Mechanisms and implications of changes in the timing of ocean freeze-up

Thesis (Ph.D.) University of Alaska Fairbanks, 2018The shift to an Arctic seasonal sea ice cover in recent years motivates a deeper understanding of freeze-up processes and implications of a lengthened open water season. As the sea ice boundary between the Arctic ocean and atmosphere covers a smaller area, the effects of enhanced wind mixing become more pronounced. Winds are important for ocean circulation and heat exchange. Ultimately, they can influence when freeze-up can occur, or can break up new ice as it forms. The chapters of this thesis are motivated by the substantial social and geophysical consequences of a lengthening open water season and linked through discussion of what controls freeze-up timing. Implications of a declining sea ice cover as it pertains to the three Arctic Alaska coastal communities of Kotzebue, Shishmaref, and Utqiaġvik are explored in depth. Indices of locally-relevant metrics are developed by using physical climate-related thresholds found by other studies to impact Alaska communities and coastal erosion rates. This allows for a large-scale climate dataset to be used to define a timeseries of these indices for each community. We found a marked increase in the number of false freeze-ups and break-ups, the number of days too windy to hunt via subsistence boat, and in Utqiaġvik, an approximate tripling of erosion-capable wind events from 1979-2014. The WRF-downscaled ERA-Interim dataset (ERA-Interim for sea ice) was also used in the analysis of all chapters. The cumulative wind energy input into the upper ocean was calculated for the Chukchi, southern Beaufort, and northeast Bering Seas at time periods up to three months prior to freeze-up, and then correlated with the timing of freeze-up. We have found that increased wind energy input into the upper ocean 2-3 months prior to freeze-up is positively and most strongly correlated with the date of freeze-up in the Chukchi Sea. Analysis of wind climatology shows winds are increasing in the period prior to freeze-up as a delayed freeze-up moves into the fall storm season. A negative correlation is found in the Bering Sea over shorter timescales, suggesting that storms promote the arrival of sea ice there. Case studies are evaluated for the Chukchi Sea and Bering Sea, to illustrate mechanisms at play that cause the positive and negative correlations in these seas, respectively. Ice advection and high winds from northerly directions are shown to hasten the timing of freeze-up in the Bering Sea. In the Chukchi Sea, higher winds from the dominant northeasterly direction promote upwelling of warm and salty water up onto the shelf, which suggests a mechanism for why high winds are associated with a delayed freeze-up there. We next examine the effect of winds on freeze-up timing by using a 1-D vertical column model of the mixed layer. The model is initialized using temperature and salinity profiles obtained from a freeze-up buoy deployed in 2015 in the north-east part of the Chukchi Sea. The meteorological forcing used to drive the model experiments comes from a WRF-downscaled ERA-Interim Reanalysis dataset. Our results show that vertical wind-driven mixing leads to enhanced heat loss. In light of the previously found positive correlation between wind energy input and freeze-up timing, the mixing model results suggest horizontal advection not captured by the 1-D column model can dominate wind-driven vertical mixing to promote freeze-up.ArcSEES NSF award 1263853, Center for Global Chang

Changes of the Arctic marginal ice zone during the satellite era

Many studies have shown a decrease in Arctic sea ice extent. It does not logically follow, however, that the extent of the marginal ice zone (MIZ), here defined as the area of the ocean with ice concentrations from 15 to 80%, is also changing. Changes in the MIZ extent has implications for the level of atmospheric and ocean heat and gas exchange in the area of partially ice-covered ocean, as well as for the extent of habitat for organisms that rely on the MIZ, from primary producers like sea ice algae to seals and birds. Here, we present, for the first time, an analysis of satellite observations of pan-Arctic averaged MIZ extent. We find no trend in the MIZ extent during the last 40 years from observations. Our results indicate that the constancy of the MIZ extent is the result of an observed increase in width of the MIZ being compensated by a decrease in the perimeter of the MIZ as it moves further north. We present simulations from a coupled sea ice-ocean mixed layer model using a prognostic floe size distribution which we find is consistent with, but poorly constrained by, existing satellite observations of pan-Arctic MIZ extent. We provide seasonal upper and lower bounds on MIZ extent based on the 4 satellite-derived sea ice concentration datasets used. We find a large and significant increase (>50%) in the August and September MIZ fraction (MIZ extent divided by sea ice extent) for the Bootstrap and OSI-450 observational datasets, which can be attributed to the reduction in total sea ice extent. Given the results of this study, we suggest that references to ‘rapid changes’ in the MIZ should remain cautious and provide a specific and clear definition of both the MIZ itself and also the property of the MIZ that is changing

Evidence for 28 genetic disorders discovered by combining healthcare and research data

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder

Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function