ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated ...with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.
This study assessed change in self-reported Big Five personality traits. We conducted a coordinated integrative data analysis using data from 16 longitudinal samples, comprising a total sample of ...over 60 000 participants. We coordinated models across multiple datasets and fit identical multi-level growth models to assess and compare the extent of trait change over time. Quadratic change was assessed in a subset of samples with four or more measurement occasions. Across studies, the linear trajectory models revealed declines in conscientiousness, extraversion, and openness. Non-linear models suggested late-life increases in neuroticism. Meta-analytic summaries indicated that the fixed effects of personality change are somewhat heterogeneous and that the variability in trait change is partially explained by sample age, country of origin, and personality measurement method. We also found mixed evidence for predictors of change, specifically for sex and baseline age. This study demonstrates the importance of coordinated conceptual replications for accelerating the accumulation of robust and reliable findings in the lifespan developmental psychological sciences. (c) 2020 European Association of Personality Psychology
All known eukaryotic topoisomerases are only able to relieve torsional stress in DNA. Nevertheless, it has been proposed that the introduction of positive DNA supercoiling is required for efficient ...sister-chromatid disjunction by Topoisomerase 2a during mitosis. Here we identify a eukaryotic enzymatic activity that introduces torsional stress into DNA. We show that the human Plk1-interacting checkpoint helicase (PICH) and Topoisomerase 3a proteins combine to create an extraordinarily high density of positive DNA supercoiling. This activity, which is analogous to that of a reverse-gyrase, is apparently driven by the ability of PICH to progressively extrude hypernegatively supercoiled DNA loops that are relaxed by Topoisomerase 3a. We propose that this positive supercoiling provides an optimal substrate for the rapid disjunction of sister centromeres by Topoisomerase 2a at the onset of anaphase in eukaryotic cells.
Carbon emissions and their ocean impactsAnthropogenic CO2 emissions directly affect atmospheric chemistry but also have a strong influence on the oceans. Gattuso et al. review how the physics, ...chemistry, and ecology of the oceans might be affected based on two CO2 emission trajectories: one business as usual and one with aggressive reductions. Ocean warming, acidification, sea-level rise, and the expansion of oxygen minimum zones will continue to have distinct impacts on marine communities and ecosystems. The path that humanity takes regarding CO2 emissions will largely determine the severity of these phenomena.Science, this issue 10.1126/science.aac4722 The ocean moderates anthropogenic climate change at the cost of profound alterations of its physics, chemistry, ecology, and services. Here, we evaluate and compare the risks of impacts on marine and coastal ecosystems-and the goods and services they provide-for growing cumulative carbon emissions under two contrasting emissions scenarios. The current emissions trajectory would rapidly and significantly alter many ecosystems and the associated services on which humans heavily depend. A reduced emissions scenario-consistent with the Copenhagen Accord's goal of a global temperature increase of less than 2 degree C-is much more favorable to the ocean but still substantially alters important marine ecosystems and associated goods and services. The management options to address ocean impacts narrow as the ocean warms and acidifies. Consequently, any new climate regime that fails to minimize ocean impacts would be incomplete and inadequate.
BACKGROUND
Assessing couple fecundity on a nation-wide basis without excluding couples who eventually remain infertile is challenging. Our aim was to describe couple fecundity (in terms of frequency ...of involuntary infertility) among the general population living in France.
METHODS
We used a current-duration design. A random sample of 64 262 households was selected in 2007–2008, allowing us to identify 15 810 women aged 18–44 years. Eligible women (n= 1089) were those having regular sexual intercourse with a male partner, not using any method of contraception and not having delivered in the previous 3 months. These women reported information on the current duration of unprotected intercourse (CDUI, the time elapsed between the start of the period of unprotected intercourse and the time of inclusion in the study). The CDUI distribution was used to estimate the frequency of involuntary infertility, using a newly developed statistical technique that does not require couples to be followed up until the end of the period of unprotected intercourse.
RESULTS
CDUI was defined for 867 women. An estimated 46% of couples had no detected pregnancy conceived during the first 6 months of unprotected intercourse 95% confidence interval (CI), 36–56%. The proportions of couples with no detected pregnancy within 12 and 24 months were 24% (19–30%) and 11% (8–14%), respectively.
CONCLUSIONS
These results constitute one of the few descriptions of the fecundity of a nation-wide representative sample of couples from the general population, not limited to couples who eventually conceived or to those resorting to medical help.
MarsSI (Acronym for Mars System of Information, https://emars.univ-lyon1.fr/MarsSI/) is a web Geographic Information System application which helps managing and processing martian orbital data. The ...MarsSI facility is part of the web portal called PSUP (Planetary SUrface Portal) developed by the Observatories of Paris Sud (OSUPS) and Lyon (OSUL) to provide users with efficient and easy access to data products dedicated to the martian surface. The portal proposes 1) the management and processing of data thanks to MarsSI and 2) the visualization and merging of high level (imagery, spectral, and topographic) products and catalogs via a web-based user interface (MarsVisu). The portal PSUP as well as the facility MarsVisu is detailed in a companion paper (Poulet et al., 2018). The purpose of this paper is to describe the facility MarsSI. From this application, users are able to easily and rapidly select observations, process raw data via automatic pipelines, and get back final products which can be visualized under Geographic Information Systems. Moreover, MarsSI also contains an automatic stereo-restitution pipeline in order to produce Digital Terrain Models (DTM) on demand from HiRISE (High Resolution Imaging Science Experiment) or CTX (Context Camera) pair-images. This application is funded by the European Union's Seventh Framework Programme (FP7/2007–2013) (ERC project eMars, No. 280168) and has been developed in the scope of Mars, but the design is applicable to any other planetary body of the solar system.
•MarsSI is a web application managing and processing Martian orbital data on demand.•MarsSI proposes on demand automatic stereo-restitution from HiRISE or CTX pair-images.•While developed in the scope of Mars, the design is applicable to any other planetary body of the solar system.
Ambient air pollution has been associated with restricted fetal growth, which is linked with adverse respiratory health in childhood. We assessed the effect of maternal exposure to low concentrations ...of ambient air pollution on birthweight.
We pooled data from 14 population-based mother-child cohort studies in 12 European countries. Overall, the study population included 74 178 women who had singleton deliveries between Feb 11, 1994, and June 2, 2011, and for whom information about infant birthweight, gestational age, and sex was available. The primary outcome of interest was low birthweight at term (weight <2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2·5 μm (PM2·5), less than 10 μm (PM10), and between 2·5 μm and 10 μm during pregnancy were estimated at maternal home addresses with temporally adjusted land-use regression models, as was PM2·5 absorbance and concentrations of nitrogen dioxide (NO2) and nitrogen oxides. We also investigated traffic density on the nearest road and total traffic load. We calculated pooled effect estimates with random-effects models.
A 5 μg/m(3) increase in concentration of PM2·5 during pregnancy was associated with an increased risk of low birthweight at term (adjusted odds ratio OR 1·18, 95% CI 1·06-1·33). An increased risk was also recorded for pregnancy concentrations lower than the present European Union annual PM2·5 limit of 25 μg/m(3) (OR for 5 μg/m(3) increase in participants exposed to concentrations of less than 20 μg/m(3) 1·41, 95% CI 1·20-1·65). PM10 (OR for 10 μg/m(3) increase 1·16, 95% CI 1·00-1·35), NO2 (OR for 10 μg/m(3) increase 1·09, 1·00-1·19), and traffic density on nearest street (OR for increase of 5000 vehicles per day 1·06, 1·01-1·11) were also associated with increased risk of low birthweight at term. The population attributable risk estimated for a reduction in PM2·5 concentration to 10 μg/m(3) during pregnancy corresponded to a decrease of 22% (95% CI 8-33%) in cases of low birthweight at term.
Exposure to ambient air pollutants and traffic during pregnancy is associated with restricted fetal growth. A substantial proportion of cases of low birthweight at term could be prevented in Europe if urban air pollution was reduced.
The European Union.
Background: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. Methods: ...We analyzed data from 6 European population-based birth cohorts—GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)—that recruited mother-infant pairs from 1997 to 2008. Air pollution levels—nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5–10 μm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup—at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. Results: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points 95% confidence interval = −1.25 to −0.11 per increase of 10 μg/m3 in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. Conclusions: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.
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