Progress in spondylarthritis. Progress in studies of the genetics of ankylosing spondylitis

The advent of high-throughput SNP genotyping methods has advanced research into the genetics of common complex genetic diseases such as ankylosing spondylitis (AS) rapidly in recent times. The identification of associations with the genes IL23R and ERAP1 have been robustly replicated, and advances have been made in studies of the major histocompatibility complex genetics of AS, and of KIR gene variants and the disease. The findings are already being translated into increased understanding of the immunological pathways involved in AS, and raising novel potential therapies. The current studies in AS remain underpowered, and no full genomewide association study has yet been reported in AS; such studies are likely to add to the significant advances that have already been made

\u3ci\u3eMasterpiece Cakeshop\u3c/i\u3e: A Formula for Legislative Accommodations of Religion

When two core identities clash, such as sexual orientation and religious belief, which one should prevail? I argue that, rather than picking a winner and a loser, the Supreme Court in Masterpiece Cakeshop allowed for a much broader solution than the Court was able to provide—legislative accommodations rooted in tolerance that protect the dignity of same-sex couples and respect sincere religious beliefs. In Masterpiece Cakeshop, a Colorado baker refused to design a cake for a same-sex wedding based on his religious beliefs. Instead of picking a broad winner and loser, the Supreme Court ruled narrowly by finding the Colorado Civil Rights Commission acted with hostility toward the baker’s religious beliefs. At the end of the opinion, the Court provided a formula for legislative accommodations: “[T]hese disputes must be resolved [1] with tolerance, [2] without undue disrespect to sincere religious beliefs, and [3] without subjecting gay persons to indignities when they seek goods and services in an open market.” In this paper, Part I looks at historical examples of legislative and judicial accommodations of religion under the Free Exercise Clause. Part II analyzes the Supreme Court’s decision in Masterpiece Cakeshop and shows how the Court by ruling narrowly left open a solution that could protect both sides. Part III looks at why the legislature is better equipped than the judiciary to solve the issue. Part IV considers several different approaches to legislative accommodations by examining proposed and enacted legislative accommodations, and Part V applies these approaches to see how they would apply to wedding vendors, government officials, and religious adoption agencies

Promise and pitfalls of the Immunochip

Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Immunochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for immunogenetics gene mapping

Spatio-Temporal Patterning in Primary Motor Cortex at Movement Onset

Voluntary movement initiation involves the engagement of large populations of motor cortical neurons around movement onset. Despite knowledge of the temporal dynamics that lead to movement, the spatial structure of these dynamics across the cortical surface remains unknown. In data from 4 rhesus macaques, we show that the timing of attenuation of beta frequency local field potential oscillations, a correlate of locally activated cortex, forms a spatial gradient across primary motor cortex (MI). We show that these spatio-temporal dynamics are recapitulated in the engagement order of ensembles of MI neurons. We demonstrate that these patterns are unique to movement onset and suggest that movement initiation requires a precise spatio-temporal sequential activation of neurons in MI

Mutation of Arabidopsis SPLICEOSOMAL TIMEKEEPER LOCUS1 Causes Circadian Clock Defects

The circadian clock plays a crucial role in coordinating plant metabolic and physiological functions with predictable environmental variables, such as dusk and dawn, while also modulating responses to biotic and abiotic challenges. Much of the initial characterization of the circadian system has focused on transcriptional initiation, but it is now apparent that considerable regulation is exerted after this key regulatory step. Transcript processing, protein stability, and cofactor availability have all been reported to influence circadian rhythms in a variety of species. We used a genetic screen to identify a mutation within a putative RNA binding protein (SPLICEOSOMAL TIMEKEEPER LOCUS1 [STIPL1]) that induces a long circadian period phenotype under constant conditions. STIPL1 is a homolog of the spliceosomal proteins TFP11 (Homo sapiens) and Ntr1p (Saccharomyces cerevisiae) involved in spliceosome disassembly. Analysis of general and alternative splicing using a high-resolution RT-PCR system revealed that mutation of this protein causes less efficient splicing of most but not all of the introns analyzed. In particular, the altered accumulation of circadian-associated transcripts may contribute to the observed mutant phenotype. Interestingly, mutation of a close homolog of STIPL1, STIP-LIKE2, does not cause a circadian phenotype, which suggests divergence in function between these family members. Our work highlights the importance of posttranscriptional control within the clock mechanism. © 2012 American Society of Plant Biologists. All rights reserved

On choosing the start time of binary black hole ringdown

The final stage of a binary black hole merger is ringdown, in which the system is described by a Kerr black hole with quasinormal mode perturbations. It is far from straightforward to identify the time at which the ringdown begins. Yet determining this time is important for precision tests of the general theory of relativity that compare an observed signal with quasinormal mode descriptions of the ringdown, such as tests of the no-hair theorem. We present an algorithmic method to analyze the choice of ringdown start time in the observed waveform. This method is based on determining how close the strong field is to a Kerr black hole (Kerrness). Using numerical relativity simulations, we characterize the Kerrness of the strong-field region close to the black hole using a set of local, gauge-invariant geometric and algebraic conditions that measure local isometry to Kerr. We produce a map that associates each time in the gravitational waveform with a value of each of these Kerrness measures; this map is produced by following outgoing null characteristics from the strong and near-field regions to the wave zone. We perform this analysis on a numerical relativity simulation with parameters consistent with GW150914- the first gravitational wave detection. We find that the choice of ringdown start time of $3\,\mathrm{ms}$ after merger used in the GW150914 study to test general relativity corresponds to a high dimensionless perturbation amplitude of $\sim 7.5 \times 10^{-3}$ in the strong-field region. This suggests that in higher signal-to-noise detections, one would need to start analyzing the signal at a later time for studies that depend on the validity of black hole perturbation theory.Comment: 23+4 pages, 22 figure

Genetic studies in osteoporosis – the end of the beginning

Osteoporosis and disorders of bone fragility are highly heritable, but despite much effort the identities of few of the genes involved has been established. Recent developments in genetics such as genome-wide association studies are revolutionizing research in this field, and it is likely that further contributions will be made through application of next-generation sequencing technologies, analysis of copy number variation polymorphisms, and high-throughput mouse mutagenesis programs. This article outlines what we know about osteoporosis genetics to date and the probable future directions of research in this field

Building capacity for dissemination and implementation research: One university’s experience

Abstract Background While dissemination and implementation (D&I) science has grown rapidly, there is an ongoing need to understand how to build and sustain capacity in individuals and institutions conducting research. There are three inter-related domains for capacity building: people, settings, and activities. Since 2008, Washington University in St. Louis has dedicated significant attention and resources toward building D&I research capacity. This paper describes our process, challenges, and lessons with the goal of informing others who may have similar aims at their own institution. Activities An informal collaborative, the Washington University Network for Dissemination and Implementation Research (WUNDIR), began with a small group and now has 49 regular members. Attendees represent a wide variety of settings and content areas and meet every 6 weeks for half-day sessions. A logic model organizes WUNDIR inputs, activities, and outcomes. A mixed-methods evaluation showed that the network has led to new professional connections and enhanced skills (e.g., grant and publication development). As one of four, ongoing, formal programs, the Dissemination and Implementation Research Core (DIRC) was our first major component of D&I infrastructure. DIRC’s mission is to accelerate the public health impact of clinical and health services research by increasing the engagement of investigators in later stages of translational research. The aims of DIRC are to advance D&I science and to develop and equip researchers with tools for D&I research. As a second formal component, the Washington University Institute for Public Health has provided significant support for D&I research through pilot projects and a small grants program. In a third set of formal programs, two R25 training grants (one in mental health and one in cancer) support post-doctoral scholars for intensive training and mentoring in D&I science. Finally, our team coordinates closely with D&I functions within research centers across the university. We share a series of challenges and potential solutions. Conclusion Our experience in developing D&I research at Washington University in St. Louis shows how significant capacity can be built in a relatively short period of time. Many of our ideas and ingredients for success can be replicated, tailored, and improved upon by others