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PubMed2004

The rad50 signature motif: essential to ATP binding and biological function.

The repair of double-strand breaks in DNA is an essential process in all organisms, and requires the coordinated activities of evolutionarily conserved protein assemblies. One of the most critical of these is the Mre11/Rad50 (M/R) complex, which is present in all three biological kingdoms, but is not well-understood at the biochemical level. Previous structural analysis of a Rad50 homolog from archaebacteria illuminated the catalytic core of the enzyme, an ATP-binding domain related to the ABC transporter family of ATPases. Here, we present the crystallographic structure of the Rad50 mutant S793R. This missense signature motif mutation changes the key serine residue in the signature motif that is conserved among Rad50 homologs and ABC ATPases. The S793R mutation is analogous to the mutation S549R in the cystic fibrosis transmembrane conductance regulator (CFTR) that results in cystic fibrosis. We show here that the serine to arginine change in the Rad50 protein prevents ATP binding and disrupts the communication among the other ATP-binding loops. This structural change, in turn, alters the communication between Rad50 monomers and thus prevents Rad50 dimerization. The equivalent mutation was made in the human Rad50 gene, and the resulting mutant protein did form a complex with Mre11 and Nbs1, but was specifically deficient in all ATP-dependent enzymatic activities. This signature motif structure-function homology extends to yeast, because the same mutation introduced into the Saccharomyces cerevisiae RAD50 gene generated an allele that failed to complement a rad50 deletion strain in DNA repair assays in vivo. These structural and biochemical results extend our understanding of the Rad50 catalytic domain and validate the use of the signature motif mutant to test the role of Rad50 ATP binding in diverse organisms.

Acid Anhydride Hydrolases↗

PubMed2005

The nucleobase-ascorbate transporter (NAT) signature motif in UapA defines the function of the purine translocation pathway.

UapA, a member of the NAT/NCS2 family, is a high affinity, high capacity, uric acid-xanthine/H+ symporter of Aspergillus nidulans. We have previously presented evidence showing that a highly conserved signature motif ([Q/E/P]408-N-X-G-X-X-X-X-T-[R/K/G])417 is involved in UapA function. Here, we present a systematic mutational analysis of conserved residues in or close to the signature motif of UapA. We show that even the most conservative substitutions of residues Q408, N409 and G411 modify the kinetics and specificity of UapA, without affecting targeting in the plasma membrane. Q408 substitutions show that this residue determines both substrate binding and transport catalysis, possibly via interactions with position N9 of the imidazole ring of purines. Residue N409 is an irreplaceable residue necessary for transport catalysis, but is not involved in substrate binding. Residue G411 determines, indirectly, both the kinetics (K(m), V) and specificity of UapA, probably due to its particular property to confer local flexibility in the binding site of UapA. In silico predictions and a search in structural databases strongly suggest that the first part of the NAT signature motif of UapA (Q(408)NNG(411)) should form a loop, the structure of which is mostly affected by mutations in G411. Finally, substitutions of residues T416 and R417, despite being much better tolerated, can also affect the kinetics or the specificity of UapA. Our results show that the NAT signature motif defines the function of the UapA purine translocation pathway and strongly suggest that this might occur by determining the interactions of UapA with the imidazole part of purines.

Amino Acid Motifs↗

PubMed2005

Molecular signature analysis: using the myocardial transcriptome as a biomarker in cardiovascular disease.

With the emergence of microarray technology, it is now possible to simultaneously assess the expression of tens of thousands of gene transcripts, providing a resolution and precision of phenotypic characterization not previously possible. In the field of cardiomyopathy, microarray studies have largely focused on gene discovery, identifying differentially expressed genes characteristic of diverse disease states, through which novel genetic pathways and potential therapeutic targets may be elucidated. However, gene expression profiling may also be used to identify a pattern of genes (a molecular signature) that serves as a biomarker for clinically relevant parameters. One study thus far does demonstrate that a molecular signature can accurately identify etiology in cardiovascular disease, supporting ongoing efforts to incorporate expression-profiling-based biomarkers in determining prognosis and response to therapy in heart failure. Microarray research in cardiomyopathy is still in its earliest stages. Nevertheless, the ultimate potential application of transcriptome-based molecular signature analysis is individualization of the management of patients with heart failure, whereby a patient with a newly diagnosed cardiomyopathy could, through molecular signature analysis, be offered an accurate assessment of prognosis and how individualized medical therapy could affect his or her outcome.

Biomarkers↗

PubMed2005

A novel method for generation of signature networks as biomarkers from complex high throughput data.

Traditionally, gene signatures are statistically deduced from large gene expression and proteomics datasets and have been applied as an experimental molecular diagnostic technique that is sensitive to experimental design and statistical treatment. We have developed and applied the approach of "signature networks" which overcomes some of the drawbacks of clustering methods. We have demonstrated signature network assembly, functional analysis and logical operations on the networks that can be generated. In addition, we have used this technique in a proof of concept study to compare the effect of differential drug treatment using 4-hydroxytamoxifen and estrogen on the MCF-7 breast cancer cell line from a previously published study. We have shown that the two compounds can be differentiated by the networks of interacting genes. Both networks consist of a core module of genes including c-Fos as part of c-Fos/c-Jun heterodimer and c-Myc which is clearly visible. Using algorithms in our MetaCore software we are able to subtract the 4-hydroxytamoxifen and estrogen networks to further understand differences between these two treatments and show that the estrogen network is assembled around the core with other modules essential for all phases of the cell cycle. For example, Cyclin D1 is present in networks for the estrogen treated cells from two separate studies. These signature networks represent an approach to identify biomarkers and a general approach for discovering new relationships in complex high throughput toxicology data.

Algorithms↗

PubMed2002

Combustion sources of particles. 1. Health relevance and source signatures.

Combustion processes result in generation of a large number of particle and gaseous products that create health and environmental risks. Of particular importance are the very small particles that are emitted in large quantities from all the combustion sources, and that have been shown to be potentially more significant in terms of their impact on health than larger particles. To control and mitigate the particles with a view of health and environmental risk reduction, a good understanding is necessary of the relative and absolute contribution from the emission sources to the airborne concentrations. This understanding could only be achieved by developing source signature libraries through direct emission measurements from the sources on one hand, and by measuring particle concentrations in the air, and apportioning them to the specific local and distant sources using the signatures, on the other hand. This paper is a review of particle characteristics that are used as source signatures as well as their general advantages and limitations. The second part of the paper reviews source signatures of the most common combustion pollution sources.

Air Pollutants↗

PubMed2002

European isotopic signatures for lead in atmospheric aerosols: a source apportionment based upon 206Pb/207Pb ratios.

To investigate the capability of the lead isotope signature technique to support a source apportionment study at a Continental scale, atmospheric particulate matter was collected at Cap Gris-Nez (Eastern Channel, northern France), over one year (1995-1996). Four days retrospective trajectories of air masses were available during each sampling experiment. Twenty-eight samples, for which the origin of aerosols was unambiguously determined, were selected for isotopic measurements. Considering the Enrichment Factors, EF(Crust) of lead and its size distribution, we show that lead is mostly from anthropogenic origin and mainly associated with [0.4 < diameter < 0.9 microm] particles. The extent to which various Continental sources influence the lead abundance in aerosols is exhibited by considering both the lead concentration and the origin of air masses. Lead concentration is higher by a factor of approximately seven, when air masses are derived from Continental Europe, by comparison with marine air masses. Taking into account these concentrations and the vertical movements of air masses, we compare the different isotopic compositions using a statistical non-parametric test (Kolmogorov-Smirnov). We produce evidence that, for most of the cases, air masses originating from Continental Europe exhibit a more radiogenic composition (1.134 < 206Pb/207Pb < 1.172) than air masses coming from the United Kingdom (1.106 < 206Pb/207Pb < 1.124). Generally, lead isotopic compositions in aerosols are clearly distinct from the gasoline signatures in European countries, strongly suggesting that automotive lead is no longer the major component of this metal in the air. Gasoline and industrial isotopic signatures could explain the origin of lead in our aerosol samples. A source apportionment based upon 206Pb/207Pb ratios, suggests that the difference between British (206Pb/207Pb = 1.122 +/- 0.038) and Continental (206Pb/207Pb = 1.155 +/- 0.022) signatures may be largely explained by differences in the petrol lead content of aerosols (23-62% in Great Britain vs. 10-36% in Continental Europe).

Aerosols↗

PubMed2001

Signatures of the immune response.

A compendium of global gene expression measurements from DNA microarray analysis of immune cells identifies gene expression signatures defining various lineages, differentiation stages, and signaling pathways. Germinal center (GC) B cells represent a discrete stage of differentiation with a unique gene expression signature. This includes genes involved in proliferation, as evidenced by high expression of G2/M phase regulators and low expression of ribosomal and metabolic genes that are transcriptional targets of c-myc. GC B cells also lack expression of the NF-kappaB signature genes, which may favor apoptosis. Finally, the transcriptional repression signature of BCL-6 reveals how this factor can prevent terminal differentiation of B cells and cause B cell lymphomas.

Animals↗

PubMed2001

Fractal signature and lacunarity in the measurement of the texture of trabecular bone in clinical CT images.

Fractal analysis is a method of characterizing complex shapes such as the trabecular structure of bone. Numerous algorithms for estimating fractal dimension have been described, but the Fourier power spectrum method is particularly applicable to self-affine fractals, and facilitates corrections for the effects of noise and blurring in an image. We found that it provided accurate estimates of fractal dimension for synthesized fractal images. For natural texture images fractality is limited to a range of scales, and the fractal dimension as a function of spatial frequency presents as a fractal signature. We found that the fractal signature was more successful at discriminating between these textures than either the global fractal dimension or other metrics such as the mean width and root-mean-square width of the spectral density plots. Different natural textures were also readily distinguishable using lacunarity plots, which explicitly characterize the average size and spatial organization of structural sub-units within an image. The fractal signatures of small regions of interest (32x32 pixels), computed in the frequency domain after corrections for imaging system noise and MTF, were able to characterize the texture of vertebral trabecular bone in CT images. Even small differences in texture due to acquisition slice thickness resulted in measurably different fractal signatures. These differences were also readily apparent in lacunarity plots, which indicated that a slice thickness of 1 mm or less is necessary if essential architectural information is not to be lost. Since lacunarity measures gap size and is not predicated on fractality, it may be particularly useful for characterizing the texture of trabecular bone.

Adult↗

PubMedDate not supplied

Investigating forensic document examiners' skill relating to opinions on photocopied signatures.

Many forensic document examiners are hesitant to express authorship opinions on photocopied handwriting as the photocopying process results in less feature information than original writing. This study aimed to test the accuracy of 15 examiners' opinions regarding whether photocopied questioned signatures were genuine or simulated. Each examiner received the same set of original signature exemplars, from one individual, and a set of eighty questioned photocopied signatures comprising of genuine and simulated signatures. The overall misleading (error) rate for the grouped examiners' opinions was 0.9% providing strong evidence that examiners can make accurate observations regarding the authorship of non-original handwriting.

Journal Article↗

PubMedDate not supplied

An evaluation of line quality in photocopied signatures.

Qualified forensic document examiners from Canada, USA, Great Britain and Australia participated in this study. They were sent one photocopied signature, together with a set of original known standards to evaluate the line quality of the photocopied signature and compare these characteristics with the standards. They were asked to assess the photocopies for the presence of tremor, hesitation, pen lifts, patching, blunt initial or terminal strokes, and abrupt changes in direction. The authors compared the assessments with the corresponding original signatures. It was possible to determine which line quality characteristics were the most difficult to detect, which indicia of simulation were concealed and what anomalies were introduced by the photocopying process. Results indicated that line quality characteristics can be identified in average quality photocopies. Furthermore, accurate judgements can be made regarding similarities and differences in line quality when comparing a photocopied signature with original known standards. In a few instances, ink line morphology was problematic when striation patterns and ink gooping were misinterpreted as pen lifts, hesitation and patching on the photocopies.

Copying Processes↗

PubMed2005

Freshwater mussel shells as environmental chronicles: geochemical and taphonomic signatures of mercury-related extirpations in the North Fork Holston River, Virginia.

This study utilized freshwater mussel shells to assess mercury (Hg) contamination in the North Fork Holston River that extirpated (caused local extinctions of) a diverse mussel fauna. Shells (n = 366) were collected from five sites situated upstream (two sites), just below (one site), and downstream (two sites) of the town of Saltville, Virginia, where Hg was used to produce chlorine and caustic soda from 1950 to 1972. Shell samples were used to test the (1) utility of geochemical signatures of shells for assessing the spatial variation in Hg levels in the river relative to the contamination source and (2) value of taphonomy (post-mortem shell alteration) for distinguishing sites that differ in extirpation histories. Geochemical signatures of 40 shells, analyzed using atomic absorption spectroscopy, indicated a strong longitudinal pattern. All shells from the two upstream sites had low Hg concentrations (<5-31 microg/kg), shells directly below Saltville had variable, but dramatically higher concentrations (23-4637 microg/kg), and shells from the two downstream sites displayed intermediate Hg levels (<5-115 microg/kg) that declined with distance from Saltville. Two pre-industrial shells, collected at Saltville in 1917, yielded very low Hg estimates (5-6 microg/kg). Hg signatures were consistent among mussel species, suggesting that Hg concentrations were invariant to species type; most likely, highly variable Hg levels, both across sites and through time, overwhelmed any interspecific differences in Hg acquisition. Also, a notable postmortem incorporation of Hg in mussel shells seemed unlikely, as the Hg content was not correlated with shell taphonomy (r= 0.18; p = 0.28). The taphonomic analysis (n = 366) showed that the degree of shell alteration reliably distinguished sites with different extirpation histories. At Saltville, where live mussels have been absent for at least 30 years, shells were most heavily altered and fragmented. Conversely, fresh-looking shells abounded upstream, where reproducing mussel populations are still present. In summary, relic shells offered valuable spatio-temporal data on Hg concentrations in a polluted ecosystem, and shell taphonomic signatures discriminated sites with different extirpation histories. The shell-based strategies exemplified here do not require sampling live specimens and may augment more standard strategies applied to environmental monitoring. The approach should prove especially useful in areas with unknown extirpation and pollution histories.

Animals↗

PubMed2005

Chiral organochlorine pesticide signatures in global background soils.

Chiral pesticides frequently undergo enantioselective degradation in soils. Prior studies to characterize chiral signatures have focused on treated agricultural soils, rather than background (untreated) soils, and tracking signatures in the atmosphere for source apportionment purposes. In this study, we investigated the chiral signatures in 65 background soils collected from different locations across the world. The soils were taken from different ecosystems (e.g., grasslands, forests), and the enantiomeric fractions (EFs) of chiral chlordanes, alpha-hexachlorocyclohexane (alpha-HCH), and o,p'-DDT were determined. Chlordanes in most of the soils showed the usual pattern of enantioselective degradation seen in agricultural soils, depletion of (+)-trans-chlordane (TC) and (-)-cis-chlordane (CC). However, some samples showed opposite enantiomer degradation patterns for TC, CC, and chlordane compound MC5. Correlations were tested between the deviation of EFs from racemic (DEVrac = absolute value of 0.500 - EF), the percent soil organic matter (% SOM), annual mean temperature, and the ratio of TC to the more stable compound trans-nonachlor (TN). Significant positive correlations were found between DEVrac and % SOM for TC and CC (p = 0.0022 and 0.0031), but not for the other OCPs. No significant correlations were found between DEVrac and annual mean temperature for any of the OCPs. DEVrac for TC was negatively correlated with the TC/TN ratio, but the regression was driven by two points with high ratios of TC/CC. Removing these two points resulted in a nonsignificant regression. The range of EFs for TC, CC, and alpha-HCH in soils was greater than in ambient air, providing evidence of in situ degradation after atmospheric deposition in some cases. Variable EFs in soil suggest that caution is needed when considering the enantiomer signatures in air as a marker of volatilization of weathered soil-derived organochlorines.

Chlordan↗

PubMed2005

Incorporating if...then...personality signatures in person perception: beyond the person-situation dichotomy.

Three studies investigated conditions in which perceivers view dispositions and situations as interactive, rather than independent, causal forces when making judgments about another's personality. Study 1 showed that perceivers associated 5 common trait terms (e.g., friendly and shy) with characteristic if...then... (if situation a, then the person does x, but if situation b, then the person does y) personality signatures. Study 2 demonstrated that perceivers used information about a target's stable if...then... signature to infer the target's motives and traits; dispositional judgments were mediated by inferences about the target's motivations. Study 3 tested whether perceivers draw on if...then... signatures when making judgments about Big Five trait dimensions. Together, the findings indicate that perceivers take account of person-situation interactions (reflected in if...then... signatures) in everyday explanations of social behavior and personality dispositions. Boundary conditions are also discussed.

Adult↗

PubMed2000

Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays.

We describe a novel sequencing approach that combines non-gel-based signature sequencing with in vitro cloning of millions of templates on separate 5 microm diameter microbeads. After constructing a microbead library of DNA templates by in vitro cloning, we assembled a planar array of a million template-containing microbeads in a flow cell at a density greater than 3x10(6) microbeads/cm2. Sequences of the free ends of the cloned templates on each microbead were then simultaneously analyzed using a fluorescence-based signature sequencing method that does not require DNA fragment separation. Signature sequences of 16-20 bases were obtained by repeated cycles of enzymatic cleavage with a type IIs restriction endonuclease, adaptor ligation, and sequence interrogation by encoded hybridization probes. The approach was validated by sequencing over 269,000 signatures from two cDNA libraries constructed from a fully sequenced strain of Saccharomyces cerevisiae, and by measuring gene expression levels in the human cell line THP-1. The approach provides an unprecedented depth of analysis permitting application of powerful statistical techniques for discovery of functional relationships among genes, whether known or unknown beforehand, or whether expressed at high or very low levels.

Cell Line↗

PubMed2004

Analysis of the transcriptional complexity of Arabidopsis thaliana by massively parallel signature sequencing.

Large-scale sequencing of short mRNA-derived tags can establish the qualitative and quantitative characteristics of a complex transcriptome. We sequenced 12,304,362 tags from five diverse libraries of Arabidopsis thaliana using massively parallel signature sequencing (MPSS). A total of 48,572 distinct signatures, each representing a different transcript, were expressed at significant levels. These signatures were compared to the annotation of the A. thaliana genomic sequence; in the five libraries, this comparison yielded between 17,353 and 18,361 genes with sense expression, and between 5,487 and 8,729 genes with antisense expression. An additional 6,691 MPSS signatures mapped to unannotated regions of the genome. Expression was demonstrated for 1,168 genes for which expression data were previously unknown. Alternative polyadenylation was observed for more than 25% of A. thaliana genes transcribed in these libraries. The MPSS expression data suggest that the A. thaliana transcriptome is complex and contains many as-yet uncharacterized variants of normal coding transcripts.

Arabidopsis↗

PubMed2002

A molecular signature of metastasis in primary solid tumors.

Metastasis is the principal event leading to death in individuals with cancer, yet its molecular basis is poorly understood. To explore the molecular differences between human primary tumors and metastases, we compared the gene-expression profiles of adenocarcinoma metastases of multiple tumor types to unmatched primary adenocarcinomas. We found a gene-expression signature that distinguished primary from metastatic adenocarcinomas. More notably, we found that a subset of primary tumors resembled metastatic tumors with respect to this gene-expression signature. We confirmed this finding by applying the expression signature to data on 279 primary solid tumors of diverse types. We found that solid tumors carrying the gene-expression signature were most likely to be associated with metastasis and poor clinical outcome (P < 0.03). These results suggest that the metastatic potential of human tumors is encoded in the bulk of a primary tumor, thus challenging the notion that metastases arise from rare cells within a primary tumor that have the ability to metastasize.

Adenocarcinoma↗

PubMed2006

Genetic regulators of large-scale transcriptional signatures in cancer.

Gene expression signatures encompassing dozens to hundreds of genes have been associated with many important parameters of cancer, but mechanisms of their control are largely unknown. Here we present a method based on genetic linkage that can prospectively identify functional regulators driving large-scale transcriptional signatures in cancer. Using this method we show that the wound response signature, a poor-prognosis expression pattern of 512 genes in breast cancer, is induced by coordinate amplifications of MYC and CSN5 (also known as JAB1 or COPS5). This information enabled experimental recapitulation, functional assessment and mechanistic elucidation of the wound signature in breast epithelial cells.

Breast Neoplasms↗

PubMed2005

Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity.

Metastasis via the lymphatics is a major risk factor in squamous cell carcinoma of the oral cavity (OSCC). We sought to determine whether the presence of metastasis in the regional lymph node could be predicted by a gene expression signature of the primary tumor. A total of 18 OSCCs were characterized for gene expression by hybridizing RNA to Affymetrix U133A gene chips. Genes with differential expression were identified using a permutation technique and verified by quantitative RT-PCR and immunohistochemistry. A predictive rule was built using a support vector machine, and the accuracy of the rule was evaluated using crossvalidation on the original data set and prediction of an independent set of four patients. Metastatic primary tumors could be differentiated from nonmetastatic primary tumors by a signature gene set of 116 genes. This signature gene set correctly predicted the four independent patients as well as associating five lymph node metastases from the original patient set with the metastatic primary tumor group. We concluded that lymph node metastasis could be predicted by gene expression profiles of primary oral cavity squamous cell carcinomas. The presence of a gene expression signature for lymph node metastasis indicates that clinical testing to assess risk for lymph node metastasis should be possible.

Adult↗