Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds

BACKGROUND: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. CONCLUSIONS/SIGNIFICANCE: A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds

Changing atmospheric CO2 concentration was the primary driver of early Cenozoic climate

The Early Eocene Climate Optimum (EECO, which occurred about 51 to 53 million years ago)1, was the warmest interval of the past 65 million years, with mean annual surface air temperature over ten degrees Celsius warmer than during the pre-industrial period2–4. Subsequent global cooling in the middle and late Eocene epoch, especially at high latitudes, eventually led to continental ice sheet development in Antarctica in the early Oligocene epoch (about 33.6 million years ago). However, existing estimates place atmospheric carbon dioxide (CO2) levels during the Eocene at 500–3,000 parts per million5–7, and in the absence of tighter constraints carbon–climate interactions over this interval remain uncertain. Here we use recent analytical and methodological developments8–11 to generate a new high-fidelity record of CO2 concentrations using the boron isotope (δ11Β) composition of well preserved planktonic foraminifera from the Tanzania Drilling Project, revising previous estimates6. Although species-level uncertainties make absolute values difficult to constrain, CO2 concentrations during the EECO were around 1,400 parts per million. The relative decline in CO2 concentration through the Eocene is more robustly constrained at about fifty per cent, with a further decline into the Oligocene12. Provided the latitudinal dependency of sea surface temperature change for a given climate forcing in the Eocene was similar to that of the late Quaternary period13, this CO2 decline was sufficient to drive the well documented high- and low-latitude cooling that occurred through the Eocene14. Once the change in global temperature between the pre-industrial period and the Eocene caused by the action of all known slow feedbacks (apart from those associated with the carbon cycle) is removed2–4, both the EECO and the late Eocene exhibit an equilibrium climate sensitivity relative to the pre-industrial period of 2.1 to 4.6 degrees Celsius per CO2 doubling (66 per cent confidence), which is similar to the canonical range (1.5 to 4.5 degrees Celsius15), indicating that a large fraction of the warmth of the early Eocene greenhouse was driven by increased CO2 concentrations, and that climate sensitivity was relatively constant throughout this period

Demonstration of Protein-Based Human Identification Using the Hair Shaft Proteome

YesHuman identification from biological material is largely dependent on the ability to characterize genetic polymorphisms in DNA. Unfortunately, DNA can degrade in the environment, sometimes below the level at which it can be amplified by PCR. Protein however is chemically more robust than DNA and can persist for longer periods. Protein also contains genetic variation in the form of single amino acid polymorphisms. These can be used to infer the status of non-synonymous single nucleotide polymorphism alleles. To demonstrate this, we used mass spectrometry-based shotgun proteomics to characterize hair shaft proteins in 66 European-American subjects. A total of 596 single nucleotide polymorphism alleles were correctly imputed in 32 loci from 22 genes of subjects’ DNA and directly validated using Sanger sequencing. Estimates of the probability of resulting individual non-synonymous single nucleotide polymorphism allelic profiles in the European population, using the product rule, resulted in a maximum power of discrimination of 1 in 12,500. Imputed non-synonymous single nucleotide polymorphism profiles from European–American subjects were considerably less frequent in the African population (maximum likelihood ratio = 11,000). The converse was true for hair shafts collected from an additional 10 subjects with African ancestry, where some profiles were more frequent in the African population. Genetically variant peptides were also identified in hair shaft datasets from six archaeological skeletal remains (up to 260 years old). This study demonstrates that quantifiable measures of identity discrimination and biogeographic background can be obtained from detecting genetically variant peptides in hair shaft protein, including hair from bioarchaeological contexts.The Technology Commercialization Innovation Program (Contracts #121668, #132043) of the Utah Governors Office of Commercial Development, the Scholarship Activitie

Classification and nomenclature of all human homeobox genes

<p>Abstract</p> <p>Background</p> <p>The homeobox genes are a large and diverse group of genes, many of which play important roles in the embryonic development of animals. Increasingly, homeobox genes are being compared between genomes in an attempt to understand the evolution of animal development. Despite their importance, the full diversity of human homeobox genes has not previously been described.</p> <p>Results</p> <p>We have identified all homeobox genes and pseudogenes in the euchromatic regions of the human genome, finding many unannotated, incorrectly annotated, unnamed, misnamed or misclassified genes and pseudogenes. We describe 300 human homeobox loci, which we divide into 235 probable functional genes and 65 probable pseudogenes. These totals include 3 genes with partial homeoboxes and 13 pseudogenes that lack homeoboxes but are clearly derived from homeobox genes. These figures exclude the repetitive <it>DUX1 </it>to <it>DUX5 </it>homeobox sequences of which we identified 35 probable pseudogenes, with many more expected in heterochromatic regions. Nomenclature is established for approximately 40 formerly unnamed loci, reflecting their evolutionary relationships to other loci in human and other species, and nomenclature revisions are proposed for around 30 other loci. We use a classification that recognizes 11 homeobox gene 'classes' subdivided into 102 homeobox gene 'families'.</p> <p>Conclusion</p> <p>We have conducted a comprehensive survey of homeobox genes and pseudogenes in the human genome, described many new loci, and revised the classification and nomenclature of homeobox genes. The classification scheme may be widely applicable to homeobox genes in other animal genomes and will facilitate comparative genomics of this important gene superclass.</p

Rapid glaciation and a two-step sea-level plunge into The Last Glacial Maximum

The approximately 10,000-year-long Last Glacial Maximum, before the termination of the last ice age, was the coldest period in Earth’s recent climate history1. Relative to the Holocene epoch, atmospheric carbon dioxide was about 100 parts per million lower and tropical sea surface temperatures were about 3 to 5 degrees Celsius lower2,3. The Last Glacial Maximum began when global mean sea level (GMSL) abruptly dropped by about 40 metres around 31,000 years ago4 and was followed by about 10,000 years of rapid deglaciation into the Holocene1. The masses of the melting polar ice sheets and the change in ocean volume, and hence in GMSL, are primary constraints for climate models constructed to describe the transition between the Last Glacial Maximum and the Holocene, and future changes; but the rate, timing and magnitude of this transition remain uncertain. Here we show that sea level at the shelf edge of the Great Barrier Reef dropped by around 20 metres between 21,900 and 20,500 years ago, to −118 metres relative to the modern level. Our findings are based on recovered and radiometrically dated fossil corals and coralline algae assemblages, and represent relative sea level at the Great Barrier Reef, rather than GMSL. Subsequently, relative sea level rose at a rate of about 3.5 millimetres per year for around 4,000 years. The rise is consistent with the warming previously observed at 19,000 years ago1,5, but we now show that it occurred just after the 20-metre drop in relative sea level and the related increase in global ice volumes. The detailed structure of our record is robust because the Great Barrier Reef is remote from former ice sheets and tectonic activity. Relative sea level can be influenced by Earth’s response to regional changes in ice and water loadings and may differ greatly from GMSL. Consequently, we used glacio-isostatic models to derive GMSL, and find that the Last Glacial Maximum culminated 20,500 years ago in a GMSL low of about −125 to −130 metres.Financial support of this research was provided by the JSPS KAKENHI (grant numbers JP26247085, JP15KK0151, JP16H06309 and JP17H01168), the Australian Research Council (grant number DP1094001), ANZIC, NERC grant NE/H014136/1 and Institut Polytechnique de Bordeaux

Design for Mobile Mental Health:An Exploratory Review

A large number of mobile mental health apps are available to the public but current knowledge about requirements of designing such solutions is scarce, especially from sociotechnical and user centred points of view. Due to the significant role of mobile apps in the mental health service models, identifying the design requirements of mobile mental health solutions is crucial. Some of those requirements have been addressed individually in the literature, but there are few research studies that show a comprehensive picture of this domain. This exploratory review aims to facilitate such holistic understanding. The main search keywords of the review were identified in a cross-disciplinary requirements workshop. The search was started by finding some core references in the healthcare databases. A wider range of references then has been explored using a snowball method. Findings showed that there is a good understanding of individual design requirements in current literature but there are few examples of implementing a combination of different design requirements in real world products. The design processes specifically developed for mobile mental health apps are also rare. Most studies on operational mobile mental health apps address major mental health issues while prevention and wellbeing areas are underdeveloped. In conclusion, the main recommendations for designing future mobile mental health solutions include: moving towards sociotechnical and open design strategies, understanding and creating shared value, recognizing all dimensions of efficacy, bridging design and medical research and development, and considering an ecosystem perspective

Understanding global sea levels: past, present and future

The coastal zone has changed profoundly during the 20th century and, as a result, society is becoming increasingly vulnerable to the impact of sea-level rise and variability. This demands improved understanding to facilitate appropriate planning to minimise potential losses. With this in mind, the World Climate Research Programme organised a workshop (held in June 2006) to document current understanding and to identify research and observations required to reduce current uncertainties associated with sea-level rise and variability. While sea levels have varied by over 120 m during glacial/interglacial cycles, there has been little net rise over the past several millennia until the 19th century and early 20th century, when geological and tide-gauge data indicate an increase in the rate of sea-level rise. Recent satellite-altimeter data and tide-gauge data have indicated that sea levels are now rising at over 3 mm year−1. The major contributions to 20th and 21st century sea-level rise are thought to be a result of ocean thermal expansion and the melting of glaciers and ice caps. Ice sheets are thought to have been a minor contributor to 20th century sea-level rise, but are potentially the largest contributor in the longer term. Sea levels are currently rising at the upper limit of the projections of the Third Assessment Report of the Intergovernmental Panel on Climate Change (TAR IPCC), and there is increasing concern of potentially large ice-sheet contributions during the 21st century and beyond, particularly if greenhouse gas emissions continue unabated. A suite of ongoing satellite and in situ observational activities need to be sustained and new activities supported. To the extent that we are able to sustain these observations, research programmes utilising the resulting data should be able to significantly improve our understanding and narrow projections of future sea-level rise and variabilit

West Antarctic Ice Sheet collapse – the fall and rise of a paradigm

It is now almost 30 years since John Mercer (1978) first presented the idea that climate change could eventually cause a rapid deglaciation, or “collapse”, of a large part of the West Antarctic ice sheet (WAIS), raising world sea levels by 5 metres and causing untold economic and social impacts. This idea, apparently simple and scientifically plausible, created a vision of the future, sufficiently alarming that it became a paradigm for a generation of researchers and provided an icon for the green movement. Through the 1990s, however, a lack of observational evidence for ongoing retreat in WAIS and improved understanding of the complex dynamics of ice streams meant that estimates of likelihood of collapse seemed to be diminishing. In the last few years, however, satellite studies over the apparently inaccessible Amundsen Sea sector of West Antarctica have shown clear evidence of ice sheet retreat showing all the features that might have been predicted for emergent collapse. These studies are re-invigorating the paradigm, albeit in a modified form, and debate about the future stability of WAIS. Since much of WAIS appears to be stable, it may, no longer be reasonable to suggest there is an imminent threat of a 5-m rise in sea level resulting from complete collapse of the West Antarctic ice sheet, but there is strong evidence that the Amundsen Sea embayment is changing rapidly. This area alone, contains the potential to raise sea level by around ~1.5 m, but more importantly it seems likely that it could, alter rapidly enough, to make a significant addition to the rate of sea-level rise over coming two centuries. Furthermore, a plausible connection between contemporary climate change and the fate of the ice sheet appears to be developing. The return of the paradigm presents a dilemma for policy-makers, and establishes a renewed set of priorities for the glaciological community. In particular, we must establish whether the hypothesized instability in WAIS is real, or simply an oversimplification resulting from inadequate understanding of the feedbacks that allow ice sheets to achieve equilibrium: and whether there is any likelihood that contemporary climate change could initiate collapse