Long-Term Results after Chiari Pelvic Osteotomy in the Skeletally Immature and the Role of the Anti-Chiari Effect.

Several authors observed a loss of correction after performing Chiari pelvic osteotomy (CPO) in young patients. Hence, the aim of this study was to answer two questions: (1) Does the Chiari pelvic osteotomy affect the development of the acetabulum in skeletally immature patients in the long term? (2) Is there any evidence of the previously described "Anti-Chiari" effect after a mean follow-up of 36 years? Data from 21 patients (27 hips) undergoing CPO before the age of 16 years were clinically assessed, and the evolution of radiological parameters over time was analyzed. The mean age at CPO was 11.2 years (±3; 4.4-15.7). The 20- and 30-year survival rates of the CPO were 100% and 92.6%, respectively. Mean postoperative medialization was 54% (±18; 23-99). The average osteotomy angle was 11° (±7; 2-28). No significant changes were found for the center-edge angle (CEA) and acetabular index (AI) over time; the angle of Idelberger and Frank (ACM) almost reached normal values at follow-up (FU); for the acetabular-head index (AHI), a slight shift toward the initial situation could be detected. The morphology of the acetabulum remained unchanged over time. The "Anti-Chiari effect" seems to be primarily caused by insufficient coverage of the femoral head rather than damage to the apophysis due to surgery.

Improving the performance of minimizers and winnowing schemes.

MOTIVATION: The minimizers scheme is a method for selecting k -mers from sequences. It is used in many bioinformatics software tools to bin comparable sequences or to sample a sequence in a deterministic fashion at approximately regular intervals, in order to reduce memory consumption and processing time. Although very useful, the minimizers selection procedure has undesirable behaviors (e.g. too many k -mers are selected when processing certain sequences). Some of these problems were already known to the authors of the minimizers technique, and the natural lexicographic ordering of k -mers used by minimizers was recognized as their origin. Many software tools using minimizers employ ad hoc variations of the lexicographic order to alleviate those issues. RESULTS: We provide an in-depth analysis of the effect of k -mer ordering on the performance of the minimizers technique. By using small universal hitting sets (a recently defined concept), we show how to significantly improve the performance of minimizers and avoid some of its worse behaviors. Based on these results, we encourage bioinformatics software developers to use an ordering based on a universal hitting set or, if not possible, a randomized ordering, rather than the lexicographic order. This analysis also settles negatively a conjecture (by Schleimer et al. ) on the expected density of minimizers in a random sequence. AVAILABILITY AND IMPLEMENTATION: The software used for this analysis is available on GitHub: https://github.com/gmarcais/minimizers.git . CONTACT: gmarcais@cs.cmu.edu or carlk@cs.cmu.edu.

On the computational complexity of the maximum parsimony reconciliation problem in the duplication-loss-coalescence model.

BACKGROUND: Phylogenetic tree reconciliation is a widely-used method for inferring the evolutionary histories of genes and species. In the duplication-loss-coalescence (DLC) model, we seek a reconciliation that explains the incongruence between a gene and species tree using gene duplication, loss, and deep coalescence events. In the maximum parsimony framework, costs are associated with these event types and a reconciliation is sought that minimizes the total cost of the events required to map the gene tree onto the species tree. RESULTS: We show that this problem is NP-hard even for the special case of minimizing the number of duplications. We then show that the problem is APX-hard when both duplications and losses are considered, implying that no polynomial-time approximation scheme can exist for the problem unless P = NP. CONCLUSIONS: These intractability results are likely to guide future research on algorithmic aspects of the DLC-reconciliation problem.

Nucleotide Interdependency in Transcription Factor Binding Sites in the Drosophila Genome.

A long-standing objective in modern biology is to characterize the molecular components that drive the development of an organism. At the heart of eukaryotic development lies gene regulation. On the molecular level, much of the research in this field has focused on the binding of transcription factors (TFs) to regulatory regions in the genome known as cis-regulatory modules (CRMs). However, relatively little is known about the sequence-specific binding preferences of many TFs, especially with respect to the possible interdependencies between the nucleotides that make up binding sites. A particular limitation of many existing algorithms that aim to predict binding site sequences is that they do not allow for dependencies between nonadjacent nucleotides. In this study, we use a recently developed computational algorithm, MARZ, to compare binding site sequences using 32 distinct models in a systematic and unbiased approach to explore nucleotide dependencies within binding sites for 15 distinct TFs known to be critical to Drosophila development. Our results indicate that many of these proteins have varying levels of nucleotide interdependencies within their DNA recognition sequences, and that, in some cases, models that account for these dependencies greatly outperform traditional models that are used to predict binding sites. We also directly compare the ability of different models to identify the known KRUPPEL TF binding sites in CRMs and demonstrate that a more complex model that accounts for nucleotide interdependencies performs better when compared with simple models. This ability to identify TFs with critical nucleotide interdependencies in their binding sites will lead to a deeper understanding of how these molecular characteristics contribute to the architecture of CRMs and the precise regulation of transcription during organismal development.