A stitch in time: Efficient computation of genomic DNA melting bubbles

Background: It is of biological interest to make genome-wide predictions of the locations of DNA melting bubbles using statistical mechanics models. Computationally, this poses the challenge that a generic search through all combinations of bubble starts and ends is quadratic. Results: An efficient algorithm is described, which shows that the time complexity of the task is O(NlogN) rather than quadratic. The algorithm exploits that bubble lengths may be limited, but without a prior assumption of a maximal bubble length. No approximations, such as windowing, have been introduced to reduce the time complexity. More than just finding the bubbles, the algorithm produces a stitch profile, which is a probabilistic graphical model of bubbles and helical regions. The algorithm applies a probability peak finding method based on a hierarchical analysis of the energy barriers in the Poland-Scheraga model. Conclusions: Exact and fast computation of genomic stitch profiles is thus feasible. Sequences of several megabases have been computed, only limited by computer memory. Possible applications are the genome-wide comparisons of bubbles with promotors, TSS, viral integration sites, and other melting-related regions.Comment: 16 pages, 10 figure

CHARGE syndrome

CHARGE syndrome was initially defined as a non-random association of anomalies (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness). In 1998, an expert group defined the major (the classical 4C's: Choanal atresia, Coloboma, Characteristic ears and Cranial nerve anomalies) and minor criteria of CHARGE syndrome. Individuals with all four major characteristics or three major and three minor characteristics are highly likely to have CHARGE syndrome. However, there have been individuals genetically identified with CHARGE syndrome without the classical choanal atresia and coloboma. The reported incidence of CHARGE syndrome ranges from 0.1–1.2/10,000 and depends on professional recognition. Coloboma mainly affects the retina. Major and minor congenital heart defects (the commonest cyanotic heart defect is tetralogy of Fallot) occur in 75–80% of patients. Choanal atresia may be membranous or bony; bilateral or unilateral. Mental retardation is variable with intelligence quotients (IQ) ranging from normal to profound retardation. Under-development of the external genitalia is a common finding in males but it is less apparent in females. Ear abnormalities include a classical finding of unusually shaped ears and hearing loss (conductive and/or nerve deafness that ranges from mild to severe deafness). Multiple cranial nerve dysfunctions are common. A behavioral phenotype for CHARGE syndrome is emerging. Mutations in the CHD7 gene (member of the chromodomain helicase DNA protein family) are detected in over 75% of patients with CHARGE syndrome. Children with CHARGE syndrome require intensive medical management as well as numerous surgical interventions. They also need multidisciplinary follow up. Some of the hidden issues of CHARGE syndrome are often forgotten, one being the feeding adaptation of these children, which needs an early aggressive approach from a feeding team. As the child develops, challenging behaviors become more common and require adaptation of educational and therapeutic services, including behavioral and pharmacological interventions

CHARGE syndrome: Genetic aspects and dental challenges, a review and case presentation

CHARGE syndrome (CS) is a rare genetic condition (OMIM #214800). The condition has a variable phenotypic expression. Historically, the diagnosis of CHARGE syndrome was based on the presence of specific clinical criteria. The genetic aetiology of CS has since been elucidated and attributed to pathogenic variation in the CHD7 gene (OMIM 608892) at chromosome locus 8q12

Suitability of 210Pbex, 137Cs and 239+240Pu as soil erosion tracers in western Kenya

Land degradation resulting from soil erosion is a global concern, with the greatest risk in developing countries where food and land resources can be limited. The use of fallout radionuclides (FRNs) is a proven method for determining short and medium-term rates of soil erosion, to help improve our understanding of soil erosion processes. There has been limited use of these methods in tropical Africa due to the analytical challenges associated with 137Cs, where inventories are an order of magnitude lower than in the Europe. This research aimed to demonstrate the usability of 239+240Pu as a soil erosion tracer in western Kenya compared to conventional isotopes 210Pbex and 137Cs through the determination of FRN depth profiles at reference sites. Across six reference sites 239+240Pu showed the greatest potential, with the lowest coefficient of variation and the greatest peak-to-detection limit ratio of 640 compared to 5 and 1 for 210Pbex and 137Cs respectively. Additionally, 239+240Pu was the only radionuclide to meet the 'allowable error' threshold, demonstrating applicability to large scale studies in Western Kenya where the selection of suitable reference sites presents a significant challenge. The depth profile of 239+240Pu followed a polynomial function, with the maximum areal activities found between depths 3 and 12 cm, where thereafter areal activities decreased exponentially. As a result, 239+240Pu is presented as a robust tracer to evaluate soil erosion patterns and amounts in western Kenya, providing a powerful tool to inform and validate mitigation strategies with improved understanding of land degradation

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Contrast and Phase Combination in Binocular Vision

BACKGROUND: How the visual system combines information from the two eyes to form a unitary binocular representation of the external world is a fundamental question in vision science that has been the focus of many psychophysical and physiological investigations. Ding & Sperling (2006) measured perceived phase of the cyclopean image, and developed a binocular combination model in which each eye exerts gain control on the other eye's signal and over the other eye's gain control. Critically, the relative phase of the monocular sine-waves plays a central role. METHODOLOGY/PRINCIPAL FINDINGS: We used the Ding-Sperling paradigm but measured both the perceived contrast and phase of cyclopean images in three hundred and eighty combinations of base contrast, interocular contrast ratio, eye origin of the probe, and interocular phase difference. We found that the perceived contrast of the cyclopean image was independent of the relative phase of the two monocular gratings, although the perceived phase depended on the relative phase and contrast ratio of the monocular images. We developed a new multi-pathway contrast-gain control model (MCM) that elaborates the Ding-Sperling binocular combination model in two ways: (1) phase and contrast of the cyclopean images are computed in separate pathways, although with shared cross-eye contrast-gain control; and (2) phase-independent local energy from the two monocular images are used in binocular contrast combination. With three free parameters, the model yielded an excellent account of data from all the experimental conditions. CONCLUSIONS/SIGNIFICANCE: Binocular phase combination depends on the relative phase and contrast ratio of the monocular images but binocular contrast combination is phase-invariant. Our findings suggest the involvement of at least two separate pathways in binocular combination

Accelerated expansion from ghost-free bigravity: a statistical analysis with improved generality

We study the background cosmology of the ghost-free, bimetric theory of gravity. We perform an extensive statistical analysis of the model using both frequentist and Bayesian frameworks and employ the constraints on the expansion history of the Universe from the observations of supernovae, the cosmic microwave background and the large scale structure to estimate the model's parameters and test the goodness of the fits. We explore the parameter space of the model with nested sampling to find the best-fit chi-square, obtain the Bayesian evidence, and compute the marginalized posteriors and mean likelihoods. We mainly focus on a class of sub-models with no explicit cosmological constant (or vacuum energy) term to assess the ability of the theory to dynamically cause a late-time accelerated expansion. The model behaves as standard gravity without a cosmological constant at early times, with an emergent extra contribution to the energy density that converges to a cosmological constant in the far future. The model can in most cases yield very good fits and is in perfect agreement with the data. This is because many points in the parameter space of the model exist that give rise to time-evolution equations that are effectively very similar to those of the $\Lambda$CDM. This similarity makes the model compatible with observations as in the $\Lambda$CDM case, at least at the background level. Even though our results indicate a slightly better fit for the $\Lambda$CDM concordance model in terms of the $p$-value and evidence, none of the models is statistically preferred to the other. However, the parameters of the bigravity model are in general degenerate. A similar but perturbative analysis of the model as well as more data will be required to break the degeneracies and constrain the parameters, in case the model will still be viable compared to the $\Lambda$CDM.Comment: 42 pages, 9 figures; typos corrected in equations (2.12), (2.13), (3.7), (3.8) and (3.9); more discussions added (footnotes 5, 8, 10 and 13) and abstract, sections 4.2, 4.3 and 5 (conclusions) modified in response to referee's comments; references added; acknowledgements modified; all results completely unchanged; matches version accepted for publication in JHE

Ancient micrometeorites suggestive of an oxygen-rich Archaean upper atmosphere

It is widely accepted that Earth’s early atmosphere contained less than 0.001 per cent of the present-day atmospheric oxygen (O2) level, until the Great Oxidation Event resulted in a major rise in O2 concentration about 2.4 billion years ago1. There are multiple lines of evidence for low O2 concentrations on early Earth, but all previous observations relate to the composition of the lower atmosphere2 in the Archaean era; to date no method has been developed to sample the Archaean upper atmosphere. We have extracted fossil micrometeorites from limestone sedimentary rock that had accumulated slowly 2.7 billion years ago before being preserved in Australia’s Pilbara region. We propose that these micrometeorites formed when sand-sized particles entered Earth’s atmosphere and melted at altitudes of about 75 to 90 kilometres (given an atmospheric density similar to that of today3). Here we show that the FeNi metal in the resulting cosmic spherules was oxidized while molten, and quench-crystallized to form spheres of interlocking dendritic crystals primarily of magnetite (Fe3O4), with wüstite (FeO)+metal preserved in a few particles. Our model of atmospheric micrometeorite oxidation suggests that Archaean upper-atmosphere oxygen concentrations may have been close to those of the present-day Earth, and that the ratio of oxygen to carbon monoxide was sufficiently high to prevent noticeable inhibition of oxidation by carbon monoxide. The anomalous sulfur isotope (Δ33S) signature of pyrite (FeS2) in seafloor sediments from this period, which requires an anoxic surface environment4, implies that there may have been minimal mixing between the upper and lower atmosphere during the Archaean

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans