Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration.

Gas1 and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. Here we demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through distinct modes of Hedgehog ligand reception. Moreover, Ptch2-mediated Hedgehog signalling induces the phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a previously unknown Ptch2-specific signal pathway. We propose that although Ptch1 and Ptch2 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch2 and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche

Color & Weak triplet scalars, the dimuon asymmetry in BsB_s decay, the top forward-backward asymmetry, and the CDF dijet excess

The new physics required to explain the anomalies recently reported by the D0 and CDF collaborations, namely the top forward-backward asymmetry (FBA), the like-sign dimuon charge asymmetry in semileptonic b decay, and the CDF dijet excess, has to feature an amount of flavor symmetry in order to satisfy the severe constrains arising from flavor violation. In this paper we show that, once baryon number conservation is imposed, color & weak triplet scalars with hypercharge $Y=1/3$ can feature the required flavor structure as a consequence of standard model gauge invariance. The color & weak triplet model can simultaneously explain the top FBA and the dimuon charge asymmetry or the dimuon charge asymmetry and the CDF dijet excess. However, the CDF dijet excess appears to be incompatible with the top FBA in the minimal framework. Our model for the dimuon asymmetry predicts the observed pattern $h_d\ll h_s$ in the region of parameter space required to explain the top FBA, whereas our model for the CDF dijet anomaly is characterized by the absence of beyond the SM b-quark jets in the excess region. Compatibility of the color & weak triplet with the electroweak constraints is also discussed. We show that a Higgs boson mass exceeding the LEP bound is typically favored in this scenario, and that both Higgs production and decay can be significantly altered by the triplet. The most promising collider signature is found if the splitting among the components of the triplet is of weak scale magnitude.Comment: references added, published versio

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Listening In on the Past: What Can Otolith δ18O Values Really Tell Us about the Environmental History of Fishes?

Oxygen isotope ratios from fish otoliths are used to discriminate marine stocks and reconstruct past climate, assuming that variations in otolith δ18O values closely reflect differences in temperature history of fish when accounting for salinity induced variability in water δ18O. To investigate this, we exploited the environmental and migratory data gathered from a decade using archival tags to study the behaviour of adult plaice (Pleuronectes platessa L.) in the North Sea. Based on the tag-derived monthly distributions of the fish and corresponding temperature and salinity estimates modelled across three consecutive years, we first predicted annual otolith δ18O values for three geographically discrete offshore sub-stocks, using three alternative plausible scenarios for otolith growth. Comparison of predicted vs. measured annual δ18O values demonstrated >96% correct prediction of sub-stock membership, irrespective of the otolith growth scenario. Pronounced inter-stock differences in δ18O values, notably in summer, provide a robust marker for reconstructing broad-scale plaice distribution in the North Sea. However, although largely congruent, measured and predicted annual δ18O values of did not fully match. Small, but consistent, offsets were also observed between individual high-resolution otolith δ18O values measured during tag recording time and corresponding δ18O predictions using concomitant tag-recorded temperatures and location-specific salinity estimates. The nature of the shifts differed among sub-stocks, suggesting specific vital effects linked to variation in physiological response to temperature. Therefore, although otolith δ18O in free-ranging fish largely reflects environmental temperature and salinity, we counsel prudence when interpreting otolith δ18O data for stock discrimination or temperature reconstruction until the mechanisms underpinning otolith δ18O signature acquisition, and associated variation, are clarified

Attentional WM is not necessarily specifically related with fluid intelligence: the case of smart children with ADHD symptoms.

Executive functions and, in particular, Attentional (active) Working Memory (WM) have been associated with fluid intelligence. The association contrasts with the hypothesis that children with ADHD exhibit problems with WM tasks requiring controlled attention and may have a good fluid intelligence. This paper examines whether children who are intelligent but present ADHD symptoms fail in attentional WM tasks. The latter result would be problematic for theories assuming the generality of a strict relationship between intelligence and WM. To study these issues, a battery of tests was administered to a group of 58 children who all displayed symptoms of ADHD. All children were between the age of 8 and 11 years, and were described by their teachers as smart. Children were compared to a control group matched for age, schooling, and gender. The battery included a test of fluid intelligence (Raven's Coloured Matrices), and a series of visuospatial WM tasks. Results showed that children with ADHD were high in intelligence but significantly lower than the controls in WM tasks requiring high attentional control, whereas there was no difference in WM tasks requiring low attentional control. Furthermore, only high attentional control WM tasks were significantly related to Raven's performance in the control group, whereas all WM tasks were similarly related in the ADHD group. It is concluded that performance in high attentional control WM tasks may be related to fluid intelligence, but also to a specific control component that is independent of intelligence and is poor in children with ADHD

Parasites, drugs and captivity: blastocystis-microbiome associations in captive water voles

(1) Background: Blastocystis is a microbial eukaryote inhabiting the gastrointestinal tract of a broad range of animals including humans. Several studies have shown that the organism is associated with specific microbial profiles and bacterial taxa that have been deemed beneficial to intestinal and overall health. Nonetheless, these studies are focused almost exclusively on humans, while there is no similar information on other animals. (2) Methods: Using a combination of conventional PCR, cloning and sequencing, we investigated presence of Blastocystis along with Giardia and Cryptosporidium in 16 captive water voles sampled twice from a wildlife park. We also characterised their bacterial gut communities. (3) Results: Overall, alpha and beta diversities between water voles with and without Blastocystis did not differ significantly. Differences were noted only on individual taxa with Treponema and Kineothrix being significantly reduced in Blastocystis positive water voles. Grouping according to antiprotozoal treatment and presence of other protists did not reveal any differences in the bacterial community composition either. (4) Conclusion: Unlike human investigations, Blastocystis does not seem to be associated with specific gut microbial profiles in water vole

Temporal Asynchrony of Trophic Status Between Mainstream and Tributary Bay Within a Giant Dendritic Reservoir: The Role of Local-Scale Regulators

Limnologists have regarded temporal coherence (synchrony) as a powerful tool for identifying the relative importance of local-scale regulators and regional climatic drivers on lake ecosystems. Limnological studies on Asian reservoirs have emphasized that climate and hydrology under the influences of monsoon are dominant factors regulating seasonal patterns of lake trophic status; yet, little is known of synchrony or asynchrony of trophic status in the single reservoir ecosystem. Based on monthly monitoring data of chlorophyll a, transparency, nutrients, and nonvolatile suspended solids (NVSS) during 1-year period, the present study evaluated temporal coherence to test whether local-scale regulators disturb the seasonal dynamics of trophic state indices (TSI) in a giant dendritic reservoir, China (Three Gorges Reservoir, TGR). Reservoir-wide coherences for TSICHL, TSISD, and TSITP showed dramatic variations over spatial scale, indicating temporal asynchrony of trophic status. Following the concept of TSI differences, algal productivity in the mainstream of TGR and Xiangxi Bay except the upstream of the bay were always limited by nonalgal turbidity (TSICHL−TSISD <0) rather than nitrogen and phosphorus (TSICHL−TSITN <0 and TSICHL−TSITP <0). The coherence analysis for TSI differences showed that local processes of Xiangxi Bay were the main responsible for local asynchrony of nonalgal turbidity limitation levels. Regression analysis further proved that local temporal asynchrony for TSISD and nonalgal turbidity limitation levels were regulated by local dynamics of NVSS, rather than geographical distance. The implications of the present study are to emphasize that the results of trophic status obtained from a single environment (reservoir mainstream) cannot be extrapolated to other environments (tributary bay) in a way that would allow its use as a sentinel site

Assessing the Performance of a Computer-Based Policy Model of HIV and AIDS

BACKGROUND. Model-based analyses, conducted within a decision analytic framework, provide a systematic way to combine information about the natural history of disease and effectiveness of clinical management strategies with demographic and epidemiological characteristics of the population. Among the challenges with disease-specific modeling include the need to identify influential assumptions and to assess the face validity and internal consistency of the model. METHODS AND FINDINGS. We describe a series of exercises involved in adapting a computer-based simulation model of HIV disease to the Women's Interagency HIV Study (WIHS) cohort and assess model performance as we re-parameterized the model to address policy questions in the U.S. relevant to HIV-infected women using data from the WIHS. Empiric calibration targets included 24-month survival curves stratified by treatment status and CD4 cell count. The most influential assumptions in untreated women included chronic HIV-associated mortality following an opportunistic infection, and in treated women, the 'clinical effectiveness' of HAART and the ability of HAART to prevent HIV complications independent of virologic suppression. Good-fitting parameter sets required reductions in the clinical effectiveness of 1st and 2nd line HAART and improvements in 3rd and 4th line regimens. Projected rates of treatment regimen switching using the calibrated cohort-specific model closely approximated independent analyses published using data from the WIHS. CONCLUSIONS. The model demonstrated good internal consistency and face validity, and supported cohort heterogeneities that have been reported in the literature. Iterative assessment of model performance can provide information about the relative influence of uncertain assumptions and provide insight into heterogeneities within and between cohorts. Description of calibration exercises can enhance the transparency of disease-specific models.National Institute of Allergy and Infectious Diseases (R37 AI042006, K24 AI062476