NASA Tropical Rainfall Measurement Mission (TRMM): Effects of tropical rainfall on upper ocean dynamics, air-sea coupling and hydrologic cycle

This was a Tropical Rainfall Measurement Mission (TRMM) modeling, analysis and applications research project. Our broad scientific goals addressed three of the seven TRMM Priority Science Questions, specifically: What is the monthly average rainfall over the tropical ocean areas of about 10(exp 5) sq km, and how does this rain and its variability affect the structure and circulation of the tropical oceans? What is the relationship between precipitation and changes in the boundary conditions at the Earth's surface (e.g., sea surface temperature, soil properties, vegetation)? How can improved documentation of rainfall improve understanding of the hydrological cycle in the tropics

The Origin and Evolution of Mutations in Acute Myeloid Leukemia

SummaryMost mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse

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

Phenotypic Characterization of <i>EIF2AK4</i> 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 &lt;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 (K co ; 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 K co 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. </jats:sec

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Regulatory and Policy Issues around Nontarget Mortality and Environmental Fate of Rodenticides

One of the goals of this Symposium was to bring together agricultural and conservation users of rodenticides to discuss the impacts of rodenticides on the environment, examine the current regulatory climate governing their use, and identify ways that users can reduce or eliminate these impacts. Some of the presentations in today’s symposium highlighted specific impacts, and the preceding talk described the scenario of what can happen if an issue related to pesticide impacts ends up in the courts. The three agencies that were represented on this panel (USDA, USFWS, and EPA) have regulatory oversight and enforcement authority for the use of rodenticides and/or the adverse effects resulting from the use of rodenticides. In addition, USDA and FWS are the primary federal users of rodenticides for agriculture and conservation. USDA holds the registrations for a number of rodenticide products for agricultural and conservation purposes. Panelists were asked to describe how Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), Migratory Bird Treaty Act (MBTA), Endangered Species Act (ESA), National Environmental Policy Act (NEPA), the Animal Damage Control Act, and the administration of USDA’s pesticide labels apply to rodenticide adverse effects. Panelists were then asked to bring up an issue within the scope of their agency that they view as problematic for conducting eradication projects. Panelists were also asked to suggest proactive measures that the rodent eradication community can undertake to improve future rodent eradication efforts. Finally, the floor was opened to audience members for questions and comments

Panel Discussion – Regulatory and Policy Issues around Non-Target Mortality and Environmental Fate of Rodenticides

One of the goals of this Symposium was to bring together agricultural and conservation users of rodenticides to discuss the impacts of rodenticides on the environment, examine the current regulatory climate governing their use, and identify ways that users can reduce or eliminate these impacts. Some of the presentations in today’s symposium highlighted specific impacts, and the preceding talk described the scenario of what can happen if an issue related to pesticide impacts ends up in the courts. The three agencies that were represented on this panel (USDA, USFWS, and EPA) have regulatory oversight and enforcement authority for the use of rodenticides and/or the adverse effects resulting from the use of rodenticides. In addition, USDA and FWS are the primary federal users of rodenticides for agriculture and conservation. USDA holds the registrations for a number of rodenticide products for agricultural and conservation purposes. Panelists were asked to describe how Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), Migratory Bird Treaty Act (MBTA), Endangered Species Act (ESA), National Environmental Policy Act (NEPA), the Animal Damage Control Act, and the administration of USDA’s pesticide labels apply to rodenticide adverse effects. Panelists were then asked to bring up an issue within the scope of their agency that they view as problematic for conducting eradication projects. Panelists were also asked to suggest proactive measures that the rodent eradication community can undertake to improve future rodent eradication efforts. Finally, the floor was opened to audience members for questions and comments

Certifying the Waste Isolation Pilot Plant: Lessons Learned from the WIPP Experience

In May 1998, the US Environmental Protection Agency (EPA) certified the US Department of Energy's (DOE) Waste Isolation Pilot Plant (WIPP) as being in compliance with applicable long-term regulations governing the permanent disposal of spent nuclear fuel, high-level, and transuranic radioactive wastes. The WIPP is the first deep geologic repository in the US to have successfully demonstrated regulatory compliance with long-term radioactive waste disposal requirements. The first disposal of TRU waste at WIPP occurred on March 26, 1999. Many of the lessons learned during the WIPP Project's transition from site characterization and experimental research to the preparation of a successful application may be of general interest to other repository programs. During a four-year period (1992 to 1996), the WIPP team [including the DOE Carlsbad Area Office (CAO), the science advisor to CAO, Sandia National Laboratories (SNL), and the management and operating contractor of the WIPP site, Westinghouse Electric Corporation (WID)] met its aggressive schedule for submitting the application without compromising the integrity of the scientific basis for the long-term safety of the repository. Strong leadership of the CAO-SNL-WID team was essential. Within SNL, a mature and robust performance assessment (PA) allowed prioritization of remaining scientific activities with respect to their impact on regulatory compliance. Early and frequent dialog with EPA staff expedited the review process after the application was submitted. Questions that faced SNL are familiar to geoscientists working in site evaluation projects. What data should be gathered during site characterization? How can we know when data are sufficient? How can we know when our understanding of the disposal system is sufficient to support our conceptual models? What constitutes adequate ''validation'' of conceptual models for processes that act over geologic time? How should we use peer review and expert judgment? Other lessons learned by SNL and the WIPP team are more specific to the regulatory context of the project and the demands imposed by pervasive review by the regulator and other external organizations. How should we document the relationship between site data and the parameter values used in computer models? How can we manage software configuration and use it to support the regulatory requirement that analyses be traceable and reproducible? Can we institute a quality assurance (QA) program that will meet the regulatory requirements and enhance the process without unreasonable budget and schedule impacts? How can we resolve technical disputes, both within the project and with external critics? How should we involve regulators and stakeholders in the compliance process? The WIPP teams answers to these questions, and others like them, were, in many cases, pragmatic solutions based on the needs of the pro-warn at the time. Some problems encountered and their solutions may be of limited interest. However, that it is possible to license a geologic repository in a regulatory proceeding while incorporating meaningful public review and criticism is a lesson of general interest to all radioactive waste management programs