A Mouse with a Loss-of-function Mutation in the c-Cbl TKB Domain Shows Perturbed Thymocyte Signaling without Enhancing the Activity of the ZAP-70 Tyrosine Kinase

The unique tyrosine kinase binding (TKB) domain of Cbl targets phosphorylated tyrosines on activated protein tyrosine kinases (PTKs); this targeting is considered essential for Cbl proteins to negatively regulate PTKs. Here, a loss-of-function mutation (G304E) in the c-Cbl TKB domain, first identified in Caenorhabditis elegans, was introduced into a mouse and its effects in thymocytes and T cells were studied. In marked contrast to the c-Cbl knockout mouse, we found no evidence of enhanced activity of the ZAP-70 PTK in thymocytes from the TKB domain mutant mouse. This finding contradicts the accepted mechanism of c-Cbl–mediated negative regulation, which requires TKB domain targeting of phosphotyrosine 292 in ZAP-70. However, the TKB domain mutant mouse does show aspects of enhanced signaling that parallel those of the c-Cbl knockout mouse, but these involve the constitutive activation of Rac and not enhanced PTK activity. Furthermore, the enhanced signaling in CD4+CD8+ double positive thymocytes appears to be compensated by the selective down-regulation of CD3 on mature thymocytes and peripheral T cells from both strains of mutant c-Cbl mice

Transverse emittance measurements on an S-band photoinjector rf electron gun

Proposed fourth generation light sources using SASE FELs to generate short pulse, coherent, X-rays require demonstration of high brightness electron sources. The Gun Test Facility (GTF) at SLAC was built to test high brightness sources for the proposed Linac Coherent Light Source at SLAC. The transverse emittance measurements are made at nearly 30 MeV by measuring the spot size on a YAG screen using the quadrupole scan technique. The emittance was measured to vary from 1 to 3.5 mm-mrad as the charge is increased from 50 to 350 pC using a laser pulse width of 2 ps FWHM. The measurements are in good agreement with simulation results using the LANL version of PARMELA.Comment: 12 pages, 4 figures, contributed to The 23rd Int. FEL Conf., Darmstadt, 20-24 Aug. 200

Periconceptional maternal mediterranean diet is associated with favorable offspring behaviors and altered CpG methylation of imprinted genes

Background: Maternal diet during pregnancy has been shown to influence the child neuro-developmental outcomes. Studies examining effects of dietary patterns on offspring behavior are sparse. Objective: Determine if maternal adherence to a Mediterranean diet is associated with child behavioral outcomes assessed early in life, and to evaluate the role of differentially methylated regions (DMRs) regulating genomically imprinted genes in these associations. Methods: Among 325 mother/infant pairs, we used regression models to evaluate the association between tertiles of maternal periconceptional Mediterranean diet adherence (MDA) scores derived from a Food Frequency Questionnaire, and social and emotional scores derived from the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire in the second year of life. Methylation of nine genomically imprinted genes was measured to determine if MDA was associated with CpG methylation. Results: Child depression was inversely associated with maternal MDA (Bonferroni-corrected p = 0.041). While controlling for false-discovery, compared to offspring of women with the lowest MDA tertile, those with MDA scores in middle and high MDA tertiles had decreased odds for atypical behaviors [OR (95% CI) = 0.40 (0.20, 0.78) for middle and 0.40 (0.17, 0.92) for highest tertile], for maladaptive behaviors [0.37 (0.18, 0.72) for middle tertile and 0.42 (0.18, 0.95) for highest tertile] and for an index of autism spectrum disorder behaviors [0.46 (0.23, 0.90) for middle and 0.35 (0.15, 0.80) for highest tertile]. Offspring of women with the highest MDA tertile were less likely to exhibit depressive [OR = 0.28 (0.12, 0.64)] and anxiety [0.42 (0.18, 0.97)] behaviors and increased odds of social relatedness [2.31 (1.04, 5.19)] behaviors when compared to low MDA mothers. Some associations varied by sex. Perinatal MDA score was associated with methylation differences for imprinted control regions of PEG10/SGCE [females: Beta (95% CI) = 1.66 (0.52, 2.80) - Bonferroni-corrected p = 0.048; males: -0.56 (-1.13, -0.00)], as well as both MEG3 and IGF2 in males [0.97 (0.00, 1.94)] and -0.92 (-1.65, -0.19) respectively. Conclusion: In this ethnically diverse cohort, maternal adherence to a Mediterranean diet in early pregnancy was associated with favorable neurobehavioral outcomes in early childhood and with sex-dependent methylation differences of MEG3, IGF2, and SGCE/PEG10 DMRs

Tobacco Retail Outlets, Neighborhood Deprivation and the Risk of Prenatal Smoke Exposure

INTRODUCTION: Smoking and smoke exposure among pregnant women remain persistent public health issues. Recent estimates suggest that approximately one out of four nonsmokers have measurable levels of cotinine, a marker indicating regular exposure to secondhand smoke. Epidemiological research has attempted to pinpoint individual-level and neighborhood-level factors for smoking during pregnancy. However, most of these studies have relied upon self-reported measures of smoking. AIMS AND METHODS: To more accurately assess smoke exposure resulting from both smoking and secondhand exposure in mothers during pregnancy, we used Bayesian regression models to estimate the association of cotinine levels with tobacco retail outlet (TRO) exposure and a neighborhood deprivation index (NDI) in six counties in North Carolina centered on Durham County. RESULTS: Results showed a significant positive association between TRO exposure (β = 0.008, 95% credible interval (CI) = [0.003, 0.013]) and log cotinine after adjusting for individual covariates (eg, age, race/ethnicity, education, marital status). TRO exposure was not significant after including the NDI, which was significantly associated with log cotinine (β = 0.143, 95% CI = [0.030, 0.267]). However, in a low cotinine stratum (indicating secondhand smoke exposure), TRO exposure was significantly associated with log cotinine (β = 0.005, 95% CI = [0.001, 0.009]), while in a high cotinine stratum (indicating active smoking), the NDI was significantly associated with log cotinine (β = 0.176, 95% CI = [0.005, 0.372]). CONCLUSIONS: In summary, our findings add to the evidence that contextual factors are important for active smoking during pregnancy. IMPLICATIONS: In this study, we found several significant associations that suggest a more nuanced understanding of the potential influence of environmental- and individual-level factors for levels of prenatal smoke exposure. Results suggested a significant positive association between TRO exposure and cotinine levels, after adjusting for the individual factors such as race, education, and marital status. Individually, NDI was similarly positively associated with cotinine levels as well. However, when combining TRO exposure alongside NDI in the same model, TROs were no longer significantly associated with overall cotinine levels

Anomalous accelerations in spacecraft flybys of the Earth

[EN] The flyby anomaly is a persistent riddle in astrodynamics. Orbital analysis in several flybys of the Earth since the Galileo spacecraft flyby of the Earth in 1990 have shown that the asymptotic post-encounter velocity exhibits a difference with the initial velocity that cannot be attributed to conventional effects. To elucidate its origin, we have developed an orbital program for analyzing the trajectory of the spacecraft in the vicinity of the perigee, including both the Sun and the Moon¿s tidal perturbations and the geopotential zonal, tesseral and sectorial harmonics provided by the EGM96 model. The magnitude and direction of the anomalous acceleration acting upon the spacecraft can be estimated from the orbital determination program by comparing with the trajectories fitted to telemetry data as provided by the mission teams. This acceleration amounts to a fraction of a mm/s2 and decays very fast with altitude. 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Provenance of the Early Mesoproterozoic Radium Creek Group in the northern Mount Painter Inlier: Correlating isotopic signatures to inform tectonic reconstructions

New in situ zircon LA-ICPMS geochronologic and Hf-isotope data from the Radium Creek Group within the Mount Painter Inlier provide important temporal constraints on the Early Mesoproterozoic palaeogeography of eastern Proterozoic Australia. The entire Radium Creek Group was deposited in a single basin forming phase, and has a maximum depositional age of 1595. ±. 3.7. Ma. Detrital zircon from these metasedimentary rocks have U-Pb age populations at ca. 1595. Ma, 1660-1680. Ma, 1710-1780. Ma, ca. 1850. Ma and ca. 2500. Ma. These grains are characterised by isotopically diverse and evolved sources, and have crystallised within predominantly felsic igneous host-rocks. The relative age spectra and isotopic character has more similarity with the Gawler Craton than the Arunta Block, Curnamona Province or the Mount Isa Inlier. These observations suggest that the Mount Painter Province was adjacent to the Gawler Craton in the Early Mesoproterozoic. Our data supports a coherent South Australian Craton at ca. 1595. Ma and a contiguous continental mass that included the North and South Australian cratons. The Mount Painter Inlier occupied a complex plate tectonic setting in the overriding plate of two convergent margins. © 2014 Elsevier B.V

Mapping the link between socio-economic factors, autistic traits and mental health across different settings

Autistic individuals experience higher rates of externalising and internalising symptoms that may vary with environmental factors. However, there is limited research on variation across settings that may highlight common factors with globally generalisable effects. Data were taken from two cohorts: a multinational European sample (n = 764; 453 autistic; 311 non-autistic; 6–30 years), and a South African sample (n = 100 non-autistic; 3–11 years). An exploratory factor analysis aggregated clinical (Verbal Comprehension and Perceptual Index), adaptive traits (Vineland Adaptive Behaviour Scale) and socio-economic variables (parental employment and education, home and family characteristics) in each cohort separately. With regression, we investigated the effect of these factors and autistic traits on internalising and externalising scores (measured with the Strengths and Difficulties Questionnaire). Cohorts showed similar four-factor structures (Person Characteristics, Family System, Parental and Material Resources). The ‘Family System’ factor captured family size and maternal factors and was associated with lower internalising and externalising symptoms in both cohorts. In the European cohort, high autistic traits reduced this effect; the opposite was found in the South Africa cohort. Our exploratory findings from two separate analyses represent consistent evidence that Family System is associated with internalising and externalising symptoms, with a context-specific impact in persons with high autism traits