Microarray-based ultra-high resolution discovery of genomic deletion mutations

BACKGROUND: Oligonucleotide microarray-based comparative genomic hybridization (CGH) offers an attractive possible route for the rapid and cost-effective genome-wide discovery of deletion mutations. CGH typically involves comparison of the hybridization intensities of genomic DNA samples with microarray chip representations of entire genomes, and has widespread potential application in experimental research and medical diagnostics. However, the power to detect small deletions is low. RESULTS: Here we use a graduated series of Arabidopsis thaliana genomic deletion mutations (of sizes ranging from 4 bp to ~5 kb) to optimize CGH-based genomic deletion detection. We show that the power to detect smaller deletions (4, 28 and 104 bp) depends upon oligonucleotide density (essentially the number of genome-representative oligonucleotides on the microarray chip), and determine the oligonucleotide spacings necessary to guarantee detection of deletions of specified size. CONCLUSIONS: Our findings will enhance a wide range of research and clinical applications, and in particular will aid in the discovery of genomic deletions in the absence of a priori knowledge of their existence

An Alternative String Landscape Cosmology: Eliminating Bizarreness

In what has become a standard eternal inflation picture of the string landscape there are many problematic consequences and a difficulty defining probabilities for the occurrence of each type of universe. One feature in particular that might be philosophically disconcerting is the infinite cloning of each individual and each civilization in infinite numbers of separated regions of the multiverse. Even if this is not ruled out due to causal separation one should ask whether the infinite cloning is a universal prediction of string landscape models or whether there are scenarios in which it is avoided. If a viable alternative cosmology can be constructed one might search for predictions that might allow one to discriminate experimentally between the models. We present one such scenario although, in doing so, we are forced to give up several popular presuppositions including the absence of a preferred frame and the homogeneity of matter in the universe. The model also has several ancillary advantages. We also consider the future lifetime of the current universe before becoming a light trapping region.Comment: 13 pages, 1 figure, minor clarifications in version

The relationship of Mirizzi syndrome and cholecystoenteric fistula: validation of a modified classification

Background Mirizzi syndrome and cholecystoenteric fistula with or without gallstone ileus are late complications of gallstone disease. We previously suggested that the natural history of Mirizzi syndrome may not end with just a cholecystobiliary fistula and that the continuous inflammation in the triangle of Calot area may result in a complex fistula involving the biliary tract and the adjacent viscera. The purpose of this study was to establish the relationship of Mirizzi syndrome with cholecystoenteric fistulas. Methods We retrospectively reviewed the records of all patients older than aged 18 years submitted to emergency or elective cholecystectomy from 1995 to 2006. Of 5,673 cholecystectomies performed during that period, we found 327 (5.7%) patients with Mirizzi syndrome and 105 (1.8%) patients with cholecystoenteric fistula. Ninety-four (89.5%) patients with cholecystoenteric fistula also had an associated Mirizzi syndrome. Results Cholecystoenteric fistula was associated with Mirizzi syndrome (p < 0.0001), increased age was associated with Mirizzi syndrome and cholecystoenteric fistula (p < 0.0001), and female gender was associated with Mirizzi syndrome (p < 0.0001). Conclusion When during surgery for gallstone disease a cholecystoenteric fistula is encountered, the possibility of an associated Mirizzi syndrome must be considered. The findings of this study confirm the association of Mirizzi syndrome with cholecystoenteric fistula

ReseqChip: Automated integration of multiple local context probe data from the MitoChip array in mitochondrial DNA sequence assembly

<p>Abstract</p> <p>Background</p> <p>The Affymetrix MitoChip v2.0 is an oligonucleotide tiling array for the resequencing of the human mitochondrial (mt) genome. For each of 16,569 nucleotide positions of the mt genome it holds two sets of four 25-mer probes each that match the heavy and the light strand of a reference mt genome and vary only at their central position to interrogate all four possible alleles. In addition, the MitoChip v2.0 carries alternative local context probes to account for known mtDNA variants. These probes have been neglected in most studies due to the lack of software for their automated analysis.</p> <p>Results</p> <p>We provide ReseqChip, a free software that automates the process of resequencing mtDNA using multiple local context probes on the MitoChip v2.0. ReseqChip significantly improves base call rate and sequence accuracy. ReseqChip is available at <url>http://code.open-bio.org/svnweb/index.cgi/bioperl/browse/bioperl-live/trunk/Bio/Microarray/Tools/</url>.</p> <p>Conclusions</p> <p>ReseqChip allows for the automated consolidation of base calls from alternative local mt genome context probes. It thereby improves the accuracy of resequencing, while reducing the number of non-called bases.</p

Network Archaeology: Uncovering Ancient Networks from Present-day Interactions

Often questions arise about old or extinct networks. What proteins interacted in a long-extinct ancestor species of yeast? Who were the central players in the Last.fm social network 3 years ago? Our ability to answer such questions has been limited by the unavailability of past versions of networks. To overcome these limitations, we propose several algorithms for reconstructing a network's history of growth given only the network as it exists today and a generative model by which the network is believed to have evolved. Our likelihood-based method finds a probable previous state of the network by reversing the forward growth model. This approach retains node identities so that the history of individual nodes can be tracked. We apply these algorithms to uncover older, non-extant biological and social networks believed to have grown via several models, including duplication-mutation with complementarity, forest fire, and preferential attachment. Through experiments on both synthetic and real-world data, we find that our algorithms can estimate node arrival times, identify anchor nodes from which new nodes copy links, and can reveal significant features of networks that have long since disappeared.Comment: 16 pages, 10 figure

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Observational constraints on conformal time symmetry, missing matter and double dark energy

The current concordance model of cosmology is dominated by two mysterious ingredients: dark matter and dark energy. In this paper, we explore the possibility that, in fact, there exist two dark-energy components: the cosmological constant $\Lambda$, with equation-of-state parameter $w_\Lambda=-1$, and a `missing matter' component $X$ with $w_X=-2/3$, which we introduce here to allow the evolution of the universal scale factor as a function of conformal time to exhibit a symmetry that relates the big bang to the future conformal singularity, such as in Penrose's conformal cyclic cosmology. Using recent cosmological observations, we constrain the present-day energy density of missing matter to be $\Omega_{X,0}=-0.034 \pm 0.075$. This is consistent with the standard $\Lambda$CDM model, but constraints on the energy densities of all the components are considerably broadened by the introduction of missing matter; significant relative probability exists even for $\Omega_{X,0} \sim 0.1$, and so the presence of a missing matter component cannot be ruled out. As a result, a Bayesian model selection analysis only slightly disfavours its introduction by 1.1 log-units of evidence. Foregoing our symmetry requirement on the conformal time evolution of the universe, we extend our analysis by allowing $w_X$ to be a free parameter. For this more generic `double dark energy' model, we find $w_X = -1.01 \pm 0.16$ and $\Omega_{X,0} = -0.10 \pm 0.56$, which is again consistent with the standard $\Lambda$CDM model, although once more the posterior distributions are sufficiently broad that the existence of a second dark-energy component cannot be ruled out. The model including the second dark energy component also has an equivalent Bayesian evidence to $\Lambda$CDM, within the estimation error, and is indistinguishable according to the Jeffreys guideline.Comment: Revised version emphasising a different version of the underlying symmetry, as published in JCA

Granulomatous hepatitis, choroiditis and aortoduodenal fistula complicating intravesical Bacillus Calmette-Guérin therapy: Case report

<p>Abstract</p> <p>Background</p> <p>Intravesical instillation of Bacillus Calmette-Guérin (BCG) is the treatment of choice for superficial bladder carcinoma. Complications of BCG therapy include local infections and disseminated BCG infection with multiple endorgan complications.</p> <p>Case Presentation</p> <p>We report a case of disseminated, post-treatment BCG infection that initially presented with granulomatous hepatitis and choroiditis. After successful anti-mycobacterial therapy and resolution of the hepatic and ocular abnormalities, the patient developed an acute upper gastrointestinal hemorrhage from an aortoduodenal fistula that required emergency surgery. The resection specimen revealed multifocal, non-caseating granulomas, indicating mycobacterial involvement.</p> <p>Conclusions</p> <p>This case highlights the varied end organ complications of disseminated BCG infection, and the need for vigilance even in immuno-competent patients with a history of intravesical BCG treatment.</p