentafunctional FAS1 genes of Saccharomyces cerevisiae and Yarrowia lipolytica are co-linear and considerably longer than previously estimated

Summary The fatty acid synthetase (FAS) gene FAS1 of the alkane-utilizing yeast Yarrowia lipolytica was cloned and sequenced. The gene is represented by an intron-free reading frame of 6228 by encoding a protein of 2076 amino acids and 229980 Da molecular weight. This protein exhibits a 58% sequence similarity to the corresponding Saccharomyces cerevisiae FAS -subunit. The sequential order of the five FAS1-encoded enzyme domains, acetyl transferase, enoyl reductase, dehydratase and malonyl/palmityl-transferase, is co-linear in both organisms. This finding agrees with available evidence that the functional organization of FAS genes is similar in related organisms but differs considerably between unrelated species. In addition, previously reported conflicting data concerning the 3 end of S. cerevisiae FAS1 were re-examined by genomic and cDNA sequencing of the relevant portion of the gene. Thereby, the translational stop codon was shown to lie considerably downstream of both published termination sites. The S. cerevisiae FAS1 gene thus has a corrected length of 6153 by and encodes a protein of 2051 amino acids and 228667 Da molecular weight.     

Bias of maximum likelihood estimator of intraclass correlation

Summary A bias correction was derived for the maximum likelihood estimator (MLE) of the intraclass correlation. The bias consisted of two parts: a correction from MLE to the analysis of variance estimator (ANOVA) and the bias of ANOVA. The total possible bias was always negative and depended upon both the degree of correlation and the design size and balance. The first part of the bias was an exact algebraic expression from MLE to ANOVA, and the corrected estimator by this part was ANOVA. It was also shown that the first correction term was equivalent to Fisher's reciprocal bias correction on hisZ scores. The total possible bias of MLE was large for small and moderate samples. Relative biases were larger for small parametric values and vice versa. To ensure a relative bias less than 10% assuming an intraclass correlation of 0.025, which is not unusual in most of the animal genetic studies, the total number of observations (N) should be not less than 500. From a design point of view, minimum bias occurred atn = 2, the minimum family size possible, underN fixed.     

Bias-reduced estimators of conditional odds ratios in matched case-control studies with unmatched confounding

We study bias-reduced estimators of exponentially transformed parameters in general linear models (GLMs) and show how they can be used to obtain bias-reduced conditional (or unconditional) odds ratios in matched case-control studies. Two options are considered and compared: the explicit approach and the implicit approach. The implicit approach is based on the modified score function where bias-reduced estimates are obtained by using iterative procedures to solve the modified score equations. The explicit approach is shown to be a one-step approximation of this iterative procedure. To apply these approaches for the conditional analysis of matched case-control studies, with potentially unmatched confounding and with several exposures, we utilize the relation between the conditional likelihood and the likelihood of the unconditional logit binomial GLM for matched pairs and Cox partial likelihood for matched sets with appropriately setup data. The properties of the estimators are evaluated by using a large Monte Carlo simulation study and an illustration of a real dataset is shown. Researchers reporting the results on the exponentiated scale should use bias-reduced estimators since otherwise the effects can be under or overestimated, where the magnitude of the bias is especially large in studies with smaller sample sizes.