Absence of neutralizing antibodies against influenza A/H5N1 virus among children in Kamphaeng Phet, Thailand

Background: Influenza A/H5N1 actively circulated in Kamphaeng Phet (KPP), Thailand from 2004 to 2006. A prospective longitudinal cohort study of influenza virus infection in 800 adults conducted during 2008–2010 in KPP suggested that subclinical or mild H5N1 infections had occurred among this adult cohort. However, this study was conducted after the peak of H5N1 activity in KPP. Coincidentally, banked serum samples were available from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses from 2004 to 2007 and lived in the same district of KPP as the adult cohort. Objectives: We sought to investigate whether subclinical or mild H5N1 infections had occurred among KPP residents during the peak of H5N1 activity from 2004 to 2006. Study design: H5N1 microneutralization (MN) assay was performed on banked serum samples from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses in KPP. Annual blood samples collected from 2004 to 2006 from 251 children were selected based on the criteria that they lived in villages with documented H5N1 infection. Result: No H5N1 neutralizing antibodies were detected in 753 annual blood samples from 251 children. Conclusion: During 2004–2006, very few subclinical or mild H5N1 infections occurred in KPP. Elevated H5N1 MN titers found in the adult cohort in 2008 were likely due to cross-reactivity from other influenza virus subtypes highlighting the complexities in interpreting influenza serological data

Innate Immune Response of Human Plasmacytoid Dendritic Cells to Poxvirus Infection Is Subverted by Vaccinia E3 via Its Z-DNA/RNA Binding Domain

Plasmacytoid dendritic cells (pDCs) play important roles in antiviral innate immunity by producing type I interferon (IFN). In this study, we assess the immune responses of primary human pDCs to two poxviruses, vaccinia and myxoma virus. Vaccinia, an orthopoxvirus, was used for immunization against smallpox, a contagious human disease with high mortality. Myxoma virus, a Leporipoxvirus, causes lethal disease in rabbits, but is non-pathogenic in humans. We report that myxoma virus infection of human pDCs induces IFN-α and TNF production, whereas vaccinia infection does not. Co-infection of pDCs with myxoma virus plus vaccinia blocks myxoma induction effects. We find that heat-inactivated vaccinia (Heat-VAC; by incubating the virus at 55°C for 1 h) gains the ability to induce IFN-α and TNF in primary human pDCs. Induction of IFN-α in pDCs by myxoma virus or Heat-VAC is blocked by chloroquine, which inhibits endosomal acidification required for TLR7/9 signaling, and by inhibitors of cellular kinases PI3K and Akt. Using purified pDCs from genetic knockout mice, we demonstrate that Heat-VAC-induced type I IFN production in pDCs requires the endosomal RNA sensor TLR7 and its adaptor MyD88, transcription factor IRF7 and the type I IFN feedback loop mediated by IFNAR1. These results indicate that (i) vaccinia virus, but not myxoma virus, expresses inhibitor(s) of the poxvirus sensing pathway(s) in pDCs; and (ii) Heat-VAC infection fails to produce inhibitor(s) but rather produces novel activator(s), likely viral RNA transcripts that are sensed by the TLR7/MyD88 pathway. Using vaccinia gene deletion mutants, we show that the Z-DNA/RNA binding domain at the N-terminus of the vaccinia immunomodulatory E3 protein is an antagonist of the innate immune response of human pDCs to poxvirus infection and TLR agonists. The myxoma virus ortholog of vaccinia E3 (M029) lacks the N-terminal Z-DNA/RNA binding domain, which might contribute to the immunostimulating properties of myxoma virus

Responses to Diotic, Dichotic, and Alternating Phase Harmonic Stimuli in the Inferior Colliculus of Guinea Pigs

Humans perceive a harmonic series as a single auditory object with a pitch equivalent to the fundamental frequency (F0) of the series. When harmonics are presented to alternate ears, the repetition rate of the waveform at each ear doubles. If the harmonics are resolved, then the pitch perceived is still equivalent to F0, suggesting the stimulus is binaurally integrated before pitch is processed. However, unresolved harmonics give rise to the doubling of pitch which would be expected from monaural processing (Bernstein and Oxenham, J. Acoust. Soc. Am., 113:3323–3334, 2003). We used similar stimuli to record responses of multi-unit clusters in the central nucleus of the inferior colliculus (IC) of anesthetized guinea pigs (urethane supplemented by fentanyl/fluanisone) to determine the nature of the representation of harmonic stimuli and to what extent there was binaural integration. We examined both the temporal and rate-tuning of IC clusters and found no evidence for binaural integration. Stimuli comprised all harmonics below 10 kHz with fundamental frequencies (F0) from 50 to 400 Hz in half-octave steps. In diotic conditions, all the harmonics were presented to both ears. In dichotic conditions, odd harmonics were presented to one ear and even harmonics to the other. Neural characteristic frequencies (CF, n = 85) were from 0.2 to 14.7 kHz; 29 had CFs below 1 kHz. The majority of clusters responded predominantly to the contralateral ear, with the dominance of the contralateral ear increasing with CF. With diotic stimuli, over half of the clusters (58%) had peaked firing rate vs. F0 functions. The most common peak F0 was 141 Hz. Almost all (98%) clusters phase locked diotically to an F0 of 50 Hz, and approximately 40% of clusters still phase locked significantly (Rayleigh coefficient >13.8) at the highest F0 tested (400 Hz). These results are consistent with the previous reports of responses to amplitude-modulated stimuli. Clusters phase locked significantly at a frequency equal to F0 for contralateral and diotic stimuli but at 2F0 for dichotic stimuli. We interpret these data as responses following the envelope periodicity in monaural channels rather than as a binaurally integrated representation

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk : a case-control study

Abstract Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P trend = 0.005) but not cases (P trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P trend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P trend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels

Chronostratigraphy and age modeling of Pleistocene drill cores from the Olduvai Basin, Tanzania (Olduvai Gorge Coring Project)

The Olduvai Gorge Coring Project drilled a total of 611.72 m of core (575.48 m recovered) of mostly fluvio-lacustrine and fan-delta volcaniclastic Pleistocene strata at three sites in the Olduvai Basin, Tanzania, in 2014. We have developed a chronostratigraphic framework for three of the cores based on 40Ar/39Ar dating of core and outcrop volcanic and volcaniclastic units, core paleomagnetic stratigraphy, and tephrochemical correlation between cores and from core to outcrop. This framework is then used to constrain Bayesian stratigraphic age models which permit age estimates for desired core levels with realistic confidence intervals. The age models reveal that the deepest core level reached at 245 mbs is ~2.24 Ma, ~210 kyr older than the oldest strata exposed at Olduvai Gorge. Strata net accretion rates in this early phase of basin history were relatively rapid (57–69 cm/kyr), but decreased within ~250 kyr to ~15 cm/kyr in Lower Bed I. Rates rebounded partially in Upper Bed I, but subsequently declined to \u3c10 cm/kyr by Middle to Upper Pleistocene. The age models also provide new estimates for the basal contacts of upper Olduvai Gorge stratigraphic units that have been previously difficult to calibrate: Bed III at 1.14 ± 0.05 (95% confidence interval), Bed IV at 0.93 ± 0.08, Masek at 0.82 ± 0.06, and Ndutu at 0.50 ± 0.04 Ma. Finally, based on recently acquired seismic imaging identifying basement another 135 m beneath the bottom of the deepest core, extrapolation of net accretion rates suggests that sedimentation began at this site in the Olduvai Basin at ~2.5 Ma

Modeling physiological and anthropometric variables known to vary with body size and other confounding variables

This review explores the most appropriate methods of identifying population differences in physiological and anthropometric variables known to differ with body size and other confounding variables. We shall provide an overview of such problems from a historical point of view. We shall then give some guidelines as to the choice of body-size covariates as well as other confounding variables, and show how these might be incorporated into the model, depending on the physiological dependent variable and the nature of the population being studied. We shall also recommend appropriate goodness-of-fit statistics that will enable researchers to confirm the most appropriate choice of model, including, for example, how to compare proportional allometric models with the equivalent linear or additive polynomial models. We shall also discuss alternative body-size scaling variables (height, fat-free mass, body surface area, and projected area of skeletal bone), and whether empirical vs. theoretical scaling methodologies should be reported. We shall offer some cautionary advice (limitations) when interpreting the parameters obtained when fitting proportional power function or allometric models, due to the fact that human physiques are not geometrically similar to each other. In conclusion, a variety of different models will be identified to describe physiological and anthropometric variables known to vary with body size and other confounding variables. These include simple ratio standards (e.g., per body mass ratios), linear and additive polynomial models, and proportional allometric or power function models. Proportional allometric models are shown to be superior to either simple ratio standards or linear and additive polynomial models for a variety of different reasons. These include: 1) providing biologically interpretable models that yield sensible estimates within and beyond the range of data; and 2) providing a superior fit based on the Akaike information criterion (AIC), Bayes information criterion (BIC), or maximum log-likelihood criteria (resulting in a smaller error variance). As such, these models will also: 3) naturally lead to a more powerful analysis-of-covariance test of significance, which will 4) subsequently lead to more correct conclusions when investigating population (epidemiological) or experimental differences in physiological and anthropometric variables known to vary with body size