bluuebunny/crossref_metadata_2025 huggingface dataset:
Cadherin-6 Mediates the Heterotypic Interactions between the Hemopoietic Osteoclast Cell Lineage and Stromal Cells in a Murine Model of Osteoclast Differentiation
Authors: Mbalaviele Gabriel , Nishimura Riko , Myoi Akira , Niewolna Maria , Reddy Sakamuri V. , Chen Di , Feng Jian , Roodman David , Mundy Gregory R. , Yoneda Toshiyuki
Published: July 2002

Osteoclasts are multinucleated cells of hemopoietic origin that are responsible for bone resorption during physiological bone remodeling and in a variety of bone diseases. Osteoclast development requires direct heterotypic cell–cell interactions of the hemopoietic osteoclast precursors with the neighboring osteoblast/stromal cells. However, the molecular mechanisms underlying these heterotypic interactions are poorly understood. We isolated cadherin-6 isoform, denoted cadherin-6/2 from a cDNA library of human osteoclast-like cells. The isolated cadherin-6/2 is 3,423 bp in size consisting of an open reading frame of 2,115 bp, which encodes 705 amino acids. This isoform lacks 85 amino acids between positions 333 and 418 and contains 9 different amino acids in the extracellular domain compared with the previously described cadherin-6. The human osteoclast-like cells also expressed another isoform denoted cadherin-6/1 together with the cadherin-6. Introduction of cadherin-6/2 into L-cells that showed no cell–cell contact caused evident morphological changes accompanied with tight cell–cell association, indicating the cadherin-6/2 we isolated here is functional. Moreover, expression of dominant-negative or antisense cadherin-6/2 construct in bone marrow–derived mouse stromal ST2 cells, which express only cadherin-6/2, markedly impaired their ability to support osteoclast formation in a mouse coculture model of osteoclastogenesis. Our results suggest that cadherin-6 may be a contributory molecule to the heterotypic interactions between the hemopoietic osteoclast cell lineage and osteoblast/bone marrow stromal cells required for the osteoclast differentiation. Since both osteoclasts and osteoblasts/bone marrow stromal cells are the primary cells controlling physiological bone remodeling, expression of cadherin-6 isoforms in these two cell types of different origin suggests a critical role of these molecules in the relationship of osteoclast precursors and cells of osteoblastic lineage within the bone microenvironment.
In Vitro Formation of the Endoplasmic Reticulum Occurs Independently of Microtubules by a Controlled Fusion Reaction
Authors: Dreier Lars , Rapoport Tom A.
Published: July 2002

We have established an in vitro system for the formation of the endoplasmic reticulum (ER). Starting from small membrane vesicles prepared from Xenopus laevis eggs, an elaborate network of membrane tubules is formed in the presence of cytosol. In the absence of cytosol, the vesicles only fuse to form large spheres. Network formation requires a ubiquitous cytosolic protein and nucleoside triphosphates, is sensitive to N-ethylmaleimide and high cytosolic Ca2+ concentrations, and proceeds via an intermediate stage in which vesicles appear to be clustered. Microtubules are not required for membrane tubule and network formation. Formation of the ER network shares significant similarities with formation of the nuclear envelope. Our results suggest that the ER network forms in a process in which cytosolic factors modify and regulate a basic reaction of membrane vesicle fusion.
A Myosin I Is Involved in Membrane Recycling from Early Endosomes
Authors: Neuhaus Eva M. , Soldati Thierry
Published: July 2002

Geometry-based mechanisms have been proposed to account for the sorting of membranes and fluid phase in the endocytic pathway, yet little is known about the involvement of the actin–myosin cytoskeleton. Here, we demonstrate that Dictyostelium discoideum myosin IB functions in the recycling of plasma membrane components from endosomes back to the cell surface. Cells lacking MyoB (myoA−/B−, and myoB− cells) and wild-type cells treated with the myosin inhibitor butanedione monoxime accumulated a plasma membrane marker and biotinylated surface proteins on intracellular endocytic vacuoles. An assay based on reversible biotinylation of plasma membrane proteins demonstrated that recycling of membrane components is severely impaired in myoA/B null cells. In addition, MyoB was specifically found on magnetically purified early pinosomes. Using a rapid-freezing cryoelectron microscopy method, we observed an increased number of small vesicles tethered to relatively early endocytic vacuoles in myoA−/B− cells, but not to later endosomes and lysosomes. This accumulation of vesicles suggests that the defects in membrane recycling result from a disordered morphology of the sorting compartment.
Targeted Ablation of the Murine Involucrin Gene
Authors: Djian Philippe , Easley Karen , Green Howard
Published: July 2002

Involucrin is synthesized in abundance during terminal differentiation of keratinocytes. Involucrin is a substrate for transglutaminase and one of the precursors of the cross-linked envelopes present in the corneocytes of the epidermis and other stratified squamous epithelia. These envelopes make an important contribution to the physical resistance of the epidermis. We have generated mice lacking involucrin from embryonic stem cells whose involucrin gene had been ablated by homologous recombination. These mice developed normally, possessed apparently normal epidermis and hair follicles, and made cornified envelopes that could not be distinguished from those of wild-type mice. No compensatory increase of mRNA for other envelope precursors was observed.
A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast
Authors: Lechler Terry , Jonsdottir Gudrun A. , Klee Saskia K. , Pellman David , Li Rong
Published: July 2002

The establishment of cell polarity in budding yeast involves assembly of actin filaments at specified cortical domains. Elucidation of the underlying mechanism requires an understanding of the machinery that controls actin polymerization and how this machinery is in turn controlled by signaling proteins that respond to polarity cues. We showed previously that the yeast orthologue of the Wiskott-Aldrich Syndrome protein, Bee1/Las17p, and the type I myosins are key regulators of cortical actin polymerization. Here, we demonstrate further that these proteins together with Vrp1p form a multivalent Arp2/3-activating complex. During cell polarization, a bifurcated signaling pathway downstream of the Rho-type GTPase Cdc42p recruits and activates this complex, leading to local assembly of actin filaments. One branch, which requires formin homologues, mediates the recruitment of the Bee1p complex to the cortical site where the activated Cdc42p resides. The other is mediated by the p21-activated kinases, which activate the motor activity of myosin-I through phosphorylation. Together, these findings provide insights into the essential processes leading to polarization of the actin cytoskeleton.
Effects of Breeding Environments on Generation and Activation of Autoreactive B-1 Cells in Anti-red Blood Cell Autoantibody Transgenic Mice
Authors: Murakami Masao , Nakajima Kazuo , Yamazaki Ken-ichi , Muraguchi Takehiko , Serikawa Tadao , Honjo Tasuku
Published: July 2002

In anti-red blood cell autoantibody transgenic (autoAb Tg) mice almost all B cells are deleted except for B-1 cells in the peritoneal cavity and the gut. About one-half of the auto Ab Tg mice suffer from autoimmune hemolytic anemia (AIHA) in the conventional condition. Oral administration of lipopolysaccharides activates B-1 cells and induces autoimmune symptoms in the Tg mice, suggesting that the autoimmune disease in anti-RBC autoAb Tg mice is triggered by infections. To examine the association of bacterial infections with the generation of B-1 cells and the occurrence of the autoimmune disease, we analyzed anti-RBC autoAb Tg mice bred in germ-free and specific pathogen-free conditions. In germ-free conditions, few peritoneal B-1 cells were detected, while a significant number of peritoneal B-1 cells existed in specific pathogen-free conditions. In both conditions, no mice suffered from AIHA. However, when these Tg mice were transferred to the conventional condition or injected with lipopolysaccharide, peritoneal B-1 cells expanded and some of these mice suffered from AIHA. These results clearly showed that bacterial infections are responsible for both the expansion of B-1 cells and the onset of the autoimmune disease in these Tg mice.
Endogenous Interleukin 4 Is Required for Development of Protective CD4+ T Helper Type 1 Cell Responses to Candida albicans
Authors: Mencacci Antonella , Del Sero Giuseppe , Cenci Elio , d'Ostiani Cristiana Fè , Bacci Angela , Montagnoli Claudia , Kopf Manfred , Romani Luigina
Published: July 2002

Interleukin (IL)-4–deficient mice were used to assess susceptibility to systemic or gastrointestinal Candida albicans infections, as well as parameters of innate and elicited T helper immunity. In the early stage of systemic infection with virulent C. albicans, an unopposed interferon (IFN)-γ response renders IL-4–deficient mice more resistant than wild-type mice to infection. Yet, IL-4–deficient mice failed to efficiently control infection in the late stage and succumbed to it. Defective IFN-γ and IL-12 production, but not IL-12 responsiveness, was observed in IL-4–deficient mice that failed to mount protective T helper type 1 cell (Th1)-mediated acquired immunity in response to a live vaccine strain of the yeast or upon mucosal immunization in vivo. In vitro, IL-4 primed neutrophils for cytokine release, including IL-12. However, late treatment with exogenous IL-4, while improving the outcome of infection, potentiated CD4+ Th1 responses even in the absence of neutrophils. These findings indicate that endogenous IL-4 is required for the induction of CD4+ Th1 protective antifungal responses, possibly through the combined activity on cells of the innate and adaptive immune systems.
Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice
Authors: Gobbi Alberto , Stoddart Cheryl A. , Malnati Mauro S. , Locatelli Giuseppe , Santoro Fabio , Abbey Nancy W. , Bare Christopher , Linquist-Stepps Valerie , Moreno Mary Beth , Herndier Brian G. , Lusso Paolo , McCune Joseph M.
Published: July 2002

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans.
Effects of Complementarity Determining Region Mutations on the Affinity of an α/β T Cell Receptor: Measuring the Energy Associated with CD4/CD8 Repertoire Skewing
Authors: Manning Thomas C. , Parke Evan A. , Teyton Luc , Kranz David M.
Published: July 2002

It has been proposed that the generally low affinities of T cell receptors (TCRs) for their peptide–major histocompatibility complex (pMHC) ligands (Kd ∼10−4 to 10−7 M) are the result of biological selection rather than an intrinsic affinity limitation imposed by the TCR framework. Using a soluble version of the 2C TCR, we have used complementarity determining region (CDR)-directed mutagenesis to investigate whether the affinity of this receptor for its allogeneic pMHC ligand can be improved upon. We report that several mutants at positions lying within CDR3α and CDR2β showed increased affinities for pMHC compared with the wild-type receptor. Additionally, we have investigated whether Vα mutations that have been implicated in the phenomenon of CD8+ repertoire skewing achieve this skewing by means of generalized increases in affinity for MHC-I molecules. Two mutants (S27F and S51P), which each promote skewing toward a CD8+ phenotype, exhibited significantly reduced affinity for pMHC-I, consistent with a quantitative-instructional model of CD4/CD8 lineage commitment. This model predicts that CD8 is downregulated on thymocytes that have TCR–ligand interactions above a minimal energy threshold. Together, the results (a) demonstrate that engineering higher affinity TCRs is feasible, and (b) provide TCR–pMHC energy values associated with CD4/CD8 repertoire skewing.
Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice
Authors: Guidotti Luca G. , McClary Heike , Loudis Jacquelyn Moorhead , Chisari Francis V.
Published: July 2002

We have previously identified two antiviral cytokines (interferon [IFN]-γ and IFN-α/β) that downregulate hepatitis B virus (HBV) replication in the liver of transgenic mice. The cytokine-inducible downstream events that inhibit HBV replication have not been identified. One possible factor is nitric oxide (NO), a pleiotropic free radical with antiviral activity that is produced in the liver by the inducible NO synthase (iNOS). To examine the role of NO in our model, we crossed transgenic mice that replicate HBV with mice that lack a functional iNOS. Importantly, iNOS-deficient mice were almost completely resistant to the noncytopathic inhibitory effect of HBV-specific cytotoxic T lymphocytes on viral replication, an effect that we have shown previously to depend on the intrahepatic induction of IFN-γ. Conversely, iNOS-deficient mice were not resistant to the antiviral effect of IFN-α/β induced by either polyinosinic-polycytidylic acid complex or by lymphocytic choriomeningitis virus (LCMV) infection. These results indicate that NO mediates the antiviral activity of IFN-γ, whereas the antiviral activity of IFN-α/β is NO independent. We also compared the relative sensitivity of LCMV to control by NO in these animals. Interestingly, LCMV replicated to higher levels in the liver of iNOS-deficient mice than control mice, indicating that NO controls LCMV replication in the liver, as well as HBV.
Host–Virus Interactions during Malaria Infection in Hepatitis B Virus Transgenic Mice
Authors: Pasquetto Valerie , Guidotti Luca G. , Kakimi Kazuhiro , Tsuji Moriya , Chisari Francis V.
Published: July 2002

We have previously shown that hepatitis B virus (HBV) replication is abolished in the liver of HBV transgenic mice by inflammatory cytokines induced by HBV-specific cytotoxic T cells and during unrelated viral infections of the liver. We now report that intrahepatic HBV replication is also inhibited in mice infected by the malaria species Plasmodium yoelii 17X NL. P. yoelii infection triggers an intrahepatic inflammatory response characterized by the influx of natural killer cells, macrophages, and T cells. During this process, interferon (IFN)-γ and IFN-α/β suppress HBV gene expression and replication in the liver. Collectively, the data suggest that malaria infection might influence the course and pathogenesis of HBV infection in coinfected humans.
Muscarinic K+ Channel in the Heart
Authors: Ivanova-Nikolova Tatyana T. , Nikolov Emil N. , Hansen Carl , Robishaw Janet D.
Published: July 2002

The membrane-delimited activation of muscarinic K+ channels by G protein βγ subunits plays a prominent role in the inhibitory synaptic transmission in the heart. These channels are thought to be heterotetramers comprised of two homologous subunits, GIRK1 and CIR, both members of the family of inwardly rectifying K+ channels. Here, we demonstrate that muscarinic K+ channels in neonatal rat atrial myocytes exhibit four distinct gating modes. In intact myocytes, after muscarinic receptor activation, the different gating modes were distinguished by differences in both the frequency of channel opening and the mean open time of the channel, which accounted for a 76-fold increase in channel open probability from mode 1 to mode 4. Because of the tetrameric architecture of the channel, the hypothesis that each of the four gating modes reflects binding of a different number of Gβγ subunits to the channel was tested, using recombinant Gβ1γ5. Gβ1γ5 was able to control the equilibrium between the four gating modes of the channel in a manner consistent with binding of Gβγ to four equivalent and independent sites in the protein complex. Surprisingly, however, Gβ1γ5 lacked the ability to stabilize the long open state of the channel that is responsible for the augmentation of the mean open time in modes 3 and 4 after muscarinic receptor stimulation. The modal regulation of muscarinic K+ channel gating by Gβγ provides the atrial cells with at least two major advantages: the ability to filter out small inputs from multiple membrane receptors and yet the ability to create the gradients of information necessary to control the heart rate with great precision.
Web strategies for professional publishers: developing an information services portal
Authors: Klein Donald C.
Published: July 2002

This paper examines how the free distribution of electronic information on the internet is rapidly changing the commercial environment for small to medium‐sized print publishers, and suggests some recommendations for publishers in the process of establishing their own web strategies. It begins by addressing the concept of the ‘network economy’ and the way in which electronic networks have changed the fundamental economics of many businesses. It then suggests seven recommendations for learned and professional society publishers adapting their own business models to the web, highlighting the need to differentiate print from electronic products by building an electronic information services portal for current members and subscribers.
Finite time blow-up for the inhomogeneous equation 𝑢_{𝑡}=Δ𝑢+𝑎(𝑥)𝑢^{𝑝}+𝜆𝜙 in 𝑅^{𝑑}
Authors: Pinsky Ross
Published: July 2002

We consider the inhomogeneous equation
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GenXref. VI: Automatic generation of links between two heterogeneous databases.
Authors: Achard F , Dessen P
Published: July 2002

MOTIVATION: A large proportion of the information found in public databases is not sufficiently cross-referenced. We developed genXref, an automated system for link inference, because embarking on a manual cross-referencing of genome data would require too much expensive human expertise. It uses information retrieval technology to generate links between objects of heterogeneous databases. RESULTS: GenXref was used to generate links between GDB genes and Genbank human sequences. It resulted in > 10,000 links with a precision of 83% and a recall of approximately 32%.
Mapper: an intelligent restriction mapping tool.
Authors: Inglehart J A , Nelson P C , Zou Y
Published: July 2002

MOTIVATION: To determine the most powerful artificial intelligence techniques for automated restriction mapping, and use them to create a powerful multiple-enzyme restriction mapping tool. RESULTS: The most effective search engine utilized model-driven exhaustive search and a form of binary logic pruning based on Pratt's separation theory. Additional experimentation led to the development of an input preprocessing module which significantly speeds up searches, and an output post-processing module which enables users to analyze large solution sets and reduce their apparent complexity. AVAILABILITY: An executable version of the resultant tool, Mapper, can be downloaded from our Web site (http://www.ai.eecs.uic.edu) by selecting the 'Software' option. CONTACT: nelson@eecs.uic.edu (http://www.ai.eecs.uic.edu/√±elson).
Analysis of DNA curvature using artificial neural networks.
Authors: Parbhane R V , Tambe S S , Kulkarni B D
Published: July 2002

MOTIVATION: Our aim is to utilize an artificial neural network (ANN) for the prediction of DNA curvature in terms of retardation anomaly. RESULTS: An ANN capturing the role of phasing, increased helix flexibility, run of poly(A) tracts and flanking base pair effects in determining the extent of DNA curvature has been developed. The network predictions validate the known experimental results and also explain how the base pairs other than ApA affect the curvature. The results suggest that ANN can be used as a model-free tool for studying DNA curvature. AVAILABILITY: The optimal weights and the procedure to compute the retardation anomaly value are available on request from the authors. CONTACT: bdk@ems. ncl.res.in
A method for comparing circular genomes from gene locations: application to mitochondrial genomes.
Authors: Horimoto K , Suyama M , Toh H , Mori K , Otsuka J
Published: July 2002

MOTIVATION: Data on the entire structures of organelle and bacterial genomes, most of which are known to be circular, have accumulated at a rapid pace. This information enables us to utilize the locations of homologous gene pairs for measuring the dissimilarity between complete genomic structures. RESULTS: A macroscopic distance is presented for comparing circular genomes from their overall structures, on the basis of the locations of two pairs of homologous genes on the compared genomes. The novel aspect of our method is that the comparison between the genomes automatically reveals a relationship based on the information on all gene locations, by incorporating the mobility of each gene, which includes not only the gene order, but also the relative location between gene pairs. The plausibility of the newly defined distances is evaluated by means of 44 mitochondrial genomes. The genome distance shows high performance for quantitatively describing the differences between the gene organizations of the genomes. AVAILABILITY: Since the programs implementing these calculations require well-arranged gene organization data, they have not been released yet. However, one of the authors will analyze circular genomes upon request. Data on the gene organizations may be submitted electronically to the address below.
WWW access to the SYSTERS protein sequence cluster set.
Authors: Krause A , Nicod√®me P , Bornberg-Bauer E , Rehmsmeier M , Vingron M
Published: July 2002

SUMMARY: We present a Web server where the SYSTERS cluster set of the non-redundant protein database consisting of sequences from SWISS-PROT and PIR is being made available for querying and browsing. The cluster set can be searched with a new sequence using the SSMAL search tool. Additionally, a multiple alignment is generated for each cluster and annotated with domain information from the Pfam protein family database. AVAILABILITY: The server address is http://www.dkfz-heidelberg.de/tbi/services/cluster/ systersform
Revealing hidden interval graph structure in STS-content data.
Authors: Harley E , Bonner A , Goodman N
Published: July 2002

MOTIVATION: STS-content data for genomic mapping contain numerous errors and anomalies resulting in cross-links among distant regions of the genome. Identification of contigs within the data is an important and difficult problem. RESULTS: This paper introduces a graph algorithm which creates a simplified view of STS-content data. The shape of the resulting structure graph provides a quality check - coherent data produce a straight line, while anomalous data produce branches and loops. In the latter case, it is sometimes possible to disentangle the various paths into subsets of the data covering contiguous regions of the genome, i.e. contigs. These straight subgraphs can then be analyzed in standard ways to construct a physical map. A theoretical basis for the method is presented along with examples of its application to current STS data from human genome centers. AVAILABILITY: Freely available on request.
A vector-based method for drawing RNA secondary structure.
Authors: Han K , Kim D , Kim H J
Published: July 2002

MOTIVATION: To produce a polygonal display of RNA secondary structure with minimal overlap and distortion of structural elements, with minimal search for positioning them, and with minimal user intervention. RESULTS: A new algorithm for automatically drawing RNA secondary structure has been developed. The algorithm represents the direction and space for a structural element using vector and vector space. Two heuristics are used. The first heuristic is concerned with ordering structural elements to be positioned and the second with positioning them in space. The algorithm and a graphical user interface have been implemented in a working program called VizQFolder on IBM PC compatibles. Experimental results demonstrate that VizQFolder is capable of automatically generating nearly overlap-free polygonal displays for long RNA molecules. The only distortion performed to avoid overlap is the rotation of helices, leading to efficient generation of a polygonal display without sacrificing its readability. VizQFolder is not coupled to a specific prediction program of RNA secondary structure, and thus can be used for visualizing secondary structure models obtained by any means. AVAILABILITY: The executable code of VizQFolder is available at http://automation.inha.ac.kr/khan. It can also be obtained from the authors upon request.
WebBLAST 2.0: an integrated solution for organizing and analyzing sequence data.
Authors: Ferlanti E S , Ryan J F , Makalowska I , Baxevanis A D
Published: July 2002

SUMMARY: WebBLAST is a suite of programs intended to assist in organizing sequencing data and to provide first-pass sequence analysis in an automated fashion. Data processing is fully automated, with end-users being presented both graphical and tabular summaries of data that can be viewed using any Web browser. AVAILABILITY: The program is free and available at http://genome.nhgri.nih. gov/webblast.
Regression trees for analysis of mutational spectra in nucleotide sequences.
Authors: Berikov V B , Rogozin I B
Published: July 2002

MOTIVATION: The study and comparison of mutational spectra is an important problem in molecular biology, because these spectra often reveal important features of the action of various mutagens and the functioning of repair/replication enzymes. As is known, mutability varies significantly along nucleotide sequences: mutations often concentrate at certain positions in a sequence, otherwise termed 'hotspots'. RESULTS: Herein, we propose a regression analysis method based on the use of regression trees in order to analyse the influence of nucleotide context on the occurrence of such hotspots. The REGRT program developed has been tested on simulated and real mutational spectra. For the G:C-->T:A mutational spectra induced by Sn1 alkylating agents (nine spectra), the prediction accuracy was 0. 99. AVAILABILITY: The REGRT program is available upon request from V.Berikov.
Integrated databases and computer systems for studying eukaryotic gene expression.
Authors: Kolchanov N A , Ponomarenko M P , Frolov A S , Ananko E A , Kolpakov F A , Ignatieva E V , Podkolodnaya O A , Goryachkovskaya T N , Stepanenko I L , Merkulova T I , Babenko V V , Ponomarenko Y V , Kochetov A V , Podkolodny N L , Vorobiev D V , Lavryushev S V , Grigorovich D A , Kondrakhin Y V , Milanesi L , Wingender E , Solovyev V , Overton G C
Published: July 2002

MOTIVATION: The goal of the work was to develop a WWW-oriented computer system providing a maximal integration of informational and software resources on the regulation of gene expression and navigation through them. Rapid growth of the variety and volume of information accumulated in the databases on regulation of gene expression necessarily requires the development of computer systems for automated discovery of the knowledge that can be further used for analysis of regulatory genomic sequences. RESULTS: The GeneExpress system developed includes the following major informational and software modules: (1) Transcription Regulation (TRRD) module, which contains the databases on transcription regulatory regions of eukaryotic genes and TRRD Viewer for data visualization; (2) Site Activity Prediction (ACTIVITY), the module for analysis of functional site activity and its prediction; (3) Site Recognition module, which comprises (a) B-DNA-VIDEO system for detecting the conformational and physicochemical properties of DNA sites significant for their recognition, (b) Consensus and Weight Matrices (ConsFrec) and (c) Transcription Factor Binding Sites Recognition (TFBSR) systems for detecting conservative contextual regions of functional sites and their recognition; (4) Gene Networks (GeneNet), which contains an object-oriented database accumulating the data on gene networks and signal transduction pathways, and the Java-based Viewer for exploration and visualization of the GeneNet information; (5) mRNA Translation (Leader mRNA), designed to analyze structural and contextual properties of mRNA 5'-untranslated regions (5'-UTRs) and predict their translation efficiency; (6) other program modules designed to study the structure-function organization of regulatory genomic sequences and regulatory proteins. AVAILABILITY: GeneExpress is available at http://wwwmgs.bionet.nsc. ru/systems/GeneExpress/ and the links to the mirror site(s) can be found at http://wwwmgs.bionet.nsc.ru/mgs/links/mirrors.html+ ++.
Fels-Rand: an Xlisp-Stat program for the comparative analysis
of data under phylogenetic uncertainty
Authors: Blomberg Simon
Published: July 2002

Motivation: Currently available programs for the comparative analysis of phylogenetic data do not perform optimally when the phylogeny is not completely specified (i.e. the phylogeny contains polytomies). Recent literature suggests that a better way to analyse the data would be to create random trees from the known phylogeny that are fully-resolved but consistent with the known tree. A computer program is presented, Fels-Rand, that performs such analyses. A randomisation procedure is used to generate trees that are fully resolved but whose structure is consistent with the original tree. Statistics are then calculated on a large number of these randomly-generated trees. Fels-Rand uses the object-oriented features of Xlisp-Stat to manipulate internal tree representations. Xlisp-Stat’s dynamic graphing features are used to provide heuristic tools to aid in analysis, particularly outlier analysis. The usefulness of Xlisp-Stat as a system for phylogenetic computation is discussed.

Availability: Available from the author or at http://www.uq.edu.au/~ansblomb/Fels-Rand.sit.hqx. Xlisp-Stat is available from http://stat.umn.edu/~luke/xls/xlsinfo/xlsinfo.html.

Contact: s.blomberg@abdn.ac.uk
QTL Express: mapping quantitative trait loci in simple and
complex pedigrees
Authors: Seaton George , Haley Chris S. , Knott Sara A. , Kearsey Mike , Visscher Peter M.
Published: July 2002

Summary: QTL Express is the first application for Quantitative Trait Locus (QTL) mapping in outbred populations with a web-based user interface. User input of three files containing a marker map, trait data and marker genotypes allows mapping of single or multiple QTL by the regression approach, with the option to perform permutation or bootstrap tests.

Availability: http://qtl.cap.ed.ac.uk/

Contact: george.seaton@ed.ac.uk

* To whom correspondence should be addressed.
The generation of long telomere overhangs in human cells:
a model and its implication
Authors: Hao Yu-hua , Tan Zheng
Published: July 2002

Motivation: Linear chromosomes carry on both ends repetitive DNA sequences called telomere. In the conventional model of semi-conservative DNA replication, the 3′-end of a linear DNA strand cannot be fully replicated, resulting in a single-stranded 3′ overhang at one end of the double-stranded DNA product. In this model, the length of the overhang is expected to be about the size of an RNA primer (about nine nucleotides for human cells). However, it has been found that the telomere overhangs in human cells can be as long as several hundred nucleotides. At present, the opinion regarding how such long overhangs are produced is controversial.

Results: In order to gain insight into the mechanism by which long telomere overhangs are produced, we derived a mathematical model that can perfectly describe the length distribution of telomere overhangs in several human cell strains. The model suggests that the production of telomere overhangs can be explained by three contributions corresponding to three regions on the G-rich telomere template strand, namely, the region occupied by the last primer, that missed out by this primer at its 5′-side and the 3′-terminus of the template strand that is inaccessible to primase. The model can also be used to simulate incomplete telomere replication.

Contact: tanclswu@public.wh.hb.cn

* To whom correspondence should be addressed.
Efficacy of the combination ethinyl oestradiol and cyproterone acetate on endocrine, clinical and ultrasonographic profile in polycystic ovarian syndrome
Authors: Falsetti Leopoldo , Gambera Alessandro , Tisi Giancarlo
Published: July 2002

This study shows the effect of a long-term treatment (60 cycles) with the ethinyl oestradiol/cyproterone acetate pill, and the follow-up after 6 months from cessation, in polycystic ovarian syndrome. The 140 studied women had polycystic ovaries and moderate or severe acne, 108 also presented hirsutism. The endocrine profile significantly modified after six cycles (P < 0.001), with a further significant decrease of gonadotrophins, oestrogens and androgens after 12 cycles, and a greater increase of sex hormone-binding globulins and insulin-like growth factor-binding globulins. Between the 12th and 60th cycle there was only a significant reduction of dehydroepiandrosterone sulphate (P < 0.05). Acne disappeared in all patients within 12–24 cycles, but hirsutism was still present in 30.6% after 60 cycles. Mild-moderate hirsutism disappeared in 36–60 cycles, whereas severe hirsutism substantially decreased, but persisted. Ovarian volume, microcyst numbers and stroma percentage significantly decreased (P < 0.01). After 6 months from the end of the therapy, endocrine parameters were identical to the starting ones, acne and hirsutism reappeared, whereas ovarian morphology was between the initial and final condition. Ovaries were polycystic in 42 (30%) patients and multifolliculars in 98 (70%). Our results show the effectiveness of this combination on androgenic symptoms, especially on acne, and suggest that acne and hirsutism are induced by different peripheral mechanisms.
Mechanisms controlling differential promoter-occupancy by the yeast forkhead proteins Fkh1p and Fkh2p: implications for regulating the cell cycle and differentiation
Authors: Hollenhorst Peter C. , Pietz Gregory , Fox Catherine A.
Published: July 2002

The roles of DNA and Mcm1p interactions in determining the overlapping and distinct functions of the yeast cell cycle regulatory transcription factors Fkh1p and Fkh2p were examined. Full-length recombinant Fkh1p and Fkh2p were purified and their binding to bona fide promoters examined in vitro. Each protein bound a variety of target promoters with similar specificity in vitro, consistent with the observation that these proteins bind common promoters in vivo. However, in vivo, the Fkh1p and Fkh2p occupied different target promoters to different extents, suggesting that each was primarily responsible for controlling a different set of genes. Additional in vitro studies provided a mechanistic explanation for this differential promoter-occupancy. Specifically, the Fkh2p, but not the Fkh1p, was capable of binding cooperatively with Mcm1p. The Mcm1p–Fkh2p cooperative binding was enhanced by, but did not require, the presence of a Mcm1p-binding site within a target promoter. Consistent with these data, Mcm1p was present at Fkh-controlled promoters in vivo regardless of whether they contained Mcm1p-binding sites, suggesting a role for Mcm1p at promoters not thought previously to be under Mcm1p control. Analysis of Fkh1p and Fkh2p binding to promoter targets in vivo by use of mutant strains indicated that the two proteins compete for promoter-occupancy at a number of target promoters. We postulate that Fkh1p and a stable Fkh2p/Mcm1p complex compete for binding to target promoters and that the levels and/or binding activity of Fkh1p, but not Fkh2p, are most limiting for promoter-occupancy in vivo. Interestingly, the in vitro DNA-binding assays, using a variety of promoter targets, revealed that bona fide Fkh target promoters contained two or more Fkh-binding sites that allowed the Fkh1p and Fkh2p proteins to form multiple protein–DNA complexes in vitro. Multiple Fkh-binding sites may be a distinguishing feature of bona fide Fkh promoters in yeast and other organisms.
A method for including redundant data in computed tomography
Authors: Silver Michael D.
Published: July 2002

A method for including redundant data in fan‐beam computed tomography (CT) is presented. It is a natural extension of the Parker [Med. Phys. 9, 254–257 (1982)] short‐scan approach applied to divergent fan‐beam (or cone‐beam) data when the data set covers between the minimally complete set of 180° plus fan angle and 360°. A virtual fan angle is introduced whose value is the difference between the angular range of the data collected and 180°. Parker‐weights are then applied as if the field‐of‐view is spanned by the virtual fan angle.
Wave and place fixed DPOAE maps of the human ear
Authors: Knight Richard D. , Kemp David T.
Published: July 2002

Human intermodulation distortion product otoacoustic emissions (DPOAE) can be a mixture of low and high latency components. They have different level, phase, and suppression characteristics, which indicate that emissions arise both from the frequency region of the primary tones directly and indirectly via the DP frequency place. Which component dominates the measured DPOAE in the ear canal depends on the stimulus parameters, especially the frequency ratio, f2/f1. Interference between the two emissions adds complexity to measurements of DPOAE. The behavior and even existence of whichever emission route is lower in level often cannot directly be deduced from the raw DPOAE data because the other emission covers it. It is therefore not known whether both emissions are present for all stimulus parameters or whether the trends seen in each emission when they are the dominant emission route continue under stimulus conditions when they are not dominant. In this study, the two DPOAE components are separated by a post-processing method. Previously, maps of raw DPOAE data against f2/f1 and DP frequency have been obtained. To separate the components, sets of data consisting of f2/f1 sweeps were transformed by an inverse Fourier transform into the time domain. The low and high latency components appeared as two distinct peaks because of their different phase gradients. These peaks were separated by windowing in the time domain and two frequency domain maps were reconstructed, representing the low and high latency DPOAEs. It was found that the low latency component of the 2 f1−f2 DP was only emitted strongly with f2/f1 between approximately 1.1 and 1.3. The removal of the high latency component revealed the low ratio edge of this region, at which the level falls sharply. However, the low latency emission has been traced at reduced amplitude over a wide range of stimulus parameters. Although previously only observed at small frequency ratios, the high latency component was found to be present widely in the lower sideband, its level reducing slowly at larger f2/f1. Its phase behavior changes in the lower sideband, being approximately constant with DP frequency at small ratios of f2/f1, but deviating from this at wider ratios. These results support the hypothesis that a DPOAE component which propagates to and is re-emitted from the DP frequency place (place fixed emission) is present across a wide parameter range. However, for all but the close primary condition the lower sideband DPOAE is dominated by direct emission from the region of f2 and f1 wave interaction (wave fixed emission). A simple transmission line model is presented to illustrate how the observed DPOAE maps can arise on the basis of this hypothesis.
Finite-difference time-domain modeling of low to moderate frequency sea-surface reverberation in the presence of a near-surface bubble layer
Authors: Keiffer Richard S. , Novarini J. C. , Zingarelli R. A.
Published: July 2002

A finite-difference time-domain (FDTD) solution to the two-dimensional linear acoustic wave equation is utilized in numerical experiments to test the hypothesis that near-surface, bubble-induced refraction can have a significant impact on low to moderate frequency sea-surface reverberation. In order to isolate the effects of bubble-modified propagation on the scattering from the air/sea interface from other possible phenomena such as scattering from bubble clouds, the bubbly environment is assumed to be range independent. Results of the study show that both the strong wind-speed dependence and the enhanced scattering levels of the order found in the reverberation data are obtained when a wind-speed-dependent bubble layer is included in the modeling.
Effects of prosodic factors on spectral dynamics. I. Analysis
Authors: Wouters Johan , Macon Michael W.
Published: July 2002

The effects of prosodic factors on the spectral rate of change of vowel transitions are investigated. Thirty two-syllable English words are placed in carrier phrases and read by a single speaker. Liquid-vowel, diphthong, and vowel–liquid transitions are extracted from different prosodic contexts, corresponding to different levels of stress, pitch accent, word position, and speaking style, following a balanced experimental design. The spectral rate of change in these transitions is measured by fitting linear regression lines to the first three formants and computing the root-mean-square of the slopes. Analysis shows that the spectral rate of change increases with linguistic prominence, i.e., in stressed syllables, in accented words, in sentence-medial words, and in hyperarticulated speech. The results are consistent with a contextual view of vowel reduction, where the extent of reduction depends both on the spectral rate of change and on vowel duration. A numerical model of spectral rate of change is proposed, which can be integrated in a system for concatenative speech synthesis, as discussed in Paper II [J. Wouters and M. Macon, J. Acoust. Soc. Am. 111, 428–438 (2002)].
Sweeping echoes perceived in a regularly shaped reverberation room
Authors: Kiyohara Kenji , Furuya Ken’ichi , Kaneda Yutaka
Published: July 2002

A very interesting new phenomenon that we call a sweeping echo is described and investigated. When we clap hands in a regularly shaped reverberant room, we hear sweeping echoes whose frequency increases linearly with time. An example of sweeping echoes observed in a rectangular reverberation room is first described. Then, the mechanism that generated the sweeping echoes is investigated by assuming a cubic room and using number theory. The reflected pulse sound train is found to have almost equal intervals between pulses on the squared-time axis. This regularity of arrival times of the reflected pulse sounds is shown to generate the sweeping echoes. Computer simulation of room acoustics shows good agreement with the theoretical results.
Toward articulatory-acoustic models for liquid approximants based on MRI and EPG data. Part II. The rhotics
Authors: Alwan Abeer , Narayanan Shrikanth , Haker Katherine
Published: July 2002

Magnetic resonance images of the vocal tract during sustained production of [ɹ] by four native American English talkers are employed for measuring vocal-tract dimensions and for morphological analysis of the 3D vocal tract and tongue shapes. Electropalatography contact profiles are used for studying inter- and intra-talker variabilities. The vocal tract during the production of [ɹ] appears to be characterized by three cavities due to the presence of two supraglottal constrictions: the primary one in the oral cavity, and a secondary one in the pharyngeal cavity. All subjects show a large volume anterior to the oral constriction, which results from an inward-drawn tongue body, an anterior tongue body that is characterized by convex cross sections, and a concave posterior tongue body shape. Inter-subject variabilities are observed in the oral-constriction location and the way the constriction is formed. No systematic differences are found between the 3-D vocal tract and tongue shapes of word-initial and syllabic [ɹ]s. Tongue-shaping mechanisms for these sounds and their acoustic implications are discussed.
Toward articulatory-acoustic models for liquid approximants based on MRI and EPG data. Part I. The laterals
Authors: Narayanan Shrikanth S. , Alwan Abeer A. , Haker Katherine
Published: July 2002

Magnetic resonance images of the vocal tract during the sustained phonation of /l/ (both dark and light allophones) by four native American English talkers are employed for measuring lengths, area functions, and cavity volumes and for the analysis of 3-D vocal tract and tongue shapes. Electropalatography contact profiles are used for studying inter- and intra-talker variabilities and as a source of converging evidence for the magnetic resonance imaging study. The general 3-D tongue body shapes for both allophones of /l/ are characterized by a linguo-alveolar contact together with inward lateral compression and convex cross sections of the posterior tongue body region. The lateral compression along the midsagittal plane enables the creation of flow channels along the sides of the tongue. The bilateral flow channels exhibit somewhat different areas, a characteristic which is talker-dependent. Dark /l/s show smaller pharyngeal areas than the light varieties due to tongue-root retraction and/or posterior tongue body raising. The acoustic implications of the observed geometries are discussed.