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Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.

Contains fulltext : 167711.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Vivian Chow,1 Ashley Weissman,2 Casey Lee O’Connell,3 Azim Mehrvar,4 Mojtaba Akhtari3 1Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, 2Department of Pharmacy, 3Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Norris Comprehensive Cancer Center, LosAngeles, CA, USA; 4Mahak Children’s Cancer Treatment and Research Center, Tehran, Iran Abstract: Myelofibrosis (MF) is a myeloid malignancy associated with a heavy symptomatic burden that decreases quality of life and presents a risk for leukemic transformation. While there are limited curative treatments, the recent discovery of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway dysregulation has led to many clinical investigations for new treatment approaches. This review provides practical knowledge on the disease state, an overview of treatment options, and specifically focuses on the efficacy and safety of pacritinib in the management of MF. Pacritinib is a novel selective inhibitor of JAK2 and FMS-related tyrosine kinase 3 (FLT3) currently in Phase III trials for the treatment of MF. Thus far, studies have demonstrated clinical efficacy in reducing splenomegaly and constitutional symptoms. Common adverse events were gastrointestinal in nature, while hematologic toxicity was limited. However, it was announced that all ongoing clinical trials on pacritinib have been placed on hold by the US Food and Drug Administration in February 2016, due to concerns for increased intracranial hemorrhage and cardiac events. With comprehensive risk-benefit analysis of clinical trial data, the utility of pacritinib in the management of MF may be more clearly defined. Keywords: JAK2, FLT3, myeloproliferative neoplasms, SB1518

The problem of traffic congestion and associated externalities has become a major focus of transport policies in recent years. In the United Kingdom legislation has been passed to empower local authorities to implement road user charging. This study investigates the effect of a hypothetical congestion charging scheme in the city of Newcastle upon Tyne. Previous studies tend to focus on measuring user's willingness to pay, often neglecting the impact on the activity schedule. This paper focuses on the way participants adapt not only their travel behavior but also their activity participation and rescheduling pattern. These changes are looked at from a two-level approach: the aggregate day level and the more disaggregate tour level from intra-day activity rescheduling. Results show that the scheme is effective in reducing car usage during peak time in the city. The overall activity participation however remains largely unchanged.

High-accuracy continuous measurements of greenhouse gases (CO2 and CH4) during the BARCA (Balanço Atmosférico Regional de Carbono na Amazônia) phase B campaign in Brazil in May 2009 were accomplished using a newly available analyzer based on the cavity ring-down spectroscopy (CRDS) technique. This analyzer was flown without a drying system or any in-flight calibration gases. Water vapor corrections associated with dilution and pressure-broadening effects for CO2 and CH4 were derived from laboratory experiments employing measurements of water vapor by the CRDS analyzer. Before the campaign, the stability of the analyzer was assessed by laboratory tests under simulated flight conditions. During the campaign, a comparison of CO2 measurements between the CRDS analyzer and a nondispersive infrared (NDIR) analyzer on board the same aircraft showed a mean difference of 0.22±0.09 ppm for all flights over the Amazon rain forest. At the end of the campaign, CO2 concentrations of the synthetic calibration gases used by the NDIR analyzer were determined by the CRDS analyzer. After correcting for the isotope and the pressure-broadening effects that resulted from changes of the composition of synthetic vs. ambient air, and applying those concentrations as calibrated values of the calibration gases to reprocess the CO2 measurements made by the NDIR, the mean difference between the CRDS and the NDIR during BARCA was reduced to 0.05±0.09 ppm, with the mean standard deviation of 0.23±0.05 ppm. The results clearly show that the CRDS is sufficiently stable to be used in flight without drying the air or calibrating in flight and the water corrections are fully adequate for high-accuracy continuous airborne measurements of CO2 and CH4.

We present the Vegetation Photosynthesis and Respiration Model (VPRM), a satellite-based assimilation scheme that estimates hourly values of Net Ecosystem Exchange (NEE) of CO2 for 12 North American biomes using the Enhanced Vegetation Index (EVI) and Land Surface Water Index (LSWI), derived from reflectance data of the Moderate Resolution Imaging Spectroradiometer (MODIS), plus high-resolution data for sunlight and air temperature. The motivation is to provide reliable, fine-grained first-guess fields of surface CO2 fluxes for application in inverse models at continental and smaller scales. An extremely simple mathematical structure, with minimal numbers of parameters, facilitates optimization using in situ data, with finesse provided by maximal infusion of observed NEE and environmental data from networks of eddy covariance towers across North America (AmeriFlux and Fluxnet Canada). Cross validation showed that the VPRM has strong prediction ability for hourly to monthly timescales for sites with similar vegetation. The VPRM also provides consistent partitioning of NEE into Gross Ecosystem Exchange (GEE, the light-dependent part of NEE) and ecosystem respiration (R, the light-independent part), half-saturation irradiance of ecosystem photosynthesis, and annual sum of NEE at all eddy flux sites for which it is optimized. The capability to provide reliable patterns of surface flux for fine-scale inversions is presently limited by the number of vegetation classes for which NEE can be constrained by the current network of eddy flux sites and by the accuracy of MODIS data and data for sunlight. [References: 87]

International audience; Observations of CO2 were made in the upper troposphere and lower stratosphere in the deep tropics in order to determine the patterns of large-scale vertical transport and age of air in the Tropical Tropopause Layer (TTL). Flights aboard the NASA WB-57F aircraft over Central America and adjacent ocean areas took place in January and February, 2004 (Pre-AURA Validation Experiment, Pre-AVE) and 2006 (Costa Rice AVE, CR-AVE), and for the same flight dates of 2006, aboard the Proteus aircraft from the surface to 15 km over Darwin, Australia (Tropical Warm Pool International Cloud Experiment, TWP-ICE). The data demonstrate that the TTL is composed of two layers with distinctive features: (1) the lower TTL, 350?360 K (potential temperature(?); approximately 12?14 km), is subject to inputs of convective outflows, as indicated by layers of variable CO2 concentrations, with air parcels of zero age distributed throughout the layer; (2) the upper TTL, from ?=~360 K to ~390 K (14?18 km), ascends slowly and ages uniformly, as shown by a linear decline in CO2 mixing ratio tightly correlated with altitude, associated with increasing age. This division is confirmed by ensemble trajectory analysis. The CO2 concentration at the level of 360 K was 380.0(±0.2) ppmv, indistinguishable from surface site values in the Intertropical Convergence Zone (ITCZ) for the flight dates. Values declined with altitude to 379.2(±0.2) ppmv at 390 K, implying that air in the upper TTL monotonically ages while ascending. In combination with the winter slope of the CO2 seasonal cycle (+10.8±0.4 ppmv/yr), the vertical gradient of ?0.78 (±0.09) ppmv gives a mean age of 26(±3) days for the air at 390 K and a mean ascent rate of 1.5(±0.3) mm s?1. The TTL near 360 K in the Southern Hemisphere over Australia is very close in CO2 composition to the TTL in the Northern Hemisphere over Costa Rica, with strong contrasts emerging at lower altitudes (2 observed unexpected input from deep convection over Amazônia deep into the TTL. The CO2 data confirm the operation of a highly accurate tracer clock in the TTL that provides a direct measure of the ascent rate of the TTL and of the age of air entering the stratosphere.

The problem of traffic congestion and associated externalities has become a major focus of transport policies in recent years. Legislation has been passed recently in the United Kingdom to empower local authorities to implement road-user charging. This study investigates the effect of a hypothetical road-user charging scheme in the city of Newcastle upon Tyne, UK. Previous studies tend to focus on measuring users' willingness to pay, often neglecting the subsequent impact on activity schedules. This paper focuses on how participants adapt not only their travel behaviour but also their activity participation and rescheduling patterns. Results suggest that the scheme is effective in reducing car use during peak times in the city but that overall activity participation remains largely unchanged.