Deletion of the Complement C5a Receptor Alleviates the Severity of Acute Pneumococcal Otitis Media following Influenza A Virus Infection in Mice

There is considerable evidence that influenza A virus (IAV) promotes adherence, colonization, and superinfection by S. pneumoniae (Spn) and contributes to the pathogenesis of otitis media (OM). The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qa−/−) or factor B (Bf −/−) exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR) demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection

Statistically-Estimated Tree Composition for the Northeastern United States at Euro-American Settlement

We present a gridded 8 km-resolution data product of the estimated composition of tree taxa at the time of Euro-American settlement of the northeastern United States and the statistical methodology used to produce the product from trees recorded by land surveyors. Composition is defined as the proportion of stems larger than approximately 20 cm diameter at breast height for 22 tree taxa, generally at the genus level. The data come from settlement-era public survey records that are transcribed and then aggregated spatially, giving count data. The domain is divided into two regions, eastern (Maine to Ohio) and midwestern (Indiana to Minnesota). Public Land Survey point data in the midwestern region (ca. 0.8-km resolution) are aggregated to a regular 8 km grid, while data in the eastern region, from Town Proprietor Surveys, are aggregated at the township level in irregularly-shaped local administrative units. The product is based on a Bayesian statistical model fit to the count data that estimates composition on the 8 km grid across the entire domain. The statistical model is designed to handle data from both the regular grid and the irregularly-shaped townships and allows us to estimate composition at locations with no data and to smooth over noise caused by limited counts in locations with data. Critically, the model also allows us to quantify uncertainty in our composition estimates, making the product suitable for applications employing data assimilation. We expect this data product to be useful for understanding the state of vegetation in the northeastern United States prior to large-scale Euro-American settlement. In addition to specific regional questions, the data product can also serve as a baseline against which to investigate how forests and ecosystems change after intensive settlement. The data product is being made available at the NIS data portal as version 1.0

A gene expression atlas of the domestic pig

<p>Abstract</p> <p>Background</p> <p>This work describes the first genome-wide analysis of the transcriptional landscape of the pig. A new porcine Affymetrix expression array was designed in order to provide comprehensive coverage of the known pig transcriptome. The new array was used to generate a genome-wide expression atlas of pig tissues derived from 62 tissue/cell types. These data were subjected to network correlation analysis and clustering.</p> <p>Results</p> <p>The analysis presented here provides a detailed functional clustering of the pig transcriptome where transcripts are grouped according to their expression pattern, so one can infer the function of an uncharacterized gene from the company it keeps and the locations in which it is expressed. We describe the overall transcriptional signatures present in the tissue atlas, where possible assigning those signatures to specific cell populations or pathways. In particular, we discuss the expression signatures associated with the gastrointestinal tract, an organ that was sampled at 15 sites along its length and whose biology in the pig is similar to human. We identify sets of genes that define specialized cellular compartments and region-specific digestive functions. Finally, we performed a network analysis of the transcription factors expressed in the gastrointestinal tract and demonstrate how they sub-divide into functional groups that may control cellular gastrointestinal development.</p> <p>Conclusions</p> <p>As an important livestock animal with a physiology that is more similar than mouse to man, we provide a major new resource for understanding gene expression with respect to the known physiology of mammalian tissues and cells. The data and analyses are available on the websites <url>http://biogps.org and http://www.macrophages.com/pig-atlas</url>.</p

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.

BACKGROUND: Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice. RESULTS: Our analysis reveals that the expression levels of most genes are generally preserved in B cell precursors isolated from aged compared with young mice. Nonetheless, age-specific expression changes are observed at numerous genes, including microRNA encoding genes. Importantly, these changes are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions, and nuclear compartmentalization. Previous work has shown that differentiation is linked to changes in promoter-regulatory element interactions. We find that aging in B cell precursors is accompanied by rewiring of such interactions. We identify transcriptional downregulation of components of the insulin-like growth factor signaling pathway, in particular downregulation of Irs1 and upregulation of Let-7 microRNA expression, as a signature of the aged phenotype. These changes in expression are associated with specific alterations in H3K27me3 occupancy, suggesting that Polycomb-mediated repression plays a role in precursor B cell aging. CONCLUSIONS: Changes in chromatin and 3D genome organization play an important role in shaping the altered gene expression profile of aged precursor B cells. Components of the insulin-like growth factor signaling pathways are key targets of epigenetic regulation in aging in bone marrow B cell precursors

Partners No More: Relational Transformation and the Turn to Litigation in Two Conservationist Organizations

The rise in litigation against administrative bodies by environmental and other political interest groups worldwide has been explained predominantly through the liberalization of standing doctrines. Under this explanation, termed here the floodgate model, restrictive standing rules have dammed the flow of suits that groups were otherwise ready and eager to pursue. I examine this hypothesis by analyzing processes of institutional transformation in two conservationist organizations: the Sierra Club in the United States and the Society for the Protection of Nature in Israel (SPNI). Rather than an eagerness to embrace newly available litigation opportunities, as the floodgate model would predict, the groups\u27 history reveals a gradual process of transformation marked by internal, largely intergenerational divisions between those who abhorred conflict with state institutions and those who saw such conflict as not only appropriate but necessary to the mission of the group. Furthermore, in contrast to the pluralist interactions that the floodgate model imagines, both groups\u27 relations with pertinent agencies in earlier eras better accorded with the partnership-based corporatist paradigm. Sociolegal research has long indicated the importance of relational distance to the transformation of interpersonal disputes. I argue that, at the group level as well, the presence or absence of a (national) partnership-centered relationship determines propensities to bring political issues to court. As such, well beyond change in groups\u27 legal capacity and resources, current increases in levels of political litigation suggest more fundamental transformations in the structure and meaning of relations between citizen groups and the state

Statistical and integrative system-level analysis of DNA methylation data

Epigenetics plays a key role in cellular development and function. Alterations to the epigenome are thought to capture and mediate the effects of genetic and environmental risk factors on complex disease. Currently, DNA methylation is the only epigenetic mark that can be measured reliably and genome-wide in large numbers of samples. This Review discusses some of the key statistical challenges and algorithms associated with drawing inferences from DNA methylation data, including cell-type heterogeneity, feature selection, reverse causation and system-level analyses that require integration with other data types such as gene expression, genotype, transcription factor binding and other epigenetic information

Reducing Disorder, Fear, and Crime in Public Housing: A Case Study of Place Specific Crime Prevention

Despite the proliferation of programs developed to address crime at a neighborhood level, our knowledge base on the effectiveness of these efforts remains quite limited. This is particularly true of crime prevention efforts in and around public housing facilities. The present study is intended to shed light on the nature and effectiveness of a crime prevention effort centered in a public housing facility in an economically disadvantaged neighborhood in Spokane, Washington. Unlike most prior research on crime in public housing that has focused on large facilities, the present study focused on a small facility where the crime problems were centered on the streets surrounding the facility as opposed to crime within the facility itself. The findings suggest that collaborative efforts at reducing fear, crime, and disorder in and around public housing facilities hold promise for improving the quality of life for residents living in smaller public housing sites. These findings are particularly relevant when considering that most public housing facilities are relatively small and in light of the move away from the construction of large, high-rise, public housing facilities for the nation\u27s poor