bluuebunny/crossref_metadata_2025 huggingface dataset:
PatSearch: a pattern matcher software that finds functional
elements in nucleotide and protein sequences and assesses their
statistical significance
Authors: Pesole Graziano , Liuni Sabino , D’Souza Mark
Published: July 2002

* To whom correspondence should be addressed.

Motivation: The identification of sequence patterns involved in gene regulation and expression is a major challenge in molecular biology. In this paper we describe a novel algorithm and the software for searching nucleotide and protein sequences for complex nucleotide patterns including potential secondary structure elements, also allowing for mismatches/mispairings below a user-fixed threshold, and assessing the statistical significance of their occurrence through a Markov chain simulation.

Results: The application of the proposed algorithm allowed the identification of some functional elements, such as the Iron Responsive Element, the Histone stem-loop structure and the Selenocysteine Insertion Sequence, located in the mRNA untranslated regions of post-transcriptionally regulated genes with the assessment of sensitivity and selectivity of the searching method.

Availability: A Web interface is available at: http://bigarea.area.ba.cnr.it:8000/EmbIT/Patsearch.html.

Contact: graziano.pesole@unimi.it
PAQ: Partition Analysis of Quasispecies
Authors: Baccam Prasith , Thompson Robert J. , Fedrigo Olivier , Carpenter Susan , Cornette James L.
Published: July 2002

Motivation: The complexities of genetic data may not be accurately described by any single analytical tool. Phylogenetic analysis is often used to study the genetic relationship among different sequences. Evolutionary models and assumptions are invoked to reconstruct trees that describe the phylogenetic relationship among sequences. Genetic databases are rapidly accumulating large amounts of sequences. Newly acquired sequences, which have not yet been characterized, may require preliminary genetic exploration in order to build models describing the evolutionary relationship among sequences. There are clustering techniques that rely less on models of evolution, and thus may provide nice exploratory tools for identifying genetic similarities. Some of the more commonly used clustering methods perform better when data can be grouped into mutually exclusive groups. Genetic data from viral quasispecies, which consist of closely related variants that differ by small changes, however, may best be partitioned by overlapping groups.

Results: We have developed an intuitive exploratory program, Partition Analysis of Quasispecies (PAQ), which utilizes a non-hierarchical technique to partition sequences that are genetically similar. PAQ was used to analyze a data set of human immunodeficiency virus type 1 (HIV-1) envelope sequences isolated from different regions of the brain and another data set consisting of the equine infectious anemia virus (EIAV) regulatory gene rev. Analysis of the HIV-1 data set by PAQ was consistent with phylogenetic analysis of the same data, and the EIAV rev variants were partitioned into two overlapping groups. PAQ provides an additional tool which can be used to glean information from genetic data and can be used in conjunction with other tools to study genetic similarities and genetic evolution of viral quasispecies.

Availability: http://www.vetmed.iastate.edu/units/carplab/PAQ/main.html

Contact: pbaccam@lanl.gov

6 To whom correspondence should be addressed at Los Alamos National Laboratory, MS K-710, Theoretical Biology and Biophysics, Los Alamos, NM 87545, USA.
Estimation of P-values for global alignments of protein
sequences
Authors: Webber Caleb , Barton Geoffrey J.
Published: July 2002

Motivation: The global alignment of protein sequence pairs is often used in the classification and analysis of full-length sequences. The calculation of a Z-score for the comparison gives a length and composition corrected measure of the similarity between the sequences. However, the Z-score alone, does not indicate the likely biological significance of the similarity. In this paper, all pairs of domains from 250 sequences belonging to different SCOP folds were aligned and Z-scores calculated. The distribution of Z-scores was fitted with a peak distribution from which the probability of obtaining a given Z-score from the global alignment of two protein sequences of unrelated fold was calculated. A similar analysis was applied to subsequence pairs found by the Smith–Waterman algorithm. These analyses allow the probability that two protein sequences share the same fold to be estimated by global sequence alignment.

Results: The relationship between Z-score and probability varied little over the matrix/gap penalty combinations examined. However, an average shift of +4.7was observed for Z-scores derived from global alignment of locally-aligned subsequences compared to global alignment of the full-length sequences. This shift was shown to be the result of pre-selection by local alignment, rather than any structural similarity in the subsequences. The search ability of both methods was benchmarked against the SCOP superfamily classification and showed that global alignment Z-scores generated from the entire sequence are as effective as SSEARCH at low error rates and more effective at higher error rates. However, global alignment Z-scores generated from the best locally-aligned subsequence were significantly less effective than SSEARCH. The method of estimating statistical significance described here was shown to give similar values to SSEARCH and BLAST, providing confidence in the significance estimation.

Availability: Software to apply the statistics to global alignments is available from http://barton.ebi.ac.uk.

Contact: geoff@ebi.ac.uk

* To whom correspondence should be addressed. Present address: School of Life Sciences, University of Dundee, Dow St., Dundee, DD1 5EH.
A hierarchical unsupervised growing neural network for
clustering gene expression patterns
Authors: Herrero Javier , Valencia Alfonso , Dopazo Joaquı́n
Published: July 2002

Motivation: We describe a new approach to the analysis of gene expression data coming from DNA array experiments, using an unsupervised neural network. DNA array technologies allow monitoring thousands of genes rapidly and efficiently. One of the interests of these studies is the search for correlated gene expression patterns, and this is usually achieved by clustering them. The Self-Organising Tree Algorithm, (SOTA) (Dopazo,J. and Carazo,J.M. (1997) J. Mol. Evol. , 44, 226–233), is a neural network that grows adopting the topology of a binary tree. The result of the algorithm is a hierarchical cluster obtained with the accuracy and robustness of a neural network.

Results: SOTA clustering confers several advantages over classical hierarchical clustering methods. SOTA is a divisive method: the clustering process is performed from top to bottom, i.e. the highest hierarchical levels are resolved before going to the details of the lowest levels. The growing can be stopped at the desired hierarchical level. Moreover, a criterion to stop the growing of the tree, based on the approximate distribution of probability obtained by randomisation of the original data set, is provided. By means of this criterion, a statistical support for the definition of clusters is proposed. In addition, obtaining average gene expression patterns is a built-in feature of the algorithm. Different neurons defining the different hierarchical levels represent the averages of the gene expression patterns contained in the clusters.

Since SOTA runtimes are approximately linear with the number of items to be classified, it is especially suitable for dealing with huge amounts of data. The method proposed is very general and applies to any data providing that they can be coded as a series of numbers and that a computable measure of similarity between data items can be used.

Availability: A server running the program can be found at: http://bioinfo.cnio.es/sotarray

Contact: jdopazo@cnio.es

* To whom correspondence should be addressed.
Automated extraction of information on protein–protein
interactions from the biological literature
Authors: Ono Toshihide , Hishigaki Haretsugu , Tanigami Akira , Takagi Toshihisa
Published: July 2002

Motivation: To understand biological process, we must clarify how proteins interact with each other. However, since information about protein–protein interactions still exists primarily in the scientific literature, it is not accessible in a computer-readable format. Efficient processing of large amounts of interactions therefore needs an intelligent information extraction method. Our aim is to develop an efficient method for extracting information on protein–protein interaction from scientific literature.

Results: We present a method for extracting information on protein–protein interactions from the scientific literature. This method, which employs only a protein name dictionary, surface clues on word patterns and simple part-of-speech rules, achieved high recall and precision rates for yeast (recall \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(=\) \end{document}86.8% and precision \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(=\) \end{document}94.3%) and Escherichia coli (recall \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(=\) \end{document}82.5% and precision \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(=\) \end{document}93.5%). The result of extraction suggests that our method should be applicable to any species for which a protein name dictionary is constructed.

Availability: The program is available on request from the authors.

Contact: ono@otsuka.gr.jp

* To whom correspondence should be addressed.
Automated image analysis for array hybridization experiments
Authors: Steinfath Matthias , Wruck Wasco , Seidel Henrik , Lehrach Hans , Radelof Uwe , O’Brien John
Published: July 2002

Motivation: Image analysis is a major part of data evaluation for array hybridization experiments in molecular biology. The program presented here is designed to analyze automatically images from hybridization experiments with various arrangements: different kinds of probes (oligonucleotides or complex probes), different supports (nylon filters or glass slides), different labeling of probes (radioactively or fluorescently). The program is currently applied to oligonucleotide fingerprinting projects and complex hybridizations. The only precondition for the use of the program is that the targets are arrayed in a grid, which can be approximately transformed to an orthogonal equidistant grid by a projective mapping.

Results: We demonstrate that our program can cope with the following problems: global distortion of the grid, missing of grid nodes, local deviation of the spot from its specified grid position. This is checked by different quality measures. The image analysis of oligonucleotide fingerprint experiments on an entire genetic library is used, in clustering procedures, to group related clones together. The results show that the program yields automatically generated high quality input data for follow up analysis such as clustering procedures.

Availability: The executable files will be available upon request for academics.

Contact: steinfat@molgen.mpg.de

* To whom correspondence should be addressed.
Predicting reliable regions in protein sequence alignments
Authors: Cline Melissa , Hughey Richard , Karplus Kevin
Published: July 2002

Motivation: Protein sequence alignments have a myriad of applications in bioinformatics, including secondary and tertiary structure prediction, homology modeling, and phylogeny. Unfortunately, all alignment methods make mistakes, and mistakes in alignments often yield mistakes in their application. Thus, a method to identify and remove suspect alignment positions could benefit many areas in protein sequence analysis.

Results: We tested four predictors of alignment position reliability, including near-optimal alignment information, column score, and secondary structural information. We validated each predictor against a large library of alignments, removing positions predicted as unreliable. Near-optimal alignment information was the best predictor, removing 70% of the substantially-misaligned positions and 58% of the over-aligned positions, while retaining 86% of those aligned accurately.

Availability: The shift score alignment comparison algorithm is available online at http://www.soe.ucsc.edu/research/compbio/HMM-apps/compare-align.html and from the authors on request.

Contact: cline@soe.ucsc.edu
The EBI SRS server—recent developments
Authors: Zdobnov Evgeni M. , Lopez Rodrigo , Apweiler Rolf , Etzold Thure
Published: July 2002

Motivation: The current data explosion is intractable without advanced data management systems. The numerous data sets become really useful when they are interconnected under a uniform interface—representing the domain knowledge. The SRS has become an integration system for both data retrieval and applications for data analysis. It provides capabilities to search multiple databases by shared attributes and to query across databases fast and efficiently.

Results: Here we present recent developments at the EBI SRS server (http://srs.ebi.ac.uk). The EBI SRS server contains today more than 130 biological databases and integrates more than 10 applications. It is a central resource for molecular biology data as well as a reference server for the latest developments in data integration. One of the latest additions to the EBI SRS server is the InterPro database—Integrated Resource of Protein Domains and Functional Sites. Distributed in XML format it became a turning point in low level XML–SRS integration. We present InterProScan as an example of data analysis applications, describe some advanced features of SRS6, and introduce the SRSQuickSearch JavaScript interfaces to SRS.

Availability: SRS6 is a licensed product of LION Bioscience AG freely available for academics. The EBI SRS server (http://srs.ebi.ac.uk) is a free central resource for molecular biology data as well as a reference server for the latest developments in data integration.

Contact: Rodrigo.Lopez@EBI.ac.uk; Evgueni.Zdobnov@EBI.ac.uk
Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells
Authors: Dinev Dragomir , Jordan Bruce W M , Neufeld Bernd , Lee Jiing‐Dwan , Lindemann Dirk , Rapp Ulf R , Ludwig Stephan
Published: July 2002

Extracellular signal regulated kinase 5 (ERK5) is a novel member of the mitogen‐activated protein kinase (MAPK) family with a poorly defined physiological function. Since ERK5 and its upstream activator MEK5 are abundant in skeletal muscle we examined a function of the cascade during muscle differentiation. We show that ERK5 is activated upon induction of differentiation in mouse myoblasts and that selective activation of the pathway results in promoter activation of differentiation‐specific genes. Moreover, myogenic differentiation is completely blocked when ERK5 expression is inhibited by antisense RNA. Thus, we conclude that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation.
Novel mutations of PKD1 gene in Chinese patients with autosomal dominant polycystic kidney disease
Authors: Ding Lan , Zhang Sizhong , Qiu Weimin , Xiao Cuiying , Wu Shaoqing , Zhang Ge , Cheng Lu , Zhang Sixiao
Published: July 2002

Background. Autosomal dominant polycystic kidney disease (ADPKD) is a common disease in China. The major gene responsible for ADPKD, PKD1, has been fully characterized and shown to encode an integral membrane protein, polycystin 1, which is thought to be involved in cell–cell and cell–matrix interaction. Until now, 82 mutations of PKD1 gene have been reported in European, American, and Asian populations. However, there has been no report on mutations of the PKD1 gene in a Chinese population.

Methods. Eighty Chinese patients in 60 families with ADPKD were screened for mutations in the 3′ region of the PKD1 gene using polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) and DNA-sequencing techniques.

Results. Three mutations were found. The first mutation is a 12593delA frameshift mutation in exon 45, and the polycystin change is 4129WfsX4197, 107 amino acids shorter than the normal polycystin (4302aa). The second mutation is a 12470InsA frameshift mutation in exon 45, producing 4088DfsX4156, and the predicted protein is 148 amino acids shorter than the normal. The third one is a 11151C→T transition in exon 37 converting Pro3648 to Leu. In addition, nine DNA variants, including IVS44delG, were identified.

Conclusions. Three mutations in Chinese ADPKD patients are described and all of them are de novo mutations. Data obtained from mutation analysis also suggests that the mutation rate of the 3′ single-copy region of PKD1 in Chinese ADPKD patients is very low, and there are no mutation hot spots in the PKD1 gene. Mutations found in Chinese ADPKD patients, including nucleotide substitution and minor frameshift, are similar to the findings reported by other researchers. Many mutations of the PKD1 gene probably exist in the duplicated region, promoter region, and the introns of PKD1.
Uncoupling of βIIPKC from its targeting protein RACK1 in response to ethanol in cultured cells and mouse brain
Authors: Ron Dorit , Vagts Alicia J. , Dohrman Douglas P. , Yaka Rami , Jiang Zhan , Yao Lina , Crabbe John , Grisel Judith E. , Diamond Ivan
Published: July 2002

ABSTRACT Protein kinase C (PKC) is involved in many neuroadaptive responses to ethanol in the nervous system. PKC activation results in translocation of the enzyme from one intracellular site to another. Compartmentalization of PKC isozymes is regulated by targeting proteins such as receptors for activated C kinase (RACKs). It is possible, therefore, that ethanol‐induced changes in the function and compartmentalization of PKC isozymes could be due to changes in PKC targeting proteins. Here we study the response of the targeting protein RACK1 and its corresponding kinase βIIPKC to ethanol, and propose a novel mechanism to explain how ethanol modulates signaling cascades. In cultured cells, ethanol induces movement of RACK1 to the nucleus without affecting the compartmentalization of βIIPKC. Ethanol also inhibits βIIPKC translocation in response to activation. These results suggest that ethanol inhibition of βIIPKC translocation is due to miscompartmentalization of the targeting protein RACK1. Similar events occurred in mouse brain. In vivo exposure to ethanol caused RACK1 to localize to nuclei in specific brain regions, but did not affect the compartmentalization of βIIPKC. Thus, some of the cellular and neuroadaptive responses to ethanol may be related to ethanol‐induced movement of RACK1 to the nucleus, thereby preventing the translocation and corresponding function of βIIPKC.— Ron, D., Vagts, A. J., Dohrman, D. P., Yaka, R., Jiang, Z., Yao, L., Crabbe, J., Grisel, J. E., Diamond, I. Uncoupling of βIIPKC from its targeting protein RACK1 in response to ethanol in cultured cells and mouse brain. FASEB J. 14, 2303–2314 (2000)
Human cortical mechanisms of visual attention during orienting and search
Authors: Corbetta Maurizio , Shulman Gordon L.
Published: July 2002

Functional anatomical studies indicate that a set of neural signals in parietal and frontal cortex mediates the covert allocation of attention to visual locations across a wide variety of visual tasks. This fronto–parietal network includes areas, such as the frontal eye field and supplementary eye field. This anatomical overlap suggests that shifts of attention to visual locations or objects recruit areas involved in oculomotor programming and execution. Finally, the fronto–parietal network may be the source of spatial attentional modulations in the ventral visual system during object recognition or discrimination.
Why are there so few resistance–associated mutations in insecticide target genes?
Authors: ffrench–Constant R. H. , Pittendrigh B. , Vaughan A. , Anthony N.
Published: July 2002

The genes encoding the three major targets of conventional insecticides are:Rdl, which encodes a γ–aminobutyric acid receptor subunit (RDL);para, which encodes a voltage–gated sodium channel (PARA) andAce, which encodes insect acetylcholinesterase (AChE). Interestingly, despite the complexity of the encoded receptors or enzymes, very few amino acid residues are replaced in different resistant insects: one within RDL, two within PARA and three or more within AChE. Here we examine the possible reasons underlying this extreme conservation by looking at the aspects of receptor and/or enzyme function that may constrain replacements to such a limited number of residues.
Evolution and origins of tobamoviruses
Authors: Gibbs Adrian
Published: July 2002

More than a dozen tobamoviruses are known. In nature, each species probably survives by moving between several closely related host species. Each infected plant contains a population of variants, but in most host populations the tobamovirus population is stable. The phylogenetic relationships of tobamovirus species broadly correlate with those of their angiosperm hosts. The simplest explanation for this correlation is that they have coevolved with the angiosperms, and hence, like them, are about 120–140 million years old. Gene sequence differences between species also indicate that the tobamoviruses are an ancient genus. Their gene sequences, and the protein motifs they encode, link them to tobraviruses, hordeiviruses and soil–borne wheat mosaic virus, more distantly to the tricornaviruses, and even to hepatitis virus E and other furoviruses, rubiviruses and alphaviruses. Their progenitors may have been associated with charophycean algae, and perhaps also plasmodiophoromycete fungi.
Evidence for a recruitment and sequestration mechanism in Huntington'sdisease
Authors: Preisinger Elizabeth , Jordan Barbara M. , Kazantsev Aleksey , Housman David
Published: July 2002

Polyglutamine (polyQ) extension in the coding sequence of mutant huntingtin causes neuronal degeneration associated with the formation of insoluble polyQ aggregates in Huntington'sdisease. We constructed an array of CAG/CAA triplet repeats, coding for a range of 25 to 300 glutamine residues, which was used to generate expression constructs with minimal flanking sequence. Normal–length (25 glutamine residues) polyQ did not aggregate when transfected alone. Remarkably, when co–transfected with extended (100 to 300 glutamine residues) polyQ tracts, normal–length polyQ–containing peptides were trapped in insoluble detergent–resistant aggregates. Aggregates formed in the cytoplasm but were visible in the nucleus only when a strong nuclear localization signal was present. Intermolecular interactions between polyQ tracts mediated the localization of heterogeneous aggregates into the nucleolus by nucleolin protein. Our results suggest that extended polyQ can interact with cellular polyQ–containing proteins, transport them to ectopic cellular locations, and form heterogeneous polyQ aggregates. We provide evidence for a recruitment mechanism for pathogenesis in the polyQ neurodegenerative disorders. In susceptible cells, extended polyQ tracts in huntingtin might interact with and sequester or deplete certain endogenous polyQ–containing cellular proteins.
Land plant biochemistry
Authors: Raven J. A.
Published: July 2002

Biochemical studies have complemented ultrastructural and, subsequently, molecular genetic evidence consistent with the Charophyceae being the closest extant algal relatives of the embryophytes. Among the genes used in such molecular phylogenetic studies is that (rbcL) for the large subunit of ribulose bisphosphate carboxylase–oxygenase (RUBISCO). The RUBISCO of the embryophytes is derived, via the Chlorophyta, from that of the cyanobacteria. This clade of the molecular phylogeny of RUBISCO shows a range of kinetic characteristics, especially of CO2affinities and of CO2/ O2selectivities. The range of these kinetic values within the bryophytes is no greater than in the rest of the embryophytes; this has implications for the evolution of the embryophytes in the high atmospheric CO2environment of the late Lower Palaeozoic. The differences in biochemistry between charophycean algae and embryophytes can to some extent be related functionally to the structure and physiology of embryophytes. Examples of components of embryophytes, which are qualitatively or quantitatively different from those of charophytes, are the water repellent/water resistant extracellular lipids, the rigid phenolic polymers functional in waterconducting elements and mechanical support in air, and in UV–B absorption, flavonoid phenolics involved in UV–B absorption and in interactions with other organisms, and the greater emphasis on lowMrorganic acids, retained in the plant as free acids or salts, or secreted to the rhizosphere. The roles of these components are discussed in relation to the environmental conditions at the time of evolution of the terrestrial embryophytes. A significant point about embryophytes is the predominance of nitrogen–free extracellular structural material (a trait shared by most algae) and UV–B screening components, by contrast with analogous components in many other organisms. An important question, which has thus far been incompletely addressed, is the extent to which the absence from bryophytes of the biochemical pathways which produce components found only in tracheophytes is the result of evolutionary loss of these functions.
RapA, a bacterial homolog of SWI2/SNF2, stimulates RNA polymerase recycling in transcription
Authors: Sukhodolets Maxim V. , Cabrera Julio E. , Zhi Huijun , Jin Ding Jun
Published: July 2002

We report that RapA, an Escherichia coli RNA polymerase (RNAP)-associated homolog of SWI2/SNF2, is capable of dramatic activation of RNA synthesis. The RapA-mediated transcriptional activation in vitro depends on supercoiled DNA and high salt concentrations, a condition that is likely to render the DNA superhelix tightly compacted. Moreover, RapA activates transcription by stimulating RNAP recycling. Mutational analyses indicate that the ATPase activity of RapA is essential for its function as a transcriptional activator, and a rapA null mutant exhibits a growth defect on nutrient plates containing high salt concentrations in vivo. Thus, RapA acts as a general transcription factor and an integral component of the transcription machinery. The mode of action of RapA in remodeling posttranscription or posttermination complexes is discussed.
Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity
Authors: Parras Carlos M. , Schuurmans Carol , Scardigli Raffaella , Kim Jaesang , Anderson David J. , Guillemot François
Published: July 2002

The neural bHLH genes Mash1 and Ngn2 are expressed in complementary populations of neural progenitors in the central and peripheral nervous systems. Here, we have systematically compared the activities of the two genes during neural development by generating replacement mutations in mice in which the coding sequences ofMash1 and Ngn2 were swapped. Using this approach, we demonstrate that Mash1 has the capacity to respecify the identity of neuronal populations normally derived fromNgn2-expressing progenitors in the dorsal telencephalon and ventral spinal cord. In contrast, misexpression of Ngn2 inMash1-expressing progenitors does not result in any overt change in neuronal phenotype. Taken together, these results demonstrate that Mash1 and Ngn2 have divergent functions in specification of neuronal subtype identity, with Mash1 having the characteristics of an instructive determinant whereas Ngn2functions as a permissive factor that must act in combination with other factors to specify neuronal phenotypes. Moreover, the ectopic expression of Ngn2 can rescue the neurogenesis defects ofMash1 null mutants in the ventral telencephalon and sympathetic ganglia but not in the ventral spinal cord and the locus coeruleus, indicating that Mash1 contribution to the specification of neuronal fates varies greatly in different lineages, presumably depending on the presence of other determinants of neuronal identity.
E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints
Authors: Ren Bing , Cam Hieu , Takahashi Yasuhiko , Volkert Thomas , Terragni Jolyon , Young Richard A. , Dynlacht Brian David
Published: July 2002

The E2F transcription factor family is known to play a key role in the timely expression of genes required for cell cycle progression and proliferation, but only a few E2F target genes have been identified. We explored the possibility that E2F regulators play a broader role by identifying additional genes bound by E2F in living human cells. A protocol was developed to identify genomic binding sites for DNA-binding factors in mammalian cells that combines immunoprecipitation of cross-linked protein–DNA complexes with DNA microarray analysis. Among ∼1200 genes expressed during cell cycle entry, we found that the promoters of 127 were bound by the E2F4 transcription factor in primary fibroblasts. A subset of these targets was also bound by E2F1. Most previously identified target genes known to have roles in DNA replication and cell cycle control and represented on the microarray were confirmed by this analysis. We also identified a remarkable cadre of genes with no previous connection to E2F regulation, including genes that encode components of the DNA damage checkpoint and repair pathways, as well as factors involved in chromatin assembly/condensation, chromosome segregation, and the mitotic spindle checkpoint. Our data indicate that E2F directly links cell cycle progression with the coordinate regulation of genes essential for both the synthesis of DNA as well as its surveillance.
The GEX-2 and GEX-3 proteins are required for tissue morphogenesis and cell migrations in C. elegans
Authors: Soto Martha C. , Qadota Hiroshi , Kasuya Katsuhisa , Inoue Makiko , Tsuboi Daisuke , Mello Craig C. , Kaibuchi Kozo
Published: July 2002

During body morphogenesis precisely coordinated cell movements and cell shape changes organize the newly differentiated cells of an embryo into functional tissues. Here we describe two genes, gex-2 andgex-3, whose activities are necessary for initial steps of body morphogenesis in Caenorhabditis elegans. In the absence ofgex-2 and gex-3 activities, cells differentiate properly but fail to become organized. The external hypodermal cells fail to spread over and enclose the embryo and instead cluster on the dorsal side. Postembryonically gex-3 activity is required for egg laying and for proper morphogenesis of the gonad. GEX-2 and GEX-3 proteins colocalize to cell boundaries and appear to directly interact. GEX-2 and GEX-3 are highly conserved, with vertebrate homologs implicated in binding the small GTPase Rac and a GEX-3Drosophila homolog, HEM2/NAP1/KETTE, that interacts genetically with Rac pathway mutants. Our findings suggest that GEX-2 and GEX-3 may function at cell boundaries to regulate cell migrations and cell shape changes required for proper morphogenesis and development.
Trimming, Weighting, and Grouping SNPs in Human Case-Control Association Studies
Authors: Hoh Josephine , Wille Anja , Ott Jurg
Published: July 2002

The search for genes underlying complex traits has been difficult and often disappointing. The main reason for these difficulties is that several genes, each with rather small effect, might be interacting to produce the trait. Therefore, we must search the whole genome for a good chance to find these genes. Doing this with tens of thousands of SNP markers, however, greatly increases the overall probability of false-positive results, and current methods limiting such error probabilities to acceptable levels tend to reduce the power of detecting weak genes. Investigating large numbers of SNPs inevitably introduces errors (e.g., in genotyping), which will distort analysis results. Here we propose a simple strategy that circumvents many of these problems. We develop a set-association method to blend relevant sources of information such as allelic association and Hardy-Weinberg disequilibrium. Information is combined over multiple markers and genes in the genome, quality control is improved by trimming, and an appropriate testing strategy limits the overall false-positive rate. In contrast to other available methods, our method to detect association to sets of SNP markers in different genes in a real data application has shown remarkable success.
Alterations in the Thickness of Motor Cortical Subregions After Motor-Skill Learning and Exercise
Authors: Anderson Brenda J. , Eckburg Paul B. , Relucio Karen I.
Published: July 2002

Behavioral manipulations such as housing in an enriched environment have been shown to increase brain weight and visual cortical thickness. The present study was designed to test whether skill learning or repetitive movements can alter the thickness of the motor cortex. One group of 6-mo-old Long-Evans female rats learned motor skills on an obstacle course that increased in difficulty over training and required balance and coordination. A second group ran voluntarily in exercise wheels attached to their home cage but had little opportunity for skill learning. The third group was handled daily but received no opportunity for learning or exercise. Each condition lasted 26–29 d. The skill-learning and exercise conditions had greater heart weight, and the exercise condition had greater adrenal gland weights than controls. The thickness of the motor cortex was measured in four coronal planes between −2.33 mm to −0.3 mm from bregma. Regions of interest that corresponded to published maps of forelimb and hind-limb representations were analyzed together. Rats in the skill-learning condition had significantly thicker medial cortical areas in the two anterior planes (−0.8 and −0.3 mm from bregma). These regions correspond to previously mapped hind-limb representations. The exercise group had greater thickness of the medial region at −0.8 mm from bregma. Cortical thickness in all conditions varied significantly along the medial to lateral axis. For both treatments, the effects were restricted to medial and anterior regions of interest rather than posterior or lateral regions of interest. The results indicate that robust exercise, in addition to skill learning, is capable of altering the thickness of the motor cortex, but that the effects are restricted rather than distributed within the regions studied.
A cofactor‐dependent phosphoglycerate mutase homolog from Bacillus stearothermophilus is actually a broad specificity phosphatase
Authors: Rigden Daniel J. , Bagyan Irina , Lamani Ejvis , Setlow Peter , Jedrzejas Mark J.
Published: July 2002

The distribution of phosphoglycerate mutase (PGM) activity in bacteria is complex, with some organisms possessing both a cofactor‐dependent and a cofactor‐independent PGM and others having only one of these enzymes. Although Bacillus species contain only a cofactor‐independent PGM, genes homologous to those encoding cofactor‐dependent PGMs have been detected in this group of bacteria, but in at least one case the encoded protein lacks significant PGM activity. Here we apply sequence analysis, molecular modeling, and enzymatic assays to the cofactor‐dependent PGM homologs from B. stearothermophilus and B. subtilis, and show that these enzymes are phosphatases with broad substrate specificity. Homologs from other gram‐positive bacteria are also likely to possess phosphatase activity. These studies clearly show that the exploration of genomic sequences through three‐dimensional modeling is capable of producing useful predictions regarding function. However, significant methodological improvements will be needed before such analysis can be carried out automatically.
Modeling of the structural features of integral‐membrane proteins reverse‐environment prediction of integral membrane protein structure (REPIMPS)
Authors: Dastmalchi Siavoush , Morris Michael B. , Church W. Bret
Published: July 2002

The Profiles‐3D application, an inverse‐folding methodology appropriate for water‐soluble proteins, has been modified to allow the determination of structural properties of integral‐membrane proteins (IMPs) and for testing the validity of solved and model structures of IMPs. The modification, known as reverse‐environment prediction of integral membrane protein structure (REPIMPS), takes into account the fact that exposed areas of side chains for many residues in IMPs are in contact with lipid and not the aqueous phase. This (1) allows lipid‐exposed residues to be classified into the correct physicochemical environment class, (2) significantly improves compatibility scores for IMPs whose structures have been solved, and (3) reduces the possibility of rejecting a three‐dimensional structure for an IMP because the presence of lipid was not included. Validation tests of REPIMPS showed that it (1) can locate the transmembrane domain of IMPs with single transmembrane helices more frequently than a range of other methodologies, (2) can rotationally orient transmembrane helices with respect to the lipid environment and surrounding helices in IMPs with multiple transmembrane helices, and (3) has the potential to accurately locate transmembrane domains in IMPs with multiple transmembrane helices. We conclude that correcting for the presence of the lipid environment surrounding the transmembrane segments of IMPs is an essential step for reasonable modeling and verification of the three‐dimensional structures of these proteins.
Technical note: Monte‐Carlo dosimetry of the HDR 12i and Plus sources
Authors: Ballester F. , Puchades V. , Lluch J. L. , Serrano‐Andrés M. A. , Limami Y. , Pérez‐Calatayud J. , Casal E.
Published: July 2002

In this study a complete set of dosimetric data for the GammaMed high dose rate (HDR) 12i and Plus sources are presented. These data have been calculated by means of the Monte Carlo simulation code GEANT3. Absolute dose rate distributions in water are presented as conventional two dimensional (2D) Cartesian look‐up tables, and in the TG43 formalism.
Entropy, information, and computation
Authors: Machta J.
Published: July 2002

The relation between entropy, information, and randomness is discussed. Algorithmic information theory is introduced and used to provide a fundamental definition of entropy. The relation between algorithmic entropy and the usual Shannon–Gibbs entropy is discussed.
Dropped objects and other motions relative to the noninertial earth
Authors: Tiersten Martin S. , Soodak Harry
Published: July 2002

Earth is a noninertial frame of reference due to its spin and its orbital free-fall acceleration in the gravity fields of the sun, moon, and other external attractors. Three particularly interesting aspects of motion relative to the earth are discussed: (a) the effect of the sun and the moon and other external gravitational attractors; (b) the Foucault pendulum at middle latitudes; (c) the venerable and surprising problem of the deviation of the path of a dropped object away from the plumb line. A selective review of the twentieth century physics literature on motion relative to the earth demonstrates that errors and omissions abound. A fourth example is also presented, the interesting textbook problem of the free motion of a particle on a frictionless horizontal plane, as a simple illustration of carelessly incorrect treatment in much of the literature.
New considerations on Talbot’s bands
Authors: Benkö Zsolt , Hilbert Margit , Bor Zsolt
Published: July 2002

In this paper a new approach is presented to explain the formation of Talbot’s bands by using the model of tilted pulse fronts. Numerical calculations of this model are presented. Another interpretation of Talbot’s original paper is also given and explained. Simple experiments, suitable for students’ laboratory practice, have been used to carefully study the dependence of the visibility of the bands on different properties of the plate: thickness, refractive index, dispersion. Photos of Talbot’s bands are also presented.
Acoustic and linguistic factors in the perception of bandpass-filtered speech
Authors: Stickney Ginger S. , Assmann Peter F.
Published: July 2002

Speech can remain intelligible for listeners with normal hearing when processed by narrow bandpass filters that transmit only a small fraction of the audible spectrum. Two experiments investigated the basis for the high intelligibility of narrowband speech. Experiment 1 confirmed reports that everyday English sentences can be recognized accurately (82%–98% words correct) when filtered at center frequencies of 1500, 2100, and 3000 Hz. However, narrowband low predictability (LP) sentences were less accurately recognized than high predictability (HP) sentences (20% lower scores), and excised narrowband words were even less intelligible than LP sentences (a further 23% drop). While experiment 1 revealed similar levels of performance for narrowband and broadband sentences at conversational speech levels, experiment 2 showed that speech reception thresholds were substantially (>30 dB) poorer for narrowband sentences. One explanation for this increased disparity between narrowband and broadband speech at threshold (compared to conversational speech levels) is that spectral components in the sloping transition bands of the filters provide important cues for the recognition of narrowband speech, but these components become inaudible as the signal level is reduced. Experiment 2 also showed that performance was degraded by the introduction of a speech masker (a single competing talker). The elevation in threshold was similar for narrowband and broadband speech (11 dB, on average), but because the narrowband sentences required considerably higher sound levels to reach their thresholds in quiet compared to broadband sentences, their target-to-masker ratios were very different (+23 dB for narrowband sentences and −12 dB for broadband sentences). As in experiment 1, performance was better for HP than LP sentences. The LP-HP difference was larger for narrowband than broadband sentences, suggesting that context provides greater benefits when speech is distorted by narrow bandpass filtering.
Duration discrimination and subjective duration for ramped and damped sounds
Authors: Schlauch Robert S. , Ries Dennis T. , DiGiovanni Jeffrey J.
Published: July 2002

The perception of stimuli with ramped envelopes (gradual attack and abrupt decay) and damped envelopes (abrupt attack and gradual decay) was studied in subjective and objective tasks. Magnitude estimation (ME) of perceived duration was measured for broadband noise, 1.0-kHz, and 8.0-kHz tones for durations between 10 and 200 ms. Damped sounds were judged to be shorter than ramped sounds. Matching experiments between sounds with ramped, damped, and rectangular envelopes also showed that damped sounds are perceived to be shorter than ramped sounds, and, additionally, the reason for the effect is a result of the damped sound being judged shorter than a rectangular-gated sound rather than the ramped sound being judged longer than a rectangular-gated sound. These matching studies also demonstrate that the size of the effect is larger for tones (factor of 2.0) than for broadband noise (factor of 1.5). There are two plausible explanations for the finding that damped sounds are judged to be shorter than ramped or rectangular-gated sounds: (1) the abrupt offset at a high level of the ramped sound (or a rectangular-gated sound) results in a persistence of perception (forward masking) that is considered in judgments of the subjective duration; and (2) listeners may ignore a portion of the decay of a damped sound because they consider it an “echo” [Stecker and Hafter, J. Acoust. Soc. Am. 107, 3358–3368 (2000)]. In another experiment, duration discrimination for broadband noise with ramped, damped, and rectangular envelopes was studied as a function of duration (10 to 100 ms) to determine if differences in perceived duration are associated with the size of measured Weber fractions. A forced-choice adaptive procedure was used. Duration discrimination was poorer for noise with ramped envelopes than for noise with damped or rectangular envelopes. This result is inconsistent with differences in perceived duration and no explanation was readily apparent.
Numerical investigations of flow and energy fields near a thermoacoustic couple
Authors: Ishikawa Haruko , Mee David J.
Published: July 2002

The flow field and the energy transport near thermoacoustic couples are simulated using a 2D full Navier–Stokes solver. The thermoacoustic couple plate is maintained at a constant temperature; plate lengths, which are “short” and “long” compared with the particle displacement lengths of the acoustic standing waves, are tested. Also investigated are the effects of plate spacing and the amplitude of the standing wave. Results are examined in the form of energy vectors, particle paths, and overall entropy generation rates. These show that a net heat-pumping effect appears only near the edges of thermoacoustic couple plates, within about a particle displacement distance from the ends. A heat-pumping effect can be seen even on the shortest plates tested when the plate spacing exceeds the thermal penetration depth. It is observed that energy dissipation near the plate increases quadratically as the plate spacing is reduced. The results also indicate that there may be a larger scale vortical motion outside the plates which disappears as the plate spacing is reduced.
Modeling sound transmission through the pulmonary system and chest with application to diagnosis of a collapsed lung
Authors: Royston T. J. , Zhang X. , Mansy H. A. , Sandler R. H.
Published: July 2002

A theoretical and experimental study was undertaken to examine the feasibility of using audible-frequency vibro-acoustic waves for diagnosis of pneumothorax, a collapsed lung. The hypothesis was that the acoustic response of the chest to external excitation would change with this condition. In experimental canine studies, external acoustic energy was introduced into the trachea via an endotracheal tube. For the control (nonpneumothorax) state, it is hypothesized that sound waves primarily travel through the airways, couple to the lung parenchyma, and then are transmitted directly to the chest wall. In contradistinction, when a pneumothorax is present the intervening air presents an added barrier to efficient acoustic energy transfer. Theoretical models of sound transmission through the pulmonary system and chest region to the chest wall surface are developed to more clearly understand the mechanisms of intensity loss when a pneumothorax is present, relative to a baseline case. These models predict significant decreases in acoustic transmission strength when a pneumothorax is present, in qualitative agreement with experimental measurements. Development of the models, their extension via finite element analysis, and comparisons with experimental canine studies are reviewed.
A time-domain, level-dependent auditory filter: The gammachirp
Authors: Irino Toshio , Patterson Roy D.
Published: July 2002

A frequency-modulation term has been added to the gammatone auditory filter to produce a filter with an asymmetric amplitude spectrum. When the degree of asymmetry in this “gammachirp” auditory filter is associated with stimulus level, the gammachirp is found to provide an excellent fit to 12 sets of notched-noise masking data from three different studies. The gammachirp has a well-defined impulse response, unlike the conventional roex auditory filter, and so it is an excellent candidate for an asymmetric, level-dependent auditory filterbank in time-domain models of auditory processing.