Primordial germ cells (PGCs) undergo dramatic rearrangements to their methylome during embryogenesis, including initial genome-wide DNA demethylation that establishes the germline epigenetic ground ...state. The role of the 5-methylcytosine (5mC) dioxygenases Tet1 and Tet2 in the initial genome-wide DNA demethylation process has not been examined directly. Using PGCs differentiated from either control or Tet2−/−; Tet1 knockdown embryonic stem cells (ESCs), we show that in vitro PGC (iPGC) formation and genome-wide DNA demethylation are unaffected by the absence of Tet1 and Tet2, and thus 5-hydroxymethylcytosine (5hmC). However, numerous promoters and gene bodies were hypermethylated in mutant iPGCs, which is consistent with a role for 5hmC as an intermediate in locus-specific demethylation. Altogether, our results support a revised model of PGC DNA demethylation in which the first phase of comprehensive 5mC loss does not involve 5hmC. Instead, Tet1 and Tet2 have a locus-specific role in shaping the PGC epigenome during subsequent development.
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► PGCs differentiated from ESCs undergo genome-wide DNA demethylation ► Tet1 and Tet2 do not regulate genome-wide DNA demethylation in PGCs ► Tet1 and Tet2 regulate locus-specific demethylation in PGCs
Tet1 and Tet2 have a stage-specific but not a global role in genomic DNA demethylation during the formation of primordial germ cells.
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository ...for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.
The explosive growth of phytoplankton under favorable conditions in subtropical coastal waters can lead to water discolouration and massive fish kills. Traditional water quality monitoring relies on ...manual field sampling and laboratory analysis of chlorophyll-a (Chl-a) concentration, which is resources intensive and time consuming. The cloudy weather of Hong Kong also precludes using satellite images for algal blooms monitoring. This study for the first time demonstrates the use of an Unmanned Aerial Vehicle (UAVs) to quantitatively map surface water Chl-a distribution in coastal waters from a low altitude. An estimation model for Chl-a concentration from visible images taken by a digital camera on a UAV has been developed and validated against one-year field data. The cost-effective and robust technology is able to map the spatial and temporal variations of Chl-a concentration during an algal bloom. The proposed method offers a useful complement to traditional field monitoring for fisheries management.
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•First time used a drone to quantitatively map surface chlorophyll-a concentration•Camera spectral response analysed as a function of chlorophyll-a concentrations•Chlorophyll-a estimation model successfully validated against one-year field data•Success in mapping spatial and temporal variation of Chl-a for an algal bloom
In eutrophic coastal waters, harmful algal blooms (HAB) often occur and present challenges to environmental and fisheries management. Despite decades of research on HAB early warning systems, the ...field validation of algal bloom forecast models have received scant attention. We propose a daily algal bloom risk forecast system based on: (i) a vertical stability theory verified against 191 past algal bloom events; and (ii) a data-driven artificial neural network (ANN) model that assimilates high frequency data to predict sea surface temperature (SST), vertical temperature and salinity differential with an accuracy of 0.35oC, 0.51oC, and 0.58 psu respectively. The model does not rely on past chlorophyll measurements and has been validated against extensive field data. Operational forecasts are illustrated for representative algal bloom events at a marine fish farm in Tolo Harbour, Hong Kong. The robust model can assist with traditional onsite monitoring as well as artificial-intelligence (AI) based methods.
•A daily algal bloom forecast system suitable for coastal fisheries management is developed for the first time.•The model is validated against 191 past algal bloom events and 4 years of real time water quality data at a fish farm.•The ANN model assimilates real time data to predict SST, vertical temperature and salinity differential.•The operational forecast does not rely on past chlorophyll measurements.•The robust model can assist with traditional onsite water quality monitoring as well as AI-based methods.
Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after ...allogeneic hematopoietic stem-cell transplantation.
We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse.
TP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P<0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (P=0.004), owing to a high risk of relapse, and the presence of JAK2 mutations was associated with shorter survival than was the absence of JAK2 mutations (P=0.001), owing to a high risk of death without relapse. The adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens. By contrast, the adverse effect of RAS pathway mutations on the risk of relapse, as compared with the absence of RAS pathway mutations, was evident only with reduced-intensity conditioning (P<0.001). In young adults, 4% of the patients had compound heterozygous mutations in the Shwachman-Diamond syndrome-associated SBDS gene with concurrent TP53 mutations and a poor prognosis. Mutations in the p53 regulator PPM1D were more common among patients with therapy-related MDS than those with primary MDS (15% vs. 3%, P<0.001).
Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen. (Funded by the Edward P. Evans Foundation and others.).
ABSTRACT
Introduction: This study seeks to characterize lesion distribution in Parsonage–Turner Syndrome (PTS) using high‐resolution MRI. Methods: MRIs of 27 patients with clinically confirmed PTS ...were reviewed. Two radiologists independently evaluated the brachial plexus proper, side and terminal plexus branches, and more distal, upper extremity nerves. Results: All patients had at least 1 clinically involved nerve. MRI revealed that the plexus appeared normal in 24 of 27 patients; in 3 other patients, signal hyperintensity was seen immediately proximal to the take‐off of abnormal side or terminal branch nerves. Focal intrinsic constrictions were detected in 32 of 38 nerves. MRI interobserver agreement was high (Cohen's κ = 0.839). Discussion: MRI findings, corroborated by electrodiagnostic testing, localized abnormalities to plexus branches and peripheral nerves, suggesting that PTS is characterized by 1 or more mononeuropathies rather than changes involving a portion of or the complete plexus proper. These results may improve diagnosis, prognostication, and management. Muscle Nerve 58: 359–366, 2018
The outcome of allogeneic HSCT varies considerably by the disease and remission status at the time of transplantation. Any retrospective or prospective HSCT study that enrolls patients across disease ...types must account for this heterogeneity; yet, current methods are neither standardized nor validated. We conducted a retrospective study of 1539 patients who underwent transplantation at Dana-Farber Cancer Institute/Brigham and Women's Hospital from 2000 to 2009. Using multivariable models for overall survival, we created a disease risk index. This tool uses readily available information about disease and disease status to categorize patients into 4 risk groups with significantly different overall survival and progression-free survival on the basis of primarily differences in the relapse risk. This scheme applies regardless of conditioning intensity, is independent of comorbidity index, and was validated in an independent cohort of 672 patients from the Fred Hutchinson Cancer Research Center. This simple and validated scheme could be used to risk-stratify patients in both retrospective and prospective HSCT studies, to calibrate HSCT outcomes across studies and centers, and to promote the design of HSCT clinical trials that enroll patients across diseases and disease states, increasing our ability to study nondisease-specific outcomes in HSCT.
The Secchi disk depth (SD) is an important parameter in aquatic ecosystem monitoring. As algal growth depends on solar irradiation, the SD - a measure of light extinction - gives an indirect ...indication of the chlorophyll concentration. However, most SD measurements are manually based and too sparse to resolve water quality variations during algal blooms.
A remotely controlled automatic system for field measurement of light extinction has been developed and installed in three marine fish culture zones in Hong Kong. The visual images of the disk at different prescribed depths and the surrounding water are taken. Based on the contrast theory and image analysis, the recorded light intensity distributions can be analyzed to give the SD and the light extinction coefficient. The method has been extensively verified by field data over a wide range of water quality and hydro-meteorological conditions. The proposed system enables high frequency SD measurements on demand for environmental management and emergency response.
•A novel simple cost-effective method to measure light intensity in coastal water•First remotely controlled method for automated monitoring of Secchi depth•Real-time monitoring of water transparency and environmental management•Direct field validation of classical visibility theory based on image contrast
Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E epsilon 4 allele (referred to here as APOE4), as well as non-genetic ...determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these-including APBA2, FYN, RNF219 and SV2A-encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.
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