Genetic Variation and Antioxidant Response Gene Expression in the Bronchial Airway Epithelium of Smokers at Risk for Lung Cancer

Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n=20), smokers without lung cancer (SNC, n=24), and never smokers (NS, n=8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure.Intramural Research Program of the National Institute of Environmental Health Sciences; National Institutes of Health (Z01 ES100475, U01ES016035, R01CA124640

Effect of oil palm sustainability certification on deforestation and fire in Indonesia.

Many major corporations and countries have made commitments to purchase or produce only "sustainable" palm oil, a commodity responsible for substantial tropical forest loss. Sustainability certification is the tool most used to fulfill these procurement policies, and around 20% of global palm oil production was certified by the Roundtable on Sustainable Palm Oil (RSPO) in 2017. However, the effect of certification on deforestation in oil palm plantations remains unclear. Here, we use a comprehensive dataset of RSPO-certified and noncertified oil palm plantations (∼188,000 km2) in Indonesia, the leading producer of palm oil, as well as annual remotely sensed metrics of tree cover loss and fire occurrence, to evaluate the impact of certification on deforestation and fire from 2001 to 2015. While forest loss and fire continued after RSPO certification, certified palm oil was associated with reduced deforestation. Certification lowered deforestation by 33% from a counterfactual of 9.8 to 6.6% y-1 Nevertheless, most plantations contained little residual forest when they received certification. As a result, by 2015, certified areas held less than 1% of forests remaining within Indonesian oil palm plantations. Moreover, certification had no causal impact on forest loss in peatlands or active fire detection rates. Broader adoption of certification in forested regions, strict requirements to avoid all peat, and routine monitoring of clearly defined forest cover loss in certified and RSPO member-held plantations appear necessary if the RSPO is to yield conservation and climate benefits from reductions in tropical deforestation

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases characterized by massive accumulation of autofluorescent storage bodies in neurons and other cells. A late-onset form of NCL occurs in Tibetan terrier dogs. Gel electrophoretic analyses of isolated storage body proteins from brains of affected dogs indicated that a protein of approximately 50 kDa was consistently prominent and a 16 kDa component was present in some brain storage body preparations. Mass spectral analysis identified the 50 kDa protein as glial fibrillary acidic protein (GFAP), isoform 2. GFAP identification was supported by immunoblot and immunohistochemical analyses. Histone H4 was the major protein in the 16 kDa component. Specific accumulation of GFAP and histone H4 in storage bodies has not been previously reported for any of the NCLs. Tibetan terrier NCL may be the canine correlate of one of the human adult-onset NCLs for which the genetic bases and storage body compositions have not yet been determined

Smartphone-based pathogen diagnosis in urinary sepsis patients.

BackgroundThere is an urgent need for rapid, sensitive, and affordable diagnostics for microbial infections at the point-of-care. Although a number of innovative systems have been reported that transform mobile phones into potential diagnostic tools, the translational challenge to clinical diagnostics remains a significant hurdle to overcome.MethodsA smartphone-based real-time loop-mediated isothermal amplification (smaRT-LAMP) system was developed for pathogen ID in urinary sepsis patients. The free, custom-built mobile phone app allows the phone to serve as a stand-alone device for quantitative diagnostics, allowing the determination of genome copy-number of bacterial pathogens in real time.FindingsA head-to-head comparative bacterial analysis of urine from sepsis patients revealed that the performance of smaRT-LAMP matched that of clinical diagnostics at the admitting hospital in a fraction of the time (~1 h vs. 18-28 h). Among patients with bacteremic complications of their urinary sepsis, pathogen ID from the urine matched that from the blood - potentially allowing pathogen diagnosis shortly after hospital admission. Additionally, smaRT-LAMP did not exhibit false positives in sepsis patients with clinically negative urine cultures.InterpretationThe smaRT-LAMP system is effective against diverse Gram-negative and -positive pathogens and biological specimens, costs less than $100 US to fabricate (in addition to the smartphone), and is configurable for the simultaneous detection of multiple pathogens. SmaRT-LAMP thus offers the potential to deliver rapid diagnosis and treatment of urinary tract infections and urinary sepsis with a simple test that can be performed at low cost at the point-of-care. FUND: National Institutes of Health, Chan-Zuckerberg Biohub, Bill and Melinda Gates Foundation

A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

The childhood neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that are progressive and ultimately fatal. An Australian Shepherd that exhibited a progressive neurological disorder with signs similar to human NCL was evaluated. The cerebral cortex, cerebellum, and retina were found to contain massive accumulations of autofluorescent inclusions characteristic of the NCLs. Nucleotide sequence analysis of DNA from the affected dog identified a T to C variant (c.829T>C) in exon 7 of CLN6. Mutations in the human ortholog underlie a late-infantile form of NCL in humans. The T-to-C transition results in a tryptophan to arginine amino acid change in the predicted protein sequence. Tryptophans occur at homologous positions in the CLN6 proteins from all 13 other vertebrates evaluated. The c.829T>C transition is a strong candidate for the causative mutation in this NCL-affected dog. Dogs with this mutation could serve as a model for the analogous human disorder

6,7,9,10-Tetra­hydro-16,22-ethano­oxyethano-5,8,11,19-tetra­oxa-16,22-diaza­dibenzo[h,q]cyclo­octa­decine-17,21-dione: a benzyl­annelated macrobicyclic diamide

The macrobicyclic title compound, C24H28N2O7, has two tertiary diamide bridgehead atoms and is composed of a 12-membered ring (N2O2 donor set) and two 18-membered rings (N2O4 donor sets). The solid-state structure shows that each of the amide groups is not coplanar with the adjacent benzene ring and NMR studies indicate that this conformational relationship persists in solution

Comments on Black Holes in Matrix Theory

The recent suggestion that the entropy of Schwarzschild black holes can be computed in matrix theory using near-extremal D-brane thermodynamics is examined. It is found that the regime in which this approach is valid actually describes black strings stretched across the longitudinal direction, near the transition where black strings become unstable to the formation of black holes. It is argued that the appropriate dynamics on the other (black hole) side of the transition is that of the zero modes of the corresponding super Yang-Mills theory. A suggestive mean field theory argument is given for the entropy of black holes in all dimensions. Consequences of the analysis for matrix theory and the holographic principle are discussed.Comment: 15 pages, harvmac, minor errors correcte

Simple sequence repeat markers useful for sorghum downy mildew (Peronosclerospora sorghi) and related species

<p>Abstract</p> <p>Background</p> <p>A recent outbreak of sorghum downy mildew in Texas has led to the discovery of both metalaxyl resistance and a new pathotype in the causal organism, <it>Peronosclerospora sorghi</it>. These observations and the difficulty in resolving among phylogenetically related downy mildew pathogens dramatically point out the need for simply scored markers in order to differentiate among isolates and species, and to study the population structure within these obligate oomycetes. Here we present the initial results from the use of a biotin capture method to discover, clone and develop PCR primers that permit the use of simple sequence repeats (microsatellites) to detect differences at the DNA level.</p> <p>Results</p> <p>Among the 55 primers pairs designed from clones from pathotype 3 of <it>P. sorghi</it>, 36 flanked microsatellite loci containing simple repeats, including 28 (55%) with dinucleotide repeats and 6 (11%) with trinucleotide repeats. A total of 22 microsatellites with CA/AC or GT/TG repeats were the most abundant (40%) and GA/AG or CT/TC types contribute 15% in our collection. When used to amplify DNA from 19 isolates from <it>P. sorghi</it>, as well as from 5 related species that cause downy mildew on other hosts, the number of different bands detected for each SSR primer pair using a LI-COR- DNA Analyzer ranged from two to eight. Successful cross-amplification for 12 primer pairs studied in detail using DNA from downy mildews that attack maize (<it>P. maydis & P. philippinensis</it>), sugar cane (<it>P. sacchari</it>), pearl millet (<it>Sclerospora graminicola</it>) and rose (<it>Peronospora sparsa</it>) indicate that the flanking regions are conserved in all these species. A total of 15 SSR amplicons unique to <it>P. philippinensis </it>(one of the potential threats to US maize production) were detected, and these have potential for development of diagnostic tests. A total of 260 alleles were obtained using 54 microsatellites primer combinations, with an average of 4.8 polymorphic markers per SSR across 34 <it>Peronosclerospora, Peronospora and Sclerospora </it>spp isolates studied. Cluster analysis by UPGMA as well as principal coordinate analysis (PCA) grouped the 34 isolates into three distinct groups (all 19 isolates of <it>Peronosclerospora sorghi </it>in cluster I, five isolates of <it>P. maydis </it>and three isolates of <it>P. sacchari </it>in cluster II and five isolates of <it>Sclerospora graminicola </it>in cluster III).</p> <p>Conclusion</p> <p>To our knowledge, this is the first attempt to extensively develop SSR markers from <it>Peronosclerospora </it>genomic DNA. The newly developed SSR markers can be readily used to distinguish isolates within several species of the oomycetes that cause downy mildew diseases. Also, microsatellite fragments likely include retrotransposon regions of DNA and these sequences can serve as useful genetic markers for strain identification, due to their degree of variability and their widespread occurrence among sorghum, maize, sugarcane, pearl millet and rose downy mildew isolates.</p

Particulate metal exposures induce plasma metabolome changes in a commuter panel study

Introduction Advances in liquid chromatography-mass spectrometry (LC-MS) have enabled high-resolution metabolomics (HRM) to emerge as a sensitive tool for measuring environmental exposures and corresponding biological response. Using measurements collected as part of a large, panel-based study of car commuters, the current analysis examines in-vehicle air pollution concentrations, targeted inflammatory biomarker levels, and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures. Methods A 60-person panel of adults participated in a crossover study, where each participant conducted a highway commute and randomized to either a side-street commute or clinic exposure session. In addition to in-vehicle exposure characterizations, participants contributed pre- and post-exposure dried blood spots for 2-hr changes in targeted proinflammatory and vascular injury biomarkers and 10-hr changes in the plasma metabolome. Samples were analyzed on a Thermo QExactive MS system in positive and negative electrospray ionization (ESI) mode. Data were processed and analyzed in R using apLCMS, xMSanalyzer, and limma. Features associated with environmental exposures or biological endpoints were identified with a linear mixed effects model and annotated through human metabolic pathway analysis in mummichog. Results HRM detected 10-hr perturbations in 110 features associated with in-vehicle, particulate metal exposures (Al, Pb, and Fe) which reflect changes in arachidonic acid, leukotriene, and tryptophan metabolism. Two-hour changes in proinflammatory biomarkers hs-CRP, IL-6, IL-8, and IL-1β were also associated with 10-hr changes in the plasma metabolome, suggesting diverse amino acid, leukotriene, and antioxidant metabolism effects. A putatively identified metabolite, 20-OH-LTB4, decreased after in-vehicle exposure to particulate metals, suggesting a subclinical immune response. Conclusions Acute exposures to traffic-related air pollutants are associated with broad inflammatory response, including several traditional markers of inflammation

D-Matter

We study the properties and phenomenology of particle-like states originating from D-branes whose spatial dimensions are all compactified. They are non-perturbative states in string theory and we refer to them as D-matter. In contrast to other non-perturbative objects such as 't Hooft-Polyakov monopoles, D-matter states could have perturbative couplings among themselves and with ordinary matter. The lightest D-particle (LDP) could be stable because it is the lightest state carrying certain (integer or discrete) quantum numbers. Depending on the string scale, they could be cold dark matter candidates with properties similar to that of wimps or wimpzillas. The spectrum of excited states of D-matter exhibits an interesting pattern which could be distinguished from that of Kaluza-Klein modes, winding states, and string resonances. We speculate about possible signatures of D-matter from ultra-high energy cosmic rays and colliders.Comment: 25 pages, 5 figures, references adde