In vivo requirement of the α-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4

α-Syntrophin is a scaffolding adapter protein expressed primarily on the sarcolemma of skeletal muscle. The COOH-terminal half of α-syntrophin binds to dystrophin and related proteins, leaving the PSD-95, discs-large, ZO-1 (PDZ) domain free to recruit other proteins to the dystrophin complex. We investigated the function of the PDZ domain of α-syntrophin in vivo by generating transgenic mouse lines expressing full-length α-syntrophin or a mutated α-syntrophin lacking the PDZ domain (ΔPDZ). The ΔPDZ α-syntrophin displaced endogenous α- and β1-syntrophin from the sarcolemma and resulted in sarcolemma containing little or no syntrophin PDZ domain. As a consequence, neuronal nitric oxide synthase (nNOS) and aquaporin-4 were absent from the sarcolemma. However, the sarcolemmal expression and distribution of muscle sodium channels, which bind the α-syntrophin PDZ domain in vitro, were not altered. Both transgenic mouse lines were bred with an α-syntrophin–null mouse which lacks sarcolemmal nNOS and aquaporin-4. The full-length α-syntrophin, not the ΔPDZ form, reestablished nNOS and aquaporin-4 at the sarcolemma of these mice. Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin. Together, these data show that the sarcolemmal localization of nNOS and aquaporin-4 in vivo depends on the presence of a dystrophin-bound α-syntrophin PDZ domain

Interventions to Improve Delivery of Isoniazid Preventive Therapy: an Overview of Systematic Reviews

Background: Uptake of isoniazid preventive therapy (IPT) to prevent tuberculosis has been poor, particularly in the highest risk populations. Interventions to improve IPT delivery could promote implementation. The large number of existing systematic reviews on treatment adherence has made drawing conclusions a challenge. To provide decision makers with the evidence they need, we performed an overview of systematic reviews to compare different organizational interventions to improve IPT delivery as measured by treatment completion among those at highest risk for the development of TB disease, namely child contacts or HIV-infected individuals. Methods: We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), and MEDLINE up to August 15, 2012. Two authors used a standardized data extraction form and the AMSTAR instrument to independently assess each review. Results: Six reviews met inclusion criteria. Interventions included changes in the setting/site of IPT delivery, use of quality monitoring mechanisms (e.g., directly observed therapy), IPT delivery integration into other healthcare services, and use of lay health workers. Most reviews reported a combination of outcomes related to IPT adherence and treatment completion rate but without a baseline or comparison rate. Generally, we found limited evidence to demonstrate that the studied interventions improved treatment completion. Conclusions: While most of the interventions were not shown to improve IPT completion, integration of tuberculosis and HIV services yielded high treatment completion rates in some settings. The lack of data from high burden TB settings limits applicability. Further research to assess different IPT delivery interventions, including those that address barriers to care in at-risk populations, is urgently needed to identify the most effective practices for IPT delivery and TB control in high TB burden settings

Meta-analysis of genome-wide expression patterns associated with behavioral maturation in honey bees

<p>Abstract</p> <p>Background</p> <p>The information from multiple microarray experiments can be integrated in an objective manner <it>via </it>meta-analysis. However, multiple meta-analysis approaches are available and their relative strengths have not been directly compared using experimental data in the context of different gene expression scenarios and studies with different degrees of relationship. This study investigates the complementary advantages of meta-analysis approaches to integrate information across studies, and further mine the transcriptome for genes that are associated with complex processes such as behavioral maturation in honey bees. Behavioral maturation and division of labor in honey bees are related to changes in the expression of hundreds of genes in the brain. The information from various microarray studies comparing the expression of genes at different maturation stages in honey bee brains was integrated using complementary meta-analysis approaches.</p> <p>Results</p> <p>Comparison of lists of genes with significant differential expression across studies failed to identify genes with consistent patterns of expression that were below the selected significance threshold, or identified genes with significant yet inconsistent patterns. The meta-analytical framework supported the identification of genes with consistent overall expression patterns and eliminated genes that exhibited contradictory expression patterns across studies. Sample-level meta-analysis of normalized gene-expression can detect more differentially expressed genes than the study-level meta-analysis of estimates for genes that were well described by similar model parameter estimates across studies and had small variation across studies. Furthermore, study-level meta-analysis was well suited for genes that exhibit consistent patterns across studies, genes that had substantial variation across studies, and genes that did not conform to the assumptions of the sample-level meta-analysis. Meta-analyses confirmed previously reported genes and helped identify genes (e.g. <it>Tomosyn</it>, <it>Chitinase 5, Adar, Innexin 2, Transferrin 1</it>, <it>Sick</it>, <it>Oatp26F</it>) and Gene Ontology categories (e.g. purine nucleotide binding) not previously associated with maturation in honey bees.</p> <p>Conclusion</p> <p>This study demonstrated that a combination of meta-analytical approaches best addresses the highly dimensional nature of genome-wide microarray studies. As expected, the integration of gene expression information from microarray studies using meta-analysis enhanced the characterization of the transcriptome of complex biological processes.</p

Interdisciplinary, Translational, and Community-Based Participatory Research: Finding a Common Language to Improve Cancer Research

Preventing cancer, downstaging disease at diagnosis, and reducing mortality require that relevant research findings be translated across scientific disciplines and into clinical and public health practice. Interdisciplinary research focuses on using the languages of different scientific disciplines to share techniques and philosophical perspectives to enhance discovery and development of innovations; (i.e., from the “left end” of the research continuum). Community-based participatory research (CBPR), whose relevance often is relegated to the “right end” (i.e., delivery and dissemination) of the research continuum, represents an important means for understanding how many cancers are caused as well as for ensuring that basic science research findings affect cancer outcomes in materially important ways. Effective interdisciplinary research and CBPR both require an ability to communicate effectively across groups that often start out neither understanding each other’s worldviews nor even speaking the same language. Both demand an ability and willingness to treat individuals from other communities with respect and understanding. We describe the similarities between CBPR and both translational and interdisciplinary research, and then illustrate our points using squamous cell carcinoma of the esophagus as an example of how to deepen understanding and increase relevance by applying techniques of CBPR and interdisciplinary engagement

Transcriptomic profiling of 39 commonly-used neuroblastoma cell lines

Neuroblastoma cell lines are an important and cost-effective model used to study oncogenic drivers of the disease. While many of these cell lines have been previously characterized with SNP, methylation, and/or mRNA expression microarrays, there has not been an effort to comprehensively sequence these cell lines. Here, we present raw whole transcriptome data generated by RNA sequencing of 39 commonly-used neuroblastoma cell lines. These data can be used to perform differential expression analysis based on a genetic aberration or phenotype in neuroblastoma (e.g., MYCN amplification status, ALK mutation status, chromosome arm 1p, 11q and/or 17q status, sensitivity to pharmacologic perturbation). Additionally, we designed this experiment to enable structural variant and/or long-noncoding RNA analysis across these cell lines. Finally, as more DNase/ATAC and histone/transcription factor ChIP sequencing is performed in these cell lines, our RNA-Seq data will be an important complement to inform transcriptional targets as well as regulatory (enhancer or repressor) elements in neuroblastoma

Chemical Signatures of the First Supernovae in the Sculptor Dwarf Spheroidal Galaxy

We present a homogeneous chemical abundance analysis of five of the most metal-poor stars in the Sculptor dwarf spheroidal galaxy. We analyze new and archival high resolution spectroscopy from Magellan/MIKE and VLT/UVES and determine stellar parameters and abundances in a consistent way for each star. Two of the stars in our sample, at [Fe/H] = -3.5 and [Fe/H] = -3.8, are new discoveries from our Ca K survey of Sculptor, while the other three were known in the literature. We confirm that Scl 07-50 is the lowest metallicity star identified in an external galaxy, at [Fe/H] = -4.1. The two most metal-poor stars both have very unusual abundance patterns, with striking deficiencies of the alpha elements, while the other three stars resemble typical extremely metal-poor Milky Way halo stars. We show that the star-to-star scatter for several elements in Sculptor is larger than that for halo stars in the same metallicity range. This scatter and the uncommon abundance patterns of the lowest metallicity stars indicate that the oldest surviving Sculptor stars were enriched by a small number of earlier supernovae, perhaps weighted toward high-mass progenitors from the first generation of stars the galaxy formed.Comment: 11 pages, 2 figures, 4 tables (2 landscape tables are at the end; for full tables, contact first author or wait for published version). Accepted for publication in Ap