bluuebunny/crossref_metadata_2025 huggingface dataset:
Independent Versus Coupled Inactivation in Sodium Channels
Authors: Mitrovic Nenad , George Alfred L. , Horn Richard
Published: July 2002

The voltage sensor of the sodium channel is mainly comprised of four positively charged S4 segments. Depolarization causes an outward movement of S4 segments, and this movement is coupled with opening of the channel. A mutation that substitutes a cysteine for the outermost arginine in the S4 segment of the second domain (D2:R1C) results in a channel with biophysical properties similar to those of wild-type channels. Chemical modification of this cysteine with methanethiosulfonate-ethyltrimethylammonium (MTSET) causes a hyperpolarizing shift of both the peak current–voltage relationship and the kinetics of activation, whereas the time constant of inactivation is not changed substantially. A conventional steady state inactivation protocol surprisingly produces an increase of the peak current at −20 mV when the 300-ms prepulse is depolarized from −190 to −110 mV. Further depolarization reduces the current, as expected for steady state inactivation. Recovery from inactivation in modified channels is also nonmonotonic at voltages more hyperpolarized than −100 mV. At −180 mV, for example, the amplitude of the recovering current is briefly almost twice as large as it was before the channels inactivated. These data can be explained readily if MTSET modification not only shifts the movement of D2/S4 to more hyperpolarized potentials, but also makes the movement sluggish. This behavior allows inactivation to have faster kinetics than activation, as in the HERG potassium channel. Because of the unique properties of the modified mutant, we were able to estimate the voltage dependence and kinetics of the movement of this single S4 segment. The data suggest that movement of modified D2/S4 is a first-order process and that rate constants for outward and inward movement are each exponential functions of membrane potential. Our results show that D2/S4 is intimately involved with activation but plays little role in either inactivation or recovery from inactivation.
μ-Conotoxin Giiia Interactions with the Voltage-Gated Na+ Channel Predict a Clockwise Arrangement of the Domains
Authors: Dudley Samuel C. , Chang Nancy , Hall Jon , Lipkind Gregory , Fozzard Harry A. , French Robert J.
Published: July 2002

Voltage-gated Na+ channels underlie the electrical activity of most excitable cells, and these channels are the targets of many antiarrhythmic, anticonvulsant, and local anesthetic drugs. The channel pore is formed by a single polypeptide chain, containing four different, but homologous domains that are thought to arrange themselves circumferentially to form the ion permeation pathway. Although several structural models have been proposed, there has been no agreement concerning whether the four domains are arranged in a clockwise or a counterclockwise pattern around the pore, which is a fundamental question about the tertiary structure of the channel. We have probed the local architecture of the rat adult skeletal muscle Na+ channel (μ1) outer vestibule and selectivity filter using μ-conotoxin GIIIA (μ-CTX), a neurotoxin of known structure that binds in this region. Interactions between the pore-forming loops from three different domains and four toxin residues were distinguished by mutant cycle analysis. Three of these residues, Gln-14, Hydroxyproline-17 (Hyp-17), and Lys-16 are arranged approximately at right angles to each other in a plane above the critical Arg-13 that binds directly in the ion permeation pathway. Interaction points were identified between Hyp-17 and channel residue Met-1240 of domain III and between Lys-16 and Glu-403 of domain I and Asp-1532 of domain IV. These interactions were estimated to contribute −1.0 ± 0.1, −0.9 ± 0.3, and −1.4 ± 0.1 kcal/mol of coupling energy to the native toxin–channel complex, respectively. μ-CTX residues Gln-14 and Arg-1, both on the same side of the toxin molecule, interacted with Thr-759 of domain II. Three analytical approaches to the pattern of interactions predict that the channel domains most probably are arranged in a clockwise configuration around the pore as viewed from the extracellular surface.
Potentiation of the Cardiac L-Type Ca2+ Channel (α1C) by Dihydropyridine Agonist and Strong Depolarization Occur via Distinct Mechanisms
Authors: Wilkens Christina M. , Grabner Manfred , Beam Kurt G.
Published: July 2002

A defining property of L-type Ca2+ channels is their potentiation by both 1,4-dihydropyridine agonists and strong depolarization. In contrast, non–L-type channels are potentiated by neither agonist nor depolarization, suggesting that these two processes may by linked. In this study, we have tested whether the mechanisms of agonist- and depolarization-induced potentiation in the cardiac L-type channel (α1C) are linked. We found that the mutant L-type channel GFP-α1C(TQ→YM), bearing the mutations T1066Y and Q1070M, was able to undergo depolarization-induced potentiation but not potentiation by agonist. Conversely, the chimeric channel GFP-CACC was potentiated by agonist but not by strong depolarization. These data indicate that the mechanisms of agonist- and depolarization-induced potentiation of α1C are distinct. Since neither GFP-CACC nor GFP-CCAA was potentiated significantly by depolarization, no single repeat of α1C appears to be responsible for depolarization-induced potentiation. Surprisingly, GFP-CACC displayed a low estimated open probability similar to that of the α1C, but could not support depolarization-induced potentiation, demonstrating that a relatively low open probability alone is not sufficient for depolarization-induced potentiation to occur. Thus, depolarization-induced potentiation may be a global channel property requiring participation from all four homologous repeats.
On the Mergelyan approximation property on pseudoconvex domains in ℂⁿ
Authors: Cho Sanghyun
Published: July 2002

Let

Ω
\Omega

be a smoothly bounded pseudoconvex domain of finite type in

C

n

\mathbb {C}^{n}

. We prove the Mergelyan approximation property in various topologies on

Ω
\Omega

when the estimates for

∂
¯

\overline {\partial }

-equation are known in the corresponding topologies.
New range theorems for the dual Radon transform
Authors: Katsevich Alexander
Published: July 2002

Three new range theorems are established for the dual Radon transform

R
∗

R^*

: on

C
∞

C^\infty

functions that do not decay fast at infinity (and admit an asymptotic expansion), on

S

(

Z
n

)

\mathcal {S}(Z_n)

, and on

C
0
∞

(

Z
n

)

C_0^\infty (Z_n)

. Here

Z
n

:=

S

n
−
1

×

R

Z_n:=S^{n-1}\times \mathbb {R}

, and

R
∗

R^*

acts on even functions

μ
(
α
,
p
)
=
μ
(
−
α
,
−
p
)
,
(
α
,
p
)
∈

Z
n

\mu (\alpha ,p)=\mu (-\alpha ,-p), (\alpha ,p)\in Z_n

.
Groups with two extreme character degrees and their normal subgroups
Authors: Fernández-Alcober Gustavo , Moretó Alexander
Published: July 2002

We study the finite groups

G
G

for which the set

cd
⁡
(
G
)

\operatorname {cd}(G)

of irreducible complex character degrees consists of the two most extreme possible values, that is,

1
1

and

|

G
:
Z
(
G
)

|

1

/

2

|G:Z(G)|^{1/2}

. We are easily reduced to finite

p
p

-groups, for which we derive the following group theoretical characterization: they are the

p
p

-groups such that

|

G
:
Z
(
G
)

|

|G:Z(G)|

is a square and whose only normal subgroups are those containing

G
′

G’

or contained in

Z
(
G
)

Z(G)

. By analogy, we also deal with

p
p

-groups such that

|

G
:
Z
(
G
)

|

=

p

2
n
+
1

|G:Z(G)|=p^{2n+1}

is not a square, and we prove that

cd
⁡
(
G
)
=
{
1
,

p
n

}

\operatorname {cd}(G) =\{1,p^n\}

if and only if a similar property holds: for any

N
⊴
G

N\trianglelefteq G

, either

G
′

≤
N

G’\le N

or

|

N
Z
(
G
)
:
Z
(
G
)

|

≤
p

|NZ(G):Z(G)|\le p

. The proof of these results requires a detailed analysis of the structure of the

p
p

-groups with any of the conditions above on normal subgroups, which is interesting for its own sake. It is especially remarkable that these groups have small nilpotency class and that, if the nilpotency class is greater than

2
2

, then the index of the centre is small, and in some cases we may even bound the order of

G
G

.
Iterated Spectra of Numbers—Elementary, Dynamical, and Algebraic Approaches
Authors: Bergelson Vitaly , Hindman Neil , Kra Bryna
Published: July 2002

I

P
∗

IP^*

sets and central sets are subsets of

N

\mathbb N

which arise out of applications of topological dynamics to number theory and are known to have rich combinatorial structure. Spectra of numbers are often studied sets of the form

{
[
n
α
+
γ
]
:
n
∈

N

}

\{[n\alpha +\gamma ]\colon n\in \mathbb N\}

. Iterated spectra are similarly defined with

n
n

coming from another spectrum. Using elementary, dynamical, and algebraic approaches we show that iterated spectra have significantly richer combinatorial structure than was previously known. For example we show that if

α
>
0

\alpha >0

and

0
>
γ
>
1

0>\gamma >1

, then

{
[
n
α
+
γ
]
:
n
∈

N

}

\{[n\alpha +\gamma ]\colon n\in \mathbb N\}

is an

I

P
∗

IP^*

set and consequently contains an infinite sequence together with all finite sums and products of terms from that sequence without repetition.
Modèles entiers des courbes hyperelliptiques sur un corps de valuation discrète
Authors: Liu Qing
Published: July 2002

Let

C
C

be a hyperelliptic curve of genus

g
≥
1

g\ge 1

over a discrete valuation field

K
K

. In this article we study the models of

C
C

over the ring of integers

O

K

\mathcal {O}_{K}

of

K
K

. To each Weierstrass model (that is a projective model arising from a hyperelliptic equation of

C
C

with integral coefficients), one can associate a (valuation of) discriminant. Then we give a criterion for a Weierstrass model to have minimal discriminant. We show also that in the most cases, the minimal regular model of

C
C

over

O

K

\mathcal {O}_{K}

dominates every minimal Weierstrass model. Some classical facts concerning Weierstrass models over

O

K

\mathcal {O}_{K}

of elliptic curves are generalized to hyperelliptic curves, and some others are proved in this new setting.
Analysis of an algorithm for generating locally optimal meshes for 𝐿₂ approximation by discontinuous piecewise polynomials
Authors: Tourigny Y. , Baines M.
Published: July 2002

This paper discusses the problem of constructing a locally optimal mesh for the best

L
2

L_2

approximation of a given function by discontinuous piecewise polynomials. In the one-dimensional case, it is shown that, under certain assumptions on the approximated function, Baines’ algorithm [M. J. Baines, Math. Comp., 62 (1994), pp. 645-669] for piecewise linear or piecewise constant polynomials produces a mesh sequence which converges to an optimal mesh. The rate of convergence is investigated. A two-dimensional modification of this algorithm is proposed in which both the nodes and the connection between the nodes are self-adjusting. Numerical results in one and two dimensions are presented.
An automated comparative analysis of 17 complete microbial
genomes
Authors: K.Bansal Arvind
Published: July 2002

Motivation: As sequenced genomes become larger and sequencing becomes faster, there is a need to develop accurate automated genome comparison techniques and databases to facilitate derivation of genome functionality; identification of enzymes, putative operons and metabolic pathways; and to derive phylogenetic classification of microbes.

Results: This paper extends an automated pair-wise genome comparison technique (Bansal, Math. Model. Sci. Comput., 9, 1–23, 1998, Bansal and Bork, in First International Workshop of Declarative Languages, Springer, pp. 275–289, 1999) used to identify orthologs and gene groups to derive orthologous genes in a group of genomes and to identify genes with conserved functionality. Seventeen microbial genomes archived at ftp://ncbi.nlm.nih.gov/genbank/genomeshave been compared using the automated technique. Data related to orthologs, gene groups, gene duplication, gene fusion, orthologs with conserved functionality, and genes specifically orthologous to Escherichia coli and pathogens has been presented and analyzed.

Availability: A prototype database is available at ftp://www.mcs.kent.edu/~arvind/intellibio/orthos.html. The software is free for academic research under an academic license. The detailed database for every microbial genome in NCBI is commercially available through intellibio software and consultancy corporation (Web site: http://www.mcs.kent.edu/~arvind/intellibio.html).

Contact: arvind@mcs.kent.edu
Classifying G-protein coupled receptors with support vector
machines
Authors: Karchin Rachel , Karplus Kevin , Haussler David
Published: July 2002

Motivation: The enormous amount of protein sequence data uncovered by genome research has increased the demand for computer software that can automate the recognition of new proteins. We discuss the relative merits of various automated methods for recognizing G-Protein Coupled Receptors (GPCRs), a superfamily of cell membrane proteins. GPCRs are found in a wide range of organisms and are central to a cellular signalling network that regulates many basic physiological processes. They are the focus of a significant amount of current pharmaceutical research because they play a key role in many diseases. However, their tertiary structures remain largely unsolved. The methods described in this paper use only primary sequence information to make their predictions. We compare a simple nearest neighbor approach (BLAST), methods based on multiple alignments generated by a statistical profile Hidden Markov Model (HMM), and methods, including Support Vector Machines (SVMs), that transform protein sequences into fixed-length feature vectors.

Results: The last is the most computationally expensive method, but our experiments show that, for those interested in annotation-quality classification, the results are worth the effort. In two-fold cross-validation experiments testing recognition of GPCR subfamilies that bind a specific ligand (such as a histamine molecule), the errors per sequence at the Minimum Error Point (MEP) were 13.7% for multi-class SVMs, 17.1% for our SVMtree method of hierarchical multi-class SVM classification, 25.5% for BLAST, 30% for profile HMMs, and 49% for classification based on nearest neighbor feature vector Kernel Nearest Neighbor (kernNN). The percentage of true positives recognized before the first false positive was 65% for both SVM methods, 13% for BLAST, 5% for profile HMMs and 4% for kernNN.

Availability: We have set up a web server for GPCR subfamily classification based on hierarchical multi-class SVMs at http://www.soe.ucsc.edu/research/compbio/gpcr-subclass. By scanning predicted peptides found in the human genome with the SVMtree server, we have identified a large number of genes that encode GPCRs. A list of our predictions for human GPCRs is available at http://www.soe.ucsc.edu/research/compbio/gpcr˙hg/class˙results. We also provide suggested subfamily classification for 18 sequences previously identified as unclassified Class A (rhodopsin-like) GPCRs in GPCRDB (Horn et al. , Nucleic Acids Res. , 26, 277–281, 1998), available at http://www.soe.ucsc.edu/research/compbio/gpcr/classA˙unclassified/.

Contact: rachelk@soe.ucsc.edu

* To whom correspondence should be addressed.
Association of nucleotide patterns with gene function classes:
application to human 3′ untranslated sequences
Authors: Conklin Darrell , Jonassen Inge , Aasland Rein , Taylor William R.
Published: July 2002

Motivation: Gene expression is dependent on two main types of signals; one involving transcription factors which initiates gene transcription, and another which regulates the translation of a nascent mRNA. These post-transcriptional events play an important yet incompletely understood role in regulating gene expression and cellular behavior. Many of the identified cis acting elements for translational regulation occur within the 3′untranslated region (3′UTR), and some have been observed to occur with surprising regularity within certain protein function classes.

Results: In this study, we present a new association rule mining method for discovering nucleotide sequence patterns that appear in more sequences than expected within protein function classes. The method is applied to a database of human 3′UTR sequences, and some significant associations between nucleotide patterns and protein function classes are discovered. Among previously identified patterns, the AU-Rich Element (ARE) is found here to occur within the 3′UTR of cytokines, providing statistical validation of an association often reported in the literature. The method has also identified some GC-rich patterns, found to occur within the 3′UTR of homeodomain transcription factors and nuclear proteins. The method should be applicable to many types of regulatory element discovery.

Contact: conklin@zgi.com

* To whom correspondence should be addressed.
TROLL—Tandem Repeat Occurrence Locator
Authors: Castelo Adalberto T. , Martins Wellington , Gao Guang R.
Published: July 2002

Summary: Tandem Repeat Occurrence Locator (TROLL), is a light-weight Simple Sequence Repeat (SSR) finder based on a slight modification of the Aho–Corasick algorithm. It is fast and only requires a standard Personal Computer (PC) to operate. We report running times of 127 s to find all SSRs of length 20 bp or more on the complete Arabdopsis genome—approx. 130 Mbases divided in five chromosomes—using a PC Athlon 650 MHz with 256 MB of RAM.

Availability: TROLL is an open source project and is available at http://finder.sourceforge.net.

Contact: castelo@capsl.udel.edu
WOMEN AND MINORITIES IN AMERICA'S VOLUNTEER MILITARY
Authors: Quester Aline O. , Gilroy Curtis L.
Published: July 2002

Since the inception of the all‐volunteer force (AVF) in 1973, the U.S. military has been considered a pioneer of equal opportunity among the nation's institutions, despite its being a unique internal labor market characterized by a hierarchical structure with little lateral entry. The authors argue that this actually helped women and minorities because (1) the advancement process is both well defined and based on merit, and (2) the promotion process looks at everyone. The pay raises that accompanied the AVF made military service competitive with civilian labor market alternatives and provided women and minorities with a viable career choice. They took advantage of this freedom of choice resulting in their ever‐increasing representation at all levels of the armed forces.
A Theory of Time Preference
Authors: Trostel Philip A. , Taylor Grant A.
Published: July 2002

This article proposes that people generally prefer present consumption to future consumption because their expected utility from consumption (eventually) falls as their mental and physical abilities (eventually) decline with age. Moreover, contrary to the ubiquitous intertemporal formulation with a constant rate of time preference and contrary to three recent theories of time preference that predict decreasing discounting as people age, this article asserts that discounting increases over the life cycle. This hypothesis is supported by data from the Panel Study of Income Dynamics as well as evidence from numerous previous studies.
JNK functions in the non‐canonical Wnt pathway to regulate convergent extension movements in vertebrates
Authors: Yamanaka Hiroaki , Moriguchi Tetsuo , Masuyama Norihisa , Kusakabe Morioh , Hanafusa Hiroshi , Takada Ritsuko , Takada Shinji , Nishida Eisuke
Published: July 2002

Recent genetic studies in Drosophila identified a novel non‐canonical Wnt pathway, the planar cell polarity (PCP) pathway, that signals via JNK to control epithelial cell polarity in Drosophila. Most recently, a pathway regulating convergent extension movements during gastrulation in vertebrate embryos has been shown to be a vertebrate equivalent of the PCP pathway. However, it is not known whether the JNK pathway functions in this non‐canonical Wnt pathway to regulate convergent extension movements in vertebrates. In addition, it is not known whether JNK is in fact activated by Wnt stimulation. Here we show that Wnt5a is capable of activating JNK in cultured cells, and present evidence that the JNK pathway mediates the action of Wnt5a to regulate convergent extension movements in Xenopus. Our results thus demonstrate that the non‐canonical Wnt/JNK pathway is conserved in both vertebrate and invertebrate and define that JNK has an activity to regulate morphogenetic cell movements.
Transcription termination factor TTF‐I exhibits contrahelicase activity during DNA replication
Authors: Pütter Vera , Grummt Friedrich
Published: July 2002

In mammals, sequence‐specific termination of DNA replication within the ribosomal RNA genes is catalyzed by a defined DNA–protein complex that includes transcription termination factor I (TTF‐I). Here we show that TTF‐I acts as a polar contrahelicase contrary to the intrinsic 3′→5′ helicase activity of SV40 large T antigen. The contrahelicase activity requires binding of TTF‐I to its cognate recognition site and the presence of an auxiliary GC‐rich sequence, which is able to form a specific secondary structure. Mutations in the GC‐rich sequence lead to a loss of folding into correct secondary structure and abrogate contrahelicase activity. The finding suggests that a specific interaction between the Sal box‐bound TTF‐I and the GC‐rich sequence is essential for the inhibition of T antigen helicase. Analyses of N‐terminally truncated mutants of TTF‐I showed inhibition of helicase by the same domain of TTF‐I, which is also responsible for replication fork arrest.
Vascular adhesion protein 1 (VAP‐1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo
Authors: TOHKA SAMI , LAUKKANEN MARJA‐LEENA , JALKANEN SIRPA , SALMI MARKO
Published: July 2002

Granulocyte extravasation from the blood into tissues is a prerequisite for a proper inflammatory response. It is regulated by a multistep adhesion cascade consisting of successive contacts between leukocyte surface receptors and their endothelial ligands on vessels. Vascular adhesion protein 1 (VAP‐1) is an endothelial surface glycoprotein with two functions. It is an enzyme (monoamine oxidase) and an adhesion molecule for lymphocytes. Its function in binding of granulocytes or in leukocyte trafficking into sites of inflammation in vivo has remained unknown. Here we show that treatment of rabbits with anti‐VAP‐1 monoclonal antibodies abrogates ~70% of granulocyte extravasation into a site of an experimental inflammation. Using intravital microscopy, VAP‐1 blockade is shown to increase the velocity of the rolling granulocytes and the frequency of their jerky skippings during the rolling. In addition, the number of firmly bound leukocytes decreased by 44% when VAP‐1 was rendered nonfunctional. Our results suggest that VAP‐1 functions as a molecular brake early in the adhesion cascade and consequently decreases the firm adherence;it may also directly influence the transmigration step. These data elucidate a new interplayer in the granulocyte extravasation process and provide a novel physiological function for a member of the monoamine oxidase family.—Tohka, S., Laukkanen, M.‐L., Jalkanen, S., Salmi, M. Vascular adhesion protein 1 (VAP‐1) functions as a molecular brake during granulocyte rolling and mediates their recruitment in vivo. FASEB J. 15, 373‐382 (2001)
T–cell proliferationin vivoand the role of cytokines
Authors: Sprent Jonathan , Zhang Xiaohong , Sun Siquan , Tough David
Published: July 2002

Unlike typical naive T cells, T cells with an activated (CD44hi) memory phenotype show a rapid rate of proliferation in vivo . The turnover of memory–phenotype CD8+T cells can be considerably augmented by injecting mice with various compounds, including polyinosinic–polycytidylic acid, lipopolysaccharide and immunostimulatory DNA (CpG DNA). Certain cytokines, notably type I (α, β) interferons (IFNI), have a similar effect. These agents appear to induce proliferation of CD44hiCD8+cellsin vivoby an indirect process involving production of effector cytokines, possibly interleukin–15, by antigen–presenting cells. Although none of the agents tested induces proliferation of naive–phenotype T cells, IFN–I has the capacity to cause upregulation of surface markers on purified naive T cells. Depending upon the experimental conditions used, IFN–I can either inhibit or enhance primary responses of naive T cells to specific antigen.
Origins of anteroposterior patterning andHoxgene regulation during chordate evolution
Authors: Schilling Thomas F. , Kinght Robert D.
Published: July 2002

All chordates share a basic body plan and many common features of early development. Anteroposterior (AP) regions of the vertebrate neural tube are specified by a combinatorial pattern ofHoxgene expression that is conserved in urochordates and cephalochordates. Another primitive feature ofHoxgene regulation in all chordates is a sensitivity to retinoic acid during embryogenesis, and recent developmental genetic studies have demonstrated the essential role for retinoid signalling in vertebrates. Two AP regions develop within the chordate neural tube during gastrulation: an anterior ‘forebrain–midbrain’ region specified byOtxgenes and a posterior ‘hindbrain–spinal cord’ region specified byHoxgenes. A third, intermediate region corresponding to the midbrain or midbrain–hindbrain boundary develops at around the same time in vertebrates, and comparative data suggest that this was also present in the chordate ancestor. Within the anterior part of theHox–expressing domain, however, vertebrates appear to have evolved unique roles for segmentation genes, such asKrox–20, in patterning the hindbrain. Genetic approaches in mammals and zebrafish, coupled with molecular phylogenetic studies in ascidians, amphioxus and lampreys, promise to reveal how the complex mechanisms that specify the vertebrate body plan may have arisen from a relatively simple set of ancestral developmental components.
Memory for events and their spatial context: models and experiments
Authors: Burgess Neil , Becker Suzanna , King John A. , O'Keefe John
Published: July 2002

The computational role of the hippocampus in memory has been characterized as: (i) an index to disparate neocortical storage sites; (ii) a time–limited store supporting neocortical long–term memory; and (iii) a content–addressable associative memory. These ideas are reviewed and related to several general aspects of episodic memory, including the differences between episodic, recognition and semantic memory, and whether hippocampal lesions differentially affect recent or remote memories. Some outstanding questions remain, such as: what characterizes episodic retrieval as opposed to other forms of read–out from memory; what triggers the storage of an event memory; and what are the neural mechanisms involved? To address these questions a neural–level model of the medial temporal and parietal roles in retrieval of the spatial context of an event is presented. This model combines the idea that retrieval of the rich context of real–life events is a central characteristic of episodic memory, and the idea that medial temporal allocentric representations are used in long–term storage while parietal egocentric representations are used to imagine, manipulate and re–experience the products of retrieval. The model is consistent with the known neural representation of spatial information in the brain, and provides an explanation for the involvement of Papez's circuit in both the representation of heading direction and in the recollection of episodic information. Two experiments relating to the model are briefly described. A functional neuroimaging study of memory for the spatial context of life–like events in virtual reality provides support for the model's functional localization. A neuropsychological experiment suggests that the hippocampus does store an allocentric representation of spatial locations.
Plasmid-only rescue of influenza A virus vaccine candidates
Authors: Schickli J. H. , Flandorfer A. , Nakaya T. , Martinez-Sobrido L. , Garcia-Sastre A. , Palese P.
Published: July 2002

The potential threat of another influenza virus pandemic stimulates discussion on how to prepare for such an event. The most reasonable prophylactic approach appears to be the use of effective vaccines. Since influenza and other negative–stranded RNA viruses are amenable to genetic manipulation using transfection by plasmids, it is possible to outline new reverse genetics–based approaches for vaccination against influenza viruses. We suggest three approaches. First, we use a plasmid–only rescue system that allows the rapid generation of high–yield recombinant vaccine strains. Second, we propose developing second–generation live influenza virus vaccines by constructing an attenuated master strain with deletions in the NS1 protein, which acts as an interferon antagonist. Third, we suggest the use of Newcastle disease virus recombinants expressing influenza virus haemagglutinin proteins of pandemic (epizootic) strains as novel vaccine vectors for use in animals and possibly humans.
Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10
Authors: Stolt C. Claus , Rehberg Stephan , Ader Marius , Lommes Petra , Riethmacher Dieter , Schachner Melitta , Bartsch Udo , Wegner Michael
Published: July 2002

Sox10 is a high-mobility-group transcriptional regulator in early neural crest. Without Sox10, no glia develop throughout the peripheral nervous system. Here we show that Sox10 is restricted in the central nervous system to myelin-forming oligodendroglia. In Sox10-deficient mice progenitors develop, but terminal differentiation is disrupted. No myelin was generated upon transplantation of Sox10-deficient neural stem cells into wild-type hosts showing the permanent, cell-autonomous nature of the defect. Sox10 directly regulates myelin gene expression in oligodendrocytes, but does not control erbB3 expression as in peripheral glia. Sox10 thus functions in peripheral and central glia at different stages and through different mechanisms.
Evolutionarily Conserved Sequences on Human Chromosome 21
Authors: Frazer Kelly A. , Sheehan John B. , Stokowski Renee P. , Chen Xiyin , Hosseini Roya , Cheng Jan-Fang , Fodor Stephen P.A. , Cox David R. , Patil Nila
Published: July 2002

Comparison of human sequences with the DNA of other mammals is an excellent means of identifying functional elements in the human genome. Here we describe the utility of high-density oligonucleotide arrays as a rapid approach for comparing human sequences with the DNA of multiple species whose sequences are not presently available. High-density arrays representing ∼22.5 Mb of nonrepetitive human chromosome 21 sequence were synthesized and then hybridized with mouse and dog DNA to identify sequences conserved between humans and mice (human–mouse elements) and between humans and dogs (human–dog elements). Our data show that sequence comparison of multiple species provides a powerful empiric method for identifying actively conserved elements in the human genome. A large fraction of these evolutionarily conserved elements are present in regions on chromosome 21 that do not encode known genes.
Cross-Referencing Eukaryotic Genomes: TIGR Orthologous Gene Alignments (TOGA)
Authors: Lee Yuandan , Sultana Razvan , Pertea Geo , Cho Jennifer , Karamycheva Svetlana , Tsai Jennifer , Parvizi Babak , Cheung Foo , Antonescu Valentin , White Joseph , Holt Ingeborg , Liang Feng , Quackenbush John
Published: July 2002

Comparative genomics promises to rapidly accelerate the identification and functional classification of biologically important human genes. We developed the TIGR Orthologous Gene Alignment (TOGA; 〈http://www.tigr.org/tdb/toga/toga.shtml〉) database to provide a cross-reference between fully and partially sequenced eukaryotic transcribed sequences. Starting with the assembled expressed sequence tag (EST) and gene sequences that comprise the 28 TIGR Gene Indices, we used high-stringency pair-wise sequence searches and a reflexive, transitive closure process to associate sequence-specific best hits, generating 32,652 tentative ortholog groups (TOGs). This has allowed us to identify putative orthologs and paralogs for known genes, as well as those that exist only as uncharacterized ESTs and to provide links to additional information including genome sequence and mapping data. TOGA provides an important new resource for the analysis of gene function in eukaryotes. In addition, an analysis of the most widely represented sequences can begin to provide insight into eukaryotic biological processes.
Ca(II)‐ and Tb(III)‐induced stabilization and refolding of anticoagulation factor I from the venom of Agkistrodon acutus
Authors: Xu Xiaolong , Liu Qingliang , Yu Huaming , Xie Yongshu
Published: July 2002

Anticoagulation factor I (ACF I) isolated from the venom of Agkistrodon acutus is an activated coagulation factor X‐binding protein in a Ca2+‐dependent fashion with marked anticoagulant activity. The equilibrium unfolding/refolding of apo‐ACF I, holo‐ACF I, and Tb3+‐reconstituted ACF I in guanidine hydrochloride (GdnHCl) solutions was studied by following the fluorescence and circular dichroism. Metal ions were found to increase the structural stability of ACF I against GdnHCl and thermal denaturation and, furthermore, influence its unfolding/refolding behavior. The GdnHCl‐induced unfolding/refolding of both apo‐ACF I and Tb3+‐ACF I is a two‐state process with no detectable intermediate state(s), whereas the GdnHCl‐induced unfolding/refolding of holo‐ACF I in the presence of 1 mM Ca2+ follows a three‐step transition, with intermediate state a (Ia) and intermediate state b (Ib). Ca2+ ions play an important role in the stabilization of the Ia and Ib states. The decalcification of holo‐ACF I shifts the ending zone of unfolding/refolding curve toward lower GdnHCl concentration, whereas the reconstitution of apo‐ACF I with Tb3+ ions shifts the initial zone of denaturation curve toward higher GdnHCl concentration. Therefore, it is possible to find a denaturant concentration (2.0 M GdnHCl) at which refolding from the fully denatured state of apo‐ACF I to the Ib state of holo‐ACF I or to the native state of Tb3+‐ACF I can be initiated merely by adding the 1 mM Ca2+ ions or 10 μM Tb3+ ions to the unfolded state of apo‐ACF I, respectively, without changing the concentration of the denaturant. Using Tb3+ as a fluorescence probe of Ca2+, the kinetic results of metal ions–induced refolding provide evidence that the compact Tb3+‐binding region forms first, and subsequently, the protein undergoes further conformational rearrangements to form the native structure.
Evaluating the performance of detection algorithms in digital mammography
Authors: Kallergi Maria , Carney Gregory M. , Gaviria Jorge
Published: July 2002

The initial and relative evaluation of computer methodologies developed for assisting diagnosis in mammography is usually done by comparing the computer output to ground truth data provided by experts and/or biopsy. Reported studies, however, give little information on how the performance indices of computer assisted diagnosis (CAD) algorithms are determined in this initial stage of evaluation. Several strategies exist in the estimation of the true positive (TP) and false positive (FP) rates with respect to ground truth. Adopting one strategy over another yields different performance rates that can be over‐ or underestimates of the true performance. Furthermore, the estimation of pairs of TP and FP rates gives a partial picture of the performance of an algorithm. It is shown in this work that new performance indices are needed to fully describe the degree of detection (part or whole) and the type of detection (single calcification, cluster of calcifications, mass, or artifact). Several evaluation strategies were tested. The one that yielded the most realistic performances included the following criteria: The detected area should be at least 50% of the true area and no more than four times the true area in order to be considered TP. At least three true calcifications should be detected to within with nearest neighbor distances of less than √2 cm for a cluster to be considered TP. Separate detection measures should be established and used for artifacts and naturally occurring structures to maximize the benefits of the evaluation. Finally, it is critical that CAD investigators provide information on the tested image set as well as the criteria used for the evaluation of the algorithms to allow comparisons and better understanding of their methodologies.
Intensity modulation delivery techniques: “Step & shoot” MLC auto‐sequence versus the use of a modulator
Authors: Chang Sha X. , Cullip Timothy J. , Deschesne Katharin M.
Published: July 2002

Two intensity modulation radiotherapy (IMRT) delivery systems, the “step & shoot” multileaf collimator (MLC) auto‐sequence and the use of an intensity modulator, are compared with emphasis on the dose optimization quality and the treatment irradiation time. The intensity modulation (IM) was created by a dose gradient optimization algorithm which maximizes the target dose uniformity while maintaining dose to critical structures below a set tolerance defined by the user in terms of either a single dose value or a dose volume histogram curve for each critical structure. Two clinical cases were studied with and without dose optimization: a three‐field sinus treatment and a six‐field nasopharyngeal treatment. The optimization goal of the latter case included the sparing of several nearby normal structures in addition to the target dose uniformity. In both cases, the target dose uniformity initially improved quickly as the IM level increased to 5, then started to approach saturation when the MLC technique was used. In the absence of the both space and intensity discreteness intrinsic to the MLC technique, the modulator technique produced greater tumor dose uniformity and normal structure sparing. The latter showed no systematic improvement with increasing IM level using the MLC technique. For the sinus tumor treatment of 2 Gy the treatment irradiation time of the modulator technique is no more than that of the conventional treatment. For the MLC technique the irradiation time increased rapidly from 4.4 min to 12.4 min as the IM level increased from 2 to 10. Both clinical cases suggested that an IM level of 5 offered a good compromise between the dose optimization quality and treatment irradiation time. We showed that a realistic photon source model is necessary for dose computation accuracy in the MLC‐IM treatments.
Navigation in curved space–time
Authors: Bahder Thomas B.
Published: July 2002

A covariant and invariant theory of navigation in curved space–time with respect to electromagnetic beacons is written in terms of J. L. Synge’s two-point invariant world function. Explicit equations are given for navigation in space–time in the vicinity of the Earth in Schwarzschild coordinates and in rotating coordinates. The restricted problem of determining an observer’s coordinate time when his or her spatial position is known is also considered.
On the rise and fall of a ball with linear or quadratic drag
Authors: Timmerman Peter , van der Weele Jacobus P.
Published: July 2002

We review the problem of a vertically thrown ball, with a drag force which is either linear or quadratic in the speed. It is stressed from the outset that these two types of drag correspond to specific ranges of the Reynolds number (Re<1 and 103<Re<2×105, respectively) and do not hold outside these intervals. We also include the buoyant force in our treatment of the problem. The equations of motion are solved analytically and several true-to-life examples are discussed. The calculations are somewhat harder than for the well-known case without drag force, but no highbrow mathematics is required and the extra effort is amply compensated by the gain in realism and surprise value.
Forward masking: Adaptation or integration?
Authors: Oxenham Andrew J.
Published: July 2002

The aim of this study was to attempt to distinguish between neural adaptation and persistence (or temporal integration) as possible explanations of forward masking. Thresholds were measured for a sinusoidal signal as a function of signal duration for conditions where the delay between the masker offset and the signal offset (the offset–offset interval) was fixed. The masker was a 200-ms broadband noise, presented at a spectrum level of 40 dB (re: 20 μPa), and the signal was a 4-kHz sinusoid, gated with 2-ms ramps. The offset–offset interval was fixed at various durations between 4 and 102 ms and signal thresholds were measured for a range of signal durations at each interval. A substantial decrease in thresholds was observed with increasing duration for signal durations up to about 20 ms. At short offset–offset intervals, the amount of temporal integration exceeded that normally found in quiet. The results were simulated using models of temporal integration (the temporal-window model) and adaptation. For both models, the inclusion of a peripheral nonlinearity, similar to that observed physiologically in studies of the basilar membrane, was essential in producing a good fit to the data. Both models were about equally successful in accounting for the present data. However, the temporal-window model provided a somewhat better account of similar data from a simultaneous-masking experiment, using the same parameters. This suggests that the linear, time-invariant properties of the temporal-window approach are appropriate for modeling forward masking. Overall the results confirm that forward masking can be described in terms of peripheral nonlinearity followed by linear temporal integration at higher levels in the auditory system. However, the difference in predictions between the adaptation and integration models is relatively small, meaning that influence of adaptation cannot be ruled out.
Children’s detection of pure-tone signals with random multitone maskers
Authors: Oh Eunmi L. , Wightman Frederic , Lutfi Robert A.
Published: July 2002

Preschoolers and adults were asked to detect a 1000-Hz signal, which was masked by a multitone complex. The frequencies and amplitudes of the components in the complex varied randomly and independently on each presentation. A staircase, cued two-interval, forced-choice procedure disguised as a “listening game” was used to obtain signal thresholds in quiet and in the presence of the multitone maskers. The number of components in the masker was fixed within an experimental condition and varied from 2 to 906 across experimental conditions. Thresholds were also measured with a broadband noise masker. Eight preschool children and eight adults were tested. Although individual differences were large, among both adults and children, there was little difference between the groups in the mean amount of masking produced by the maskers with large numbers of components (400 and 906). There was also a small but significant difference between adults and children in the mean amount of masking produced by the broadband noise. The difference between the groups was much larger with smaller numbers of components. Data obtained from the adults were basically similar to that previously reported [cf. Neff and Green, Percept. Psychophys. 41, 409–415 (1987); Oh and Lutfi, J. Acoust. Soc. Am. 104, 3489–3499 (1998)]: maskers comprised of 10–40 components produced as much as 30 to 60 dB of masking in some, but not all listeners. Those same maskers produced larger amounts of masking (70–83 dB) in many of the preschool children, although, as in the adult group, individual differences were large. The component-relative-entropy (CoRE) model [Lutfi, J. Acoust. Soc. Am. 94, 748–758 (1993)] was used to describe the differences in performance between the children and adults. According to this model the average child appears to integrate information over a larger number of auditory filters than the average adult.
A new procedure for measuring peripheral compression in normal-hearing and hearing-impaired listeners
Authors: Nelson David A. , Schroder Anna C. , Wojtczak Magdalena
Published: July 2002

Forward-masking growth functions for on-frequency (6-kHz) and off-frequency (3-kHz) sinusoidal maskers were measured in quiet and in a high-pass noise just above the 6-kHz probe frequency. The data show that estimates of response-growth rates obtained from those functions in quiet, which have been used to infer cochlear compression, are strongly dependent on the spread of probe excitation toward higher frequency regions. Therefore, an alternative procedure for measuring response-growth rates was proposed, one that employs a fixed low-level probe and avoids level-dependent spread of probe excitation. Fixed-probe-level temporal masking curves (TMCs) were obtained from normal-hearing listeners at a test frequency of 1 kHz, where the short 1-kHz probe was fixed in level at about 10 dB SL. The level of the preceding forward masker was adjusted to obtain masked threshold as a function of the time delay between masker and probe. The TMCs were obtained for an on-frequency masker (1 kHz) and for other maskers with frequencies both below and above the probe frequency. From these measurements, input/output response-growth curves were derived for individual ears. Response-growth slopes varied from >1.0 at low masker levels to <0.2 at mid masker levels. In three subjects, response growth increased again at high masker levels (>80 dB SPL). For the fixed-level probe, the TMC slopes changed very little in the presence of a high-pass noise masking upward spread of probe excitation. A greater effect on the TMCs was observed when a high-frequency cueing tone was used with the masking tone. In both cases, however, the net effects on the estimated rate of response growth were minimal.
Acoustic attenuation in a three-gas mixture: Results
Authors: Dain Yefim , Lueptow Richard M.
Published: July 2002

Acoustic attenuation in a mixture of gases results from the combined effects of molecular relaxation and the classical mechanisms of viscosity and heat conduction. Consequently, the attenuation depends on the composition of the gas mixture, acoustic frequency, temperature, and pressure. A model of the relaxational attenuation that permits the calculation of acoustic attenuation is used to predict the effect of composition, frequency, temperature, and pressure on the acoustic attenuation in a three-component gas mixture of nitrogen, methane, and water vapor. The attenuation spectrum is dependent upon the composition through the appearance of peaks in the spectrum related to the relaxation frequencies of the particular components and their relaxing complexes. The relaxation peak related to methane dominates except at low methane concentrations, where the nitrogen peak, which is dependent upon the water vapor and methane concentration, is evident. Temperature and pressure significantly alter the relaxation frequency and the degree of attenuation, but water vapor plays little role in the attenuation.