The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

Acknowledgements This work was funded by NERC Standard Grant NE/N011228/1. We thank the Alfred Wegner Institute, and particularly Hicham Rafiq and Daniel Steinhage, for their significant logistic support through the iGRIFF project. Additional support was provided from Station Nord (Jørgen Skafte), Nordland Air, Air Greenland, the Joint Arctic Command and the Department of Geography, Durham University. Naalakkersuisut, Government of Greenland, provided Scientific Survey (VU-00121) and Export (046/2017) licences for this work. We would also like to thank our Field Ranger Isak (Nanu-Travel) and dog Ooni for keeping us safe in the field. TCN Sample preparation was carried out at the National Environmental Isotope Facility, Scottish Universities Environmental Research Centre under grant allocation 9185.0814. Chris Orton in the Cartographic Unit, Geography, Durham University edited several figures. This paper is dedicated to Mr Arnold Jones – a true Quaternarist.Peer reviewe

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

The Northeast Greenland Ice Stream (NEGIS) is the main artery for ice discharge from the northeast sector of the Greenland Ice Sheet (GrIS) to the North Atlantic. Understanding the past, present and future stability of the NEGIS with respect to atmospheric and oceanic forcing is of global importance as it drains around 17% of the GrIS and has a sea-level equivalent of 1.6 m. This paper reconstructs the deglacial and Holocene history of Nioghalvfjerdsbræ (or 79N Glacier); a major outlet of the NEGIS.At high elevation (>900 m asl) autochthonous blockfield, a lack of glacially moulded bedrock and pre LGM exposure ages point to a complex exposure/burial history extending back over half a million years. However, post Marine Isotope Stage 12, enhanced glacial erosion led to fjord incision and plateaux abandonment. Between 900 and 600 m asl the terrain is largely unmodified by glacial scour but post LGM erratics indicate the advection of cold-based ice through the fjord. In contrast, below ∼600 m asl Nioghalvfjerdsfjorden exhibits a geomorphological signal indicative of a warm-based ice stream operating during the last glacial cycle. Dated ice marginal landforms and terrain along the fjord walls show initial thinning rates were slow between ∼23 and 10 ka, but post-10 ka it is evident that Nioghalvfjerdsfjorden deglaciated extremely quickly with complete fjord deglaciation below ∼500 m asl between 10.0 and 8.5 ka.Both increasing air and ocean temperatures were pivotal in driving surface lowering and submarine melt during deglaciation, but the final withdrawal of ice through Nioghalvfjerdsfjorden was facilitated by the action of marine ice sheet instability. Our estimates show that thinning and retreat rates reached a maximum of 5.29 ma−1 and 613 ma−1, respectively, as the ice margin withdrew westwards. This would place the Early Holocene disintegration of this outlet of the NEGIS at the upper bounds of contemporary thinning and retreat rates seen both in Greenland and Antarctica. Combined with recent evidence of ice stream shutdown during the Holocene, as well as predictions of changing ice flow dynamics within downstream sections of the NEGIS catchment, this suggests that significant re-organisation of the terminal zone of the ice stream is imminent over the next century

"Monkey see, monkey do" : peers’ behaviors predict preschoolers’ physical activity and dietary intake in childcare centers

Abstract : Preschoolers observe and imitate the behaviors of those who are similar to them. Therefore, peers may be important role models for preschoolers’ dietary intake and physical activity in childcare centers. This study examined whether peers’ behaviors predict change in preschoolers’ dietary intake and physical activity in childcare centers over 9 months. A total of 238 preschoolers (3 to 5 years old) from 23 childcare centers in two Canadian provinces provided data at the beginning (October 2013 and 2014) and the end (June 2014 and 2015) of a 9-month period for this longitudinal study. Dietary intake was collected at lunch using weighed plate waste and digital photography on two consecutive weekdays. Physical activity was assessed using accelerometers over five days. Multilevel linear regressions were used to estimate the influence of peers’ behaviors on preschoolers’ change in dietary intake and physical activity over 9 months. Results showed that preschoolers whose dietary intake or physical activity level deviated the most from those of their peers at the beginning of the year demonstrated greater change in their intakes and activity levels over 9 months (all p values<0.05), which enabled them to become more similar to their peers. This study suggests that preschoolers’ dietary intake and physical activity may be influenced by the behaviors of their peers in childcare centers. Since peers could play an important role in promoting healthy eating behaviors and physical activity in childcare centers, future studies should test interventions based on positive role modeling by children

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

The Northeast Greenland Ice Stream (NEGIS) is the main artery for ice discharge from the northeast sector of the Greenland Ice Sheet (GrIS) to the North Atlantic. Understanding the past, present and future stability of the NEGIS with respect to atmospheric and oceanic forcing is of global importance as it drains around 17% of the GrIS and has a sea-level equivalent of 1.6 m. This paper reconstructs the deglacial and Holocene history of Nioghalvfjerdsbræ (or 79N Glacier); a major outlet of the NEGIS. At high elevation (>900 m asl) autochthonous blockfield, a lack of glacially moulded bedrock and pre LGM exposure ages point to a complex exposure/burial history extending back over half a million years. However, post Marine Isotope Stage 12, enhanced glacial erosion led to fjord incision and plateaux abandonment. Between 900 and 600 m asl the terrain is largely unmodified by glacial scour but post LGM erratics indicate the advection of cold-based ice through the fjord. In contrast, below ∼600 m asl Nioghalvfjerdsfjorden exhibits a geomorphological signal indicative of a warm-based ice stream operating during the last glacial cycle. Dated ice marginal landforms and terrain along the fjord walls show initial thinning rates were slow between ∼23 and 10 ka, but post-10 ka it is evident that Nioghalvfjerdsfjorden deglaciated extremely quickly with complete fjord deglaciation below ∼500 m asl between 10.0 and 8.5 ka. Both increasing air and ocean temperatures were pivotal in driving surface lowering and submarine melt during deglaciation, but the final withdrawal of ice through Nioghalvfjerdsfjorden was facilitated by the action of marine ice sheet instability. Our estimates show that thinning and retreat rates reached a maximum of 5.29 ma−1 and 613 ma−1, respectively, as the ice margin withdrew westwards. This would place the Early Holocene disintegration of this outlet of the NEGIS at the upper bounds of contemporary thinning and retreat rates seen both in Greenland and Antarctica. Combined with recent evidence of ice stream shutdown during the Holocene, as well as predictions of changing ice flow dynamics within downstream sections of the NEGIS catchment, this suggests that significant re-organisation of the terminal zone of the ice stream is imminent over the next century

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention

A multilevel intervention to increase physical activity and improve healthy eating and physical literacy among young children (ages 3-5) attending early childcare centres: the Healthy Start-Départ Santé cluster randomised controlled trial study protocol

Abstract: Background: Childhood obesity is a growing concern for public health. Given a majority of children in many countries spend approximately 30 h per week in early childcare centers, this environment represents a promising setting for implementing strategies to foster healthy behaviours for preventing and controlling childhood obesity. Healthy Start-Départ Santé was designed to promote physical activity, physical literacy, and healthy eating among preschoolers. The objectives of this study are to assess the effectiveness of the Healthy Start-Départ Santé intervention in improving physical activity levels, physical literacy, and healthy eating among preschoolers attending early childcare centers. Methods/Design: This study follows a cluster randomized controlled trial design in which the childcare centers are randomly assigned to receive the intervention or serve as usual care controls. The Healthy Start-Départ Santé intervention is comprised of interlinked components aiming to enable families and educators to integrate physical activity and healthy eating in the daily lives of young children by influencing factors at the intrapersonal, interpersonal, organizational, community, physical environment and policy levels. The intervention period, spanning 6-8 months, is preceded and followed by data collections. Participants are recruited from 61 childcare centers in two Canadian provinces, New Brunswick and Saskatchewan. Centers eligible for this study have to prepare and provide meals for lunch and have at least 20 children between the ages of 3 and 5. Centers are excluded if they have previously received a physical activity or nutrition promoting intervention. Eligible centers are stratified by province, geographical location (urban or rural) and language (English or French), then recruited and randomized using a one to one protocol for each stratum. Data collection is ongoing. The primary study outcomes are assessed using accelerometers (physical activity levels), the Test of Gross Motor Development-II (physical literacy), and digital photography-assisted weighted plate waste (food intake). Discussion: The multifaceted approach of Healthy Start-Départ Santé positions it well to improve the physical literacy and both dietary and physical activity behaviors of children attending early childcare centers. The results of this study will be of relevance given the overwhelming prevalence of overweight and obesity in children worldwide. Trial registration: NCT02375490 (ClinicalTrials.gov registry)

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre