Detection of Neptune-size planetary candidates with CoRoT data. Comparison with the planet occurrence rate derived from Kepler

[Abridged] Context. The CoRoT space mission has been searching for transiting planets since the end of December 2006. Aims. We aim to investigate the capability of CoRoT to detect small-size transiting planets in short-period orbits, and to compare the number of CoRoT planets with 2 \leq R_p \leq 4 Rearth with the occurrence rate of small-size planets provided by the distribution of Kepler planetary candidates (Howard et al. 2012). Methods. We performed a test that simulates transits of super-Earths and Neptunes in real CoRoT light curves and searches for them blindly by using the LAM transit detection pipeline. Results. The CoRoT detection rate of planets with radius between 2 and 4 Rearth and orbital period P \leq 20 days is 59% (31%) around stars brighter than r'=14.0 (15.5). By properly taking the CoRoT detection rate for Neptune-size planets and the transit probability into account, we found that according to the Kepler planet occurrence rate, CoRoT should have discovered 12 \pm 2 Neptunes orbiting G and K dwarfs with P \leq 17 days in six observational runs. This estimate must be compared with the validated Neptune CoRoT-24b and five CoRoT planetary candidates in the considered range of planetary radii. We thus found a disagreement with expectations from Kepler at 3 \sigma or 5 \sigma, assuming a blend fraction of 0% (six Neptunes) and 100% (one Neptune) for these candidates. Conclusions. This underabundance of CoRoT Neptunes with respect to Kepler may be due to several reasons. Regardless of the origin of the disagreement, which needs to be investigated in more detail, the noticeable deficiency of CoRoT Neptunes at short orbital periods seems to indirectly support the general trend found in Kepler data, i.e. that the frequency of small-size planets increases with increasing orbital periods and decreasing planet radii.Comment: 10 pages, 7 figures. Accepted for publication in A&

C-Mpl Is Expressed on Osteoblasts and Osteoclasts and Is Important in Regulating Skeletal Homeostasis

C-Mpl is the receptor for thrombopoietin (TPO), the main megakaryocyte (MK) growth factor, and c-Mpl is believed to be expressed on cells of the hematopoietic lineage. As MKs have been shown to enhance bone formation, it may be expected that mice in which c-Mpl was globally knocked out (c-Mpl(-/-) mice) would have decreased bone mass because they have fewer MKs. Instead, c-Mpl(-/-) mice have a higher bone mass than WT controls. Using c-Mpl(-/-) mice we investigated the basis for this discrepancy and discovered that c-Mpl is expressed on both osteoblasts (OBs) and osteoclasts (OCs), an unexpected finding that prompted us to examine further how c-Mpl regulates bone. Static and dynamic bone histomorphometry parameters suggest that c-Mpl deficiency results in a net gain in bone volume with increases in OBs and OCs. In vitro, a higher percentage of c-Mpl(-/-) OBs were in active phases of the cell cycle, leading to an increased number of OBs. No difference in OB differentiation was observed in vitro as examined by real-time PCR and functional assays. In co-culture systems, which allow for the interaction between OBs and OC progenitors, c-Mpl(-/-) OBs enhanced osteoclastogenesis. Two of the major signaling pathways by which OBs regulate osteoclastogenesis, MCSF/OPG/RANKL and EphrinB2-EphB2/B4, were unaffected in c-Mpl(-/-) OBs. These data provide new findings for the role of MKs and c-Mpl expression in bone and may provide insight into the homeostatic regulation of bone mass as well as bone loss diseases such as osteoporosis

Differential Stem and Progenitor Cell Trafficking by Prostaglandin E2

SUMMARY To maintain lifelong production of blood cells, hematopoietic stem cells (HSC) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSC (LT-HSC) reside in several, perhaps overlapping, niches that produce regulatory molecules/signals necessary for homeostasis and increased output following stress/injury 1–5. Despite significant advances in specific cellular or molecular mechanisms governing HSC/niche interactions, little is understood about regulatory function within the intact mammalian hematopoietic niche. Recently, we and others described a positive regulatory role for Prostaglandin E2 (PGE2) on HSC function ex vivo 6,7. While exploring the role of endogenous PGE2 we unexpectedly observed hematopoietic egress after nonsteroidal anti-inflammatory drug (NSAID) treatment. Surprisingly, this was independent of the SDF-1/CXCR4 axis. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin (OPN). Hematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in higher species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced EP4 receptor signaling. These results not only uncover unique regulatory roles for EP4 signaling in HSC retention in the niche but also define a rapidly translatable strategy to therapeutically enhance transplantation

Co-benefits from sustainable dietary shifts for population and environmental health: an assessment from a large European cohort study

Funding European Commission (DG-SANCO) , the International Agency for Research on Cancer (IARC) , MRC Early Career Fellowship (MR/M501669/1) .Background Unhealthy diets, the rise of non-communicable diseases, and the declining health of the planet are highly intertwined, where food production and consumption are major drivers of increases in greenhouse gas emissions, substantial land use, and adverse health such as cancer and mortality. To assess the potential co-benefits from shifting to more sustainable diets, we aimed to investigate the associations of dietary greenhouse gas emissions and land use with all-cause and cause-specific mortality and cancer incidence rates. Methods Using data from 443 991 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a multicentre prospective cohort, we estimated associations between dietary contributions to greenhouse gas emissions and land use and all-cause and cause-specific mortality and incident cancers using Cox proportional hazards regression models. The main exposures were modelled as quartiles. Co-benefits, encompassing the potential effects of alternative diets on all-cause mortality and cancer and potential reductions in greenhouse gas emissions and land use, were estimated with counterfactual attributable fraction intervention models, simulating potential effects of dietary shifts based on the EAT–Lancet reference diet. Findings In the pooled analysis, there was an association between levels of dietary greenhouse gas emissions and allcause mortality (adjusted hazard ratio [HR] 1·13 [95% CI 1·10–1·16]) and between land use and all-cause mortality (1·18 [1·15–1·21]) when comparing the fourth quartile to the first quartile. Similar associations were observed for cause-specific mortality. Associations were also observed between all-cause cancer incidence rates and greenhouse gas emissions, when comparing the fourth quartile to the first quartile (adjusted HR 1·11 [95% CI 1·09–1·14]) and between all-cause cancer incidence rates and land use (1·13 [1·10–1·15]); however, estimates differed by cancer type. Through counterfactual attributable fraction modelling of shifts in levels of adherence to the EAT–Lancet diet, we estimated that up to 19–63% of deaths and up to 10–39% of cancers could be prevented, in a 20-year risk period, by different levels of adherence to the EAT–Lancet reference diet. Additionally, switching from lower adherence to the EAT–Lancet reference diet to higher adherence could potentially reduce food-associated greenhouse gas emissions up to 50% and land use up to 62%. Interpretation Our results indicate that shifts towards universally sustainable diets could lead to co-benefits, such as minimising diet-related greenhouse gas emissions and land use, reducing the environmental footprint, aiding in climate change mitigation, and improving population health.European Commission European Commission Joint Research CentreWorld Health OrganizationUK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M501669/

Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12–14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international group working together to develop a core outcome set (COS) for clinical trials in eczema (synonymous with atopic eczema and atopic dermatitis). HOME is coordinated from the Centre of Evidence Based Dermatology, University of Nottingham, U.K. Participation in HOME is open to anyone with an interest in outcomes for eczema. A COS is the agreed upon minimum set of instruments that should be included in all clinical trials for a particular condition. Use of a COS does not preclude using other instruments; other domains and instruments can also be included to meet the specific requirements of individual trials. COS initiatives are active across many fields of medicine and should enable better synthesis of trial data and reduce selective outcome reporting bias. The HOME initiative follows the best current guidance on developing a COS. Four core domains have been identified: clinician-reported signs; patient-reported symptoms; quality of life; and long-term control. The core outcome measurement instruments for clinician-reported signs and patient-reported symptoms have been established: the Eczema Area and Severity Index (EASI) for measuring clinician reported signs was agreed on at the HOME III meeting, and the Patient-Oriented Eczema Measure (POEM) was chosen to measure patient-reported symptoms at the HOME IV meeting. This is a report from the fifth consensus meeting of the HOME initiative (HOME V), which was held on 12–14 June 2017 in Nantes, France. The local organizers were Sebastien Barbarot and Jean-Francois Stalder of Nantes University Hospital, France

On the Variability of the Length Weight Relationship for Atlantic Bluefin Tuna, Thunnus thynnus (L.)

Following extensive review, a model of the Atlantic bluefin tuna (ABFT), Thunnus thynnus (L.), length–weight relationship for the eastern Atlantic and Mediterranean (RW = 0.0000188 SFL3.01247; Ec 1) is presented on the basis of samples of ABFT spawners, with an average value of index K = 2.03 ± 0.15SD, collected by the Atlantic traps of Portugal and Spain in the Strait of Gibraltar (1963; 1996–1998; 2000–2012), and a set of samples of juvenile fishes from ICCAT–GBYP (n = 707). The resulting model (Ec 1), together with the model used for the eastern stock assessment (RW = 0.000019607 SFL3.0092; Ec 2) and a recently adopted by ICCAT Standing Committee on Research and Statistics (SCRS) (RW = 0.0000315551 SFL2.898454; EAST) are analyzed in using a bi-variant sample [SFL (cm), RW (kg)] of 474 pairs of data with the aim of validating them and establishing which model(s) best fit the reality represented by the sample and, therefore, will have the greatest descriptive and predictive power. The result of the analysis indicates that the model EAST clearly underestimates the weight of spawning ABFT and that model Ec 2 overestimates it slightly, being model Ec 1 that best explains the data of the sample. The result of the classical statistical analysis is confirmed by means of the quantile regression technique, selecting the quantiles 5, 25, 50, 75, and 95%. Other fisheries and biological indicators also conclude that the model EAST gradually underestimates the weight of ABFT spawners (of 2–3 m) by 9–12.5 %, and does not meet the criterion that for RW = 725 kg (Wmax), SFL = 319.93 ± 11.3 cm (Lmax).Cort, JL.; Estruch Fuster, VD.; Neves Dos Santos, M.; Di Natale, A.; Abid, N.; De La Serna, JM. (2015). On the Variability of the Length Weight Relationship for Atlantic Bluefin Tuna, Thunnus thynnus (L.). Reviews in Fisheries Science & Aquaculture. 23(1):23-38. doi:10.1080/23308249.2015.1008625S2338231Aguado-Giménez, F., & García-García, B. (2005). Changes in some morphometric relationships in Atlantic bluefin tuna (Thunnus thynnus thynnus Linnaeus, 1758) as a result of fattening process. Aquaculture, 249(1-4), 303-309. doi:10.1016/j.aquaculture.2005.04.064Block, B. A., Teo, S. L. H., Walli, A., Boustany, A., Stokesbury, M. J. W., Farwell, C. J., … Williams, T. D. (2005). Electronic tagging and population structure of Atlantic bluefin tuna. Nature, 434(7037), 1121-1127. doi:10.1038/nature03463Chapman, E. W., Jørgensen, C., & Lutcavage, M. E. (2011). Atlantic bluefin tuna (Thunnus thynnus): a state-dependent energy allocation model for growth, maturation, and reproductive investment. Canadian Journal of Fisheries and Aquatic Sciences, 68(11), 1934-1951. doi:10.1139/f2011-109Cort, J. L., Arregui, I., Estruch, V. D., & Deguara, S. (2014). Validation of the Growth Equation Applicable to the Eastern Atlantic Bluefin Tuna,Thunnus thynnus(L.), UsingLmax, Tag-Recapture, and First Dorsal Spine Analysis. Reviews in Fisheries Science & Aquaculture, 22(3), 239-255. doi:10.1080/23308249.2014.931173Cort, J. L., Deguara, S., Galaz, T., Mèlich, B., Artetxe, I., Arregi, I., … Idrissi, M. (2013). Determination ofLmaxfor Atlantic Bluefin Tuna,Thunnus thynnus(L.), from Meta-Analysis of Published and Available Biometric Data. Reviews in Fisheries Science, 21(2), 181-212. doi:10.1080/10641262.2013.793284Fraser, K.Possessed. World Record Holder for Bluefin Tuna. Kingstown, Nova Scotia: T & S Office Essentials and printing, 243 pp. (2008).Fromentin, J.-M., & Powers, J. E. (2005). Atlantic bluefin tuna: population dynamics, ecology, fisheries and management. Fish and Fisheries, 6(4), 281-306. doi:10.1111/j.1467-2979.2005.00197.xHattour, A.Contribution a l’étude des Scombridés de Tunisie. Université de Tunis. Faculté des Sciences, 168 pp. (1979).Karakulak, S., Oray, I., Corriero, A., Deflorio, M., Santamaria, N., Desantis, S., & De Metrio, G. (2004). Evidence of a spawning area for the bluefin tuna (Thunnus thynnus L.) in the eastern Mediterranean. Journal of Applied Ichthyology, 20(4), 318-320. doi:10.1111/j.1439-0426.2004.00561.xKoenker, R., & Bassett, G. (1978). Regression Quantiles. Econometrica, 46(1), 33. doi:10.2307/1913643Koenker, R. (2005). Quantile Regression. doi:10.1017/cbo9780511754098Milatou, N., & Megalofonou, P. (2014). Age structure and growth of bluefin tuna (Thunnus thynnus, L.) in the capture-based aquaculture in the Mediterranean Sea. Aquaculture, 424-425, 35-44. doi:10.1016/j.aquaculture.2013.12.037Perçin, F., & Akyol, O. (2009). Lengthâ weight and lengthâ length relationships of the bluefin tuna,Thunnus thynnusL., in the Turkish part of the eastern Mediterranean Sea. Journal of Applied Ichthyology, 25(6), 782-784. doi:10.1111/j.1439-0426.2009.01288.xPercin, F., & Akyol, O. (2010). Some Morphometric Relationships in Fattened Bluefin Tuna, Thunnus thynnus L., from the Turkish Aegean Sea. Journal of Animal and Veterinary Advances, 9(11), 1684-1688. doi:10.3923/javaa.2010.1684.1688Rooker, J. R., Alvarado Bremer, J. R., Block, B. A., Dewar, H., de Metrio, G., Corriero, A., … Secor, D. H. (2007). Life History and Stock Structure of Atlantic Bluefin Tuna (Thunnus thynnus). Reviews in Fisheries Science, 15(4), 265-310. doi:10.1080/10641260701484135Sinovcic, G., Franicevic, M., Zorica, B., & Cikes-Kec, V. (2004). Length-weight and length-length relationships for 10 pelagic fish species from the Adriatic Sea (Croatia). Journal of Applied Ichthyology, 20(2), 156-158. doi:10.1046/j.1439-0426.2003.00519.xTičina, V., Grubišić, L., Šegvić Bubić, T., & Katavić, I. (2011). Biometric characteristics of small Atlantic bluefin tuna (Thunnus thynnus, Linnaeus, 1758) of Mediterranean Sea origin. Journal of Applied Ichthyology, 27(4), 971-976. doi:10.1111/j.1439-0426.2011.01752.

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual