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PubMed2005

Multi-way clustering of microarray data using probabilistic sparse matrix factorization.

MOTIVATION: We address the problem of multi-way clustering of microarray data using a generative model. Our algorithm, probabilistic sparse matrix factorization (PSMF), is a probabilistic extension of a previous hard-decision algorithm for this problem. PSMF allows for varying levels of sensor noise in the data, uncertainty in the hidden prototypes used to explain the data and uncertainty as to the prototypes selected to explain each data vector. RESULTS: We present experimental results demonstrating that our method can better recover functionally-relevant clusterings in mRNA expression data than standard clustering techniques, including hierarchical agglomerative clustering, and we show that by computing probabilities instead of point estimates, our method avoids converging to poor solutions.

Algorithms↗
PubMed1985

Influence of the carcinogen 4-aminobiphenyl on DNA conformation.

The conformation of the deoxydinucleoside monophosphate dCpdG modified by the carcinogen 4-aminobiphenyl has been elucidated by minimized semi-empirical potential energy calculations. The most important conformers relevant to A or B and Z helices are shown, and the structures of carcinogen-modified polymers, obtained from computer-generated models that incorporate the dimer conformations, are presented. Forms with carcinogen-base stacking and with base-base stacking are found, for both A-B type helices and Z-type helices. In random sequence DNA, the most favored state places the carcinogen at the A or B helix exterior, in the large groove, where it causes no distortion. In this position it might escape repair till a round of replication. At the replication fork, where the DNA is unwound, a low energy carcinogen-base stacked state, easily achieved by rotation primarily about the C5' - O5' bond, could occur. A mutagenic outcome resulting from this conformation might be envisioned.

Aminobiphenyl Compounds↗
PubMed1981

Experimental population genetics of meiotic drive systems. III. Neutralization of sex-ratio distortion in Drosophila through sex-chromosome aneuploidy.

Laboratory populations of Drosophila melanogaster were challenged by pseudo-Y drive, which mimics true Y-chromosome meiotic drive through the incorporation of Segregation Distorter (SD) in a T(Y;2) complex. This causes extreme sex-ratio distortion and can ultimately lead to population extinction. Populations normally respond by the gradual accumulation of drive suppressors, and this reduction in strength of distortion allows the sex ratio to move rapidly able to neutralize the effects of sex-ration distortion by the accumulation of sex-chromosome aneuploids (XXy, XYY). THis apparently occurs because XX-bearing eggs, produced in relatively high numbers ( approximately 4%) by XXY genotypes, become the main population source of females under strong Y-chromosome drive. Computer simulation for a discrete generation model incorporating random mating with differences in fitness and segregation permits several predictions that can be compared to the data. First, sex-chromosome aneuploids should rapidly attain equilibrium, while stabilizing the population at approximately 60% males. This sex ratio should be roughly independent of the strength of the meiotic drive. Moreover, conditions favoring the accumulation of drive suppressors (e.g., weak distortion, slow population extinction) are insufficient for maintaining aneuploidy, while conditions favoring aneuploidy (e.g., strong distortion, low production of females) lead to population extinction before drive suppressors can accumulate. Thus, the different mechanisms for neutralizing sex-ratio distortion are complementary. In addition, Y drive and sex-chromosome aneuploidy are potentially co-adaptive, since under some conditions neither will survive alone. Finally, these results suggest the possibility that genetic variants promoting sex-chromosome nondisjunction may have a selective advantage in natural populations faced with sex-ratio distortion.

Aneuploidy↗
PubMed2004

A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester.

BACKGROUND: Misoprostol is an effective agent for pre-operative cervical priming before surgical termination of pregnancy in the first trimester. Previous studies have shown that both oral and vaginal routes are equally effective for such a purpose. This study aimed to compare a new route of sublingual administration to the vaginal route of administration for pre-operative cervical priming in first trimester surgical abortion. METHODS: Eighty women with gestational age <12 weeks were randomized by a computer-generated model to receive 400 micro g of misoprostol either sublingually or vaginally 3 h prior to vacuum aspiration. The primary outcome measure was the degree of cervical dilatation, and secondary outcomes included the force required to dilate the cervix from 3 to 8 mm, intra-operative blood loss and incidence of pre-operative side-effects. RESULTS: There was no significant difference in the baseline cervical dilatation (sublingual: 7.6 +/- 1.3 mm; vaginal: 7.7 +/- 0.73 mm), cumulative force required to dilate the cervix from 3 to 8 mm (sublingual: 9.0 +/- 9.8 N; vaginal: 6.6 +/- 5.4 N) and total blood loss (sublingual: 52.1 +/- 20.2 ml; vaginal: 48.3 +/- 12.3 ml). Pre-operative side-effects were also similar. CONCLUSIONS: Both sublingual and vaginal misoprostol are effective in cervical priming before surgical termination of pregnancy in the first trimester. Sublingual misoprostol has the advantage of being more convenient to administer and may be more suitable for day surgery.

Abortifacient Agents, Nonsteroidal↗
PubMed1984

Composite human VK genes and a model of their evolution.

A phage library and two cosmid libraries were screened for human VK genes. Two recombinant phage and four cosmid clones were analysed in detail by restriction mapping and sequencing. Each one contained a single VKI sequence. Two of these six sequences are potentially functional VK genes and four are pseudogenes. Two pseudogenes derived from different genomic DNAs are highly homologous and are therefore either allelic variants or the products of a recent duplication event. Comparisons of our sequences with all fully determined human VKI amino acid and DNA sequences reveal identical segments which at first sight appear like minigenes. But these segments do not coincide with the subregions and some of the segments include both, framework and complementarity determining regions (FR, CDR, ref. 2). The findings may be explained by an evolutionary model generating composite genes by gene conversion and selection.

Alleles↗
PubMed1984

Structure and origin of a novel class of defective interfering particle of vesicular stomatitis virus.

The genome structure and terminal sequences of a 'copyback' defective interfering (DI) particle ST1, and a novel complexly rearranged 'snapback' DI particle ST2 of vesicular stomatitis virus have been determined. The ST1 DI genome RNA possesses 54 base long inverted complementary termini, the 5' end of which is homologous to the standard virus genome 5' end. Following this region of inverted complementarity the DI RNA 5' end continues to be homologous to standard virus RNA 5' sequences, whereas the 3' end diverges into sequences within the virus L gene internal sequences. ST2 DI genome RNA does not contain colinear covalently linked plus and minus sense RNA copies of the standard infectious virus RNA 5' terminus as predicted from the prototype snapback DI structure, but instead appears to be a hairpin copy of the ST1 DI RNA genome. This is the first evidence suggesting that DI particles may be generated from RNA templates other than the standard virus RNA. Generation models and the implications of these findings for RNA virus evolution are discussed.

Base Composition↗
PubMed2000

tmRDB (tmRNA database).

The tmRNA database (tmRDB) is maintained at the University of Texas Health Science Center at Tyler, Texas, and is accessible on the WWW at URL http://psyche.uthct.edu/dbs/tmRDB/tmRDB.++ +html. A tmRDB mirror site is located on the campus of Auburn University, Auburn, Alabama, reachable at the URL http://www.ag.auburn.edu/mirror/tmRDB/. Since April 1997, the tmRDB has provided sequences of tmRNA (previously called 10Sa RNA), a molecule present in most bacteria and some organelles. This release adds 17 new sequences for a total of 60 tmRNAs. Sequences and corresponding tmRNA-encoded tag peptides are tabulated in alphabetical and phylo-genetic order. The updated tmRNA alignment improves the secondary structures of known tmRNAs on the level of individual basepairs. tmRDB also provides an introduction to tmRNA function in trans-translation (with links to relevant literature), a limited number of tmRNA secondary structure diagrams, and numerous three-dimensional models generated interactively with the program ERNA-3D.

Databases, Factual↗
PubMed1981

The conformation of adenovirus VAI-RNA in solution.

The secondary structure of an adenovirus associated low molecular weight RNA (VAI-RNA) has been studied by partial digestion with T1-RNase and S1-endonuclease followed by T1-fingerprint analysis. The empirical secondary structure has been compared with two computer generated models based on minimal free energy of the structure. The results suggest that VAI-RNA in solution has a compact structure with a free energy of around -60 kcal with two stems and four bulge regions. The implication of this structure for the function of VAI-RNA is discussed.

Adenoviridae↗
PubMed2004

AthaMap: an online resource for in silico transcription factor binding sites in the Arabidopsis thaliana genome.

Gene expression is controlled mainly by the binding of transcription factors to regulatory sequences. To generate a genomic map for regulatory sequences, the Arabidopsis thaliana genome was screened for putative transcription factor binding sites. Using publicly available data from the TRANSFAC database and from publications, alignment matrices for 23 transcription factors of 13 different factor families were used with the pattern search program Patser to determine the genomic positions of more than 2.4 x 10(6) putative binding sites. Due to the dense clustering of genes and the observation that regulatory sequences are not restricted to upstream regions, the prediction of binding sites was performed for the whole genome. The genomic positions and the underlying data were imported into the newly developed AthaMap database. This data can be accessed by positional information or the Arabidopsis Genome Initiative identification number. Putative binding sites are displayed in the defined region. Data on the matrices used and on the thresholds applied in these screens are given in the database. Considering the high density of sites it will be a valuable resource for generating models on gene expression regulation. The data are available at http://www.athamap.de.

Arabidopsis↗
PubMed2000

Electron microscopy of satellite tobacco mosaic virus crystals: metal-coated, negatively stained and stereo pairs.

Highly purified virions of satellite tobacco mosaic virus (STMV) were found to crystallize at relatively low concentrations (300-500 microg ml(-1)) in pure water. Small crystals of these preparations were examined in the transmission electron microscope after either being rotary shadowcast with metal or negatively stained with 4% uranyl acetate. Stereo views were also obtained of both types of preparations. Stereo pairs of metal-coated crystals provided good three-dimensional images. When stereo pairs of negatively stained crystals were printed from second negatives, they provided striking images although the three-dimensional aspect was not so pronounced. Images of both types of preparations were compared with a computer-generated model of the virus. This model was based on data obtained in earlier X-ray diffraction crystallographic studies. Measurements of crystal axes on the EM images were somewhat lower than those of the computer model. It is assumed the reason for this is the dehydration of crystals during preparation for electron microscopy. The EM images did verify the type of crystal lattice determined in the X-ray diffraction studies. Conversely, knowing the exact unit cell parameters and the distribution of virions in the crystal from X-ray diffraction data aids in the further interpretation of electron micrographs of virus crystals.

Crystallography↗
PubMed1998

The core domain of retrotransposon integrase in Hordeum: predicted structure and evolution.

Propagation of long terminal repeat (LTR)-bearing retrotransposons and retroviruses requires integrase (IN, EC 2.7.7.-), encoded by the retroelements themselves, which mediates the insertion of cDNA copies back into the genome. An active retrotransposon family, BARE-1, comprises approximately 7% of the barley (Hordeum vulgare subsp. vulgare) genome. We have generated models for the secondary and tertiary structure of BARE-1 IN and demonstrate their similarity to structures for human immunodeficiency virus 1 and avian sarcoma virus INs. The IN core domains were compared for 80 clones from 28 Hordeum accessions representative of the diversity of the genus. Based on the structural model, variations in the predicted, aligned translations from these clones would have minimal structural and functional effects on the encoded enzymes. This indicates that Hordeum retrotransposon IN has been under purifying selection to maintain a structure typical of retroviral INs. These represent the first such analyses for plant INs.

Amino Acid Sequence↗
PubMed1999

Recombinant anti-polyamine antibodies: identification of a conserved binding site motif.

Polyamines are small linear polycations found ubiquitously in eukaryotic cells. They are involved in nucleic acid and protein synthesis and rises in cellular polyamine levels have been correlated with cell proliferation. Antibodies to these molecules have potential as prognostic indicators of disease conditions and indicators of treatment efficacy. Antipolyamine monoclonal antibodies of differing but defined specificities have been generated in our laboratory using polyamine ovalbumin conjugates as immunogens. These antibodies show small but significant cross reactivities with other polyamine species; IAG-1 cross reacts with spermidine (8%), JAC-1 with spermine (6%) and JSJ-1 with both putrescine (11%) and spermine (6%). We have rescued and sequenced the heavy and light chain variable regions of all three of these antibodies. While the light chains of two antibodies, IAG-1 and JSJ-1, were 93% homologous at the amino acid level, none of the heavy chains displayed any significant sequence homology. However, computer-generated models of all three antibody binding sites revealed a three-dimensionally conserved polyamine binding site motif. The polyamine appears to bind into a negatively charged cleft lined with acidic and polar residues. The cleft is partially or completely closed at one end and the specificity of the interaction is determined by placement of acidic residues in the cleft. Aromatic residues contribute to polyamine binding interacting with the carbon backbone. The polyamine-binding motif we have identified is very similar to that observed in the crystal structure of PotD, the primary receptor of the polyamine transport system in Escherichia coli.

Amino Acid Sequence↗
PubMed1990

Fractal geometry in mosaic organs: a new interpretation of mosaic pattern.

Fractal geometries have been widely observed in nature. The formulation of mathematical treatments of non-Euclidean geometry has generated models of highly complex natural phenomena. In the field of developmental biology, branching morphogenesis has been explained in terms of self-similar iterating branching rules that have done much toward explaining branch patterns observed in a range of real tissue. In solid viscera the problem is more complicated because there is no readily available marker of geometry in parenchymal tissue. Mosaic pattern provides such a marker. The patches observed in mosaic liver are shown to be fractal, indicating that the pattern may have arisen from a self-similar process (i.e., a process that creates an object in which small areas are representative of, although not necessarily identical to, the whole object). This observation offers a new analytical approach to the study of biologic structure in organogenesis.

Animals↗
PubMed1995

The potential of computerized representations of anatomy in the training of health care providers.

The purpose of anatomy education is to develop the skills for anatomical reasoning, which is a requirement for performing a number of clinical tasks. Anatomical reasoning integrates an understanding of the three-dimensional (3-D) geometry of the body and its parts (the spatial domain of anatomical information) with an understanding of functional, developmental, pathological, and other relationships among anatomic entities (the symbolic domain of anatomical information). Traditional methods in anatomy have substantial shortcomings for representing and integrating these two information domains. Computer-based methods of knowledge representation have a great potential for overcoming the shortcomings and for promoting anatomical reasoning. To realize this potential, there is a need for (1) establishing 3-D electronic atlases of the human body; (2) generating models of symbolic anatomical information, and (3) developing computer programs (user interfaces) that integrate these knowledge sources and serve the needs of trainees and practitioners in different fields of the health sciences. The Digital Anatomist Program at the University of Washington has begun to build such a client-server framework for anatomical information, and its application for biomedical education is being evaluated.

Anatomy↗
PubMedDate not supplied

Comparison of projection algorithms used for the construction of maximum intensity projection images.

OBJECTIVE: Four methods of producing maximum intensity projection (MIP) images were studied and compared. MATERIALS AND METHODS: Three of the projection methods differ in the interpolation kernel used for ray tracing. The interpolation kernels include nearest neighbor interpolation, linear interpolation, and cubic convolution interpolation. The fourth projection method is a voxel projection method that is not explicitly a ray-tracing technique. The four algorithms' performance was evaluated using a computer-generated model of a vessel and using real MR angiography data. The evaluation centered around how well an algorithm transferred an object's width to the projection plane. RESULTS: The voxel projection algorithm does not suffer from artifacts associated with the nearest neighbor algorithm. Also, a speed-up in the calculation of the projection is seen with the voxel projection method. Linear interpolation dramatically improves the transfer of width information from the 3D MRA data set over both nearest neighbor and voxel projection methods. Even though the cubic convolution interpolation kernel is theoretically superior to the linear kernel, it did not project widths more accurately than linear interpolation. A possible advantage to the nearest neighbor interpolation is that the size of small vessels tends to be exaggerated in the projection plane, thereby increasing their visibility. CONCLUSION: The results confirm that the way in which an MIP image is constructed has a dramatic effect on information contained in the projection. The construction method must be chosen with the knowledge that the clinical information in the 2D projections in general will be different from that contained in the original 3D data volume.

Algorithms↗
PubMedDate not supplied

The effects of femoral shaft malrotation on lower extremity anatomy.

OBJECTIVE: To determine how axial rotation around the anatomic axis of the femur, as would occur with malrotation of a femoral fracture, affects frontal and sagittal plane alignment and knee joint orientation. DESIGN: Computer-generated models of the lower extremity were constructed using standardized dimensions. To simulate a malrotated fracture, these models were rotated in the shaft around the anatomic axis in 15 degrees increments from 60 degrees internal to 60 degrees external rotation. Rotation was performed at the proximal fourth, mid-shaft, and distal fourth. MAIN OUTCOME MEASUREMENTS: At each rotational position, the mechanical axis deviation in millimeters and the changes in mechanical lateral distal femoral angle in degrees were measured to quantify frontal plane malalignment and malorientation, respectively. The mechanical axis deviation in millimeters in the sagittal plane was also measured at each rotatory position. RESULTS: Femoral shaft malrotation greater than 30 degrees internal rotation of a subtrochanteric fracture or more than 45 degrees of a midshaft fracture or external rotation of 30 degrees or greater of a supracondylar fracture resulted in frontal plane malalignment. External rotation of a supracondylar fracture of 45 degrees or more results in knee joint malorientation. Any external rotation at all 3 fracture levels caused posterior displacement of the weight-bearing axis in the sagittal plane. CONCLUSIONS: Malrotation of a femoral shaft fracture is not just a cosmetic problem. Internal and external rotation causes malalignment and malorientation in the frontal plane, depending on the level of the fracture and the magnitude of malrotation. External rotation of any degree at the proximal fourth, mid-shaft, and distal fourth causes a posterior shift of the weight-bearing axis in the sagittal plane.

Biomechanical Phenomena↗
PubMed2001

Computer-assisted orthopedic surgery with individual templates and comparison to conventional operation method.

STUDY DESIGN: Comparison was made of the accuracy of a pedicle bore performed by conventional technique and by using an individual template in the lumbar spine of cadavers. OBJECTIVES: The fixation of pedicle screws necessitates a high amount of surgical skill and experience to avoid lesions of nerves and vessels. By using individual templates in a cadaver study the goal was to prove the accuracy and efficiency of this less-invasive image-guided surgery in comparison with the conventional technique by fluoroscopy and computed tomographic (CT) scan. SUMMARY OF BACKGROUND DATA: Based on three-dimensional models generated from CT scans of the lumbar spine, precise preoperative planning of the position and trajectory of pedicle screws is possible. In comparison with other means of computer-assisted spine surgery with navigation systems, in which a time-consuming intraoperative matching of the bone surface structure is necessary, the use of individual templates enables the surgeon to reduce the operation time considerably. METHODS: Individual templates are customized on the basis of three-dimensional reconstructions of the bone structures extracted from CT image data and depending on the individual preoperative surgical planning, which uses the desktop image processing system for orthopedic surgery (DISOS). A desktop-computer-controlled milling device is used as a three-dimensional printer to automatically mold the shape of small reference areas of the bone surface into the body of the template. Postoperative CT scans were obtained and the accuracy of the pedicle bore rated by two independent observers. RESULTS: The preparation time with the individual template lasted slightly longer than with the conventional operation technique (555 seconds and 482 seconds, respectively). Fluoroscopic study took a mean time of 31.5 seconds, with the conventional operation technique and 5.5 seconds with the individual template. The assessment of the postoperative CT scans demonstrated a higher accuracy of the pedicle bore with the individual template. CONCLUSIONS: This cadaveric study has shown that overall operation time including the fluoroscopy time can be shortened by using the individual template for the pedicle bore. The individual template is an alternative to the computer-assisted navigation systems with a good cost-performance ratio without excessive technical workload on the physicians or the surgical personnel. Further investigations must be conducted to validate the clinical applicability of this system.

Bone Screws↗
PubMed2001

The structure of anti-Gal immunoglobulin genes in naïve and stimulated Gal knockout mice.

BACKGROUND: Naturally occurring antibodies (Nabs) that bind to terminal galactose alpha1,3-galactose carbohydrate structures (Gal) are present in humans and Old World monkeys but are negatively regulated in other mammalian species because they express Gal epitopes on their cell surfaces. A Gal knockout mouse (Gal-/-) model, generated by homologous disruption of alpha1,3-galactosyltransferase gene, is capable of producing natural anti-Gal Abs. METHODS: To study the genetic control of the anti-Gal response, we have generated anti-Gal hybridomas from Gal-/- mice and analyzed VH genes of anti-Gal Abs from naïve animals and from mice stimulated by rat heterotopic heart transplantation. RESULTS: Six immunoglobulin (Ig)M anti-Gal hybridomas derived from naïve Gal-/- mice exhibited anti-Gal binding activity with some cross-reactivity to related carbohydrate structures. These naïve anti-Gal Abs used five different VH genes in a germline configuration. Anti-Gal IgM hybridomas isolated after a rat heterotopic heart xenograft (4 days) utilized germline VH gene segments from the VH7183 family and exhibited less cross-reactivity. In contrast to mice 4 days after xenograft, we have predominantly isolated IgG anti-Gal hybridomas from mice 21 days after rat heterotopic heart xenografts, indicating an isotype switch. Nine of the IgG anti-Gal hybridomas secreted IgG3 subclass and one produced IgG1. Sequence analysis of the VH gene usage from the induced anti-Gal IgG antibodies demonstrated a restricted gene utilization (VHJ606-V14A). CONCLUSION: Our results demonstrate that the anti-Gal response in naïve Gal-/- mice is encoded by multiple germline progenitors. In response to a xenograft, the induced anti-Gal Abs exhibited a restricted gene usage and somatic mutations, indicating a positive selection.

Animals↗