Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.

Effect of peak inert-mode temperature on elemental carbon measured using thermal-optical analysis

Thermal-optical analysis is a conventional method for classifying carbonaceous aerosols as organic carbon (OC) and elemental carbon (EC). This article examines the effects of three different temperature protocols on the measured EC. For analyses of parallel punches from the same ambient sample, the protocol with the highest peak helium-mode temperature (870°C) gives the smallest amount of EC, while the protocol with the lowest peak helium-mode temperature (550°C) gives the largest amount of EC. These differences are observed when either sample transmission or reflectance is used to define the OC/EC split. An important issue is the effect of the peak helium-mode temperature on the relative rate at which different types of carbon with different optical properties evolve from the filter. Analyses of solvent-extracted samples are used to demonstrate that high temperatures (870°C) lead to premature EC evolution in the helium-mode. For samples collected in Pittsburgh, this causes the measured EC to be biased low because the attenuation coefficient of pyrolyzed carbon is consistently higher than that of EC. While this problem can be avoided by lowering the peak helium-mode temperature, analyses of wood smoke dominated ambient samples and levoglucosan-spiked filters indicate that too low helium-mode peak temperatures (550°C) allow non-light absorbing carbon to slip into the oxidizing mode of the analysis. If this carbon evolves after the OC/EC split, it biases the EC measurements high. Given the complexity of ambient aerosols, there is unlikely to be a single peak helium-mode temperature at which both of these biases can be avoided. Copyright © American Association for Aerosol Research.

Comparison of extramedullary versus intramedullary referencing for tibial component alignment in total ankle arthroplasty.

BACKGROUND: The majority of total ankle arthroplasty (TAA) systems use extramedullary alignment guides for tibial component placement. However, at least 1 system offers intramedullary referencing. In total knee arthroplasty, studies suggest that tibial component placement is more accurate with intramedullary referencing. The purpose of this study was to compare the accuracy of extramedullary referencing with intramedullary referencing for tibial component placement in total ankle arthroplasty. METHODS: The coronal and sagittal tibial component alignment was evaluated on the postoperative weight-bearing anteroposterior (AP) and lateral radiographs of 236 consecutive fixed-bearing TAAs. Radiographs were measured blindly by 2 investigators. The postoperative alignment of the prosthesis was compared with the surgeon's intended alignment in both planes. The accuracy of tibial component alignment was compared between the extramedullary and intramedullary referencing techniques using unpaired t tests. Interrater and intrarater reliabilities were assessed with intraclass correlation coefficients (ICCs). RESULTS: Eighty-three tibial components placed with an extramedullary referencing technique were compared with 153 implants placed with an intramedullary referencing technique. The accuracy of the extramedullary referencing was within a mean of 1.5 ± 1.4 degrees and 4.1 ± 2.9 degrees in the coronal and sagittal planes, respectively. The accuracy of intramedullary referencing was within a mean of 1.4 ± 1.1 degrees and 2.5 ± 1.8 degrees in the coronal and sagittal planes, respectively. There was a significant difference (P < .001) between the 2 techniques with respect to the sagittal plane alignment. Interrater ICCs for coronal and sagittal alignment were high (0.81 and 0.94, respectively). Intrarater ICCs for coronal and sagittal alignment were high for both investigators. CONCLUSIONS: Initial sagittal plane tibial component alignment was notably more accurate when intramedullary referencing was used. Further studies are needed to determine the effect of this difference on clinical outcomes and long-term survivability of the implants. LEVEL OF EVIDENCE: Level III, retrospective comparative study.