Although it is well established that air pollutants can exacerbate asthma, the link with new asthma onset in children is less clear.
We assessed the association between the onset of childhood asthma ...with both time of birth and time-varying exposures to outdoor air pollutants.
An open cohort of children born in the province of Québec, Canada, was created using linked medical-administrative databases. New cases of asthma were defined as one hospital discharge with a diagnosis of asthma or two physician claims for asthma within a 2 year period. Annual ozone (O3) levels were estimated at the child's residence for all births 1999-2010, and nitrogen dioxide (NO2) levels during 1996-2006 were estimated for births on the Montreal Island. Satellite based concentrations of fine particles (PM2.5) were estimated at a 10 km × 10 km resolution and assigned to residential postal codes throughout the province (1996-2011). Hazard ratios (HRs) were assessed with Cox models for the exposure at the birth address and for the time-dependent exposure. We performed an indirect adjustment for secondhand smoke (SHS).
We followed 1,183,865 children (7,752,083 person-years), of whom 162,752 became asthmatic. After controlling for sex and material and social deprivation, HRs for an interquartile range increase in exposure at the birth address to NO2 (5.45 ppb), O3 (3.22 ppb), and PM2.5 (6.50 μg/m3) were 1.04 (95% CI: 1.02, 1.05), 1.11 (95% CI: 1.10, 1.12), and 1.31 (95% CI: 1.28, 1.33), respectively. Effects of O3 and PM2.5 estimated with time-varying Cox models were similar to those estimated using exposure at birth, whereas the effect of NO2 was slightly stronger (HR = 1.07; 95% CI: 1.05, 1.09).
Asthma onset in children appears to be associated with residential exposure to PM2.5, O3 and NO2.
Tétreault LF, Doucet M, Gamache P, Fournier M, Brand A, Kosatsky T, Smargiassi A. 2016. Childhood exposure to ambient air pollutants and the onset of asthma: an administrative cohort study in Québec. Environ Health Perspect 124:1276-1282; http://dx.doi.org/10.1289/ehp.1509838.
Quadrotor drones equipped with high-quality cameras have rapidly raised as novel, cheap, and stable devices for filmmakers. While professional drone pilots can create aesthetically pleasing videos in ...short time, the smooth—and cinematographic—control of a camera drone remains challenging for most users, despite recent tools that either automate part of the process or enable the manual design of waypoints to create drone trajectories.
This article moves a step further by offering high-level control of cinematographic drones for the specific task of framing dynamic targets. We propose techniques to automatically and interactively plan quadrotor drone motions in dynamic three-dimensional (3D) environments while satisfying both cinematographic and physical quadrotor constraints. We first propose the
Drone Toric Space
, a dedicated camera parameter space with embedded constraints, and derive some intuitive on-screen viewpoint manipulators. Second, we propose a dedicated path planning technique that ensures both that cinematographic properties can be enforced along the path and that the path is physically feasible by a quadrotor drone. At last, we build on the
Drone Toric Space
and the specific path planning technique to coordinate the motion of multiple drones around dynamic targets. A number of results demonstrate the interactive and automated capacities of our approaches on different use-cases.
The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during ...pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels
. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia
. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids
and trophoblast stem cells
. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.
Neovascularization is a critical process in tumor progression and malignant transformation associated with neurofibromatosis type 1 (NF1). Indeed, fibroblasts are known to play a key role in the ...tumoral microenvironment modification by producing an abundant collagenous matrix, but their contribution in paracrine communication pathways is poorly understood. Here, we hypothesized that NF1 heterozygosis in human dermal fibroblasts could promote angiogenesis through exosomes secretion. The purposes of this study are to identify the NF1 fibroblast-derived exosome protein contents and to determine their proangiogenic activity. Angiogenic proteome measurement confirmed the overexpression of VEGF and other proteins involved in vascularization. Tube formation of microvascular endothelial cells was also enhanced in presence of exosomes derived from NF1 skin fibroblasts. NF1 tissue-engineered skin (NF1-TES) generation showed a significantly denser microvessels networks compared to healthy controls. The reduction of exosomes production with an inhibitor treatment demonstrated a drastic decrease in blood vessel formation within the dermis. Our results suggest that NF1 haploinsufficiency alters the dermal fibroblast function and creates a pro-angiogenic signal via exosomes, which increases the capillary formation. This study highlights the potential of targeting exosome secretion and angiogenesis for therapeutic interventions in NF1.
Concerns over climate change are motivated in large part because of their impact on human
society. Assessing the effect of that uncertainty on specific potential impacts is demanding, since it ...requires a systematic survey over both climate and impacts models. We provide a comprehensive evaluation of uncertainty in projected crop yields for maize, spring and winter wheat, rice, and soybean, using a suite of nine crop models and up to 45 CMIP5 and 34 CMIP6 climate projections for three different forcing scenarios. To make this task computationally tractable, we use a new set of statistical crop model emulators. We find that climate and crop models contribute about equally to overall uncertainty. While the ranges of yield uncertainties under CMIP5 and CMIP6 projections are similar, median impact in aggregate total caloric production is typically more negative for the CMIP6 projections (+1% to −19%) than for CMIP5 (+5% to −13%). In the first half of the 21st century and for individual crops is the spread across crop models typically wider than that across climate models, but we find distinct differences between crops: globally, wheat and maize uncertainties are dominated by the crop models, but soybean and rice are more sensitive to the climate projections. Climate models with very similar global mean warming can lead to very different aggregate impacts so that climate model uncertainties remain a significant contributor to agricultural impacts uncertainty. These results show the utility of large-ensemble methods that allow comprehensively evaluating factors affecting crop yields or other impacts under climate change. The crop model ensemble used here is unbalanced and pulls the assumption that all projections are equally plausible into question. Better methods for consistent model testing, also at the level of individual processes, will have to be developed and applied by the crop modeling community.
Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete ...genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.
J. Neurochem. (2010) 113, 1188-1199. The finding of a secretion pathway and toxicity for mutant superoxide dismutase 1 (SOD1) raised up the possibility of using immunization approaches to reduce or ...neutralize the burden of toxic SOD1 species in the nervous system. Here we tested a passive immunization approach based on intracerebroventricular infusion in G93A-SOD1 mice of monoclonal antibodies specific to misfolded forms of SOD1 (mSOD1). We tested two monoclonal antibodies that bind distinct epitopes in mSOD1 and that do not bind to intact wild-type (WT) SOD1. One antibody succeeded in reducing the level of mSOD1 by 23% in the spinal cord and in prolonging the lifespan of G93A-SOD1 mice in proportion to the duration of treatment. However, another monoclonal antibody binding to a different SOD1 epitope failed to confer protection indicating that not all anti-SOD1 antibodies might be suitable for immunotherapy. Interestingly, the variable Fab fragment of an anti-SOD1 antibody was sufficient to confer some protection in G93A-SOD1 mice. The partial dispensability of Fc region should offer some advantages for development of immunotherapy with antibodies of smaller molecular size and low immunogenicity. From these results, we propose that passive immunization strategies should be considered as potential avenues for treatment of familial amyotrophic lateral sclerosis caused by SOD1 mutations.
Monitoring the evolution of snowpack properties in mountainous areas is crucial for avalanche hazard forecasting and water resources management. In situ and remotely sensed observations provide ...precious information on the state of the snowpack but usually offer limited spatio-temporal coverage of bulk or surface variables only. In particular, visible–near-infrared (Vis–NIR) reflectance observations can provide information about the snowpack surface properties but are limited by terrain shading and clouds. Snowpack modelling enables the estimation of any physical variable virtually anywhere, but it is affected by large errors and uncertainties. Data assimilation offers a way to combine both sources of information and to propagate information from observed areas to non-observed areas. Here, we present CrocO (Crocus-Observations), an ensemble data assimilation system able to ingest any snowpack observation (applied as a first step to the height of snow (HS) and Vis–NIR reflectances) in a spatialised geometry. CrocO uses an ensemble of snowpack simulations to represent modelling uncertainties and a particle filter (PF) to reduce them. The PF is prone to collapse when assimilating too many observations. Two variants of the PF were specifically implemented to ensure that observational information is propagated in space while tackling this issue. The global algorithm ingests all available observations with an iterative inflation of observation errors, while the klocal algorithm is a localised approach performing a selection of the observations to assimilate based on background correlation patterns. Feasibility testing experiments are carried out in an identical twin experiment setup, with synthetic observations of HS and Vis–NIR reflectances available in only one-sixth of the simulation domain. Results show that compared against runs without assimilation, analyses exhibit an average improvement of the snow water equivalent continuous rank probability score (CRPS) of 60 % when assimilating HS with a 40-member ensemble and an average 20 % CRPS improvement when assimilating reflectance with a 160-member ensemble. Significant improvements are also obtained outside the observation domain. These promising results open a possibility for the assimilation of real observations of reflectance or of any snowpack observations in a spatialised context.
Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, ...classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes.
What's new?
TP53 is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between tumor subclasses. The authors investigated p53 mutations in breast tumors from the luminal, basal, and molecular apocrine molecular subgroups. They found that subgroups differ not only in TP53 mutation frequency but also in mutation types and consequences. They detected a high prevalence of missense mutations in luminal tumors and truncating mutations in basal tumors. In apocrine molecular tumors, despite high prevalence of insertions/deletions, p53 truncation was not increased. The observations point to different mutational mechanisms, functional consequences, and/or selective pressures in different breast cancers subtypes.
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