Accelerated Evolution of the Prdm9 Speciation Gene across Diverse Metazoan Taxa

The onset of prezygotic and postzygotic barriers to gene flow between populations is a hallmark of speciation. One of the earliest postzygotic isolating barriers to arise between incipient species is the sterility of the heterogametic sex in interspecies' hybrids. Four genes that underlie hybrid sterility have been identified in animals: Odysseus, JYalpha, and Overdrive in Drosophila and Prdm9 (Meisetz) in mice. Mouse Prdm9 encodes a protein with a KRAB motif, a histone methyltransferase domain and several zinc fingers. The difference of a single zinc finger distinguishes Prdm9 alleles that cause hybrid sterility from those that do not. We find that concerted evolution and positive selection have rapidly altered the number and sequence of Prdm9 zinc fingers across 13 rodent genomes. The patterns of positive selection in Prdm9 zinc fingers imply that rapid evolution has acted on the interface between the Prdm9 protein and the DNA sequences to which it binds. Similar patterns are apparent for Prdm9 zinc fingers for diverse metazoans, including primates. Indeed, allelic variation at the DNA–binding positions of human PRDM9 zinc fingers show significant association with decreased risk of infertility. Prdm9 thus plays a role in determining male sterility both between species (mouse) and within species (human). The recurrent episodes of positive selection acting on Prdm9 suggest that the DNA sequences to which it binds must also be evolving rapidly. Our findings do not identify the nature of the underlying DNA sequences, but argue against the proposed role of Prdm9 as an essential transcription factor in mouse meiosis. We propose a hypothetical model in which incompatibilities between Prdm9-binding specificity and satellite DNAs provide the molecular basis for Prdm9-mediated hybrid sterility. We suggest that Prdm9 should be investigated as a candidate gene in other instances of hybrid sterility in metazoans

Comparative Transcriptional and Genomic Analysis of Plasmodium falciparum Field Isolates

Mechanisms for differential regulation of gene expression may underlie much of the phenotypic variation and adaptability of malaria parasites. Here we describe transcriptional variation among culture-adapted field isolates of Plasmodium falciparum, the species responsible for most malarial disease. It was found that genes coding for parasite protein export into the red cell cytosol and onto its surface, and genes coding for sexual stage proteins involved in parasite transmission are up-regulated in field isolates compared with long-term laboratory isolates. Much of this variability was associated with the loss of small or large chromosomal segments, or other forms of gene copy number variation that are prevalent in the P. falciparum genome (copy number variants, CNVs). Expression levels of genes inside these segments were correlated to that of genes outside and adjacent to the segment boundaries, and this association declined with distance from the CNV boundary. This observation could not be explained by copy number variation in these adjacent genes. This suggests a local-acting regulatory role for CNVs in transcription of neighboring genes and helps explain the chromosomal clustering that we observed here. Transcriptional co-regulation of physical clusters of adaptive genes may provide a way for the parasite to readily adapt to its highly heterogeneous and strongly selective environment

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

The Knee Osteoarthritis Grading System (KOGS) for arthroplasty

Background The aim of this study is to validate the Knee Osteoarthritis Grading system (KOGS) of progressive osteoarthritic (OA) degeneration for the Tri-compartmental knee. This system defines the site and severity of OA to determine a specific knee replacement. Methods The radiographic sequence for KOGS includes standing coronal (antero-posterior), lateral, 30° skyline patella, 15° and 45° Rosenberg and stress views in 20° of flexion. Cohen’s Kappa and related agreement statistical methods were used to assess the level of concordance of the seven evaluators between A and B cohorts for each evaluator and also against the actual arthroplasty used. Sensitivity and specificity was also assessed for the KOGS in identifying true partial knee replacements (PKR) and total knee replacements (TKR) as decided from the cohort A evaluations. Results From a cohort of 330 patients who were included in the study, 71 (22.5%) underwent a TKR procedure, 258 (78.2%) a PKR and 1 (0.3%) was neither a TKR nor PKR. KOGS was able to identify true PKRs (sensitivity) in the range of 92.2% to 98.5% across all the different evaluators. The KOGS method was able to identify a PKR or a TKR with an accuracy ranging from 92% to 98.8% across all different evaluators. The surgical results after 20 months are at least comparable with the expected average in the academic literature. Conclusion The KOGS classification provides a reliable and accurate tool to assess suitability of an individual patient for undergoing partial or total knee replacement

High-Precision Limb-Darkening Measurement of a K3 Giant Using Microlensing

We obtain high-precision limb-darkening measurements in five bands (V, VE, IE, I, and H) for the K3 III (Teff = 4200 K, [Fe/H] = +0.3, log g = 2.3) source of the Galactic bulge microlensing event EROS BLG-2000-5. These measurements are inconsistent with the predictions of atmospheric models at higher than 10 σ. While the disagreement is present in all bands, it is most apparent in I, IE, and VE, in part because the data are better and in part because the intrinsic disagreement is stronger. We find that when limb-darkening profiles are normalized to have unit total flux, the I-band models for a broad range of temperatures all cross each other at a common point. The solar profile also passes through this point. However, the profile as measured by microlensing does not. We hypothesize that the models have incorporated some aspect of solar physics that is not shared by giant atmospheres

The colors of change revisited: Situating and describing the theory and its practical applications

The colors of change is an overview of change paradigms, created about two decades ago, that has been intensively used, tested, refined, shared, and elaborated by practitioners and academics alike. Here, the “color theory” is presented as it is now, and is situated within the literature. Its four main applications are described as well as rules of thumb that have been derived from reflective practice. This chapter illustrates that the color theory is clearly not one thing to all people, as it is understood in very different ways, both in terms of its theoretical foundations as well as the complexity of its applications. This probably adds to the versatility of the theory. Bringing together key insights about the color theory for academics and practitioners, this chapter strives both to give a concise overview and to explore its richness