Improvement of variant calling in next-generation sequence data requires a comprehensive, genome-wide catalog of high-confidence variants called in a set of genomes for use as a benchmark. We ...generated deep, whole-genome sequence data of 17 individuals in a three-generation pedigree and called variants in each genome using a range of currently available algorithms. We used haplotype transmission information to create a phased "Platinum" variant catalog of 4.7 million single-nucleotide variants (SNVs) plus 0.7 million small (1-50 bp) insertions and deletions (indels) that are consistent with the pattern of inheritance in the parents and 11 children of this pedigree. Platinum genotypes are highly concordant with the current catalog of the National Institute of Standards and Technology for both SNVs (>99.99%) and indels (99.92%) and add a validated truth catalog that has 26% more SNVs and 45% more indels. Analysis of 334,652 SNVs that were consistent between informatics pipelines yet inconsistent with haplotype transmission ("nonplatinum") revealed that the majority of these variants are de novo and cell-line mutations or reside within previously unidentified duplications and deletions. The reference materials from this study are a resource for objective assessment of the accuracy of variant calls throughout genomes.
Osteoporosis mainly occurs in postmenopausal women, which is characterized by low bone mineral density (BMD) due to unbalanced bone resorption by osteoclasts and formation by osteoblasts. Circulating ...monocytes play important roles in osteoclastogenesis by acting as osteoclast precursors and secreting osteoclastogenic factors, such as IL-1, IL-6 and TNF-α. MicroRNAs (miRNAs) have been implicated as important biomarkers in various diseases. The present study aimed to find significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis.
We used ABI TaqMan® miRNA array followed by qRT-PCR validation in circulating monocytes to identify miRNA biomarkers in 10 high and 10 low BMD postmenopausal Caucasian women. MiR-133a was upregulated (P=0.007) in the low compared with the high BMD groups in the array analyses, which was also validated by qRT-PCR (P=0.044). We performed bioinformatic target gene analysis and found three potential osteoclast-related target genes, CXCL11, CXCR3 and SLC39A1. In addition, we performed Pearson correlation analyses between the expression levels of miR-133a and the three potential target genes in the 20 postmenopausal women. We did find negative correlations between miR-133a and all the three genes though not significant.
This is the first in vivo miRNA expression analysis in human circulating monocytes to identify novel miRNA biomarkers underlying postmenopausal osteoporosis. Our results suggest that miR-133a in circulating monocytes is a potential biomarker for postmenopausal osteoporosis.
MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that regulate gene expression by targeting mRNAs. Recently, miRNAs have been shown to play important roles in the etiology of various ...diseases. However, little is known about their roles in the development of osteoporosis. Circulating monocytes are osteoclast precursors that also produce various factors important for osteoclastogenesis. Previously, we have identified a potential biomarker miR-133a in circulating monocytes for postmenopausal osteoporosis. In this study, we aimed to further identify significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis.
We used ABI TaqMan miRNA array followed by qRT-PCR validation in human circulating monocytes from 10 high BMD and 10 low BMD postmenopausal Caucasian women to identify miRNA biomarkers. MiR-422a was up-regulated with marginal significance (P = 0.065) in the low compared with the high BMD group in the array analysis. However, a significant up-regulation of miR-422a was identified in the low BMD group by qRT-PCR analysis (P = 0.029). We also performed bioinformatic target gene analysis and found several potential target genes of miR-422a which are involved in osteoclastogenesis. Further qRT-PCR analyses of the target genes in the same study subjects showed that the expression of five of these genes (CBL, CD226, IGF1, PAG1, and TOB2) correlated negatively with miR-422a expression.
Our study suggests that miR-422a in human circulating monocytes (osteoclast precursors) is a potential miRNA biomarker underlying postmenopausal osteoporosis.
Abstract
Linkages between extreme precipitation events (EPEs) in the central and eastern United States and synoptic-scale Rossby wave breaking are investigated using 1979–2015 climatologies of EPEs ...and upper-level potential vorticity (PV) streamers. The investigation focuses on two domains over the central and eastern United States, respectively, and emphasizes widespread EPEs, events exhibiting exceptionally large precipitation volumes. The relative frequency of PV streamers is found to be significantly enhanced relative to climatology immediately upstream of each domain during widespread EPEs. Majorities of the widespread EPEs in the central (~79%) and eastern (~56%) U.S. domains co-occur with a PV streamer positioned immediately upstream. Odds ratios of EPEs for days when a PV streamer occurs upstream of each domain indicate a strong, statistically significant association between EPEs and Rossby wave breaking. The strength of the EPE–Rossby wave breaking linkage, as measured by co-occurrence fractions and odds ratios, tends to increase with increasing EPE precipitation volume, such that the strongest linkage exists for widespread EPEs. Composite analyses reveal that Rossby wave breaking can result in widespread EPEs by establishing a persistent high-amplitude synoptic-scale wave pattern, within which strong poleward water vapor transport and ascent are forced over the EPE region immediately downstream of an elongated upper-level trough. Additional analyses demonstrate that, compared to corresponding null cases, Rossby wave breaking cases resulting in widespread EPEs exhibit a significantly higher-amplitude wave pattern that favors greater poleward transport of moist, conditionally unstable air and stronger ascent over the EPE region.
Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline
. The spread of tau aggregates ...(neurofibrillary tangles) across the cerebral cortex parallels symptom severity
. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.
This study investigates the evolution of two zonally elongated atmospheric rivers (ARs) that produced >200 mm of rainfall over mountainous regions of Northern California in late October 2010. ...Synoptic-scale analysis and air parcel trajectory analysis indicate that the ARs developed within high-CAPE environments characterized by troposphere-deep ascent as water vapor was transported directly from western North Pacific tropical cyclones (TCs) toward the equatorward entrance region of an intensifying North Pacific jet stream (NPJ). The same ARs were subsequently maintained as water vapor was transported from extratropical and subtropical regions over the central and eastern North Pacific in an environment characterized by quasigeostrophic forcing for ascent and strong frontogenesis along the anticyclonic shear side of an intense and zonally extended NPJ. Although the ARs developed in conjunction with water vapor transported from regions near TCs and in the presence of troposphere-deep ascent, an atmospheric water vapor budget illustrates that decreases in integrated water vapor (IWV) via precipitation are largely offset by the horizontal aggregation of water vapor along the AR corridors via IWV flux convergence in the presence of frontogenesis. The frameworks used for investigations of predecessor rain events ahead of TCs and of interactions between recurving TCs and the NPJ are also utilized to illustrate many dynamically similar processes related to AR development and evolution. Similarities include the following: water vapor transport directly from a TC, troposphere-deep ascent in a high-CAPE environment beneath the equatorward entrance region of an intensifying upper-tropospheric jet streak, interactions between diabatic outflow and an upper-tropospheric jet streak, and strong frontogenesis.
Mammalian chromosomes fold into arrays of megabase‐sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal ...substructures that are often cell type specific, but their higher‐order organization remains elusive. Here, we investigate TAD higher‐order interactions with Hi‐C through neuronal differentiation and show that they form a hierarchy of domains‐within‐domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree‐like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.
Synopsis
Genome‐wide mapping of chromatin architecture reveals a hierarchical folding of chromatin that involves higher‐order domains interactions across the whole chromosomes, reflects epigenomic features and reorganizes upon differentiation‐induced gene expression changes.
Chromatin architecture is mapped genome‐wide using Hi‐C and a neuronal differentiation model from mESC to post‐mitotic neurons.
Mammalian chromosomes fold hierarchically in a manner that reflects epigenomic features and involves higher‐order domains (metaTADs) up to the chromosome scale.
metaTAD topologies are relatively conserved through differentiation, and their reorganization is related to gene expression changes.
Polymer modelling shows that hierarchical chromatin folding promotes efficient packaging without the loss of contact specificity.
Genome‐wide mapping of chromatin architecture reveals a hierarchical folding of chromatin that involves higher‐order domains interactions across the whole chromosomes, reflects epigenomic features and reorganizes upon differentiation‐induced gene expression changes.
During winter 2016/17, California experienced numerous heavy precipitation events linked to land-falling atmospheric rivers (ARs) that filled reservoirs and ended a severe, multiyear drought. These ...events also caused floods, mudslides, and debris flows, resulting in major socioeconomic disruptions. During 2–11 February 2017, persistent heavy precipitation in the northern Sierra Nevada culminated in a rapid increase in the water level on Lake Oroville, necessitating the activation of an emergency spillway for the first time since the Oroville Dam was installed and forcing the evacuation of 188,000 people. The precipitation, which mostly fell as rain due to elevated freezing levels, was focused on the western slope of the Sierra Nevada in connection with orographic forcing linked to two successive ARs. Heavy rain fell on saturated soils and a snowpack produced by antecedent storms and thereby resulted in excessive runoff into Lake Oroville that led to a damaged spillway and complicated reservoir operations.
Standardized benchmarking approaches are required to assess the accuracy of variants called from sequence data. Although variant-calling tools and the metrics used to assess their performance ...continue to improve, important challenges remain. Here, as part of the Global Alliance for Genomics and Health (GA4GH), we present a benchmarking framework for variant calling. We provide guidance on how to match variant calls with different representations, define standard performance metrics, and stratify performance by variant type and genome context. We describe limitations of high-confidence calls and regions that can be used as truth sets (for example, single-nucleotide variant concordance of two methods is 99.7% inside versus 76.5% outside high-confidence regions). Our web-based app enables comparison of variant calls against truth sets to obtain a standardized performance report. Our approach has been piloted in the PrecisionFDA variant-calling challenges to identify the best-in-class variant-calling methods within high-confidence regions. Finally, we recommend a set of best practices for using our tools and evaluating the results.
ObjectiveThe life expectancy of patients with congenital heart disease (CHD) has significantly improved with advances in their paediatric medical care. Mortality patterns are changing as a result. ...Our study aims to describe survival and causes of death in a contemporary cohort of adult patients with CHD.MethodsWe reviewed 3068 patients in our adult CHD database (age ≥16 years, seen at least once in our centre between 2000 and 2015), and documented the number and causes of death, via Australia’s National Death Index. Survival and mortality patterns were analysed by complexity of CHD and by underlying congenital diagnosis.ResultsOur cohort comprised 3068 adult patients (53% male). The distribution of patients (per the Bethesda classification) was 47% simple, 34% moderate and 18% complex (1% not classifiable). Over a median follow-up of 6.2 years (IQR 3.5–10.4), 341 patients (11%) died with an incidence of 0.4 deaths/100 patient years (py). Survival was significantly worse with increasing complexity of CHD (p<0.001); mortality rate in the simple group was 0.3 deaths/100 py with a median age of death 70 years, and in the complex group was 1.0 death/100 py with a median age of death 34 years. Overall, non-cardiac causes of death outnumbered cardiac causes, at 54% and 46%, respectively. The leading single cause of death was heart failure (17%), followed by malignancy (13%). Simple adult CHD patients mostly died due to non-cardiac causes such as malignancy. Perioperative mortality only accounted for 5% of deaths.ConclusionsPremature death is common in adults with CHD. Although heart failure remains the most common cause of death, in the contemporary era in a specialist CHD centre, non-cardiac related deaths outnumber cardiac deaths, particularly in those with simple CHD lesions.
PDF
