bluuebunny/crossref_metadata_2025 huggingface dataset:
Issues in developing integrated genomic databases and application to the human X chromosome.
Authors: Leser U , Lehrach H , Roest Crollius H
Published: July 2002

MOTIVATION: In the past decade, a vast amount of mapping data has been generated on the human X chromosome, without a mechanism which would provide a global view of exactly what has been achieved. Large datasets are available electronically, but in heterogeneous formats and with incompatible access modes. In addition, relationships between objects in different datasets are often not specified. RESULTS: We discuss the problem of integrating these data into one database and define a number of requirements that are vital for any integration approach. We have developed IXDB, the Integrated X chromosome database, which fulfils those requirements and aims at providing a global view on genomic data at a chromosomal level. IXDB represents a conceptual framework based on identifying, storing and analysing relationships between biological objects, and includes a series of tools to automate the integration of such information. It currently focuses on physical mapping data, as a starting point towards a map of the human X chromosome that should provide a uniform and global research resource for ongoing and future sequencing and functional studies. AVAILABILITY: IXDB is available at http://ixdb.mpimg-berlin-dahlem.mpg.de. The iace2ixdb software and a description of the Iace data format are available from the authors. CONTACT: hrc@genoscope.cns.fr
Recognition of splice junctions on DNA sequences by BRAIN learning algorithm.
Authors: Rampone S
Published: July 2002

MOTIVATION: The problem addressed in this paper is the prediction of splice site locations in human DNA. The aims of the proposed approach are explicit splicing rule description, high recognition quality, and robust and stable 'one shot' data processing. RESULTS: These results are achieved by means of a new learning algorithm [BRAIN (Batch Relevance-based Artificial INtelligence)], described in the paper, inferring Boolean formulae from examples, and by considering the splicing rules as disjunctive normal form (DNF) formulae. The formula terms are computed in an iterative way, by identifying from the training set a relevance coefficient for each attribute. The classification is then refined by a neural network and combined with a discriminant analysis procedure. This splice site recognition method shows low error rates (0.0002 and 0.0003) and high correlation coefficient measures (0.83 and 0.81) for donor and acceptor sites, respectively; better than other methods. AVAILABILITY: The BRAIN package (Borland Turbo Pascal for Windows) is available on the EMBL file server. (ftp://ftp.ebi.ac.uk/pub/software/dos under nnbrain$.exe). CONTACT: rampo@vaxsa.csied.unisa.it
Prediction of RNA secondary structure based on helical regions distribution.
Authors: WuJu L , JiaJin W
Published: July 2002

MOTIVATION: RNAs play an important role in many biological processes and knowing their structure is important in understanding their function. Due to difficulties in the experimental determination of RNA secondary structure, the methods of theoretical prediction for known sequences are often used. Although many different algorithms for such predictions have been developed, this problem has not yet been solved. It is thus necessary to develop new methods for predicting RNA secondary structure. The most-used at present is Zuker's algorithm which can be used to determine the minimum free energy secondary structure. However many RNA secondary structures verified by experiments are not consistent with the minimum free energy secondary structures. In order to solve this problem, a method used to search a group of secondary structures whose free energy is close to the global minimum free energy was developed by Zuker in 1989. When considering a group of secondary structures, if there is no experimental data, we cannot tell which one is better than the others. This case also occurs in combinatorial and heuristic methods. These two kinds of methods have several weaknesses. Here we show how the central limit theorem can be used to solve these problems. RESULTS: An algorithm for predicting RNA secondary structure based on helical regions distribution is presented, which can be used to find the most probable secondary structure for a given RNA sequence. It consists of three steps. First, list all possible helical regions. Second, according to central limit theorem, estimate the occurrence probability of every helical region based on the Monte Carlo simulation. Third, add the helical region with the biggest probability to the current structure and eliminate the helical regions incompatible with the current structure. The above processes can be repeated until no more helical regions can be added. Take the current structure as the final RNA secondary structure. In order to demonstrate the confidence of the program, a test on three RNA sequences: tRNAPhe, Pre-tRNATyr, and Tetrahymena ribosomal RNA intervening sequence, is performed. AVAILABILITY: The program is written in Turbo Pascal 7.0. The source code is available upon request. CONTACT: Wujj@nic.bmi.ac.cn or Liwj@mail.bmi.ac.cn
GeneTree: comparing gene and species phylogenies using reconciled trees.
Authors: Page R D
Published: July 2002

SUMMARY: GeneTree is a program for comparing gene and species trees using reconciled trees. The program can compute the cost of embedding a gene tree within a species tree, visually display the location and number of gene duplications and losses, and search for optimal species trees. AVAILABILITY: The program is free and is available at ((http://taxonomy.zoology.gla.ac. uk/rod/genetree/genetree.html)).
SPEM: a parser for EMBL style flat file database entries.
Authors: Pocock M R , Hubbard T , Birney E
Published: July 2002

SUMMARY: We present a set of Perl modules for the flexible and robust parsing and editing of EMBL/SWISS-PROT databases. AVAILABILITY: The Web page at http://www.sanger.ac. uk/Software/PerlModule/ provides information about downloading the SPEM and PrEMBL modules, and provides links to documentation and example code.
An Internet linkage and mutation database for the complex phenotype asthma.
Authors: Wjst M , Immervoll T
Published: July 2002

SUMMARY: The paper presents details of database construction, website installation and server architecture of the asthma and allergy gene database. AVAILABILITY: Database and server templates are available on request from the first author. SUPPLEMENTARY INFORMATION: The URL of the asthma and allergy gene database is http://cooke.gsf.de
ORBIT: an integrated environment for user-customized bioinformatics tools.
Authors: Bellgard M I , Hiew H L , Hunter A , Wiebrands M
Published: July 2002

MOTIVATION: There are a large number of computational programs freely available to bioinformaticians via a client/server, web-based environment. However, the client interface to these tools (typically an html form page) cannot be customized from the client side as it is created by the service provider. The form page is usually generic enough to cater for a wide range of users. However, this implies that a user cannot set as 'default' advanced program parameters on the form or even customize the interface to his/her specific requirements or preferences. Currently, there is a lack of end-user interface environments that can be modified by the user when accessing computer programs available on a remote server running on an intranet or over the Internet. RESULTS: We have implemented a client/server system called ORBIT (Online Researcher's Bioinformatics Interface Tools) where individual clients can have interfaces created and customized to command-line-driven, server-side programs. Thus, Internet-based interfaces can be tailored to a user's specific bioinformatic needs. As interfaces are created on the client machine independent of the server, there can be different interfaces to the same server-side program to cater for different parameter settings. The interface customization is relatively quick (between 10 and 60 min) and all client interfaces are integrated into a single modular environment which will run on any computer platform supporting Java. The system has been developed to allow for a number of future enhancements and features. ORBIT represents an important advance in the way researchers gain access to bioinformatics tools on the Internet.
A simple algorithm for detecting circular permutations in
proteins
Authors: Uliel S. , Fliess A. , Amir A. , Unger R.
Published: July 2002

Motivation: Circular permutation of a protein is a genetic operation in which part of the C-terminal of the protein is moved to its N-terminal. Recently, it has been shown that proteins that undergo engineered circular permutations generally maintain their three dimensional structure and biological function. This observation raises the possibility that circular permutation has occured in Nature during evolution. In this scenario a protein underwent circular permutation into another protein, thereafter both proteins further diverged by standard genetic operations. To study this possibility one needs an efficient algorithm that for a given pair of proteins can detect the underlying event of circular permutations. A possible formal description of the question is: given two sequences, find a circular permutation of one of them under which the edit distance between the proteins is minimal. A naive algorithm might take time proportional to N3 or even N4, which is prohibitively slow for a large-scale survey. A sophisticated algorithm that runs in asymptotic time of N2 was recently suggested, but it is not practical for a large-scale survey.

Results: A simple and efficient algorithm that runs in time N2 is presented. The algorithm is based on duplicating one of the two sequences, and then performing a modified version of the standard dynamic programming algorithm. While the algorithm is not guaranteed to find the optimal results, we present data that indicate that in practice the algorithm performs very well.

Availability: A Fortran program that calculates the optimal edit distance under circular permutation is available upon request from the authors.

Contact: ron@biocom1.ls.biu.ac.il
Interpolated markov chains for eukaryotic promoter recognition.
Authors: Ohler U , Harbeck S , Niemann H , N√∂th E , Reese M G
Published: July 2002

MOTIVATION: We describe a new content-based approach for the detection of promoter regions of eukaryotic protein encoding genes. Our system is based on three interpolated Markov chains (IMCs) of different order which are trained on coding, non-coding and promoter sequences. It was recently shown that the interpolation of Markov chains leads to stable parameters and improves on the results in microbial gene finding (Salzberg et al., Nucleic Acids Res., 26, 544-548, 1998). Here, we present new methods for an automated estimation of optimal interpolation parameters and show how the IMCs can be applied to detect promoters in contiguous DNA sequences. Our interpolation approach can also be employed to obtain a reliable scoring function for human coding DNA regions, and the trained models can easily be incorporated in the general framework for gene recognition systems. RESULTS: A 5-fold cross-validation evaluation of our IMC approach on a representative sequence set yielded a mean correlation coefficient of 0.84 (promoter versus coding sequences) and 0.53 (promoter versus non-coding sequences). Applied to the task of eukaryotic promoter region identification in genomic DNA sequences, our classifier identifies 50% of the promoter regions in the sequences used in the most recent review and comparison by Fickett and Hatzigeorgiou ( Genome Res., 7, 861-878, 1997), while having a false-positive rate of 1/849 bp.
Complete genomes in WWW Entrez: data representation and analysis.
Authors: Tatusova T A , Karsch-Mizrachi I , Ostell J A
Published: July 2002

MOTIVATION: The large amount of genome sequence data now publicly available can be accessed through the National Center for Biotechnology Information (NCBI) Entrez search and retrieval system, making it possible to explore data of a breadth and scope exceeding traditional flatfile views. RESULTS: Here we report recent improvements for completely sequenced genomes from viruses, bacteria, and yeast. Flexible web based views, precomputed relationships, and immediate access to analytical tools provide scientists with a portal into the new insights to be gained from completed genome sequences. AVAILABILITY: Entrez Genomes can be accessed on the World Wide Web at http://www.ncbi.nlm.nih.gov/Entrez/Genome/ org.html.
POWER_SAGE: comparing statistical tests for SAGE experiments
Authors: Man Michael Z. , Wang Xuning , Wang Yixin
Published: July 2002

Motivation: The Serial Analysis of Gene Expression (SAGE) technology determines the expression level of a gene by measuring the frequency of a sequence tag derived from the corresponding mRNA transcript. Several statistical tests have been developed to detect significant differences in tag frequency between two samples. However, which one of these tests has the greatest power to detect real changes remains undetermined.

Results: This paper compares three statistical tests for detecting significant changes of gene expression in SAGE experiments. The comparison makes use of Monte Carlo simulation that, in essence, generates ‘virtual’ SAGE experiments. Our analysis shows that the Chi-square test has the best power and robustness. Since the POWER_ SAGE program can easily run ‘virtual’ SAGE studies with different combinations of sample size and tag frequency and determine the power for each combination, it can serve as a useful tool for planning SAGE experiments.

Availability: The POWER_ SAGE software is available upon request from the authors.

Contact: michael.man@pfizer.com

To whom correspondence should be addressed.
Comparing systemic properties of ensembles of biological
networks by graphical and statistical methods
Authors: Alves Rui , Savageau Michael A.
Published: July 2002

Motivation: When dealing with questions that concern a general class of models for biological networks, large numbers of distinct models within the class can be grouped into an ensemble that gives a statistical view of the properties for the general class. Comparing properties of different ensembles through the use of point measures (e.g. medians, standard deviations, correlation coefficients) can mask inhomogeneities in the correlations between properties. We are therefore motivated to develop strategies that allow these inhomogeneities to be more easily detected.

Results: Methods are described for constructing ensembles of models within the context of a Mathematically Controlled Comparison. A Density of Ratios Plot for a given systemic property is then defined as follows: the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(y\) \end{document}axis represents the value of the systemic property in a reference model divided by the value in the alternative model, and the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(x\) \end{document}axis represents the value of the systemic property in the reference model. Techniques involving moving quantiles are introduced to generate secondary plots in which correlations and inhomogeneities in correlations are more easily detected. Several examples that illustrate the advantages of these techniques are presented and discussed.

Contact: Savageau@umich.edu

* To whom correspondence should be addressed.
TRES: comparative promoter sequence analysis
Authors: Katti Mukund V. , Sakharkar Meena K. , Ranjekar Prabhakar K. , Gupta Vidya S.
Published: July 2002

Summary: Comparative promoter analysis is a promising strategy for elucidation of common regulatory modules conserved in evolutionarily related sequences or in genes showing common expression profiles. To facilitate such analysis, we have developed a software tool that detects conserved transcription factor binding sites, cis-elements, palindromes and k-tuples simultaneously in a set of sequences, and thus helps to identify putative motifs for designing further experiments.

Availability: The program TRES can be accessed at URL: http://www.bic.nus.edu.sg:8888/tres

Contact: vidya@ems.ncl.res.in

*** To whom correspondance should be addressed Vidya S. Gupta, Division of Biochemical Sciences, National Chemical Laboratory, Pune-411 008, INDIA
ISYS: a decentralized, component-based approach to the

integration of heterogeneous bioinformatics resources
Authors: Siepel A. , Farmer A. , Tolopko A. , Zhuang M. , Mendes P. , Beavis W. , Sobral B.
Published: July 2002

Motivation: Heterogeneity of databases and software resources continues to hamper the integration of biological information. Top-down solutions are not feasible for the full-scale problem of integration across biological species and data types. Bottom-up solutions so far have not integrated, in a maximally flexible way, dynamic and interactive graphical-user-interface components with data repositories and analysis tools.

Results: We present a component-based approach that relies on a generalized platform for component integration. The platform enables independently-developed components to synchronize their behavior and exchange services, without direct knowledge of one another. An interface-based data model allows the exchange of information with minimal component interdependency. From these interactions an integrated system results, which we call ISYS\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(^{TM}\) \end{document}. By allowing services to be discovered dynamically based on selected objects, ISYS encourages a kind of exploratory navigation that we believe to be well-suited for applications in genomic research.

Availability: A ‘developer’s kit’ for creating software that uses the ISYS platform is available at www.ncgr.org/research/isys/devrel.html. It includes a more refined and fully documented version of the platform and a starting set of ISYS-ready components. Up-to-date descriptions of the ISYS project can be found at www.ncgr.org/research/isys.

Contact: isys@ncgr.org

* To whom correspondence should be addressed.
PrimeArray: genome-scale primer design for DNA-microarray
construction
Authors: Raddatz Günter , Dehio Michaela , Meyer Thomas F. , Dehio Christoph
Published: July 2002

Summary: PrimeArray is a Windows program that computes oligonuceotide primer pairs for genome-scale gene amplification by the Polymerase Chain Reaction (PCR). The program supports the automated extraction of coding sequences (CDS) from various input-file formats and allows highly automated primer pair-optimization.

Availability: The program is freely available for non-profit use via request from the authors.

Contact: christoph.dehio@unibas.ch
GeneOrder: comparing the order of genes in small genomes
Authors: Mazumder Raja , Kolaskar Ashok , Seto Donald
Published: July 2002

Motivation: The recent rapid rise in the availability of whole genome DNA sequence data has led to bottlenecks in their complete analysis. Specifically, there is a need for software tools that will allow mining of gene and putative gene data at a whole genome level. These new tools will complement the current set already in use for studying specific aspects of individual genes and putative genes in detail. A key software challenge is to make them user-friendly, without losing their flexibility and capability for use in research.

Results: The creation of GeneOrder—a web-based interactive, computational tool—allows researchers to compare the order of genes in two genomes. It has been tested on full genome sequence data for viruses, mitochondria and chloroplasts that were obtained from the NCBI GenBank database. It is accessible at http://www.bif.atcc.org/GENEOrder/index.html. GeneOrder prepares the comparison in table form, listing the order of similar genes. Hyperlinks are provided from this output; these lead to the ‘Protein Coding Regions’ in the NCBI database.

* To whom correspondence should be addressed.
Trev: a DNA trace editor and viewer
Authors: Bonfield James K. , Beal Kathryn F. , Betts Matthew J. , Staden Rodger
Published: July 2002

Trev is a DNA trace editor and viewer, which is available free for UNIX and Microsoft Windows platforms. It can read all the commonly used file formats, including the new, compact ZTR files.

Availability: ftp://ftp.mrc-lmb.cam.ac.uk/pub/staden/trev

Contact: jkb@mrc-lmb.cam.ac.uk

* To whom correspondence should be addressed.
Unsupervised technique for robust target separation and
analysis of DNA microarray spots through adaptive pixel
clustering
Authors: Bozinov Daniel , Rahnenführer Jörg
Published: July 2002

Motivation: Microarray images challenge existing analytical methods in many ways given that gene spots are often comprised of characteristic imperfections. Irregular contours, donut shapes, artifacts, and low or heterogeneous expression impair corresponding values for red and green intensities as well as their ratio R/G. New approaches are needed to ensure accurate data extraction from these images.

Results: Herein we introduce a novel method for intensity assessment of gene spots. The technique is based on clustering pixels of a target area into foreground and background. For this purpose we implemented two clustering algorithms derived from k-means and Partitioning Around Medoids (PAM), respectively. Results from the analysis of real gene spots indicate that our approach performs superior to other existing analytical methods. This is particularly true for spots generally considered as problematic due to imperfections or almost absent expression. Both PXPAM and PXKMEANS prove to be highly robust against various types of artifacts through adaptive partitioning, which more correctly assesses expression intensity values.

Availability: The implementation of this method is a combination of two complementary tools Extractiff (Java) and Pixclust (free statistical language R), which are available upon request from the authors.

Contact: dbozinov@unmc.edu

* To whom correspondence should be addressed.

† Both authors contributed equally to this manuscript.
Gavel‐to‐Gavel Congressional Television Coverage as Political Advertising: The Impact of C‐Span on Legislative Sessions
Authors: Mixon Franklin G. , Hobson David L. , Upadhyaya Kamal P.
Published: July 2002

This article examines the effect of television on the length of legislative sessions at the federal level in the United States. Data from the U.S. Congress during the period 1972–96 are employed, during part of which time each house of Congress received significant television coverage by C‐SPAN and C‐SPAN2. Evidence from a Parks regression suggests that the presence of C‐SPAN has increased House sessions by 88–250 hours and the presence of C‐SPAN2 has increased Senate sessions by a striking 252–431 hours, other things constant. Additional estimates suggest that House sessions are about two minutes longer per bill introduced under the eye of C‐SPAN, and Senate sessions are about four minutes longer per bill introduced in the presence of C‐SPAN2. Longer sessions, which represent low‐cost forms of advertising for incumbents, are not without costs to taxpayers. We estimate that these costs lie somewhere between $16 million and $392 million in real terms per session of Congress.
JAB1/CSN5 and the COP9 signalosome
Authors: Chamovitz Daniel A , Segal Daniel
Published: July 2002

The Jun activating binding protein (JAB1) specifically stabilizes complexes of c‐Jun or JunD with AP‐1 sites, increasing the specificity of target gene activation by AP‐1 proteins. JAB1 is also known as COP9 signalosome subunit 5 (CSN5), which is a component of the COP9 signalosome regulatory complex (CSN). Over the past year, JAB1/CSN5 has been implicated in numerous signaling pathways including those that regulate light signaling in plants, larval development in Drosophila, and integrin signaling, cell cycle control, and steroid hormone signaling in a number of systems. However, the general role of the CSN complex, and the specific role of JAB1/CSN5, still remain obscure. This review attempts to integrate the available data to help explain the role of JAB1/CSN5 and the COP9 signalosome in regulating multiple pathways (in this review, both JAB1 and CSN5 terminologies are used interchangeably, depending on the source material).
The socio-economic burden of influenza
Authors: Szucs Thomas
Published: July 2002

Influenza epidemics and pandemics have a huge impact on society and individuals. The weight and scope of the burden of influenza varies with the age and underlying health of the patient. The disease imposes a significant burden on all individuals, but hospitalization and treatment occur more frequently in high-risk patients (the elderly and those with certain underlying medical conditions); patient populations that are increasing in size. Escalating medical costs have increased the need to quantify the burden of influenza. The first step in any such analysis is to determine the incidence of the disease; with influenza, this is often under-reported, since the illness may be confused with other viral illnesses. In addition to the direct costs of medical care, the indirect costs of influenza are substantial and stem largely from absenteeism and loss of work productivity. Estimates of the cost of influenza in the USA, France and Germany have shown that indirect costs can be five– to 10–fold higher than direct costs. Other intangible costs associated with influenza include impaired performance, which can reduce reaction times, and adverse effects on the quality of life of patients and their families. The costs of interventions should, therefore, be considered in this context. The main approach to the control of influenza and its associated costs is the administration of vaccines. Although vaccines are widely effective, the greatest potential benefits are observed within high-risk groups; vaccination is therefore recommended in many countries for high-risk patients, their carers and healthcare workers. However, the shortcomings of present vaccines, which include manufacturing limitations that prevent guaranteed adequate supply of vaccine, the difficulty in matching vaccines to circulating strains and the need for administration by injection, highlight the need for complementary treatment.
Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension
Authors: TARASEVICIENE‐STEWART LAIMUTE , KASAHARA YASUNORI , ALGER LORI , HIRTH PETER , MAHON GERALD MC , WALTENBERGER JOHANNES , VOELKEL NORBERT F. , TUDER RUBIN M.
Published: July 2002

Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR‐2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR‐2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416‐treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z‐Asp‐CH2DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.—Taraseviciene‐Stewart, L., Kasahara, Y., Alger, L., Hirth, P., McMahon, G., Waltenberger, J., Voelkel, N. F., Tuder, R. M. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15, 427‐438 (2001)
Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies
Authors: Goedert Michel
Published: July 2002

Alzheimer'sdisease and Parkinson'sdisease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer'sdisease are made of the microtubule–associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson'sdisease are made of the protein α–synuclein and that rare, familial forms of Parkinson'sdisease are caused by missense mutations in the α–synuclein gene. Besides Parkinson'sdisease, the filamentous inclusions of two additional neurodegenerative diseases, namely dementia with Lewy bodies and multiple system atrophy, have also been found to be made of α–synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer'sdisease. They are the defining neuropathological characteristic of frontotemporal dementias such as Pick'sdisease, and of progressive supranuclear palsy and corticobasal degeneration. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfunction and dementing disease. The new work has established that tauopathies and α–synucleinopathies account for most late–onset neurodegenerative diseases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells.
Mapping the bacterial cell architecture into the chromosome
Authors: Danchin Antoine , Guerdoux-Jamet Pascale , Moszer Ivan , Nitschké Patrick
Published: July 2002

A genome is not a simple collection of genes. We propose here that it can be viewed as being organized as a ;‘celluloculus’ similar to the homunculus of preformists, but pertaining to the category of programmes (or algorithms) rather than to that of architectures or structures: a significant correlation exists between the distribution of genes along the chromosome and the physical architecture of the cell. W e review here data supporting this observation, stressing physical constraints operating on the cell's architecture and dynamics, and their consequences in terms of gene and genome structure. If such a correlation exists, it derives from some selection pressure: simple and general physical principles acting at the level of the cell structure are discussed. As a first case in point we see the piling up of planar modules as a stable, entropy–driven, architectural principle that could be at the root of the coupling between the architecture of the cell and the location of genes at specific places in the chromosome. W e propose that the specific organization of certain genes whose products have a general tendency to form easily planar modules is a general motor for architectural organization in the bacterial cell. A second mechanism, operating at the transcription level, is described that could account for the efficient building up of complex structures. As an organizing principle we suggest that exploration by biological polymers of the vast space of possible conformation states is constrained by anchoring points. In particular, we suggest that transcription does not always allow the 5
′
–end of the transcript to go free and explore the many conformations available, but that, in many cases, it remains linked to the transcribing RNA polymerase complex in such a way that loops of RNA, rather than threads with a free end, explore the surrounding medium. In bacteria, extension of the loops throughout the cytoplasm would therefore be mediated by the
de novo
synthesis of ribosomes in growing cells. Termination of transcription and mRNA turnover would accordingly be expected to be controlled by sequence features at both the 3
′
– and 5
′
–ends of the molecule. These concepts are discussed taking into account
in vitro
analysis of genome sequences and experimental data about cell compartmentalization, mRNA folding and turnover, as well as known structural features of protein and membrane complexes.
Genetic control of size inDrosophila
Authors: Oldham Sean , Böhni Ruth , Stocker Hugo , Brogiolo Walter , Hafen Ernst
Published: July 2002

During the past ten years, significant progress has been made in understanding the basic mechanisms of the development of multicellular organisms. Genetic analysis of the development ofCaenorhabditis elegansandDrosophilahas unearthed a fruitful number of genes involved in establishing the basic body plan, patterning of limbs, specification of cell fate and regulation of programmed cell death. The genes involved in these developmental processes have been conserved throughout evolution and homologous genes are involved in the patterning of insect and human limbs. Despite these important discoveries, we have learned astonishingly little about one of the most obvious distinctions between animals: their difference in body size. The mass of the smallest mammal, the bumble–bee bat, is 2g while that of the largest mammal, the blue whale, is 150t or 150 million grams. Remarkably, even though they are in the same class, body size can vary up to 75–million–fold. Furthermore, this body growth can be finite in the case of most vertebrates or it can occur continuously throughout life, as for trees, molluscs and large crustaceans. Currently, we know comparatively little about the genetic control of body size. In this article we will review recent evidence from vertebrates and particularly from Drosophila that implicates insulin/insulin–like growth factor–I and other growth pathways in the control of cell, organ and body size.
Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae
Authors: Briggs Scott D. , Bryk Mary , Strahl Brian D. , Cheung Wang L. , Davie Judith K. , Dent Sharon Y.R. , Winston Fred , Allis C. David
Published: July 2002

Histone methylation is known to be associated with both transcriptionally active and repressive chromatin states. Recent studies have identified SET domain–containing proteins such as SUV39H1 and Clr4 as mediators of H3 lysine 9 (Lys9) methylation and heterochromatin formation. Interestingly, H3 Lys9 methylation is not observed from bulk histones isolated from asynchronous populations ofSaccharomyces cerevisiae or Tetrahymena thermophila. In contrast, H3 lysine 4 (Lys4) methylation is a predominant modification in these smaller eukaryotes. To identify the responsible methyltransferase(s) and to gain insight into the function of H3 Lys4 methylation, we have developed a histone H3 Lys4 methyl-specific antiserum. With this antiserum, we show that deletion of SET1, but not of other putative SET domain–containing genes, in S. cerevisiae, results in the complete abolishment of H3 Lys4 methylation in vivo. Furthermore, loss of H3 Lys4 methylation in aset1Δ strain can be rescued by SET1. Analysis of histone H3 mutations at Lys4 revealed a slow-growth defect similar to aset1Δ strain. Chromatin immunoprecipitation assays show that H3 Lys4 methylation is present at the rDNA locus and that Set1-mediated H3 Lys4 methylation is required for repression of RNA polymerase II transcription within rDNA. Taken together, these data suggest that Set1-mediated H3 Lys4 methylation is required for normal cell growth and transcriptional silencing.
mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family
Authors: Chen Hua-Wei , Chen Xiu , Oh Su-Wan , Marinissen Maria J. , Gutkind J. Silvio , Hou Steven X.
Published: July 2002

The JAK/STAT signal transduction pathway controls numerous events inDrosophila melanogaster development. Receptors for the pathway have yet to be identified. Here we have identified a Drosophilagene that shows embryonic mutant phenotypes identical to those in the hopscotch (hop)/JAK kinase and marelle(mrl)/Stat92e mutations. We named this genemaster of marelle (mom). Genetic analyses placemom's function between upd (the ligand) andhop. We further show that cultured cells transfected with themom gene bind UPD and activate the HOP/STAT92E signal transduction pathway. mom encodes a protein distantly related to the mammalian cytokine receptor family. These data show thatmom functions as a receptor of the Drosophila JAK/STAT signal transduction pathway.
Dynamics of global histone acetylation and deacetylation in vivo: rapid restoration of normal histone acetylation status upon removal of activators and repressors
Authors: Katan-Khaykovich Yael , Struhl Kevin
Published: July 2002

DNA-binding activators and repressors recruit histone acetylases and deacetylases to promoters, thereby generating localized domains of modified histones that influence transcriptional activity. At the end of a transcriptional response, alterations in histone acetylation status are reversed, but the dynamics of this process are poorly understood. Here, we recruit histone deacetylases and acetylases to a well-defined yeast promoter in a regulated manner. Following dissociation of the recruiting protein from the promoter, targeted deacetylation and acetylation are reversed with rapid, yet distinct, kinetics. Reversal of targeted deacetylation occurs within 5–8 min, whereas reversal of targeted acetylation is more rapid, taking 1.5 min. These findings imply that untargeted, globally acting enzymes generate a highly dynamic equilibrium of histone acetylation and deacetylation reactions across chromatin. Targeted acetylases and deacetylases can locally perturb this equilibrium, yet once they are removed, the global activities mediate a rapid return to the steady-state level of histone acetylation. Our results also indicate that TBP occupancy depends on the presence of the activator, not histone acetylation status.
Evolutionary History of Cer Elements and Their Impact on the C. elegans Genome
Authors: Ganko Eric W. , Fielman Kevin T. , McDonald John F.
Published: July 2002

We report the results of sequence analysis and chromosomal distribution of all distinguishable long terminal repeat (LTR) retrotransposons (Cer elements) in the Caenorhabditis elegans genome. Included in this analysis are all readily recognizable full-length and fragmented elements, as well as solo LTRs. Our results indicate that there are 19 families of Cerelements, some of which display significant subfamily structure.Cer elements can be clustered based on their tRNA primer binding sites (PBSs). These clusters are in concordance with our reverse transcriptase- and LTR-based phylogenies. Although we find that most Cer elements are located in the gene depauperate chromosome ends, some elements are located in or near putative genes and may contribute to gene structure and function. The results of RT-PCR analyses are consistent with this prediction.
Evolution of Gene Order in the Genomes of Two Related Yeast Species
Authors: Fischer Gilles , Neuvéglise Cécile , Durrens Pascal , Gaillardin Claude , Dujon Bernard
Published: July 2002

Changes in gene order between the genomes of two related yeast species, Saccharomyces cerevisiae and Saccharomyces bayanus var. uvarum were studied. From the dataset of a previous low coverage sequencing of the S. bayanus var.uvarum genome, 35 different synteny breakpoints between neighboring genes and two cases of local gene inversion were characterized in detail. The number and the type of the chromosomal rearrangements that have lead to these differences were identified. We show that evolution of gene order in the genomes of these two yeast species is driven mainly by gene duplication onto different chromosomes followed by differential loss of the repeated copies. In addition, local gene inversions also would result from a mechanism of gene duplication, but in an inverted orientation, followed by loss of the original copy. The identification of traces of anciently duplicated genes, called relics, show that the loss of duplicates is more frequently caused by the accumulation of numerous mutations in one of the two copies than by DNA deletion. Surprisingly, gross chromosomal rearrangements such as translocations have only a minor effect on gene order reshuffling as they account for <10% of the synteny breakpoints.

[The sequence data have been submitted to the EMBL Library under accession nos. AJ316068 and AJ316069.]
Propagation of a single destabilizing mutation throughout the Escherichia coli ribonuclease HI native state
Authors: Spudich Giulietta , Lorenz Sonja , Marqusee Susan
Published: July 2002

A point mutation (I53A) in the core of Escherichia coli RNase H* is known to destabilize both the native conformation (ΔGUN) and the kinetic intermediate (ΔGUI) by 2 kcal/mole. Here, we have used native‐state hydrogen deuterium exchange to ask how this destabilization is propagated throughout the molecule. Stability parameters were obtained for individual residues in I53A and compared with those from the wild‐type protein. A destabilization of 2 kcal/mole was observed in residues in the core but was not detected in the periphery of the molecule. These results are consistent with the localized destabilization of the core observed in the early intermediate of the kinetic folding pathway, supporting the resemblance of this kinetic intermediate to the partially unfolded form detected in the native state at equilibrium. A thermodynamic cycle also shows no interaction between Ile 53 and a residue in the periphery. There is, however, an increase in the number of denaturant‐independent exchange events in the periphery of I53A, showing that effects of the point mutation are communicated to regions outside the core, although perhaps not through changes in stability. In sum, this work shows that localized regions within a protein can be destabilized independently. Furthermore, it implies a correspondence between the kinetic intermediate and the equilibrium PUF, as the magnitude and localization of the destabilization are the same in both.
Cone‐beam volume CT breast imaging: Feasibility study
Authors: Chen Biao , Ning Ruola
Published: July 2002

X‐ray projection mammography, using a film/screen combination, or digital techniques, has proven to be the most effective imaging modality currently available for early detection of breast cancer. However, the inherent superimposition of structures makes a small carcinoma (a few millimeters in size) difficult to detect when it is occult or in dense breasts, leading to a high false‐positive biopsy rate. Cone‐beam x‐ray‐projection‐based volume imaging using flat panel detectors (FPDs) may allow obtaining three‐dimensional breast images, resulting in more accurate diagnosis of structures and patterns of lesions while eliminating the hard compression of breasts. This article presents a novel cone‐beam volume computed tomographic breast imaging (CBVCTBI) technique based on the above techniques. Through a variety of computer simulations, the key issues of the system and imaging techniques were addressed, including the x‐ray imaging geometry and corresponding reconstruction algorithms, x‐ray characteristics of breast tissue and lesions, x‐ray setting techniques, the absorbed dose estimation, and the quantitative effect of x‐ray scattering on image quality. The preliminary simulation results support the proposed CVBCTBI modality for breast imaging in respect to its feasibility and practicability. The absorbed dose level is comparable to that of current mammography and will not be a prominent problem for this imaging technique. Compared to conventional mammography, the proposed imaging technique with isotropic spatial resolution will potentially provide significantly better low‐contrast detectability of breast tumors and more accurate location of breast lesions.
Comment on the adiabatic condition
Authors: Aguiar Pinto A. C. , Nemes M. C. , Peixoto de Faria J. G. , Thomaz M. T.
Published: July 2002

The experimental observation of effects due to Berry’s phase in quantum systems is certainly one of the most impressive demonstrations of the correctness of the superposition principle in quantum mechanics. Since Berry’s original paper in 1984, the spin 12 coupled with a rotating external magnetic field has been one of the most studied models where those phases appear. We also consider a special case of this soluble model. A detailed analysis of the coupled differential equations and comparison with exact results teach us why the usual procedure (of neglecting nondiagonal terms) is mathematically sound.
Relativistic hydrogen atom revisited
Authors: Martı́nez-y-Romero R. P.
Published: July 2002

The hydrogen atom is solved using a simple method. We show that this system has an exact solution that can be written in terms of Laguerre polynomials of noninteger index, instead of the hypergeometric series. This point is important because Laguerre polynomials of integer index appear in the solution of the nonrelativistic hydrogen atom, giving students a more unified point of view for this system.
Simple chaotic systems and circuits
Authors: Sprott J. C.
Published: July 2002

Many new chaotic systems with algebraically simple representations are described. These systems involve a single third-order autonomous ordinary differential equation (jerk equation) with various nonlinearities. Piecewise linear functions are emphasized to permit easy electronic implementation with diodes and operational amplifiers. Several new simple and robust chaotic electrical circuits are described and evaluated.
Sex-specific fundamental and formant frequency patterns in a cross-sectional study
Authors: Whiteside Sandra P.
Published: July 2002

An extensive developmental acoustic study of the speech patterns of children and adults was reported by Lee and colleagues [Lee et al., J. Acoust. Soc. Am. 105, 1455–1468 (1999)]. This paper presents a reexamination of selected fundamental frequency and formant frequency data presented in their report for ten monophthongs by investigating sex-specific and developmental patterns using two different approaches. The first of these includes the investigation of age- and sex-specific formant frequency patterns in the monophthongs. The second, the investigation of fundamental frequency and formant frequency data using the critical band rate (bark) scale and a number of acoustic-phonetic dimensions of the monophthongs from an age- and sex-specific perspective. These acoustic-phonetic dimensions include: vowel spaces and distances from speaker centroids; frequency differences between the formant frequencies of males and females; vowel openness/closeness and frontness/backness; the degree of vocal effort; and formant frequency ranges. Both approaches reveal both age- and sex-specific development patterns which also appear to be dependent on whether vowels are peripheral or nonperipheral. The developmental emergence of these sex-specific differences are discussed with reference to anatomical, physiological, sociophonetic, and culturally determined factors. Some directions for further investigation into the age-linked sex differences in speech across the lifespan are also proposed.