On universal common ancestry, sequence similarity, and phylogenetic structure: the sins of P-values and the virtues of Bayesian evidence

<p>Abstract</p> <p>Background</p> <p>The universal common ancestry (UCA) of all known life is a fundamental component of modern evolutionary theory, supported by a wide range of qualitative molecular evidence. Nevertheless, recently both the status and nature of UCA has been questioned. In earlier work I presented a formal, quantitative test of UCA in which model selection criteria overwhelmingly choose common ancestry over independent ancestry, based on a dataset of universally conserved proteins. These model-based tests are founded in likelihoodist and Bayesian probability theory, in opposition to classical frequentist null hypothesis tests such as Karlin-Altschul E-values for sequence similarity. In a recent comment, Koonin and Wolf (K&W) claim that the model preference for UCA is "a trivial consequence of significant sequence similarity". They support this claim with a computational simulation, derived from universally conserved proteins, which produces similar sequences lacking phylogenetic structure. The model selection tests prefer common ancestry for this artificial data set.</p> <p>Results</p> <p>For the real universal protein sequences, hierarchical phylogenetic structure (induced by genealogical history) is the overriding reason for why the tests choose UCA; sequence similarity is a relatively minor factor. First, for cases of conflicting phylogenetic structure, the tests choose independent ancestry even with highly similar sequences. Second, certain models, like star trees and K&W's profile model (corresponding to their simulation), readily explain sequence similarity yet lack phylogenetic structure. However, these are extremely poor models for the real proteins, even worse than independent ancestry models, though they explain K&W's artificial data well. Finally, K&W's simulation is an implementation of a well-known phylogenetic model, and it produces sequences that mimic homologous proteins. Therefore the model selection tests work appropriately with the artificial data.</p> <p>Conclusions</p> <p>For K&W's artificial protein data, sequence similarity is the predominant factor influencing the preference for common ancestry. In contrast, for the real proteins, model selection tests show that phylogenetic structure is much more important than sequence similarity. Hence, the model selection tests demonstrate that real universally conserved proteins are homologous, a conclusion based primarily on the specific nested patterns of correlations induced in genetically related protein sequences.</p> <p>Reviewers</p> <p>This article was reviewed by Rob Knight, Robert Beiko (nominated by Peter Gogarten), and Michael Gilchrist.</p

Accurate Structural Correlations from Maximum Likelihood Superpositions

The cores of globular proteins are densely packed, resulting in complicated networks of structural interactions. These interactions in turn give rise to dynamic structural correlations over a wide range of time scales. Accurate analysis of these complex correlations is crucial for understanding biomolecular mechanisms and for relating structure to function. Here we report a highly accurate technique for inferring the major modes of structural correlation in macromolecules using likelihood-based statistical analysis of sets of structures. This method is generally applicable to any ensemble of related molecules, including families of nuclear magnetic resonance (NMR) models, different crystal forms of a protein, and structural alignments of homologous proteins, as well as molecular dynamics trajectories. Dominant modes of structural correlation are determined using principal components analysis (PCA) of the maximum likelihood estimate of the correlation matrix. The correlations we identify are inherently independent of the statistical uncertainty and dynamic heterogeneity associated with the structural coordinates. We additionally present an easily interpretable method (“PCA plots”) for displaying these positional correlations by color-coding them onto a macromolecular structure. Maximum likelihood PCA of structural superpositions, and the structural PCA plots that illustrate the results, will facilitate the accurate determination of dynamic structural correlations analyzed in diverse fields of structural biology

A novel methodology for simulating skin injury risk on synthetic playing surfaces

Artificial turf provides a consistent and durable surface; however, it has historically been associated with a high skin injury risk, or a ‘friction burn’, when a player falls or slides. Second-generation surfaces feature a short carpet pile, whilst third generation (3G) carpet piles are longer, enabling the integration of a performance infill. 3G surfaces provide sufficient energy absorption characteristics to be approved as Rugby Turf; however, such pitches can still cause skin injuries, despite being assessed using a friction-based test. Reducing skin injury risk motivates this study to develop a more sensitive testing methodology. A new test apparatus and impactor are proposed, achieving kinematics representative of an elite male rugby tackle. A commercially available skin simulant is employed to ensure the collection of repeatable and valid data. Photography and thresholding were used to assess surface abrasion and material transfer, whilst a thermal camera captured surface temperature change. Accelerometers quantified the surface resistance during the impact and sliding phases. These metrics were compiled into the Maxwell Tribo Index (MTI), providing a single measure of skin injury risk. The results demonstrated good repeatability and validity when four teams tested four different 3G surfaces. These results compared favourably to an expert panel’s ranked order

Potassium-selective block of barium permeation through single KcsA channels

Ba2+, a doubly charged analogue of K+, specifically blocks K+ channels by virtue of electrostatic stabilization in the permeation pathway. Ba2+ block is used here as a tool to determine the equilibrium binding affinity for various monovalent cations at specific sites in the selectivity filter of a noninactivating mutant of KcsA. At high concentrations of external K+, the block-time distribution is double exponential, marking at least two Ba2+ sites in the selectivity filter, in accord with a Ba2+-containing crystal structure of KcsA. By analyzing block as a function of extracellular K+, we determined the equilibrium dissociation constant of K+ and of other monovalent cations at an extracellular site, presumably S1, to arrive at a selectivity sequence for binding at this site: Rb+ (3 µM) > Cs+ (23 µM) > K+ (29 µM) > NH4+ (440 µM) >> Na+ and Li+ (>1 M). This represents an unusually high selectivity for K+ over Na+, with |ΔΔG0| of at least 7 kcal mol−1. These results fit well with other kinetic measurements of selectivity as well as with the many crystal structures of KcsA in various ionic conditions

Improving risk management for violence in mental health services: a multimethods approach

contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-2015contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-2015contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-2015contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-201

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)