bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Binding of Three Tight Junction-Associated Maguks, Zo-1, Zo-2, and Zo-3, with the Cooh Termini of Claudins
Authors: Itoh Masahiko , Furuse Mikio , Morita Kazumasa , Kubota Koji , Saitou Mitinori , Tsukita Shoichiro
Published: July 2002

ZO-1, ZO-2, and ZO-3, which contain three PDZ domains (PDZ1 to -3), are concentrated at tight junctions (TJs) in epithelial cells. TJ strands are mainly composed of two distinct types of four-transmembrane proteins, occludin, and claudins, between which occludin was reported to directly bind to ZO-1/ZO-2/ZO-3. However, in occludin-deficient intestinal epithelial cells, ZO-1/ZO-2/ZO-3 were still recruited to TJs. We then examined the possible interactions between ZO-1/ZO-2/ZO-3 and claudins. ZO-1, ZO-2, and ZO-3 bound to the COOH-terminal YV sequence of claudin-1 to -8 through their PDZ1 domains in vitro. Then, claudin-1 or -2 was transfected into L fibroblasts, which express ZO-1 but not ZO-2 or ZO-3. Claudin-1 and -2 were concentrated at cell–cell borders in an elaborate network pattern, to which endogenous ZO-1 was recruited. When ZO-2 or ZO-3 were further transfected, both were recruited to the claudin-based networks together with endogenous ZO-1. Detailed analyses showed that ZO-2 and ZO-3 are recruited to the claudin-based networks through PDZ2 (ZO-2 or ZO-3)/PDZ2 (endogenous ZO-1) and PDZ1 (ZO-2 or ZO-3)/COOH-terminal YV (claudins) interactions. In good agreement, PDZ1 and PDZ2 domains of ZO-1/ZO-2/ZO-3 were also recruited to claudin-based TJs, when introduced into cultured epithelial cells. The possible molecular architecture of TJ plaque structures is discussed.
RNA-Binding Proteins Tia-1 and Tiar Link the Phosphorylation of Eif-2α to the Assembly of Mammalian Stress Granules
Authors: Kedersha Nancy L. , Gupta Mita , Li Wei , Miller Ira , Anderson Paul
Published: July 2002

In response to environmental stress, the related RNA-binding proteins TIA-1 and TIAR colocalize with poly(A)+ RNA at cytoplasmic foci that resemble the stress granules (SGs) that harbor untranslated mRNAs in heat shocked plant cells (Nover et al. 1989; Nover et al. 1983; Scharf et al. 1998). The accumulation of untranslated mRNA at SGs is reversible in cells that recover from a sublethal stress, but irreversible in cells subjected to a lethal stress. We have found that the assembly of TIA-1/R+ SGs is initiated by the phosphorylation of eIF-2α. A phosphomimetic eIF-2α mutant (S51D) induces the assembly of SGs, whereas a nonphosphorylatable eIF-2α mutant (S51A) prevents the assembly of SGs. The ability of a TIA-1 mutant lacking its RNA-binding domains to function as a transdominant inhibitor of SG formation suggests that this RNA-binding protein acts downstream of the phosphorylation of eIF-2α to promote the sequestration of untranslated mRNAs at SGs. The assembly and disassembly of SGs could regulate the duration of stress- induced translational arrest in cells recovering from environmental stress.
Vesicular and nonvesicular transport of ceramide from ER to the Golgi apparatus in yeast
Authors: Funato Kouichi , Riezman Howard
Published: July 2002

Transport and sorting of lipids must occur with specific mechanisms because the membranes of intracellular organelles differ in lipid composition even though most lipid biosynthesis begins in the ER. In yeast, ceramide is synthesized in the ER and transferred to the Golgi apparatus where inositolphosphorylceramide (IPC) is formed. These two facts imply that ceramide can be transported to the Golgi independent of vesicular traffic because IPC synthesis still continues when vesicular transport is blocked in sec mutants. Nonvesicular IPC synthesis in intact cells is not affected by ATP depletion. Using an in vitro assay that reconstitutes the nonvesicular pathway for transport of ceramide, we found that transport is temperature and cytosol dependent but energy independent. Preincubation of ER and Golgi fractions together at 4°C, where ceramide transport does not occur, rendered the transport reaction membrane concentration independent, providing biochemical evidence that ER-Golgi membrane contacts stimulate ceramide transport. A cytosolic protease-sensitive factor is required after establishment of ER-Golgi contacts.
Clnk, a Novel Slp-76–Related Adaptor Molecule Expressed in Cytokine-Stimulated Hemopoietic Cells
Authors: Cao Ming Yu , Davidson Dominique , Yu Jie , Latour Sylvain , Veillette André
Published: July 2002

We have identified a novel Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)–related molecule which we have termed Clnk (for cytokine-dependent hemopoietic cell linker). Unlike its relatives SLP-76 and B cell linker protein (Blnk), Clnk is not expressed uniformly within a given hemopoietic cell lineage. Even though it can be detected in several cell types, including T cells, natural killer cells, and mast cells, its expression seems to be strictly dependent on sustained exposure to cytokines such as interleukin (IL)-2 and IL-3. Strong support for the notion that Clnk is involved in immunoreceptor signaling was provided by the observation that it inducibly associated with at least one tyrosine-phosphorylated polypeptide (p92) in response to immunoreceptor stimulation. Moreover, transient expression of Clnk caused an increase in immunoreceptor-mediated signaling events in a T cell line. Taken together, these results show that Clnk is a novel member of the SLP-76 family selectively expressed in cytokine-stimulated hemopoietic cells. Furthermore, they suggest that Clnk may be involved in a cross-talk mechanism between cytokine receptor and immunoreceptor signaling.
Arthritogenic Monoclonal Antibodies from K/BxN Mice
Authors: Maccioni Mariana , Zeder-Lutz Gabrielle , Huang Haochu , Ebel Claudine , Gerber Philippe , Hergueux Josiane , Marchal Patricia , Duchatelle Veronique , Degott Claude , van Regenmortel Marc , Benoist Christophe , Mathis Diane
Published: July 2002

Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patientswe have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10−9 M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs.
Dominant-Negative Mutants Identify a Role for Girk Channels in D3 Dopamine Receptor-Mediated Regulation of Spontaneous Secretory Activity
Authors: Kuzhikandathil Eldo V. , Oxford Gerry S.
Published: July 2002

The human D3 dopamine receptor can activate G-protein–coupled inward rectifier potassium channels (GIRKs), inhibit P/Q-type calcium channels, and inhibit spontaneous secretory activity in AtT-20 neuroendocrine cells (Kuzhikandathil, E.V., W. Yu, and G.S. Oxford. 1998. Mol. Cell. Neurosci. 12:390–402; Kuzhikandathil, E.V., and G.S. Oxford. 1999. J. Neurosci. 19:1698–1707). In this study, we evaluate the role of GIRKs in the D3 receptor-mediated inhibition of secretory activity in AtT-20 cells. The absence of selective blockers for GIRKs has precluded a direct test of the hypothesis that they play an important role in inhibiting secretory activity. However, the tetrameric structure of these channels provides a means of disrupting endogenous GIRK function using a dominant negative approach. To develop a dominant-negative GIRK mutant, the K+ selectivity amino acid sequence -GYG- in the putative pore domain of the human GIRK2 channels was mutated to -AAA-, -GLG-, or -GFG-. While the mutation of -GYG- to -GFG- did not affect channel function, both the -AAA- and -GLG- GIRK2 mutants were nonfunctional. This suggests that the aromatic ring of the tyrosine residue rather than its hydroxyl group is involved in maintaining the pore architecture of human GIRK2 channels. When expressed in AtT-20 cells, the nonfunctional AAA-GIRK2 and GLG-GIRK2 acted as effective dominant-negative mutants and significantly attenuated endogenous GIRK currents. Furthermore, these dominant-negative mutants interfered with the D3 receptor-mediated inhibition of secretion in AtT-20 cells, suggesting they are centrally involved in the signaling pathway of this secretory response. These results indicate that dominant-negative GIRK mutants are effective molecular tools to examine the role of GIRK channels in vivo.
Copyright vs. freedom of scientific communication
Authors: Hugenholtz P. Bernt
Published: July 2002

Recent developments in copyright law and practice, all inspired or triggered by the new digital networked environment, have the potential of negatively affecting the freedom of scientific communication. In this paper a number of these developments will be briefly examined. The author concludes that it is critically important for the global scientific community to become actively involved in the international, European, and national legislative process to protect scientific freedoms against further erosion.
The BIBLINK project: linking publishers and national bibliographic agencies
Authors: Clayphan Robina
Published: July 2002

The BIBLINK project is described and some of the issues arising from it are discussed. BIBLINK is a project funded by the European Commission. It began in May 1996 and is due for completion in February 2000. The aim of the project is to establish an automated flow of information, between publishers and national bibliographic services, in order to create authoritative bibliographic data that benefits both sectors. The project examined the way in which electronic publications are described for catalogues and other listings and developed a software system to allow the transmission of bibliographic metadata between the two sectors.
A new way of information retrieval: 3‐D indexing and concept mapping
Authors: Ross Jan
Published: July 2002

After a brief discussion of mind mapping and concept mapping, a model for a ‘3‐D index’ is developed which combines a concept map with an index to enable hierarchical and relational data retrieval. It is suggested that such sophisticated information retrieval methods are required for the complex and extensive electronic data sources and encyclopaedic‐type titles now being compiled.
The journal as an overlay on preprint databases
Authors: Smith Arthur P.
Published: July 2002

The Physical Review journals, particularly Physical Review D (PRD) on particle and gravitational physics, have been near the centre of a revolution in electronic publishing caused by the Los Alamos eprint archive, which began posting papers in theoretical particle physics nearly eight years ago. This paper describes how the journals, particularly PRD, have responded and thrived with this revolution in scientific communication, and how we expect things to continue to develop in the future.
Exorcising the spectre of interlibrary loans
Authors: Brown David J.
Published: July 2002

Many publishers believe that journal subscriptions are being cancelled in favour of purchasing the occasional article through document delivery (docdel) and interlibrary loan (ILL) services. This brief review suggests that commercial docdel is not necessarily the threat it is perceived to be by publishers, and that instead a co‐operative campaign to eliminate what for them is the real ogre of interlibrary loan (ILL) would be financially beneficial to journal publishers.
Successful journal publishing on the Internet: hit or myth?
Authors: Hemingway Clive
Published: July 2002

If publishers of learned journals are going to make a success of their web publishing, they should not forget all the skills they have developed in publishing in print. This paper reviews the application of familiar journal publishing skills in the context of electronic journals or electronic editions of printed journals, and pinpoints areas where these skills apply in web publishing and where new skills are necessary.
Editorial issues
Authors: Roberts Rosemary
Published: July 2002

The sequence of events in much electronic publishing is to transform material prepared for publication in print into an electronic product post hoc. This paper describes the editorial thinking and planning behind the preparation of the New Dictionary of National Biography for publication in print and electronic form, in particular the issues arising from the attempt to capture ‘clean’ information from literary prose.
Book Reviews
Authors: Bell Hazel K. , Deeley Sue
Published: July 2002

Indexing from A to Z Second edition by Hans H. Wellisch, New York and Dublin: H.W. Wilson, 1996, 569 pp, $45, ISBN 0 8242 0882 X

Winning the Publications Game by Tim Albert, Oxford and New York: Radcliffe Medical Press, 1997 100pp £15, ISBN 1‐85775 183 3
Requirements for an Online electronic journal service
Authors: Penfold David
Published: July 2002

This article is based on a report made to the Electronic Journal and Learned Societies Project, part of the Electronic Libraries (eLib) Programme. It is concerned with investigations undertaken in late 1996 into the commercial services able to provide an online electronic document delivery service for academic journals on behalf of the small society publisher unwilling or unable to provide an independent service. Thirteen organizations were approached and a questionnaire circulated to them was returned by the majority. The results indicated that at that stage there was no obvious choice of one supplier to meet the needs of any small society publisher. The reasons for this are discussed and possible ways forward considered.
On the telescopic homotopy theory of spaces
Authors: Bousfield A.
Published: July 2002

In telescopic homotopy theory, a space or spectrum

X
X

is approximated by a tower of localizations

L

n

f

X

L^{f}_{n}X

,

n
≥
0

n\ge 0

, taking account of

v

n

v_{n}

-periodic homotopy groups for progressively higher

n
n

. For each

n
≥
1

n\ge 1

, we construct a telescopic Kuhn functor

Φ

n

\Phi _{n}

carrying a space to a spectrum with the same

v

n

v_{n}

-periodic homotopy groups, and we construct a new functor

Θ

n

\Theta _{n}

left adjoint to

Φ

n

\Phi _{n}

. Using these functors, we show that the

n
n

th stable monocular homotopy category (comprising the

n
n

th fibers of stable telescopic towers) embeds as a retract of the

n
n

th unstable monocular homotopy category in two ways: one giving infinite loop spaces and the other giving “infinite

L

n

f

L^{f}_{n}

-suspension spaces.” We deduce that Ravenel’s stable telescope conjectures are equivalent to unstable telescope conjectures. In particular, we show that the failure of Ravenel’s

n
n

th stable telescope conjecture implies the existence of highly connected infinite loop spaces with trivial Johnson-Wilson

E
(
n

)

∗

E(n)_{*}

-homology but nontrivial

v

n

v_{n}

-periodic homotopy groups, showing a fundamental difference between the unstable chromatic and telescopic theories. As a stable chromatic application, we show that each spectrum is

K
(
n
)

K(n)

-equivalent to a suspension spectrum. As an unstable chromatic application, we determine the

E
(
n

)

∗

E(n)_{*}

-localizations and

K
(
n

)

∗

K(n)_{*}

-localizations of infinite loop spaces in terms of

E
(
n

)

∗

E(n)_{*}

-localizations of spectra under suitable conditions. We also determine the

E
(
n

)

∗

E(n)_{*}

-localizations and

K
(
n

)

∗

K(n)_{*}

-localizations of arbitrary Postnikov

H
H

-spaces.
Trapezoidal and midpoint splittings for initial-boundary value problems
Authors: Hundsdorfer Willem
Published: July 2002

In this paper we consider various multi-component splittings based on the trapezoidal rule and the implicit midpoint rule. It will be shown that an important requirement on such methods is internal stability. The methods will be applied to initial-boundary value problems. Along with a theoretical analysis, some numerical test results will be presented.
Continuity of Hausdorff dimension of Julia-Lavaurs sets as a function of the phase
Authors: Urbanski Mariusz , Zinsmeister Michel
Published: July 2002

Let

f

0

(
z
)
=

z

2

+
1

/

4

f_{0}(z)=z^{2}+1/4

and

E

0

{\mathcal E}_{0}

the set of phases

σ
¯

\overline {\sigma }

such that the critical point

0
0

escapes in one step by the Lavaurs map

g

σ

g_{\sigma }

; it is a topological strip in the cylinder of phases whose boundary consists of two Jordan curves symmetric wrt

R

/

Z

\mathbb R/ \mathbb Z

. We prove that if

σ
¯

n

∈

E

0

\overline {\sigma }_{n}\in {\mathcal E}_{0}

converges to

σ
¯

∈
∂

E

0

\overline {\sigma }\in \partial {\mathcal E}_{0}

in such a way that

g

σ

n

(
0
)

g_{\sigma _{n}}(0)

converges to

g

σ

(
0
)

g_{\sigma }(0)

along an external ray, then the Hausdorff dimension of the Julia-Lavaurs set

J
(

f

0

,

g

σ

n

)

J(f_{0}, g_{\sigma _{n}})

converges to the Hausdorff dimension of

J
(

f

0

,

g

σ

)

J(f_{0},g_{\sigma })

.
Arbor 3D: an interactive environment for examining phylogenetic

and taxonomic trees in multiple dimensions
Authors: Ruths Derek A. , Chen Edward S. , Ellis Leland
Published: July 2002

This paper examines a new technique for the visualization of and the interaction with trees, objects frequently used to convey hierarchical relationships in biological data. Motivated by the quality of 2D tree interaction, we adapt the planar tree-of-life metaphor to a virtual, semi-immersive 3D environment. A 3D environment extends the utility of this metaphor by allowing the user to view an entire data set in a single screen. Interrogation of the tree is implemented using 3D input devices. This real-time interrogation of the tree itself provides a quick means by which to qualitatively analyse the hierarchical data. In this paper, we describe the techniques underlying the implementation of such an environment. We conclude by considering the utility of tree metaphors as a basis for the representation of highly dimensional data sets.

Availability: Arbor3D (source code, a binary executable for SGI IRIX 6.4, Perl parsers, and sample Newick data files) are available via the Internet (http://xian.tamu.edu/Arbor3D/). Arbor3D can be displayed in ‘CAVE simulator’ mode on an SGI workstation screen, or as an interactive virtual environment on a projection workbench.

Contact: druths@rice.edu; echen@cs.rice.edu; leland@xian.tamu.edu

To whom correspondence should be addressed.
Genesis: cluster analysis of microarray data
Authors: Sturn Alexander , Quackenbush John , Trajanoski Zlatko
Published: July 2002

Summary: A versatile, platform independent and easy to use Java suite for large-scale gene expression analysis was developed. Genesis integrates various tools for microarray data analysis such as filters, normalization and visualization tools, distance measures as well as common clustering algorithms including hierarchical clustering, self-organizing maps, k-means, principal component analysis, and support vector machines. The results of the clustering are transparent across all implemented methods and enable the analysis of the outcome of different algorithms and parameters. Additionally, mapping of gene expression data onto chromosomal sequences was implemented to enhance promoter analysis and investigation of transcriptional control mechanisms.

Availability: http://genome.tugraz.at

Contact: zlatko.trajanoski@tugraz.at

* To whom correspondence should be addressed.
Probabilistic Boolean networks: a rule-based uncertainty model
for gene regulatory networks
Authors: Shmulevich Ilya , Dougherty Edward R. , Kim Seungchan , Zhang Wei
Published: July 2002

Motivation: Our goal is to construct a model for genetic regulatory networks such that the model class: (i) incorporates rule-based dependencies between genes; (ii) allows the systematic study of global network dynamics; (iii) is able to cope with uncertainty, both in the data and the model selection; and (iv) permits the quantification of the relative influence and sensitivity of genes in their interactions with other genes.

Results: We introduce Probabilistic Boolean Networks (PBN) that share the appealing rule-based properties of Boolean networks, but are robust in the face of uncertainty. We show how the dynamics of these networks can be studied in the probabilistic context of Markov chains, with standard Boolean networks being special cases. Then, we discuss the relationship between PBNs and Bayesian networks—a family of graphical models that explicitly represent probabilistic relationships between variables. We show how probabilistic dependencies between a gene and its parent genes, constituting the basic building blocks of Bayesian networks, can be obtained from PBNs. Finally, we present methods for quantifying the influence of genes on other genes, within the context of PBNs. Examples illustrating the above concepts are presented throughout the paper.

Contact: is@ieee.org
Generating samples under a Wright–Fisher neutral model of
genetic variation
Authors: Hudson Richard R.
Published: July 2002

Summary: A Monte Carlo computer program is available to generate samples drawn from a population evolving according to a Wright–Fisher neutral model. The program assumes an infinite-sites model of mutation, and allows recombination, gene conversion, symmetric migration among subpopulations, and a variety of demographic histories. The samples produced can be used to investigate the sampling properties of any sample statistic under these neutral models.

Availability: The source code for the program (in the language C) is available at http://home.uchicago.edu/~rhudson1/source/mksamples.html.

Contact: rr-hudson@uchicago.edu
Reactive oxygen species mediate tumor necrosis factor alpha‐converting, enzyme‐dependent ectodomain shedding induced by phorbol myristate acetate
Authors: Zhang Zili , Oliver Peter , Jr. Lancaster Jack R. , Schwarzenberger Paul O. , Joshi Mahesh S. , Cork John , Kolls Jay K.
Published: July 2002

Ectodomain shedding of cell surface membrane‐anchoring proteins is an important process in a wide variety of physiological events(1, 2). Tumor necrosis factor α (TNF‐α) converting enzyme (TACE) is the first discovered mammalian sheddase responsible for cleavage of several important surface proteins, including TNF‐α, TNF p75 receptor, L‐selectin, and transforming growth factor‐α. Phorbol myristate acetate (PMA) has long been known as a potent agent to enhance ectodomain shedding. However, it is not fully understood how PMA activates TACE and induces ectodomain shedding. Here, we demonstrate that PMA induces both reactive oxygen species (ROS) generation and TNF p75 receptor shedding in Mono Mac 6 cells, a human monocytic cell line, and l‐selectin shedding in Jurkat T‐cells. ROS scavengers significantly attenuated PMA‐induced TNF p75 receptor shedding. Exogenous H2O2 mimicked PMA‐induced enhancement of ectodomain shedding, and H2O2‐induced shedding was blocked by TAPI, a TACE inhibitor. Furthermore, both PMA and H2O2 failed to cause ectodomain shedding in a cell line that lacks TACE activity. By use of an in vitro TACE cleavage assay, H2O2 activated TACE that had been rendered inactive by the addition of the TACE inhibitory pro‐domain sequence. We presume that the mechanism of TACE activation by H2O2 is due to an oxidative attack of the pro‐domain thiol group and disruption of its inhibitory coordination with the Zn++ in the catalytic domain of TACE. These results demonstrate that ROS production is involved in PMA‐induced ectodomain shedding and implicate a role for ROS in other shedding processes.
Cytochrome P450 monooxygenases and insecticide resistance in insects
Authors: Bergé J. , Feyereisen R. , Amichot M.
Published: July 2002

Cytochrome P450 monooxygenases are involved in many cases of resistance of insects to insecticides. Resistance has long been associated with an increase in monooxygenase activities and with an increase in cytochrome P450 content. However, this increase does not always account for all of the resistance. In
Drosophila melanogaster
, we have shown that the overproduction of cytochrome P450 can be lost by the fly without a corresponding complete loss of resistance. These results prompted the sequencing of a cytochrome P450 candidate for resistance in resistant and susceptible flies. Several mutations leading to amino–acid substitutions have been detected in the P450 gene
CYP6A2
of a resistant strain. The location of these mutations in a model of the 3D structure of the CYP6A2 protein suggested that some of them may be important for enzyme activity of this molecule. This has been verified by heterologous expression of wild–type and mutated cDNA in
Escherichia coli
. When other resistance mechanisms are considered, relatively few genetic mutations are involved in insecticide resistance, and this has led to an optimistic view of the management of resistance. Our observations compel us to survey in more detail the genetic diversity of cytochrome P450 genes and alleles involved in resistance.
Electroencephalographic imaging of higher brain function
Authors: Gevins Alan , Smith Michael E. , McEvoy Linda K. , Leong Harrison , Le Jian
Published: July 2002

High temporal resolution is necessary to resolve the rapidly changing patterns of brain activity that underlie mental function. Electroencephalography (EEG) provides temporal resolution in the millisecond range. However, traditional EEG technology and practice provide insufficient spatial detail to identify relationships between brain electrical events and structures and functions visualized by magnetic resonance imaging or positron emission tomography. Recent advances help to overcome this problem by recording EEGs from more electrodes, by registering EEG data with anatomical images, and by correcting the distortion caused by volume conduction of EEG signals through the skull and scalp. In addition, statistical measurements of sub-second interdependences between EEG time-series recorded from different locations can help to generate hypotheses about the instantaneous functional networks that form between different cortical regions during perception, thought and action. Example applications are presented from studies of language, attention and working memory. Along with its unique ability to monitor brain function as people perform everyday activities in the real world, these advances make modern EEG an invaluable complement to other functional neuroimaging modalities.
The microfossil record of early land plants
Authors: Wellman Charles H. , Gray Jane
Published: July 2002

Dispersed microfossils (spores and phytodebris) provide the earliest evidence for land plants. They are first reported from the Llanvirn (Mid–Ordovician). More or less identical assemblages occur from the Llanvirn (Mid–Ordovician) to the late Llandovery (Early Silurian), suggesting a period of relative stasis some 40 Myr in duration. Various lines of evidence suggest that these early dispersed microfossils derive from parent plants that were bryophyte–like if not in fact bryophytes. In the late Llandovery (late Early Silurian) there was a major change in the nature of dispersed spore assemblages as the separated products of dyads (hilate monads) and tetrads (trilete spores) became relatively abundant. The inception of trilete spores probably represents the appearance of vascular plants or their immediate progenitors. A little later in time, in the Wenlock (early Late Silurian), the earliest unequivocal land plant megafossils occur. They are represented by rhyniophytoids. It is only from the Late Silurian onwards that the microfossil / megafossil record can be integrated and utilized in interpretation of the flora. Dispersed microfossils are preserved in vast numbers, in a variety of environments, and have a reasonable spatial and temporal fossil record. The fossil record of plant megafossils by comparison is poor and biased, with only a dozen or so known pre–Devonian assemblages. In this paper, the early land plant microfossil record, and its interpretation, are reviewed. New discoveries, novel techniques and fresh lines of inquiry are outlined and discussed.
Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence
Authors: Cleaveland S. , Laurenson M.K. , Taylor L.H.
Published: July 2002

Pathogens that can be transmitted between different host species are of fundamental interest and importance from public health, conservation and economic perspectives, yet systematic quantification of these pathogens is lacking. Here, pathogen characteristics, host range and risk factors determining disease emergence were analysed by constructing a database of disease–causing pathogens of humans and domestic mammals. The database consisted of 1415 pathogens causing disease in humans, 616 in livestock and 374 in domestic carnivores. Multihost pathogens were very prevalent among human pathogens (61.6%) and even more so among domestic mammal pathogens (livestock 77.3%, carnivores 90.0%). Pathogens able to infect human, domestic and wildlife hosts contained a similar proportion of disease–causing pathogens for all three host groups. One hundred and ninety–six pathogens were associated with emerging diseases, 175 in humans, 29 in livestock and 12 in domestic carnivores. Across all these groups, helminths and fungi were relatively unlikely to emerge whereas viruses, particularly RNA viruses, were highly likely to emerge. The ability of a pathogen to infect multiple hosts, particularly hosts in other taxonomic orders or wildlife, were also risk factors for emergence in human and livestock pathogens. There is clearly a need to understand the dynamics of infectious diseases in complex multihost communities in order to mitigate disease threats to public health, livestock economies and wildlife.
Recovery after mass extinction: evolutionary assembly in large–scale biosphere dynamics
Authors: Solé Ricard V. , Montoya José M. , Erwin Douglas H.
Published: July 2002

Biotic recoveries following mass extinctions are characterized by a process in which whole ecologies are reconstructed from low–diversity systems, often characterized by opportunistic groups. The recovery process provides an unexpected window to ecosystem dynamics. In many aspects, recovery is very similar to ecological succession, but important differences are also apparently linked to the innovative patterns of niche construction observed in the fossil record. In this paper, we analyse the similarities and differences between ecological succession and evolutionary recovery to provide a preliminary ecological theory of recoveries. A simple evolutionary model with three trophic levels is presented, and its properties (closely resembling those observed in the fossil record) are compared with characteristic patterns of ecological response to disturbances in continuous models of three–level ecosystems.
The structure and properties of gluten: an elastic protein from wheat grain
Authors: Shewry P. R. , Halford N. G. , Belton P. S. , Tatham A. S.
Published: July 2002

The wheat gluten proteins correspond to the major storage proteins that are deposited in the starchy endosperm cells of the developing grain. These form a continuous proteinaceous matrix in the cells of the mature dry grain and are brought together to form a continuous viscoelastic network when flour is mixed with water to form dough. These viscoelastic properties underpin the utilization of wheat to give bread and other processed foods. One group of gluten proteins, the HMM subunits of glutenin, is particularly important in conferring high levels of elasticity (i.e. dough strength). These proteins are present in HMM polymers that are stabilized by disulphide bonds and are considered to form the ‘elastic backbone’ of gluten. However, the glutamine–rich repetitive sequences that comprise the central parts of the HMM subunits also form extensive arrays of interchain hydrogen bonds that may contribute to the elastic properties via a ‘loop and train’ mechanism. Genetic engineering can be used to manipulate the amount and composition of the HMM subunits, leading to either increased dough strength or to more drastic changes in gluten structure and properties.
TGF-β inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3
Authors: Liu Dong , Black Brian L. , Derynck Rik
Published: July 2002

Transforming growth factor-β (TGF-β) is a potent inhibitor of skeletal muscle differentiation, but the molecular mechanism and signaling events that lead to this inhibition are poorly characterized. Here we show that the TGF-β intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. The Smad3-mediated repression was directed at the E-box sequence motif within muscle gene enhancers and the bHLH region of MyoD, the domain required for its association with E-protein partners such as E12 and E47. The repression could be overcome by supplying an excess of E12, and covalent tethering of E47 to MyoD rendered the E-box-dependent transcriptional activity refractory to the effects of Smad3 and TGF-β. Smad3 physically interacted with the HLH domain of MyoD, and this interaction correlated with the ability of Smad3 to interfere with MyoD/E protein heterodimerization and binding of MyoD complexes to oligomerized E-box sites. Together, these results reveal a model for how TGF-β, through Smad3-mediated transcriptional repression, inhibits myogenic differentiation.
Octamerization of λ CI repressor is needed for effective repression of PRM and efficient switching from lysogeny
Authors: Dodd Ian B. , Perkins Alison J. , Tsemitsidis Daniel , Egan J. Barry
Published: July 2002

The CI repressor of bacteriophage λ is a model for the role of cooperativity in the efficient functioning of genetic switches. Pairs of CI dimers interact to cooperatively occupy adjacent operator sites at OR and at OL. These CI tetramers repress the lytic promoters and activate transcription of thecI gene from PRM. CI is also able to octamerize, forming a large DNA loop between OR andOL, but the physiological role of this is unclear. Another puzzle is that, although a dimer of CI is able to repressPRM by binding to the third operator atOR, OR3, this binding seems too weak to affect CI production in the lysogenic state. Here we show that repression of PRM at lysogenic CI concentrations is absolutely dependent on OL, in this case 3.8 kb away. A mutant defective in this CI negative autoregulation forms a lysogen with elevated CI levels that cannot efficiently switch from lysogeny to lytic development. Our results invalidate previous evidence that Cro binding to OR3 is important in prophage induction. We propose the octameric CI:OR–OL complex increases the affinity of CI for OR3 by allowing a CI tetramer to link OR3 and the third operator atOL, OL3.
SSAHA: A Fast Search Method for Large DNA Databases
Authors: Ning Zemin , Cox Anthony J. , Mullikin James C.
Published: July 2002

We describe an algorithm, SSAHA (SequenceSearch and Alignment by HashingAlgorithm), for performing fast searches on databases containing multiple gigabases of DNA. Sequences in the database are preprocessed by breaking them into consecutive k-tuples ofk contiguous bases and then using a hash table to store the position of each occurrence of each k-tuple. Searching for a query sequence in the database is done by obtaining from the hash table the “hits” for each k-tuple in the query sequence and then performing a sort on the results. We discuss the effect of the tuple length k on the search speed, memory usage, and sensitivity of the algorithm and present the results of computational experiments which show that SSAHA can be three to four orders of magnitude faster than BLAST or FASTA, while requiring less memory than suffix tree methods. The SSAHAalgorithm is used for high-throughput single nucleotide polymorphism (SNP) detection and very large scale sequence assembly. Also, it provides Web-based sequence search facilities for Ensembl projects.
Probability‐based protein secondary structure identification using combined NMR chemical‐shift data
Authors: Wang Yunjun , Jardetzky Oleg
Published: July 2002

For a long time, NMR chemical shifts have been used to identify protein secondary structures. Currently, this is accomplished through comparing the observed 1Hα, 13Cα, 13Cβ, or 13C′ chemical shifts with the random coil values. Here, we present a new protocol, which is based on the joint probability of each of the three secondary structural types (β‐strand, α‐helix, and random coil) derived from chemical‐shift data, to identify the secondary structure. In combination with empirical smooth filters/functions, this protocol shows significant improvements in the accuracy and the confidence of identification. Updated chemical‐shift statistics are reported, on the basis of which the reliability of using chemical shift to identify protein secondary structure is evaluated for each nucleus. The reliability varies greatly among the 20 amino acids, but, on average, is in the order of: 13Cα>13C′>1Hα>13Cβ>15N>1HN to distinguish an α‐helix from a random coil; and 1Hα>13Cβ >1HN ∼13Cα∼13C′∼15N for a β‐strand from a random coil. Amide 15N and 1HN chemical shifts, which are generally excluded from the application, in fact, were found to be helpful in distinguishing a β‐strand from a random coil. In addition, the chemical‐shift statistical data are compared with those reported previously, and the results are discussed. A JAVA User Interface program has been developed to make the entire procedure fully automated and is available via http://ccsr3150‐p3.stanford.edu.
The EF‐hand domain: A globally cooperative structural unit
Authors: Nelson Melanie R. , Thulin Eva , Fagan Patricia A. , Forsén Sture , Chazin Walter J.
Published: July 2002

EF‐hand Ca2+‐binding proteins participate in both modulation of Ca2+signals and direct transduction of the ionic signal into downstream biochemical events. The range of biochemical functions of these proteins is correlated with differences in the way in which they respond to the binding of Ca2+. The EF‐hand domains of calbindin D9kand calmodulin are homologous, yet they respond to the binding of calcium ions in a drastically different manner. A series of comparative analyses of their structures enabled the development of hypotheses about which residues in these proteins control the calcium‐induced changes in conformation. To test our understanding of the relationship between protein sequence and structure, we specifically designed the F36G mutation of the EF‐hand protein calbindin D9kto alter the packing of helices I and II in the apoprotein. The three‐dimensional structure of apo F36G was determined in solution by nuclear magnetic resonance spectroscopy and showed that the design was successful. Surprisingly, significant structural perturbations also were found to extend far from the site of mutation. The observation of such long‐range effects provides clear evidence that four‐helix EF‐hand domains should be treated as a single globally cooperative unit. A hypothetical mechanism for how the long‐range effects are transmitted is described. Our results support the concept of energetic and structural coupling of the key residues that are crucial for a protein's fold and function.
A statistical methodology for mammographic density detection
Authors: Heine John J. , Velthuizen Robert P.
Published: July 2002

A statistical methodology is presented based on a chi‐square probability analysis that allows the automated discrimination of radiolucent tissue (fat) from radiographic densities (fibroglandular tissue) in digitized mammograms. The method is based on earlier work developed at this facility that shows mammograms may be considered as evolving from a linear filtering operation where a random input field is passed through a filtering process. The filtering process is reversible which allows the solution of the input field with knowledge obtained from the raw image (the output). The input field solution is analogous to a prewhitening technique or deconvolution. This field contains all the information of the raw image in a much simplified format that can be approximated and analyzed with parametric methods. In the work presented here evidence indicates that there are two random events occurring in the input field with differing variances: (1) one relating to fat tissue with the smaller variance, and (2) the second relating to all other tissue with the larger variance. A statistical comparison of the variances is made by scanning the image with a small search window. A relaxation method allows for making a reliable estimate of the smaller variance which is considered as the global reference. If a local variance deviates significantly from the reference variance, based on chi‐square analysis, it is labeled as nonfat; otherwise it is labeled as fat. This statistical test procedure results in a region by region continuous labeling of fat and nonfat tissue across the image. In the work presented here, the emphasis is on the methodology development with supporting preliminary results that are very encouraging. It is widely accepted that mammographic density is a breast cancer risk factor. An important application of this work is to incorporate density‐based risk analysis into the ongoing statistical‐based detection work developed at this facility. Additional applications include risk analysis dependent on either percentages or total amounts of fat or dense tissue. This work may be considered as the initial step in introducing many of the known breast cancer risk factors into the actual image data analysis.
Calculation of effective dose
Authors: McCollough Cynthia H. , Schueler Beth A.
Published: July 2002

The concept of “effective dose” was introduced in 1975 to provide a mechanism for assessing the radiation detriment from partial body irradiations in terms of data derived from whole body irradiations. The effective dose is the mean absorbed dose from a uniform whole‐body irradiation that results in the same total radiation detriment as from the nonuniform, partial‐body irradiation in question. The effective dose is calculated as the weighted average of the mean absorbed dose to the various body organs and tissues, where the weighting factor is the radiation detriment for a given organ (from a whole‐body irradiation) as a fraction of the total radiation detriment. In this review, effective dose equivalent and effective dose, as established by the International Commission on Radiological Protection in 1977 and 1990, respectively, are defined and various methods of calculating these quantities are presented for radionuclides, radiography, fluoroscopy, computed tomography and mammography. In order to calculate either quantity, it is first necessary to estimate the radiation dose to individual organs. One common method of determining organ doses is through Monte Carlo simulations of photon interactions within a simplified mathematical model of the human body. Several groups have performed these calculations and published their results in the form of data tables of organ dose per unit activity or exposure. These data tables are specified according to particular examination parameters, such as radiopharmaceutical, x‐ray projection, x‐ray beam energy spectra or patient size. Sources of these organ dose conversion coefficients are presented and differences between them are examined. The estimates of effective dose equivalent or effective dose calculated using these data, although not intended to describe the dose to an individual, can be used as a relative measure of stochastic radiation detriment. The calculated values, in units of sievert (or rem), indicate the amount of whole‐body irradiation that would yield the equivalent radiation detriment as the exam in question. In this manner, the detriment associated with partial or organ‐specific irradiations, as are common in diagnostic radiology, can be assessed.
Analysis of standing vertical jumps using a force platform
Authors: Linthorne Nicholas P.
Published: July 2002

A force platform analysis of vertical jumping provides an engaging demonstration of the kinematics and dynamics of one-dimensional motion. The height of the jump may be calculated (1) from the flight time of the jump, (2) by applying the impulse–momentum theorem to the force–time curve, and (3) by applying the work–energy theorem to the force-displacement curve.
Speech recognition in noise as a function of the number of spectral channels: Comparison of acoustic hearing and cochlear implants
Authors: Friesen Lendra M. , Shannon Robert V. , Baskent Deniz , Wang Xiaosong
Published: July 2002

Speech recognition was measured as a function of spectral resolution (number of spectral channels) and speech-to-noise ratio in normal-hearing (NH) and cochlear-implant (CI) listeners. Vowel, consonant, word, and sentence recognition were measured in five normal-hearing listeners, ten listeners with the Nucleus-22 cochlear implant, and nine listeners with the Advanced Bionics Clarion cochlear implant. Recognition was measured as a function of the number of spectral channels (noise bands or electrodes) at signal-to-noise ratios of +15, +10, +5, 0 dB, and in quiet. Performance with three different speech processing strategies (SPEAK, CIS, and SAS) was similar across all conditions, and improved as the number of electrodes increased (up to seven or eight) for all conditions. For all noise levels, vowel and consonant recognition with the SPEAK speech processor did not improve with more than seven electrodes, while for normal-hearing listeners, performance continued to increase up to at least 20 channels. Speech recognition on more difficult speech materials (word and sentence recognition) showed a marginally significant increase in Nucleus-22 listeners from seven to ten electrodes. The average implant score on all processing strategies was poorer than scores of NH listeners with similar processing. However, the best CI scores were similar to the normal-hearing scores for that condition (up to seven channels). CI listeners with the highest performance level increased in performance as the number of electrodes increased up to seven, while CI listeners with low levels of speech recognition did not increase in performance as the number of electrodes was increased beyond four. These results quantify the effect of number of spectral channels on speech recognition in noise and demonstrate that most CI subjects are not able to fully utilize the spectral information provided by the number of electrodes used in their implant.
On the emergence of the Green’s function in the correlations of a diffuse field
Authors: Lobkis Oleg I. , Weaver Richard L.
Published: July 2002

A diffuse acoustic field is shown to have correlations equal to the Green’s function of the body. Simple plausibility arguments for this assertion are followed by a more detailed proof. A careful version of the statement is found to include caveats in regard to how diffuse the field truly is, the spectrum of the diffuse field, and the phase of the receivers. Ultrasonic laboratory tests confirm the assertion. The main features of the direct signal between two transducers are indeed recovered by cross correlating their responses to a diffuse field generated by a third transducer. The quality of the recovery improves with increased averaging and the use of multiple sources. Applications are discussed.