Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology

Interactions between the atmosphere, cryosphere, and ecosystems at northern high latitudes

The Nordic Centre of Excellence CRAICC (CRyosphere-Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, was the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic Region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual Centre with the objectives to identify and quantify the major processes controlling Arctic warming and related feedback mechanisms, to outline strategies to mitigate Arctic warming and to develop Nordic Earth System modelling with a focus on the short-lived climate forcers (SLCF), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special-issue of the journal Atmospheric Chemistry and Physics. This manuscript presents an overview on the main scientific topics investigated in the Centre and provides the reader a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Facing the vast amount of outcomes we are not claiming to cover all results from CRAICC in this manuscript but concentrate here on the main results which are related to the feedback loops in the climate change-cryosphere interaction scheme affecting the Arctic amplification.The Nordic Centre of Excellence CRAICC (CRyosphere-Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, was the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic Region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual Centre with the objectives to identify and quantify the major processes controlling Arctic warming and related feedback mechanisms, to outline strategies to mitigate Arctic warming and to develop Nordic Earth System modelling with a focus on the short-lived climate forcers (SLCF), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special-issue of the journal Atmospheric Chemistry and Physics. This manuscript presents an overview on the main scientific topics investigated in the Centre and provides the reader a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Facing the vast amount of outcomes we are not claiming to cover all results from CRAICC in this manuscript but concentrate here on the main results which are related to the feedback loops in the climate change-cryosphere interaction scheme affecting the Arctic amplification.The Nordic Centre of Excellence CRAICC (CRyosphere-Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, was the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic Region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual Centre with the objectives to identify and quantify the major processes controlling Arctic warming and related feedback mechanisms, to outline strategies to mitigate Arctic warming and to develop Nordic Earth System modelling with a focus on the short-lived climate forcers (SLCF), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special-issue of the journal Atmospheric Chemistry and Physics. This manuscript presents an overview on the main scientific topics investigated in the Centre and provides the reader a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Facing the vast amount of outcomes we are not claiming to cover all results from CRAICC in this manuscript but concentrate here on the main results which are related to the feedback loops in the climate change-cryosphere interaction scheme affecting the Arctic amplification.Peer reviewe

Interactions between the atmosphere, cryosphere, and ecosystems at northern high latitudes

The Nordic Centre of Excellence CRAICC (Cryosphere–Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, is the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual centre with the objectives of identifying and quantifying the major processes controlling Arctic warming and related feedback mechanisms, outlining strategies to mitigate Arctic warming, and developing Nordic Earth system modelling with a focus on short-lived climate forcers (SLCFs), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special issue of the journal Atmospheric Chemistry and Physics. This paper presents an overview of the main scientific topics investigated in the centre and provides the reader with a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Faced with a vast amount of scientific discovery, we do not claim to completely summarize the results from CRAICC within this paper, but rather concentrate here on the main results which are related to feedback loops in climate change–cryosphere interactions that affect Arctic amplification

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

International audienceGray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet alpha-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B-12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease

Interactions between the atmosphere, cryosphere, and ecosystems at northern high latitudes

Abstract The Nordic Centre of Excellence CRAICC (Cryosphere–Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, is the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual centre with the objectives of identifying and quantifying the major processes controlling Arctic warming and related feedback mechanisms, outlining strategies to mitigate Arctic warming, and developing Nordic Earth system modelling with a focus on short-lived climate forcers (SLCFs), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special issue of the journal Atmospheric Chemistry and Physics. This paper presents an overview of the main scientific topics investigated in the centre and provides the reader with a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Faced with a vast amount of scientific discovery, we do not claim to completely summarize the results from CRAICC within this paper, but rather concentrate here on the main results which are related to feedback loops in climate change–cryosphere interactions that affect Arctic amplification

Interactions between the atmosphere, cryosphere, and ecosystems at northern high latitudes

The Nordic Centre of Excellence CRAICC (Cryosphere–Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, is the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual centre with the objectives of identifying and quantifying the major processes controlling Arctic warming and related feedback mechanisms, outlining strategies to mitigate Arctic warming, and developing Nordic Earth system modelling with a focus on short-lived climate forcers (SLCFs), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special issue of the journal Atmospheric Chemistry and Physics. This paper presents an overview of the main scientific topics investigated in the centre and provides the reader with a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Faced with a vast amount of scientific discovery, we do not claim to completely summarize the results from CRAICC within this paper, but rather concentrate here on the main results which are related to feedback loops in climate change–cryosphere interactions that affect Arctic amplification.The CRAICC team acknowledges the following institutions for financial support: the Finnish Cultural Foundation grant, Markku Kulmala “International Working Groups”; Russian mega-grant no. 11.G34.31.0048 (University of Nizhny Novgorod); Academy of Finland contracts 259537, 257411, and 254195; Beautiful Beijing (Finland–China collaboration project) funded by TEKES; Nordforsk CRAICC-PEEX (amendment to contract 26060); CRAICC-CRUCIAL (project no. 81257); Icelandic Research Fund (Rannis) grant no. 152248- 051; Danish Environmental Protection Agency with means from the Dancea fund for environmental support to the Arctic region (M 112 002700); the Villum Foundation; the Carlsberg Foundation (project 009_1_0515); COST1303 (TOPROF); COST ES1404 (HarmoSnow); and the Pan-Eurasian Experiment (PEEX). The development and use of NorESM1 was supported by the Norwegian Research Council through the projects Earth-Clim (207711/E10), EVA (grant no. 229771), NOTUR (nn2345k), and NorStore (ns2345k) and through the Nordic Centre of Excellence eSTICC (57001) and the EU H2020 project CRESCENDO (grant no. 641816). The CRAICC team also thanks Rogier Floors for providing Fig. 8 and Christoph Münkel for Fig. 9. The authors and entire CRAICC community would like to thank and acknowledge the work and inspiration of Jon Egill Kristjansson, whose life was cut short during these collaborations. Jon Egill Kristjansson is deeply missed, but his scientific legacy continues.Peer Reviewe