Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Metabolomics of dates (Phoenix dactylifera) reveals a highly dynamic ripening process accounting for major variation in fruit composition

BACKGROUND: Dates are tropical fruits with appreciable nutritional value. Previous attempts at global metabolic characterization of the date metabolome were constrained by small sample size and limited geographical sampling. In this study, two independent large cohorts of mature dates exhibiting substantial diversity in origin, varieties and fruit processing conditions were measured by metabolomics techniques in order to identify major determinants of the fruit metabolome. RESULTS: Multivariate analysis revealed a first principal component (PC1) significantly associated with the dates’ countries of production. The availability of a smaller dataset featuring immature dates from different development stages served to build a model of the ripening process in dates, which helped reveal a strong ripening signature in PC1. Analysis revealed enrichment in the dry type of dates amongst fruits with early ripening profiles at one end of PC1 as oppose to an overrepresentation of the soft type of dates with late ripening profiles at the other end of PC1. Dry dates are typical to the North African region whilst soft dates are more popular in the Gulf region, which partly explains the observed association between PC1 and geography. Analysis of the loading values, expressing metabolite correlation levels with PC1, revealed enrichment patterns of a comprehensive range of metabolite classes along PC1. Three distinct metabolic phases corresponding to known stages of date ripening were observed: An early phase enriched in regulatory hormones, amines and polyamines, energy production, tannins, sucrose and anti-oxidant activity, a second phase with on-going phenylpropanoid secondary metabolism, gene expression and phospholipid metabolism and a late phase with marked sugar dehydration activity and degradation reactions leading to increased volatile synthesis. CONCLUSIONS: These data indicate the importance of date ripening as a main driver of variation in the date metabolome responsible for their diverse nutritional and economical values. The biochemistry of the ripening process in dates is consistent with other fruits but natural dryness may prevent degenerative senescence in dates following ripening. Based on the finding that mature dates present varying extents of ripening, our survey of the date metabolome essentially revealed snapshots of interchanging metabolic states during ripening empowering an in-depth characterization of underlying biology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12870-015-0672-5) contains supplementary material, which is available to authorized users

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm

N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function © 2010 Marcos et al

An advanced open-path atmospheric monitor design

The conceptual design of an open-path atmospheric monitor combines an acousto-optic tunable filter for emission spectroscopy (3-14 {mu}m) with a mid-IR (4.6-5.4 {mu}m) for absorption spectroscopy. It utilizes mostly commercially available components, covers a large area ({approximately}4 km radius), measures the distance to any reflecting object, can take measurements along any line-of-sight, and is eye safe. Of twenty test pollutants it is to detect, the concentrations of all twenty will be measurable via emission spectroscopy and ten by the more sensitive absorption spectroscopy

An advanced open path atmospheric pollution monitor for large areas

Over 100 million gallons of radioactive and toxic waste materials generated in weapon materials production are stored in 322 tanks buried within large areas at DOE sites. Toxic vapors occur in the tank headspace due to the solvents used and chemical reactions within the tanks. To prevent flammable or explosive concentration of volatile vapors, the headspace are vented, either manually or automatically, to the atmosphere when the headspace pressure exceeds preset values. Furthermore, 67 of the 177 tanks at the DOE Hanford Site are suspected or are known to be leaking into the ground. These underground storage tanks are grouped into tank farms which contain closely spaced tanks in areas as large as 1 km{sup 2}. The objective of this program is to protect DOE personnel and the public by monitoring the air above these tank farms for toxic air pollutants without the monitor entering the tanks farms, which can be radioactive. A secondary objective is to protect personnel by monitoring the air above buried 50 gallon drums containing moderately low radioactive materials but which could also emit toxic air pollutants

Deep-Sea Debris in the Central and Western Pacific Ocean

Marine debris is a growing problem in the world’s deep ocean. The naturally slow biological and chemical processes operating at depth, coupled with the types of materials that are used commercially, suggest that debris is likely to persist in the deep ocean for long periods of time, ranging from hundreds to thousands of years. However, the realized scale of marine debris accumulation in the deep ocean is unknown due to the logistical, technological, and financial constraints related to deep-ocean exploration. Coordinated deep-water exploration from 2015 to 2017 enabled new insights into the status of deep-sea marine debris throughout the central and western Pacific Basin via ROV expeditions conducted onboard NOAA Ship Okeanos Explorer and RV Falkor. These expeditions included sites in United States protected areas and monuments, other Exclusive Economic Zones, international protected areas, and areas beyond national jurisdiction. Metal, glass, plastic, rubber, cloth, fishing gear, and other marine debris were encountered during 17.5% of the 188 dives from 150 to 6,000 m depth. Correlations were observed between deep-sea debris densities and depth, geological features, and distance from human-settled land. The highest densities occurred off American Samoa and the main Hawaiian Islands. Debris, mostly consisting of fishing gear and plastic, were also observed in most of the large-scale marine protected areas, adding to the growing body of evidence that even deep, remote areas of the ocean are not immune from human impacts. Interactions with and impacts on biological communities were noted, though further study is required to understand the full extent of these impacts. We also discuss potential sources and long-term implications of this debris.This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms

Spectral Analysis of Airborne Effluents from Nuclear Facilities and Design of AOTF Spectroradiometer

This report summarizes the spectral analysis and design of an acousto optic tunable filter (AOTF) imaging spectroradiometer for the project SR003. This system will use passive open-path infrared absorption to detect the presence of various source gases

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10−8) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10−17; rs715 at 2q34, P = 9.97 × 10−14; rs477992 at 1p12, P = 2.60 × 10−12) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1,134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences in blood serum levels of glycine (P = 4.04 × 10−6) and serine (P = 2.48 × 10−4) between MacTel cases and controls

An acousto-optic tunable filter enhanced CO₂ lidar atmospheric monitor

The atmospheric monitor conceptual design is based on a pulsed CO{sub 2} laser. The narrow laser lines provide high spectral selectivity in the 9-11 {mu}m region, within the 8-14 {mu}m ``fingerprint`` region where most large molecules have unique spectral absorption signatures. Laser power has been chosen so that topological objects, e.g., trees or buildings, as far as 4 km can be used as backreflectors, but the laser intensity is sufficiently low that the laser beam is eye-safe. Time-of-flight measurements give the distance to the topological reflector. The lidar system is augmented with an acousto-optic tunable filter (AOTF) which measures the thermal emission spectra from 3 to 14 {mu}m with a 3 cm{sup -1} passband. Sensitivity to narrow emission lines is enhanced by derivative spectroscopy in which the passband of the AOTF is dithered via the rf drive. Path-averaged concentrations are determined from the emission intensity and laser- determined range