The Cepheid Period-Luminosity Relation at Mid-Infrared Wavelengths: I. First-Epoch LMC Data

We present the first mid-infrared Period-Luminosity (PL) relations for Large Magellanic Cloud (LMC) Cepheids. Single-epoch observations of 70 Cepheids were extracted from Spitzer IRAC observations at 3.6, 4.5, 5.8 and 8.0 microns, serendipitously obtained during the SAGE (Surveying the Agents of a Galaxy's Evolution) imaging survey of the LMC. All four mid-infrared PL relations have nearly identical slopes over the period range 6 - 88 days, with a small scatter of only +/-0.16 mag independent of period for all four of these wavelengths. We emphasize that differential reddening is not contributing significantly to the observed scatter, given the nearly two orders of magnitude reduced sensitivity of the mid-IR to extinction compared to the optical. Future observations, filling in the light curves for these Cepheids, should noticeably reduce the residual scatter. These attributes alone suggest that mid-infrared PL relations will provide a practical means of significantly improving the accuracy of Cepheid distances to nearby galaxies.Comment: 19 pages, 4 figures, 1 table, Accepted for publication in the Astrophysical Journa

Human Cytomegalovirus Intrahost Evolution--A New Avenue for Understanding and Controlling Herpesvirus Infections [preprint]

Human cytomegalovirus (HCMV) is exquisitely adapted to the human host, and much research has focused on its evolution over long timescales spanning millennia. Here, we review recent data exploring the evolution of the virus on much shorter timescales, on the order of days or months. We describe the intrahost genetic diversity of the virus isolated from humans, and how this diversity contributes to HCMV spatiotemporal evolution. We propose mechanisms to explain the high levels of intrahost diversity and discuss how this new information may shed light on HCMV infection and pathogenesis

A Corpus Investigation of Syntactic Embedding in Piraha

The Pirahã language has been at the center of recent debates in linguistics, in large part because it is claimed not to exhibit recursion, a purported universal of human language. Here, we present an analysis of a novel corpus of natural Pirahã speech that was originally collected by Dan Everett and Steve Sheldon. We make the corpus freely available for further research. In the corpus, Pirahã sentences have been shallowly parsed and given morpheme-aligned English translations. We use the corpus to investigate the formal complexity of Pirahã syntax by searching for evidence of syntactic embedding. In particular, we search for sentences which could be analyzed as containing center-embedding, sentential complements, adverbials, complementizers, embedded possessors, conjunction or disjunction. We do not find unambiguous evidence for recursive embedding of sentences or noun phrases in the corpus. We find that the corpus is plausibly consistent with an analysis of Pirahã as a regular language, although this is not the only plausible analysis

Cytomegalovirus-Specific T Cell Epitope Recognition in Congenital Cytomegalovirus Mother-Infant Pairs

Background: Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth and from which about 20% of infants develop permanent neurodevelopmental effects regardless of presence or absence of symptoms at birth. Viral escape from host immune control may be a mechanism of CMV transmission and infant disease severity. We sought to identify and compare CMV epitopes recognized by mother-infant pairs. We also hypothesized that if immune escape were occurring, then one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype) of CMV epitope recognition. Methods: The study population consisted of 6 women with primary CMV infection during pregnancy and their infants with cCMV infection. CMV UL83 and UL123 peptides with known or predicted restriction by maternal MHC class I alleles were identified, and a subset was selected for testing based on several criteria. Maternal or infant cells were stimulated with CMV peptides in the IFN-gamma ELISpot assay. Results: Overall, 14 of 25 (56%; 8 UL83 and 6 UL123) peptides recognized by mother-infant pairs were not previously reported as CD8 T cell epitopes. Of three pairs with longitudinal samples, one showed maternal loss and infant gain of responses to a CMV epitope restricted by a shared HLA allele. Conclusions: CD8 T cell responses to multiple novel CMV epitopes were identified, particularly in infants. Moreover, the hypothesized pattern of CMV immune escape was observed in one mother-infant pair. These findings emphasize that knowledge of paired CMV epitope recognition allows exploration of viral immune escape that may operate within the maternal-fetal system. Our work provides rationale for future studies of this potential mechanism of CMV transmission during pregnancy or clinical outcomes of infants with cCMV infection

A framework for assessing the lifetime economic burden of congenital cytomegalovirus in the United States

Background: In the United States (US), congenital cytomegalovirus infection (cCMVi) is a major cause of permanent disabilities and the most common etiology of non-genetic sensorineural hearing loss. Evaluations of prevention strategies will require estimates of the economic implications of cCMVi. We aimed to develop a conceptual framework to characterize the lifetime economic burden of cCMVi in the US and to use that framework to identify data gaps. Methods: Direct health care, direct non-health care, indirect, and intangible costs associated with cCMVi were considered. An initial framework was constructed based on a targeted literature review, then validated and refined after consultation with experts. Published costs were identified and used to populate the framework. Data gaps were identified. Results: The framework was constructed as a chance tree, categorizing clinical event occurrence to form patient profiles associated with distinct economic trajectories. The distribution and magnitude of costs varied by patient life stage, cCMVi diagnosis, severity of impairment, and developmental delays/disabilities. Published studies could not fully populate the framework. The literature best characterized direct health care costs associated with the birth period. Gaps existed for direct non-health care, indirect, and intangible costs, as well as health care costs associated with adult patients and those severely impaired. Conclusions: Data gaps exist concerning the lifetime economic burden of cCMVi in the US. The conceptual framework provides the basis for a research agenda to address these gaps. Understanding the full lifetime economic burden of cCMVi would inform clinicians, researchers, and policymakers, when assessing the value of cCMVi interventions

Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection

Populations of human cytomegalovirus (HCMV), a large DNA virus, are highly polymorphic in patient samples, which may allow for rapid evolution within human hosts. To understand HCMV evolution, longitudinally sampled genomic populations from the urine and plasma of 5 infants with symptomatic congenital HCMV infection were analyzed. Temporal and compartmental variability of viral populations were quantified using high throughput sequencing and population genetics approaches. HCMV populations were generally stable over time, with ~88% of SNPs displaying similar frequencies. However, samples collected from plasma and urine of the same patient at the same time were highly differentiated with approximately 1700 consensus sequence SNPs (1.2% of the genome) identified between compartments. This inter-compartment differentiation was comparable to the differentiation observed in unrelated hosts. Models of demography (i.e., changes in population size and structure) and positive selection were evaluated to explain the observed patterns of variation. Evidence for strong bottlenecks (\u3e90% reduction in viral population size) was consistent among all patients. From the timing of the bottlenecks, we conclude that fetal infection occurred between 13-18 weeks gestational age in patients analyzed, while colonization of the urine compartment followed roughly 2 months later. The timing of these bottlenecks is consistent with the clinical histories of congenital HCMV infections. We next inferred that positive selection plays a small but measurable role in viral evolution within a single compartment. However, positive selection appears to be a strong and pervasive driver of evolution associated with compartmentalization, affecting \u3e/= 34 of the 167 open reading frames (~20%) of the genome. This work offers the most detailed map of HCMV in vivo evolution to date and provides evidence that viral populations can be stable or rapidly differentiate, depending on host environment. The application of population genetic methods to these data provides clinically useful information, such as the timing of infection and compartment colonization

Observational Study Design in Veterinary Pathology, Part 1: Study Design

Observational studies are the basis for much of our knowledge of veterinary pathology and are highly relevant to the daily practice of pathology. However, recommendations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offer advice on planning and conducting an observational study with examples from the veterinary pathology literature. Investigators should recognize the importance of creativity, insight, and innovation in devising studies that solve problems and fill important gaps in knowledge. Studies should focus on specific and testable hypotheses, questions, or objectives. The methodology is developed to support these goals. We consider the merits and limitations of different types of analytic and descriptive studies, as well as of prospective vs retrospective enrollment. Investigators should define clear inclusion and exclusion criteria and select adequate numbers of study subjects, including careful selection of the most appropriate controls. Studies of causality must consider the temporal relationships between variables and the advantages of measuring incident cases rather than prevalent cases. Investigators must consider unique aspects of studies based on archived laboratory case material and take particular care to consider and mitigate the potential for selection bias and information bias. We close by discussing approaches to adding value and impact to observational studies. Part 2 of the series focuses on methodology and validation of methods

Neurotrophins Regulate Bone Marrow Stromal Cell IL-6 Expression through the MAPK Pathway

The host's response to infection is characterized by altered levels of neurotrophins and an influx of inflammatory cells to sites of injured tissue. Progenitor cells that give rise to the differentiated cellular mediators of inflammation are derived from bone marrow progenitor cells where their development is regulated, in part, by cues from bone marrow stromal cells (BMSC). As such, alteration of BMSC function in response to elevated systemic mediators has the potential to alter their function in biologically relevant ways, including downstream alteration of cytokine production that influences hematopoietic development.In the current study we investigated BMSC neurotrophin receptor expression by flow cytometric analysis to determine differences in expression as well as potential to respond to NGF or BDNF. Intracellular signaling subsequent to neurotrophin stimulation of BMSC was analyzed by western blot, microarray analysis, confocal microscopy and real-time PCR. Analysis of BMSC Interleukin-6 (IL-6) expression was completed using ELISA and real-time PCR.BMSC established from different individuals had distinct expression profiles of the neurotrophin receptors, TrkA, TrkB, TrkC, and p75(NTR). These receptors were functional, demonstrated by an increase in Akt-phosphorylation following BMSC exposure to recombinant NGF or BDNF. Neurotrophin stimulation of BMSC resulted in increased IL-6 gene and protein expression which required activation of ERK and p38 MAPK signaling, but was not mediated by the NFkappaB pathway. BMSC response to neurotrophins, including the up-regulation of IL-6, may alter their support of hematopoiesis and regulate the availability of inflammatory cells for migration to sites of injury or infection. As such, these studies are relevant to the growing appreciation of the interplay between neurotropic mediators and the regulation of hematopoiesis