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Results for “reduced representation sequencing”

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PubMed2005

Genetic contributions to human gyrification: sulcal morphometry in Williams syndrome.

Although gyral and sulcal patterns are highly heritable, and emerge in a tightly controlled sequence during development, very little is known about specific genetic contributions to abnormal gyrification or the resulting functional consequences. Williams syndrome (WS), a genetic disorder caused by hemizygous microdeletion on chromosome 7q11.23 and characterized by abnormal brain structure and striking cognitive (impairment in visuospatial construction) and behavioral (hypersocial/anxious) phenotypes, offers a unique opportunity to study these issues. We performed a detailed analysis of sulcal depth based on geometric cortical surface representations constructed from high-resolution magnetic resonance imaging scans acquired from participants with WS and from healthy controls who were matched for age, sex, and intelligence quotient, and compared between-group differences with those obtained from a voxel-based morphometry analysis. We found bilateral reductions in sulcal depth in the intraparietal/occipitoparietal sulcus (PS) in the brains of participants with WS, as well as in the collateral sulcus and the orbitofrontal region in the left hemisphere. The left-hemisphere PS in the WS group averaged 8.5 mm shallower than in controls. Sulcal depth findings in the PS corresponded closely to measures of reduced gray matter volume in the same area, providing evidence that the gray matter volume loss and abnormal sulcal geometry may be related. In the context of previous functional neuroimaging findings demonstrating functional alterations in the same cortical regions, our results further define the neural endophenotype underlying visuoconstructive deficits in WS, set the stage for defining the effects of specific genes, and offer insight into genetic mechanisms of cortical gyrification.

Adolescent↗

PubMed1994

Predicting location and structure of beta-sheet regions using stochastic tree grammars.

We describe and demonstrate the effectiveness of a method of predicting protein secondary structures, beta-sheet regions in particular, using a class of stochastic tree grammars as representational language for their amino acid sequence patterns. The family of stochastic tree grammars we use, the Stochastic Ranked Node Rewriting Grammars (SRNRG), is one of the rare families of stochastic grammars that are expressive enough to capture the kind of long-distance dependencies exhibited by the sequences of beta-sheet regions, and at the same time enjoy relatively efficient processing. We applied our method on real data obtained from the HSSP database and the results obtained are encouraging: Using an SRNRG trained by data of a particular protein, our method was actually able to predict the location and structure of beta-sheet regions in a number of different proteins, whose sequences are less than 25 per cent homologous to the training sequences. The learning algorithm we use is an extension of the 'Inside-Outside' algorithm for stochastic context free grammars, but with a number of significant modifications. First, we restricted the grammars used to be members of the 'linear' subclass of SRNRG, and devised simpler and faster algorithms for this subclass. Secondly, we reduced the alphabet size (i.e. the number of amino acids) by clustering them using their physicochemical properties, gradually through the iterations of the learning algorithm. Finally, we parallelized our parsing algorithm to run on a highly parallel computer, a 32-processor CM-5, and were able to obtain a nearly linear speed-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗

PubMed1991

Metastable motion anisotropy.

The phenomenon of apparent motion can arise when two spatially separated visual tokens are presented in temporal sequence. If tokens at opposite corners of a hypothetical square are presented simultaneously followed by simultaneous presentation of tokens at the remaining two corners, an apparent motion percept may occur along either the vertical or horizontal axis. The display is perceptually metastable since most observers will perceive motion along only one axis at a time. The metastable display, however, produces anisotropic results, in that with central fixation, vertical motion is seen more frequently than horizontal motion. The ratio of the vertical to horizontal length of the sides of a rectangle needed to achieve equal frequencies of motion judgments along the respective axes falls in the range of 1.18-1.92 for different observers in our experiments. It appears that signal transmission across the vertical midline is a major determinant of the vertical bias, since the anisotropic effects disappear when the fixation point is sufficiently offset along the horizontal meridian so as to cause a fully homonymous representation of all of the metastable tokens. One of the factors may be signal degradation or delay in callosal transmission which could reduce the strength of the motion signal along the horizontal axis. In addition, there appears to be a strip along the vertical midline with a width of 30-50 min arc within which reduced levels of anisotropy are found. The possibility that this strip is a consequence of a zone of naso-temporal overlap in the projection of the retina to the brain along the vertical meridian will be discussed.

Anisotropy↗

PubMed2026

Ionizing radiation induces bidirectional transcriptomic reprogramming and dynamic NOS2/TREM2 regulation in triple-negative breast cancer cells.

PURPOSE: To characterize irradiation-associated transcriptomic changes in murine triple-negative breast cancer cells and examine dose- and time-response patterns of selected radiation-responsive candidates. MATERIALS AND METHODS: RNA sequencing (RNA-seq) was performed in 4T1 cells collected 24 h after 4 Gy irradiation, followed by Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and gene set enrichment analyses. Representative RNA-seq-derived genes were examined by reverse transcription quantitative PCR (RT-qPCR), and selected immune- and inflammation-related transcripts were further assessed across additional radiation doses and post-irradiation time points. Inducible nitric oxide synthase (NOS2) and triggering receptor expressed on myeloid cells 2 (TREM2) protein abundance was assessed by Western blotting, and nitrite accumulation in culture supernatants was measured using a Griess reagent-based assay as an indirect readout of nitric oxide production. RESULTS: RNA sequencing identified 757 differentially expressed genes, including 285 upregulated and 472 downregulated genes. Irradiation was associated with enrichment of inflammatory, interferon-related, immune-system, and cell-adhesion transcriptional signatures, whereas downregulated genes were enriched in cell-cycle-, chromosome-cohesion-, DNA-damage-response-, DNA-repair-, and SUMOylation-related pathways. Selected immune- and inflammation-related transcripts showed distinct temporal patterns. Nos2 mRNA increased across the examined 0-6 Gy dose range and at later post-irradiation time points, whereas NOS2 protein showed different kinetics, with an early peak after 4 Gy irradiation and no clear further increase above 6 Gy. Nitrite accumulation increased after irradiation. Trem2 showed the largest fold increase among strongly upregulated transcripts identified by RNA-seq, but RT-qPCR detected a significant increase only at 24 h, and TREM2 protein abundance remained unchanged across the examined doses and time points. CONCLUSIONS: Ionizing radiation was associated with broad bidirectional transcriptional remodeling in 4T1 cells, involving immune-, inflammatory-, and interferon-related signatures together with reduced representation of cell-cycle- and DNA-repair-related gene sets. The discordant mRNA and protein patterns of NOS2 and TREM2 indicate that transcript-level responses do not necessarily translate into corresponding protein-level changes. These findings define irradiation-associated molecular responses requiring further functional investigation.

Triple-negative breast cancer↗

PubMed2001

Quantitative analysis of mRNA amplification by in vitro transcription.

Effective transcript profiling in animal systems requires isolation of homogenous tissue or cells followed by faithful mRNA amplification. Linear amplification based on cDNA synthesis and in vitro transcription is reported to maintain representation of mRNA levels, however, quantitative data demonstrating this as well as a description of inherent limitations is lacking. We show that published protocols produce a template-independent product in addition to amplifying real target mRNA thus reducing the specific activity of the final product. We describe a modified amplification protocol that minimizes the generation of template-independent product and can therefore generate the desired microgram quantities of message-derived material from 100 ng of total RNA. Application of a second, nested round of cDNA synthesis and in vitro transcription reduces the required starting material to 2 ng of total RNA. Quantitative analysis of these products on Caenorhabditis elegans Affymetrix GeneChips shows that this amplification does not reduce overall sensitivity and has only minor effects on fidelity.

Animals↗

PubMed2006

Reduced heterozygosity depresses sperm quality in wild rabbits, Oryctolagus cuniculus.

When close relatives are forced to reproduce, the resulting offspring inherit above average homozygosity and reduced fitness. Biologists now recognize inbreeding depression in the wild, a phenomenon that will probably increase as natural populations become depleted and fragmented. Inbreeding depression is most commonly expressed as compromised fertility and embryogenesis, but actual mechanisms remain poorly understood, especially for wild populations. Here, we examine how reduced heterozygosity influences spermatozoal and gonadal traits in wild rabbits (Oryctolagus cuniculus) sampled across the United Kingdom. By using a suite of 29 microsatellite markers (analyzed to confirm representation of individual heterozygosity across our sample), we found a significant negative relationship between heterozygosity and the production of normal sperm; the relationship was significant both between (n = 12) and within (n = 91 [total males], 42 [island], 49 [mainland]) populations. Reduced heterozygosity was also associated with decreased testis size across males (n = 112), but no relationship was seen at the population level, suggesting environmental confounds. Our results show, for a wild mammal, that inbreeding is associated with decreased sperm quality, confirming suggestions of links between inbreeding and elevated sperm abnormalities in rare felids . These findings could explain why inbreeding depression so frequently arises via compromised fertility and embryogenesis .

Animals↗

PubMed1994

Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme.

A new hierarchical method for the simulation of the protein folding process and the de novo prediction of protein three-dimensional structure is proposed. The reduced representation of the protein alpha-carbon backbone employs lattice discretizations of increasing geometrical resolution and a single ball representation of side chain rotamers. In particular, coarser and finer lattice backbone descriptions are used. The coarser (finer) lattice represents C alpha traces of native proteins with an accuracy of 1.0 (0.7) A rms. Folding is simulated by means of very fast Monte Carlo lattice dynamics. The potential of mean force, predominantly of statistical origin, contains several novel terms that facilitate the cooperative assembly of secondary structure elements and the cooperative packing of the side chains. Particular contributions to the interaction scheme are discussed in detail. In the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulation of protein folding. II. Application to protein A, ROP, and crambin. Proteins 18:353-366, 1994), the method is applied to three small globular proteins.

Amino Acid Sequence↗

PubMed1997

Recovery of protein structure from contact maps.

BACKGROUND: Prediction of a protein's structure from its amino acid sequence is a key issue in molecular biology. While dynamics, performed in the space of two-dimensional contact maps, eases the necessary conformational search, it may also lead to maps that do not correspond to any real three-dimensional structure. To remedy this, an efficient procedure is needed to reconstruct three-dimensional conformations from their contact maps. RESULTS: We present an efficient algorithm to recover the three-dimensional structure of a protein from its contact map representation. We show that when a physically realizable map is used as target, our method generates a structure whose contact map is essentially similar to the target. furthermore, the reconstructed and original structures are similar up to the resolution of the contact map representation. Next, we use nonphysical target maps, obtained by corrupting a physical one; in this case, our method essentially recovers the underlying physical map and structure. Hence, our algorithm will help to fold proteins, using dynamics in the space of contact maps. Finally, we investigate the manner in which the quality of the recovered structure degrades when the number of contacts is reduced. CONCLUSIONS: The procedure is capable of assigning quickly and reliably a three-dimensional structure to a given contact map. It is well suited for use in parallel with dynamics in contact map space to project a contact map onto its closest physically allowed structural counterpart.

Algorithms↗

PubMed2003

Corrected small-sample estimation of the Bayes error.

MOTIVATION: A major problem of pattern classification is estimation of the Bayes error when only small samples are available. One way to estimate the Bayes error is to design a classifier based on some classification rule applied to sample data, estimate the error of the designed classifier, and then use this estimate as an estimate of the Bayes error. Relative to the Bayes error, the expected error of the designed classifier is biased high, and this bias can be severe with small samples. RESULTS: This paper provides a correction for the bias by subtracting a term derived from the representation of the estimation error. It does so for Boolean classifiers, these being defined on binary features. Although the general theory applies to any Boolean classifier, a model is introduced to reduce the number of parameters. A key point is that the expected correction is conservative. Properties of the corrected estimate are studied via simulation. The correction applies to binary predictors because they are mathematically identical to Boolean classifiers. In this context the correction is adapted to the coefficient of determination, which has been used to measure nonlinear multivariate relations between genes and design genetic regulatory networks. An application using gene-expression data from a microarray experiment is provided on the website http://gspsnap.tamu.edu/smallsample/ (user:'smallsample', password:'smallsample)').

Algorithms↗

PubMed2000

Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau.

The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIepsilon), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIepsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIepsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.

Alleles↗

PubMed2006

Validation of bone segmentation and improved 3-D registration using contour coherency in CT data.

A method is presented to validate the segmentation of computed tomography (CT) image sequences, and improve the accuracy and efficiency of the subsequent registration of the three-dimensional surfaces that are reconstructed from the segmented slices. The method compares the shapes of contours extracted from neighborhoods of slices in CT stacks of tibias. The bone is first segmented by an automatic segmentation technique, and the bone contour for each slice is parameterized as a one-dimensional function of normalized arc length versus inscribed angle. These functions are represented as vectors within a K-dimensional space comprising the first K amplitude coefficients of their Fourier Descriptors. The similarity or coherency of neighboring contours is measured by comparing statistical properties of their vector representations within this space. Experimentation has demonstrated this technique to be very effective at identifying low-coherency segmentations. Compared with experienced human operators, in a set of 23 CT stacks (1,633 slices), the method correctly detected 87.5% and 80% of the low-coherency and 97.7% and 95.5% of the high coherency segmentations, respectively from two different automatic segmentation techniques. Removal of the automatically detected low-coherency segmentations also significantly improved the accuracy and time efficiency of the registration of 3-D bone surface models. The registration error was reduced by over 500% (i.e., a factor of 5) and 280%, and the computational performance was improved by 540% and 791% for the two respective segmentation methods.

Algorithms↗

PubMed2003

RNA structure comparison, motif search and discovery using a reduced representation of RNA conformational space.

Given the wealth of new RNA structures and the growing list of RNA functions in biology, it is of great interest to understand the repertoire of RNA folding motifs. The ability to identify new and known motifs within novel RNA structures, to compare tertiary structures with one another and to quantify the characteristics of a given RNA motif are major goals in the field of RNA research; however, there are few systematic ways to address these issues. Using a novel approach for visualizing and mathematically describing macromolecular structures, we have developed a means to quantitatively describe RNA molecules in order to rapidly analyze, compare and explore their features. This approach builds on the alternative eta,theta convention for describing RNA torsion angles and is executed using a new program called PRIMOS. Applying this methodology, we have successfully identified major regions of conformational change in the 50S and 30S ribosomal subunits, we have developed a means to search the database of RNA structures for the prevalence of known motifs and we have classified and identified new motifs. These applications illustrate the powerful capabilities of our new RNA structural convention, and they suggest future adaptations with important implications for bioinformatics and structural genomics.

Algorithms↗

PubMed2004

[Histopathologic validation of the tissue-microarray technology of urothelial cancer. Our experience].

INTRODUCTION: The array technology offers: a big advance to clinic and basic investigator, it provides a variety of technics (immunohistochemistry, FISH, proteomics) to understand the molecular mechanisms of cancer. It offers scale economy in reagents versus the conventional methods. Array most be ratified because the sample is so reduced. MATERIAL AND METHODS: 52 consecutive cases have been chosen from paraffin blocks of bladder and ureteral cancer which are 5-7 years old, a tissue array has been made; disks have been arranged in lines and columns, in an aleatory way, in order to guide it's reading. It has been evaluated by a pathologist with any relation to specimen selection. RESULTS: 87 sheets ha been obtained. Number 1 has been dyed with HE. Has been discrepancy in 27% of sample's stage. Has not been a discrepancy in histopathologic diagnostic. There is no sample's representation in 11 points (17%). DISCUSSION: Our results offer good results in sample's validation. The sample's antigenicity of tissue is conserved. Array sample's represent a 97%, similarly to all unit of conventional sections of the specimen.

Humans↗

PubMedDate not supplied

The latent process decomposition of cDNA microarray data sets.

We present a new computational technique (a software implementation, data sets, and supplementary information are available at http://www.enm.bris.ac.uk/lpd/) which enables the probabilistic analysis of cDNA microarray data and we demonstrate its effectiveness in identifying features of biomedical importance. A hierarchical Bayesian model, called Latent Process Decomposition (LPD), is introduced in which each sample in the data set is represented as a combinatorial mixture over a finite set of latent processes, which are expected to correspond to biological processes. Parameters in the model are estimated using efficient variational methods. This type of probabilistic model is most appropriate for the interpretation of measurement data generated by cDNA microarray technology. For determining informative substructure in such data sets, the proposed model has several important advantages over the standard use of dendrograms. First, the ability to objectively assess the optimal number of sample clusters. Second, the ability to represent samples and gene expression levels using a common set of latent variables (dendrograms cluster samples and gene expression values separately which amounts to two distinct reduced space representations). Third, in constrast to standard cluster models, observations are not assigned to a single cluster and, thus, for example, gene expression levels are modeled via combinations of the latent processes identified by the algorithm. We show this new method compares favorably with alternative cluster analysis methods. To illustrate its potential, we apply the proposed technique to several microarray data sets for cancer. For these data sets it successfully decomposes the data into known subtypes and indicates possible further taxonomic subdivision in addition to highlighting, in a wholly unsupervised manner, the importance of certain genes which are known to be medically significant. To illustrate its wider applicability, we also illustrate its performance on a microarray data set for yeast.

Algorithms↗

PubMed2000

The Biological System of the Elements (BSE). Part II: a theoretical model for establishing the essentiality of chemical elements. The application of stoichiometric network analysis to the biological system of the elements

Stoichiometric Network Analysis (SNA), originally developed by the Canadian chemist Bruce L. Clarke during the 1970s, provides a most efficient means of reducing the background topology of complex interaction networks to some skeleton topology around which systems dynamics can be understood without jeopardising insight into complex dynamics by over- or miss-simplification. Since it focuses on the corresponding autocatalytic (AC) features of a feedback system as those which control overall behaviour to some extent, SNA deals with reaction kinetics in and beyond chemistry, e.g. with nuclear reactions. It is therefore quite straightforward to apply this manner of simplification, which in turn is supported by a number of mathematical theorems on systems behaviour and properties of AC cycles, to biological systems although their 'full' complexity may not even be assessed in the yet rare cases of complete genetic sequencing. Assuming there is a relationship between the kinds of metal or metalloid species and key biological/biochemical transformations to be promoted with their aid--this relationship being the subject of bio-inorganic chemistry--and that biochemistry is, in effect, about systems which can reproduce and thus behave autocatalytically, one can expect SNA to yield formally sound statements on basic features of biology and biochemistry too. If we sum up the facts and considerations concerning essentiality or possible essentiality in a biological system of elements (Markert, 1994), this means joining the triangular representation of BSE, including statements on (the degree of biological) evolution and aggregation levels, to SNA treatment of autocatalysis within hierarchical systems from metalloenzymes to entire biocoenoses. Arguments using preferred cluster sizes and aggregation tendencies from coordination chemistry are then employed to circumscribe possible functions within the BSE. They are also extended to metals hitherto not known to be essential, such as tellurium or scandium.

Journal Article↗

PubMed1997

An "augmented-reality" aid for plastic and reconstructive surgeons.

Starting from MR and CT images for a given patient, a new single image representation of all parameters has been generated by using false-color techniques in a standard UNIX and X-11 environment. A transformation linking together the MR, CT parameters and the RGB (red, green, blue) color components has been used. Moreover an unsupervised segmentation method based on a number of neural and fuzzy models may directly produce segmented image volumes. Each image of the various sequences has been interactively displayed by using a specifically designed application. The resulting images have been displayed on a stereo monitor allowing the three-dimensional rendering of visual data through LCD shuttered glasses. Moreover, a 3-D control system based on low frequency magnetic fields has been used, while a bandheld Polhemus stylus could be used as an electronic knife for dissecting the 3-D data set and for defining flaps and grafts. Bone or soft-tissue contour can be analyzed, and sections can be removed from the model to allow a view of the underlying structures. Flaps and grafts obtained utilizing the above-reported techniques can be fitted exactly, without repeated removal and recarving. Nuances of depth, tapering, and arc are carved directly into the bone, while chances of asymmetry are markedly diminished. In this way, moreover, anesthetic times are reduced by more efficient utilization of operative time, which usually offsets the increased cost of imaging.

Artificial Intelligence↗

PubMed2005

PPC: an algorithm for accurate estimation of SNP allele frequencies in small equimolar pools of DNA using data from high density microarrays.

Robust estimation of allele frequencies in pools of DNA has the potential to reduce genotyping costs and/or increase the number of individuals contributing to a study where hundreds of thousands of genetic markers need to be genotyped in very large populations sample sets, such as genome wide association studies. In order to make accurate allele frequency estimations from pooled samples a correction for unequal allele representation must be applied. We have developed the polynomial based probe specific correction (PPC) which is a novel correction algorithm for accurate estimation of allele frequencies in data from high-density microarrays. This algorithm was validated through comparison of allele frequencies from a set of 10 individually genotyped DNA's and frequencies estimated from pools of these 10 DNAs using GeneChip 10K Mapping Xba 131 arrays. Our results demonstrate that when using the PPC to correct for allelic biases the accuracy of the allele frequency estimates increases dramatically.

Algorithms↗

PubMed1992

Computing the geometry of a molecule in dihedral angle space using n.m.r.-derived constraints. A new algorithm based on optimal filtering.

We have developed a method based on optimal filtering to determine the three-dimensional structure of a protein from n.m.r.-derived constraints, using the dihedral angle internal representation of the molecule. It differs from currently proposed methods in that it directly produces estimates of errors on the parameters that are refined, hence providing an image of the minimum that has been found. A similar algorithm had already been proposed using cartesian co-ordinates as independent parameters, encoded in PROTEAN2. We found that using dihedral angles significantly reduces the computational burden of the technique, and provides better control over a priori informations that can be used, such as geometric restrictions for proline residues and informations from vicinal coupling constants. Performance of the method, encoded in FILMAN, is demonstrated by application to the folding of a ten-residue alanine polypeptide, to the geometric cyclization of an 11-residue peptide, as well as on the folding of a medium size protein, i.e. tendamistat. The validity of the error estimates on the dihedral angles produced by FILMAN is discussed.

Algorithms↗