Toxicogenomic analysis of Caenorhabditis elegans reveals novel genes and pathways involved in the resistance to cadmium toxicity

Global analysis of the transcriptional response to cadmium exposure in Caenorhabditis elegans reveals roles for genes involved in cellular trafficking, metabolic processes and proteolysis, and for the signaling protein KEL-8

Caenorhabditis elegans generates biologically relevant levels of genotoxic metabolites from aflatoxin B1 but not benzo[a]pyrene in vivo

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Toxicological Sciences 118 (2010): 444-453, doi:10.1093/toxsci/kfq295.There is relatively little information regarding the critical xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in Caenorhabditis elegans, despite this organism’s increasing use as a model in toxicology and pharmacology. We carried out experiments to elucidate the capacity of C. elegans to metabolically activate important promutagens via CYPs. Phylogenetic comparisons confirmed an earlier report indicating a lack of CYP1 family enzymes in C. elegans. Exposure to aflatoxin B1 (AFB1), which is metabolized in mammals by CYP1, CYP2, and CYP3 family enzymes, resulted in significant DNA damage in C. elegans. However, exposure to benzo[a]pyrene (BaP), which is metabolized in mammals by CYP1 family enzymes only, produced no detectable damage. To further test whether BaP exposure caused DNA damage, the toxicities of AFB1 and BaP were compared in nucleotide excision repair-deficient (xpa-1) and - proficient (N2) strains of C. elegans. Exposure to AFB1 inhibited growth more in xpa-1 than N2 nematodes, but the growth-inhibitory effects of BaP were indistinguishable in the two strains. Finally, a CYP-NADPH reductase- deficient strain (emb-8) of C. elegans was found to be more resistant to the growth inhibitory effect of AFB1 exposure than N2, confirming that the AFB1- mediated growth inhibition resulted from CYP-mediated metabolism. Together, these results indicate that C. elegans lacks biologically significant CYP1 family-mediated enzymatic metabolism of xenobiotics. Interestingly, we also found that xpa-1 nematodes were slightly more sensitive to chlorpyrifos than were wild-type. Our results highlight the importance of considering differences between xenobiotic metabolism in C. elegans and mammals when using this alternative model in pharmaceutical and toxicological research.This work was supported in part by NIH R21 NS065468 (JNM); the National Toxicology Program Z01ES102046 (WAB), the Intramural Research Program of the National Institute of Environmental Health Sciences Z01ES102045 (JHF). JVG was supported by NIH Grants to John Stegeman (R01-ES015912, and the Superfund Basic Research Program at Boston University 5- P42-ES007381)

Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans

Repair of UVC-induced DNA damage in Caenorhabditis elegans is similar kinetically and genetically to repair in humans, and it slows significantly in aging C. elegans

Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

Contrast-enhanced micro-computed tomography (CE mu CT) with cationic and anionic contrast agents reveals glycosaminoglycan (GAG) content and distribution in articular cartilage (AC). The advantage of using cationic stains (e.g., CA4+) compared to anionic stains (e.g., Hexabrix (R)), is that it distributes proportionally with GAGs, while anionic stain distribution in AC is inversely proportional to the GAG content. To date, studies using cationic stains have been conducted with sufficient resolution to study its distributions on the macro-scale, but with insufficient resolution to study its distributions on the micro-scale. Therefore, it is not known whether the cationic contrast agents accumulate in extra/pericellular matrix and if they interact with chondrocytes. The insufficient resolution has also prevented to answer the question whether CA4+ accumulation in chondrons could lead to an erroneous quantification of GAG distribution with low-resolution mu CT setups. In this study, we use high-resolution mu CT to investigate whether CA4+ accumulates in chondrocytes, and further, to determine whether it affects the low-resolution ex vivo mu CT studies of CA4+ stained human AC with varying degree of osteoarthritis. Human osteochondral samples were immersed in three different concentrations of CA4+ (3 mgI/ml, 6 mgI/ml, and 24 mgI/ml) and imaged with high-resolution mu CT at several timepoints. Different uptake diffusion profiles of CA4+ were observed between the segmented chondrons and the rest of the tissue. While the X-ray -detected CA4+ concentration in chondrons was greater than in the rest of the AC, its contribution to the uptake into the whole tissue was negligible and in line with macro-scale GAG content detected from histology. The efficient uptake of CA4+ into chondrons and surrounding territorial matrix can be explained by the micro-scale distribution of GAG content. CA4+ uptake in chondrons occurred regardless of the progression stage of osteoarthritis in the samples and the relative difference between the interterritorial matrix and segmented chondron area was less than 4%. To conclude, our results suggest that GAG quantification with CE mu CT is not affected by the chondron uptake of CA4+. This further confirms the use of CA4+ for macro-scale assessment of GAG throughout the AC, and highlight the capability of studying chondron properties in 3D at the micro scale.Peer reviewe

D-term inflation in non-minimal supergravity

D-term inflation is one of the most interesting and versatile models of inflation. It is possible to implement naturally D-term inflation within high energy physics, as for example SUSY GUTs, SUGRA, or string theories. D-term inflation avoids the $\eta$-problem, while in its standard form it always ends with the formation of cosmic strings. Given the recent three-year WMAP data on the cosmic microwave background temperature anisotropies, we examine whether D-term inflation can be successfully implemented in non-minimal supergravity theories. We show that for all our choices of K\"ahler potential, there exists a parameter space for which the predictions of D-term inflation are in agreement with the measurements. The cosmic string contribution on the measured temperature anisotropies is always dominant, unless the superpotential coupling constant is fine tuned; a result already obtained for D-term inflation within minimal supergravity. In conclusion, cosmic strings and their r\^ole in the angular power spectrum cannot be easily hidden by just considering a non-flat K\"ahler geometry.Comment: 29 pages, 9 figures; minor changes to match publihed versio

An infinite family of convex Brunnian links in RnR^n

This paper proves that convex Brunnian links exist for every dimension $n \geq 3$ by constructing explicit examples. These examples are three-component links which are higher-dimensional generalizations of the Borromean rings.Comment: 10 pages, 4 figure

Canonical Coordinates and Meson Spectra for Scalar Deformed N=4 SYM from the AdS/CFT Correspondence

Five supersymmetric scalar deformations of the AdS_5xS^5 geometry are investigated. By switching on condensates for the scalars in the N=4 multiplet with a form which preserves a subgroup of the original R-symmetry, disk and sphere configurations of D3-branes are formed in the dual supergravity background. The analytic, canonical metric for each geometry is formulated and the singularity structure is studied. Quarks are introduced into two of the corresponding field theories using D7-brane probes and the pseudoscalar meson spectrum is calculated. For one of the condensate configurations, a mass gap is found and shown analytically to be present in the massless limit. It is also found that there is a stepped spectrum with eigenstate degeneracy in the limit of small quark masses. In the case of a second, similar deformation, it is necessary to understand the full D3-D7 brane interaction to study the limit of small quark masses. It is seen that simple solutions to the equations of motion for the other three geometries are unlikely to exist.Comment: 16 pages, 7 figures, references added, typos correcte

Rapid genotype imputation from sequence without reference panels

Inexpensive genotyping methods are essential for genetic studies requiring large sample sizes. In human studies, array-based microarrays and high-density haplotype reference panels allow efficient genotype imputation for this purpose. However, these resources are typically unavailable in non-human settings. Here we describe a method (STITCH) for imputation based only on sequencing read data, without requiring additional reference panels or array data. We demonstrate its applicability even in settings of extremely low sequencing coverage, by accurately imputing 5.7 million SNPs at a mean r(2) value of 0.98 in 2,073 outbred laboratory mice (0.15× sequencing coverage). In a sample of 11,670 Han Chinese (1.7× coverage), we achieve accuracy similar to that of alternative approaches that require a reference panel, demonstrating that our approach can work for genetically diverse populations. Our method enables straightforward progression from low-coverage sequence to imputed genotypes, overcoming barriers that at present restrict the application of genome-wide association study technology outside humans

A Discrete Time Model for the Analysis of Medium-Throughput C. elegans Growth Data

BACKGROUND: As part of a program to predict the toxicity of environmental agents on human health using alternative methods, several in vivo high- and medium-throughput assays are being developed that use C. elegans as a model organism. C. elegans-based toxicological assays utilize the COPAS Biosort flow sorting system that can rapidly measure size, extinction (EXT) and time-of-flight (TOF), of individual nematodes. The use of this technology requires the development of mathematical and statistical tools to properly analyze the large volumes of biological data. METHODOLOGY/PRINCIPAL FINDINGS: Findings A Markov model was developed that predicts the growth of populations of C. elegans. The model was developed using observations from a 60 h growth study in which five cohorts of 300 nematodes each were aspirated and measured every 12 h. Frequency distributions of log(EXT) measurements that were made when loading C. elegans L1 larvae into 96 well plates (t = 0 h) were used by the model to predict the frequency distributions of the same set of nematodes when measured at 12 h intervals. The model prediction coincided well with the biological observations confirming the validity of the model. The model was also applied to log(TOF) measurements following an adaptation. The adaptation accounted for variability in TOF measurements associated with potential curling or shortening of the nematodes as they passed through the flow cell of the Biosort. By providing accurate estimates of frequencies of EXT or TOF measurements following varying growth periods, the model was able to estimate growth rates. Best model fits showed that C. elegans did not grow at a constant exponential rate. Growth was best described with three different rates. Microscopic observations indicated that the points where the growth rates changed corresponded to specific developmental events: the L1/L2 molt and the start of oogenesis in young adult C. elegans. CONCLUSIONS: Quantitative analysis of COPAS Biosort measurements of C. elegans growth has been hampered by the lack of a mathematical model. In addition, extraneous matter and the inability to assign specific measurements to specific nematodes made it difficult to estimate growth rates. The present model addresses these problems through a population-based Markov model