bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of host contact network structure on pathogen diversity and strain structure
Authors: Buckee Caroline O'F. , Koelle Katia , Mustard Matthew J. , Gupta Sunetra
Published: July 2004

For many important pathogens, mechanisms promoting antigenic variation, such as mutation and recombination, facilitate immune evasion and promote strain diversity. However, mathematical models have shown that host immune responses to polymorphic antigens can structure pathogen populations into discrete strains with nonoverlapping antigenic repertoires, despite recombination. Until now, models of strain evolution incorporating host immunity have assumed a randomly mixed host population. Here, we illustrate the effects of different host contact networks on strain diversity and dynamics by using a stochastic, spatially heterogeneous analogue of this model. For randomly mixed populations, our model confirms that cross-immunity to strains sharing alleles at antigenic loci may structure the pathogen population into discrete, nonoverlapping strains. However, this structure breaks down once the assumption of random mixing is relaxed, and an increasingly diverse pathogen population emerges as contacts between hosts become more localized. These results imply that host contact network structure plays a significant role in mediating the emergence of pathogen strain structure and dynamics.
Variable
var
transition rates underlie antigenic variation in malaria
Authors: Horrocks Paul , Pinches Robert , Christodoulou Zóe , Kyes Sue A. , Newbold Chris I.
Published: July 2004

Plasmodium falciparum
erythrocyte membrane protein 1 (PfEMP1) is expressed on the surface of infected erythrocytes where it plays a central role in both infected erythrocytes cytoadhesion and immune evasion. Switches in clonal expression of PfEMP1 result in antigenic variation that facilitates long-term chronic infection of the host. The
var
gene family encodes PfEMP1 variants, with transcriptional switching between different
var
variants providing the molecular basis for antigenic variation. Despite the importance of
var
transcriptional switching in the evasion of the immune response, little is known about the way in which this process is regulated. Here we report the measurement of transition on and off rates for a series of
var
gene variants. We find (
i
) that on and off rates for a given variant are dissimilar, (
ii
) that these rates vary dramatically among different variants, and (
iii
) that in isogenic clones expressing the same
var
gene, both on and off rates are constant and appear to be an intrinsic property of that particular gene. These data would suggest that the information that determines the probability of the activation or silencing of
var
genes is present in their surrounding DNA. Furthermore, some transitions appear to be disallowed depending on the recent variant antigen expression history of the parasite clone. These findings have important implications for both the underlying molecular mechanisms of antigenic variation and the processes that promote chronicity of infection
in vivo
.
Design of a directed molecular network
Authors: Ashkenasy Gonen , Jagasia Reshma , Yadav Maneesh , Ghadiri M. Reza
Published: July 2004

An ability to rationally design complex networks from the bottom up can offer valuable quantitative model systems for use in gaining a deeper appreciation for the principles governing the self-organization and functional characteristics of complex systems. We report herein the
de novo
design, graph prediction, experimental analysis, and characterization of simple self-organized, nonlinear molecular networks. Our approach makes use of the sequence-dependant auto- and cross-catalytic functional characteristics of template-directed peptide fragment condensation reactions in neutral aqueous solutions. Starting with an array of 81 sequence similar 32-residue coiled-coil peptides, we estimated the relative stability difference between all plausible A
2
B-type coiled-coil ensembles and used this information to predict the auto- and cross-catalysis pathways and the resulting plausible network motif and connectivities. Similar to most complex systems, the generated graph displays clustered nodes with an overall hierarchical architecture. To test the validity of the design principles used, nine nodes composing a main segment of the graph were experimentally analyzed for their capacity in establishing the predicted network connectivity. The resulting self-organized chemical network is shown to display 25 directed edges in good agreement with the graph analysis estimations. Moreover, we show that by varying the system parameters (presence or absence of certain substrates or templates), its operating network motif can be altered, even to the extremes of turning pathways on or off. We suggest that this approach can be expanded for the construction of large-scale networks, offering a means to study and to understand better the emergent, collective behaviors of networks.
Directed evolution of ligand dependence: Small-molecule-activated protein splicing
Authors: Buskirk Allen R. , Ong Yi-Ching , Gartner Zev J. , Liu David R.
Published: July 2004

Artificial molecular switches that modulate protein activities in response to synthetic small molecules would serve as tools for exerting temporal and dose-dependent control over protein function. Self-splicing protein elements (inteins) are attractive starting points for the creation of such switches, because their insertion into a protein blocks the target protein's function until splicing occurs. Natural inteins, however, are not known to be regulated by small molecules. We evolved an intein-based molecular switch that transduces binding of a small molecule into the activation of an arbitrary protein of interest. Simple insertion of a natural ligand-binding domain into a minimal intein destroys splicing activity. To restore activity in a ligand-dependent manner, we linked protein splicing to cell survival or fluorescence inSaccharomyces cerevisiae. Iterated cycles of mutagenesis and selection yielded inteins with strong splicing activities that highly depend on 4-hydroxytamoxifen. Insertion of an evolved intein into four unrelated proteins in living cells revealed that ligand-dependent activation of protein function is general, fairly rapid, dose-dependent, and posttranslational. Our directed-evolution approach therefore evolved small-molecule dependence in a protein and also created a general tool for modulating the function of arbitrary proteins in living cells with a single cell-permeable, synthetic small molecule.
Structure of the C-terminal domain of the clock protein KaiA in complex with a KaiC-derived peptide: Implications for KaiC regulation
Authors: Vakonakis Ioannis , LiWang Andy C.
Published: July 2004

Circadian clocks are widespread endogenous mechanisms that control the temporal pattern of diverse biological processes, including gene transcription. KaiA is the positive element of the cyanobacterial clock because KaiA overexpression elevates transcription levels of clock components. Recently, we showed that the structure of KaiA is that of a domain-swapped homodimer. The N-terminal domain is a pseudo-receiver; thus, it is likely to be involved in signal transduction in the clock-resetting pathway. The C-terminal domain of KaiA is structurally novel and enhances the KaiC autokinase activity directly. Here, we report the NMR structure of the C-terminal domain of KaiA (ThKaiA180C) in complex with a KaiC-derived peptide from the cyanobacterium
Thermosynechococcus elongatus
BP-1. The protein–peptide interface is revealed to be different from a model that was proposed earlier, is stabilized by a combination of hydrophobic and electrostatic interactions, and includes many residues known to produce a circadian-period phenotype upon substitution. Although the structure of the monomeric subunit of ThKaiA180C is largely unchanged upon peptide binding, the intersubunit dimerization angle changes. It is proposed that modulation of the C-terminal KaiA domain dimerization angle regulates KaiA–KaiC interactions.
Ethanol toxicity in pancreatic acinar cells: Mediation by nonoxidative fatty acid metabolites
Authors: Criddle David N. , Raraty Michael G. T. , Neoptolemos John P. , Tepikin Alexei V. , Petersen Ole H. , Sutton Robert
Published: July 2004

Ethanol causes pancreatic damage by an unknown mechanism. Previously, we demonstrated that a sustained rise of the cytosolic Ca
2+
concentration ([Ca
2+
]
i
) causes pancreatic acinar cell injury. Here we have investigated the effects of ethanol and its metabolites on Ca
2+
signaling in pancreatic acinar cells. Most cells exposed to ethanol (up to 850 mM) showed little or no increase in [Ca
2+
]
i
(and never at concentrations <50 mM). During sustained exposure to 850 mM ethanol, acetylcholine (ACh) evoked a normal [Ca
2+
]
i
elevation and following ACh removal there was a normal and rapid recovery to a low resting level. The oxidative metabolite acetaldehyde (up to 5 mM) had no effect, whereas the nonoxidative unsaturated metabolite palmitoleic acid ethyl ester (10–100 μM, added on top of 850 mM ethanol) induced sustained, concentration-dependent increases in [Ca
2+
]
i
that were acutely dependent on external Ca
2+
and caused cell death. These actions were shared by the unsaturated metabolite arachidonic acid ethyl ester, the saturated equivalents palmitic and arachidic acid ethyl esters, and the fatty acid palmitoleic acid. In the absence of external Ca
2+
, releasing all Ca
2+
from the endoplasmic reticulum by ACh (10 μM) or the specific Ca
2+
pump inhibitor thapsigargin (2 μM) prevented such Ca
2+
signal generation. We conclude that nonoxidative fatty acid metabolites, rather than ethanol itself, are responsible for the marked elevations of [Ca
2+
]
i
that mediate toxicity in the pancreatic acinar cell and that these compounds act primarily by releasing Ca
2+
from the endoplasmic reticulum.
Integration of
Caenorhabditis elegans
MAPK pathways mediating immunity and stress resistance by MEK-1 MAPK kinase and VHP-1 MAPK phosphatase
Authors: Kim Dennis H. , Liberati Nicole T. , Mizuno Tomoaki , Inoue Hideki , Hisamoto Naoki , Matsumoto Kunihiro , Ausubel Frederick M.
Published: July 2004

The p38 and JNK classes of mitogen-activated protein kinases (MAPKs) have evolutionarily conserved roles in the control of cellular responses to microbial and abiotic stresses. The mechanisms by which crosstalk between distinct p38 and c-Jun N-terminal kinase (JNK) MAPK pathways occurs with resultant integration of signaling information have been difficult to establish, particularly in the context of whole organism physiology. In
Caenorhabditis elegans
a PMK-1 p38 MAPK pathway is required for resistance to bacterial infection, and a KGB-1 JNK-like MAPK pathway has recently been shown to mediate resistance to heavy metal stress. Here, we show that two components of the KGB-1 pathway, MEK-1 MAPK kinase (MAPKK), a homolog of mammalian MKK7, and VHP-1 MAPK phosphatase (MKP), a homolog of mammalian MKP7, also regulate pathogen resistance through the modulation of PMK-1 activity. The regulation of p38 and JNK-like MAPK pathways mediating immunity and heavy metal stress by common MAPKK and MKP signaling components suggests pivotal roles for MEK-1 and VHP-1 in the integration of diverse stress signals contributing to pathogen resistance in
C. elegans
. In addition, these data point to mechanisms in multicellular organisms by which signals transduced by distinct MAPK pathways may be subject to physiological integration at the level of regulation of MAPK activity by MAPKKs and MKPs.
Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication
Authors: Coskun Pinar E. , Beal M. Flint , Wallace Douglas C.
Published: July 2004

Defects in mitochondrial oxidative phosphorylation have frequently been associated with Alzheimer's disease (AD), and both inherited and somatic mtDNA mutations have been reported in certain AD cases. To determine whether mtDNA mutations contribute more generally to the etiology of AD, we have investigated the sequence of the mtDNA control region (CR) from AD brains for possible disease-causing mutations. Sixty-five percent of the AD brains harbored the T414G mutation, whereas this mutation was absent from all controls. Moreover, cloning and sequencing of the mtDNA CR from patient and control brains revealed that all AD brains had an average 63% increase in heteroplasmic mtDNA CR mutations and that AD brains from patients 80 years and older had a 130% increase in heteroplasmic CR mutations. In addition, these mutations preferentially altered known mtDNA regulatory elements. Certain AD brains harbored the disease-specific CR mutations T414C and T477C, and several AD brains between 74 and 83 years of age harbored the CR mutations T477C, T146C, and T195C, at levels up to 70–80% heteroplasmy. AD patient brains also had an average 50% reduction in the mtDNA L-strand ND6 transcript and in the mtDNA/nuclear DNA ratio. Because reduced ND6 mRNA and mtDNA copy numbers would reduce brain oxidative phosphorylation, these CR mutations could account for some of the mitochondrial defects observed in AD.
Emx2 homeodomain transcription factor interacts with eukaryotic translation initiation factor 4E (eIF4E) in the axons of olfactory sensory neurons
Authors: Nédélec Stéphane , Foucher Isabelle , Brunet Isabelle , Bouillot Colette , Prochiantz Alain , Trembleau Alain
Published: July 2004

We report thatEmx2homeogene is expressed at the mRNA and protein levels in the adult mouse olfactory neuroepithelium. As expected for a transcription factor, Emx2 is present in the nucleus of immature and mature olfactory sensory neurons. However, the protein is also detected in the axonal compartment of these neurons, both in the olfactory mucosa axon bundles and in axon terminals within the olfactory bulb. Emx2 axonal staining is heterogeneous, suggesting an association with particles. Subcellular fractionations of olfactory bulb synaptosomes, combined with chemical lesions of olfactory neurons, confirm the presence of Emx2 in axon terminals. Significant amounts of Emx2 protein cosediment with high density synaptosomal subfractions containing eukaryotic translation initiation factor 4E (eIF4E). Nonionic detergents and RNase treatments failed to detach eIF4E and Emx2 from these high-density fractions enriched in vesicles and granular structures. In addition, Emx2 and eIF4E can be coimmunoprecipitated from olfactory mucosa and bulb extracts and interact directly, as demonstrated in pull-down experiments. Emx2 axonal localization, association with high-density particles and interaction with eIF4E strongly suggest that this transcription factor has new nonnuclear functions most probably related to the local control of protein translation in the olfactory sensory neuron axons. Finally, we show that two other brain-expressed homeoproteins, Otx2 and Engrailed 2, also bind eIF4E, indicating that several homeoproteins may modulate eIF4E functions in the developing and adult nervous system.
MRI detection of single particles for cellular imaging
Authors: Shapiro Erik M. , Skrtic Stanko , Sharer Kathryn , Hill Jonathan M. , Dunbar Cynthia E. , Koretsky Alan P.
Published: July 2004

There is rapid growth in the use of MRI for molecular and cellular imaging. Much of this work relies on the high relaxivity of nanometer-sized, ultrasmall dextran-coated iron oxide particles. Typically, millions of dextran-coated ultrasmall iron oxide particles must be loaded into cells for efficient detection. Here we show that single, micrometer-sized iron oxide particles (MPIOs) can be detected by MRI
in vitro
in agarose samples, in cultured cells, and in mouse embryos. Experiments studying effects of MRI resolution and particle size from 0.76 to 1.63 μm indicated that

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effects can be readily detected from single MPIOs at 50-μm resolution and significant signal effects could be detected at resolutions as low as 200 μm. Cultured cells were labeled with fluorescent MPIOs such that single particles were present in individual cells. These single particles in single cells could be detected both by MRI and fluorescence microscopy. Finally, single particles injected into single-cell-stage mouse embryos could be detected at embryonic day 11.5, demonstrating that even after many cell divisions, daughter cells still carry individual particles. These results demonstrate that MRI can detect single particles and indicate that single-particle detection will be useful for cellular imaging.
Identification of 315 genes essential for early zebrafish development
Authors: Amsterdam Adam , Nissen Robert M. , Sun Zhaoxia , Swindell Eric C. , Farrington Sarah , Hopkins Nancy
Published: July 2004

We completed a large insertional mutagenesis screen in zebrafish to identify genes essential for embryonic and early larval development. We isolated 525 mutants, representing lesions in ≈390 different genes, and we cloned the majority of these. Here we describe 315 mutants and the corresponding genes. Our data suggest that there are roughly 1,400 embryonic-essential genes in the fish. Thus, we have mutations in ≈25% of these genes and have cloned ≈22% of them. Re-screens of our collection to identify mutants with specific developmental defects suggest that ≈50 genes are essential for the development of some individual organs or cell types. Seventy-two percent of the embryonic-essential fish genes have homologues in yeast, 93% have homologues in invertebrates (fly or worm), and 99% have homologues in human. Yeast and worm orthologues of genes that are essential for early zebrafish development have a strong tendency to be essential for viability in yeast and for embryonic development in the worm. Thus, the trait of being a genetically essential gene is conserved in evolution. This mutant collection should be a valuable resource for diverse studies of cell and developmental biology.
MS analysis of single-nucleotide differences in circulating nucleic acids: Application to noninvasive prenatal diagnosis
Authors: Ding Chunming , Chiu Rossa W. K. , Lau Tze K. , Leung Tse N. , Chan Li C. , Chan Amy Y. Y. , Charoenkwan Pimlak , Ng Ivy S. L. , Law Hai-yang , Ma Edmond S. K. , Xu Xiangmin , Wanapirak Chanane , Sanguansermsri Torpong , Liao Can , Ai Mary Anne Tan Jin , Chui David H. K. , Cantor Charles R. , Lo Y. M. Dennis
Published: July 2004

The analysis of circulating nucleic acids has revealed applications in the noninvasive diagnosis, monitoring, and prognostication of many clinical conditions. Circulating fetal-specific sequences have been detected and constitute a fraction of the total DNA in maternal plasma. The diagnostic reliability of circulating DNA analysis depends on the fractional concentration of the targeted sequence, the analytical sensitivity, and the specificity. The robust discrimination of single-nucleotide differences between circulating DNA species is technically challenging and demands the adoption of highly sensitive and specific analytical systems. We have developed a method based on single-allele base extension reaction and MS, which allows for the reliable detection of fetal-specific alleles, including point mutations and single-nucleotide polymorphisms, in maternal plasma. The approach was applied to exclude the fetal inheritance of the four most common Southeast Asian β-thalassemia mutations in at-risk pregnancies between weeks 7 and 21 of gestation. Fetal genotypes were correctly predicted in all cases studied. Fetal haplotype analysis based on a single-nucleotide polymorphism linked to the β-globin locus,HBB, in maternal plasma also was achieved. Consequently, noninvasive prenatal diagnosis in a mother and father carrying identical β-thalassemia mutations was accomplished. These advances will help in catalyzing the clinical applications of fetal nucleic acids in maternal plasma. This analytical approach also will have implications for many other applications of circulating nucleic acids in areas such as oncology and transplantation.
Varicella-zoster virus infection of human neural cells
in vivo
Authors: Baiker Armin , Fabel Klaus , Cozzio Antonio , Zerboni Leigh , Fabel Konstanze , Sommer Marvin , Uchida Nobuko , He Dongping , Weissman Irving , Arvin Ann M.
Published: July 2004

Varicella-zoster virus (VZV) establishes latency in sensory ganglia and causes herpes zoster upon reactivation. These investigations in a nonobese diabetic severe combined immunodeficient mouse-human neural cell model showed that VZV infected both neurons and glial cells and spread efficiently from cell to cell
in vivo
. Neural cell morphology and protein synthesis were preserved, in contrast to destruction of epithelial cells by VZV. Expression of VZV genes in neural cells was characterized by nuclear retention of the major viral transactivating protein and a block in synthesis of the predominant envelope glycoprotein. The attenuated VZV vaccine strain retained infectivity for neurons and glial cells
in vivo
. VZV gene expression in differentiated human neural cells
in vivo
differs from neural infection by herpes simplex virus, which is characterized by latency-associated transcripts, and from lytic VZV replication in skin. The chimeric nonobese diabetic severe combined immunodeficient mouse model may be useful for investigating other neurotropic human viruses.
Absence of a reductase, NCB5OR, causes insulin-deficient diabetes
Authors: Xie Jianxin , Zhu Hao , Larade Kevin , Ladoux Annie , Seguritan Ayden , Chu Michelle , Ito Susumu , Bronson Roderick T. , Leiter Edward H. , Zhang Chen-Yu , Rosen Evan D. , Bunn H. Franklin
Published: July 2004

NCB5OR is a highly conserved NAD(P)H reductase that contains a cytochrome b5-like domain at the N terminus and a cytochrome b5 reductase-like domain at the C terminus. The enzyme is located in the endoplasmic reticulum (ER) and is widely expressed in organs and tissues. Targeted inactivation of this gene in mice has no impact on embryonic or fetal viability. At 4 weeks of age,
Ncb5or
-/- mice have normal blood glucose levels but impaired glucose tolerance. Isolated
Ncb5or
-/- islets have markedly impaired glucose- or arginine-stimulated insulin secretion. By 7 weeks of age, these mice develop severe hyperglycemia with markedly decreased serum insulin levels and nearly normal insulin tolerance. As the animals age, there is a progressive loss of beta cells in pancreatic islets, but there is no loss of alpha, delta, or PP cells. Electron microscopy reveals degranulation of beta cells and hypertrophic and hyperplastic mitochondria, some of which contain electron dense inclusions. Four-week-old
Ncb5or
-/- mice have enhanced sensitivity to the diabetogenic agent streptozotocin. NCB5OR appears to play a critical role in protecting pancreatic beta cells against oxidant stress.
Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins
Authors: Huffman Danielle L. , Abrami Laurence , Sasik Roman , Corbeil Jacques , van der Goot F. Gisou , Aroian Raffi V.
Published: July 2004

Cytolytic pore-forming toxins are important for the virulence of many disease-causing bacteria. How target cells molecularly respond to these toxins and whether or not they can mount a defense are poorly understood. By using microarrays, we demonstrate that the nematode
Caenorhabditis elegans
responds robustly to Cry5B, a member of the pore-forming Crystal toxin family made by
Bacillus thuringiensis
. This genomic response is distinct from that seen with a different stressor, the heavy metal cadmium. A p38 mitogen-activated protein kinase (MAPK) kinase and a c-Jun N-terminal-like MAPK are both transcriptionally up-regulated by Cry5B. Moreover, both MAPK pathways are functionally important because elimination of either leads to animals that are (
i
) hypersensitive to a low, chronic dose of toxin and (
ii
) hypersensitive to a high, brief dose of toxin such that the animal might naturally encounter in the wild. These results extend to mammalian cells because inhibition of p38 results in the hypersensitivity of baby hamster kidney cells to aerolysin, a pore-forming toxin that targets humans. Furthermore, we identify two downstream transcriptional targets of the p38 MAPK pathway,
ttm-1
and
ttm-2
, that are required for defense against Cry5B. Our data demonstrate that cells defend against pore-forming toxins by means of conserved MAPK pathways.
Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury
in vivo
Authors: Ikeda Yuichi , Imai Yasushi , Kumagai Hidetoshi , Nosaka Tetsuya , Morikawa Yoshihiro , Hisaoka Tomoko , Manabe Ichiro , Maemura Koji , Nakaoka Takashi , Imamura Takeshi , Miyazono Kohei , Komuro Issei , Nagai Ryozo , Kitamura Toshio
Published: July 2004

Growth factors, cell-surface receptors, adhesion molecules, and extracellular matrix proteins play critical roles in vascular pathophysiology by affecting growth, migration, differentiation, and survival of vascular cells. In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using a retrovirus-mediated signal sequence trap method, we isolated a cell-surface protein named vasorin. Vasorin is a typical type I membrane protein, containing tandem arrays of a characteristic leucine-rich repeat motif, an epidermal growth factor-like motif, and a fibronectin type III-like motif at the extracellular domain. Expression analyses demonstrated that vasorin is predominantly expressed in vascular smooth muscle cells, and that its expression is developmentally regulated. To clarify biological functions of vasorin, we searched for its binding partners and found that vasorin directly binds to transforming growth factor (TGF)-β and attenuates TGF-β signaling
in vitro
. Vasorin expression was down-regulated during vessel repair after arterial injury, and reversal of vasorin down-regulation, by using adenovirus-mediated
in vivo
gene transfer, significantly diminished injury-induced vascular lesion formation, at least in part, by inhibiting TGF-β signaling
in vivo
. These results suggest that down-regulation of vasorin expression contributes to neointimal formation after vascular injury and that vasorin modulates cellular responses to pathological stimuli in the vessel wall. Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders.
Personality correlates of the disposition towards interpersonal forgiveness: A Chinese perspective
Authors: Fu Hong , Watkins David , Hui Eadaoin K. P
Published: July 2004

This paper presents the results of three studies that investigated the nature of forgiveness, its measurement, and personality correlates in the People's Republic of China (PRC). Study 1 involved in‐depth interviews with 27 PRC cultural scholars about the concept of forgiveness and factors influencing the tendency to forgive in Chinese philosophy and everyday life. The respondents supported the relevance of this concept for Chinese societies and were able to give examples both from classical Chinese texts and their own lives. However, they also considered that preserving group harmony was the main reason to forgive and discounted the personality or religious influences commonly reported in the Western literature. Study 2 reported the adaptation of a Western forgiveness questionnaire for use with PRC respondents. Study 3 involved administering this questionnaire together with measures of self‐esteem, anxiety, impression management, and culturally appropriate constructs of face, relationship orientation, and harmony to 336 college students and 432 teachers from the PRC. As predicted, it was the latter two constructs that had the strongest correlations with the tendency to forgive in both samples. It was concluded that, in the PRC, willingness to forgive is influenced largely by social solidarity needs rather than the individualistic personality variables or religiosity reported in Western research. We hypothesize that this is due to the collectivist nature of PRC society and the results may well generalize to other collectivist cultures.
Police officers' credibility judgments: Accuracy and estimated ability
Authors: Garrido Eugenio , Masip Jaume , Herrero Carmen
Published: July 2004

A study was conducted to examine Spanish police officers' and nonofficers' lie‐ and truth‐detection accuracy, as well as their estimated detection ability. The participants were 121 police officers and 146 undergraduates who watched videotaped truthful and deceptive statements. They had to indicate: (1) whether each statement was truthful or deceptive, and (2) how good police officers were, in comparison with the general population, at detecting the truthfulness or deceptiveness of a statement. Results indicate that police officers' accuracy was not higher than that of nonofficers, rather, while the officers reached an accuracy rate close to chance probability, the undergraduates surpassed that probability. Officers had a very strong tendency to judge the statements as deceptive; this made them less accurate than the students in judging the truthful accounts, while both groups reached a similar accuracy when judging the deceptive ones. Both occupational samples considered that the police are more capable of identifying truths and lies than the general population. However, this belief was stronger among the officers themselves than among the nonofficers. No significant correlation between estimated ability and accuracy was found for either sample. The results are explained in terms of the participants' wrong beliefs about the cues to deceit and the socialization process that police officers undergo, which would increase their confidence and perceived ability while hindering their learning of the actual indicators of deceit. The need for officers to receive training is emphasized, and some directions are given on how this training should be carried out.
Need for cognitive closure and politics: Voting, political attitudes and attributional style
Authors: Chirumbolo Antonio , Areni Alessandra , Sensales Gilda
Published: July 2004

This paper examines the impact of dispositional Need for Cognitive Closure (NFC) on different political attitudes and on the “person blame” and the “system blame” dimensions. Two hundred and thirty‐four psychology students completed a questionnaire containing the Italian version of the Need for Closure scale, a measure of political and ideological attitudes, a measure of the person‐system blame dimensions, and a measure of past voting. Results showed that high NFC individuals (vs. low NFCs) reported having voted for a right‐wing party and holding more conservative attitudes. High NFCs (vs. low NFCs) turned out to have stronger anti‐immigrant attitudes, to be more nationalistic, to prefer an autocratic leadership and a centralized form of political power. High NFCs also value religiosity more highly than low NFCs. High NFCs (vs. low NFCs) scored lower on pluralism and multiculturalism. Furthermore, high NFCs (vs. low NFCs) revealed a tendency to blame individuals for social problems, but no significant difference was found with regard to the system blame dimension. Results are discussed in the light of the motivated social cognition approach (Jost, Glaser, Kruglanski, & Sulloway, 2003).
DNA structure constraint is probably a fundamental factor inducing CpG deficiency in bacteria
Authors: Wang Yong , Leung Frederick C. C.
Published: July 2004

Motivation: It has been speculated that CpG dinucleotide deficiency in genomes is a consequence of DNA methylation. However, this hypothesis does not adequately explain CpG deficiency in bacteria. The hypothesis based on DNA structure constraint as an alternative explanation was therefore examined.

Results: By comparing real bacterial genomes and Markov artificial genomes in the second order, we found that the core structure of a restricted pattern, the TTCGAA pattern, was under represented in low GC content bacterial genomes regardless of CpG dinucleotide level. This is in contrast to the AACGTT pattern, indicating that the counterselection is context-dependent. Further study discovered nine underrepresented patterns that were supposed to be capable of inducing DNA structure constraint. In summary, most of them are in TTCGNA and TTCGAN patterns in both DNA strands. An explanation is also proposed for the strong correlation between GC content and CpG deficiency. The result of random sequence simulation showed that the occurrences of these patterns were correlated with GC content, as well as the percentage of CpG dinucleotides being trapped in these patterns. Finally, we suggest that the degree of counter-selection against these restricted patterns could be influenced by global GC content of a genome.
Importing MAGE-ML format microarray data into BioConductor
Authors: Durinck Steffen , Allemeersch Joke , Carey Vincent J. , Moreau Yves , De Moor Bart
Published: July 2004

The microarray gene expression markup language (MAGE-ML) is a widely used XML (eXtensible Markup Language) standard for describing and exchanging information about microarray experiments. It can describe microarray designs, microarray experiment designs, gene expression data and data analysis results. We describe RMAGEML, a new Bioconductor package that provides a link between cDNA microarray data stored in MAGE-ML format and the Bioconductor framework for preprocessing, visualization and analysis of microarray experiments.

Availability:  http://www.bioconductor.org. Open Source
PLPMDB: Pyridoxal-5′-phosphate dependent enzymes mutants database
Authors: Di Giovine Paolo
Published: July 2004

Summary: The searchable mutant database PLPMDB has been developed to provide rapid and simple access to relevant mutant information on pyridoxal-5′-phosphate dependent enzymes. All data have been extracted from publications and publicly available databases, then organized in a relational database to enable searching via a web-based search form. The current version of PLPMDB contains 688 mutants described in 220 research papers. The database is a useful tool for planning mutant experiments and for interpretation of information from such experiments.

Availability: PLPMDB is freely accessible from http://www.studiofmp.com/plpmdb/index.htm
VisRD—visual recombination detection
Authors: Forslund Kristoffer , Huson Daniel H. , Moulton Vincent
Published: July 2004

Summary: VisRD, a program for visual recombination detection in a sequence alignment is presented. VisRD is written in Java and is designed to complement the multi-purpose phylogenetic software package SplitsTree4.

Availability: The software is freely available from http://www.lcb.uu.se/~vmoulton/software/visrd/
DNMAD: web-based diagnosis and normalization for microarray data
Authors: Vaquerizas Juan M. , Dopazo Joaquín , Díaz-Uriarte Ramón
Published: July 2004

Summary: We present a web server for Diagnosis and Normalization of MicroArray Data (DNMAD). DNMAD includes several common data transformations such as spatial and global robust local regression or multiple slide normalization, and allows for detecting several kinds of errors that result from the manipulation and the image analysis of the arrays. This tool offers a user-friendly interface, and is completely integrated within the Gene Expression Pattern Analysis Suite (GEPAS).

Availability: The tool is accessible on-line at http://dnmad.bioinfo.cnio.es
Conserved network motifs allow protein–protein interaction prediction
Authors: Albert István , Albert Réka
Published: July 2004

Motivation: High-throughput protein interaction detection methods are strongly affected by false positive and false negative results. Focused experiments are needed to complement the large-scale methods by validating previously detected interactions but it is often difficult to decide which proteins to probe as interaction partners. Developing reliable computational methods assisting this decision process is a pressing need in bioinformatics.

Results: We show that we can use the conserved properties of the protein network to identify and validate interaction candidates. We apply a number of machine learning algorithms to the protein connectivity information and achieve a surprisingly good overall performance in predicting interacting proteins. Using a ‘leave-one-out’ approach we find average success rates between 20 and 40% for predicting the correct interaction partner of a protein. We demonstrate that the success of these methods is based on the presence of conserved interaction motifs within the network.

Availability: A reference implementation and a table with candidate interacting partners for each yeast protein are available at http://www.protsuggest.org.
A graph-theoretic approach to testing associations between disparate sources of functional genomics data
Authors: Balasubramanian Raji , LaFramboise Thomas , Scholtens Denise , Gentleman Robert
Published: July 2004

Motivation: The last few years have seen the advent of high-throughput technologies to analyze various properties of the transcriptome and proteome of several organisms. The congruency of these different data sources, or lack thereof, can shed light on the mechanisms that govern cellular function. A central challenge for bioinformatics research is to develop a unified framework for combining the multiple sources of functional genomics information and testing associations between them, thus obtaining a robust and integrated view of the underlying biology.

Results: We present a graph-theoretic approach to test the significance of the association between multiple disparate sources of functional genomics data by proposing two statistical tests, namely edge permutation and node label permutation tests. We demonstrate the use of the proposed tests by finding significant association between a Gene Ontology-derived predictome and data obtained from mRNA expression and phenotypic experiments for Saccharomyces cerevisiae. Moreover, we employ the graph-theoretic framework to recast a surprising discrepancy presented elsewhere between gene expression and knockout phenotype, using expression data from a different set of experiments.

Availability: An R software package, GraphAT, containing the data and statistical procedures is available from Bioconductor: http://www.bioconductor.org
Reducing storage requirements for biological sequence comparison
Authors: Roberts Michael , Hayes Wayne , Hunt Brian R. , Mount Stephen M. , Yorke James A.
Published: July 2004

Motivation: Comparison of nucleic acid and protein sequences is a fundamental tool of modern bioinformatics. A dominant method of such string matching is the ‘seed-and-extend’ approach, in which occurrences of short subsequences called ‘seeds’ are used to search for potentially longer matches in a large database of sequences. Each such potential match is then checked to see if it extends beyond the seed. To be effective, the seed-and-extend approach needs to catalogue seeds from virtually every substring in the database of search strings. Projects such as mammalian genome assemblies and large-scale protein matching, however, have such large sequence databases that the resulting list of seeds cannot be stored in RAM on a single computer. This significantly slows the matching process.

Results: We present a simple and elegant method in which only a small fraction of seeds, called ‘minimizers’, needs to be stored. Using minimizers can speed up string-matching computations by a large factor while missing only a small fraction of the matches found using all seeds.
Extracting gene pathway relations using a hybrid grammar: the Arizona Relation Parser
Authors: McDonald Daniel M. , Chen Hsinchun , Su Hua , Marshall Byron B.
Published: July 2004

Motivation: Text-mining research in the biomedical domain has been motivated by the rapid growth of new research findings. Improving the accessibility of findings has potential to speed hypothesis generation.

Results: We present the Arizona Relation Parser that differs from other parsers in its use of a broad coverage syntax-semantic hybrid grammar. While syntax grammars have generally been tested over more documents, semantic grammars have outperformed them in precision and recall. We combined access to syntax and semantic information from a single grammar. The parser was trained using 40 PubMed abstracts and then tested using 100 unseen abstracts, half for precision and half for recall. Expert evaluation showed that the parser extracted biologically relevant relations with 89% precision. Recall of expert identified relations with semantic filtering was 35 and 61% before semantic filtering. Such results approach the higher-performing semantic parsers. However, the AZ parser was tested over a greater variety of writing styles and semantic content.

Availability: Relations extracted from over 600 000 PubMed abstracts are available for retrieval and visualization at http://econport.arizona.edu:8080/NetVis/index.html
CRH_Server: an online comparative and radiation hybrid mapping server for the canine genome
Authors: Hitte Christophe , Derrien Thomas , André Catherine , Ostrander Elaine A. , Galibert Francis
Published: July 2004

Summary: CRH_Server is an on line Comparative and Radiation Hybrid mapping Server dedicated to canine genomics. CRH_Server allows users to compute their own RH data using the current canine RH map, and allows comparative dog/human mapping analyses. Finally, it suggests multiple options for storage and queries of the dog RH database.

Availability:  http://idefix.univ-rennes1.fr:8080/Dogs/rh-server.html

Supplementary information: All information is available at http://idefix.univ-rennes1.fr:8080/Dogs/help_rh-server.html
Mining HIV protease cleavage data using genetic programming with a sum-product function
Authors: Yang Zheng Rong , Dalby Andrew R. , Qiu Jing
Published: July 2004

Motivation: In order to design effective HIV inhibitors, studying and understanding the mechanism of HIV protease cleavage specification is critical. Various methods have been developed to explore the specificity of HIV protease cleavage activity. However, success in both extracting discriminant rules and maintaining high prediction accuracy is still challenging. The earlier study had employed genetic programming with a min–max scoring function to extract discriminant rules with success. However, the decision will finally be degenerated to one residue making further improvement of the prediction accuracy difficult. The challenge of revising the min–max scoring function so as to improve the prediction accuracy motivated this study.

Results: This paper has designed a new scoring function called a sum–product function for extracting HIV protease cleavage discriminant rules using genetic programming methods. The experiments show that the new scoring function is superior to the min–max scoring function.

Availability: The software package can be obtained by request to Dr Zheng Rong Yang.
Dimension reduction methods for microarrays with application to censored survival data
Authors: Li Lexin , Li Hongzhe
Published: July 2004

Motivation: Recent research has shown that gene expression profiles can potentially be used for predicting various clinical phenotypes, such as tumor class, drug response and survival time. While there has been extensive studies on tumor classification, there has been less emphasis on other phenotypic features, in particular, patient survival time or time to cancer recurrence, which are subject to right censoring. We consider in this paper an analysis of censored survival time based on microarray gene expression profiles.

Results: We propose a dimension reduction strategy, which combines principal components analysis and sliced inverse regression, to identify linear combinations of genes, that both account for the variability in the gene expression levels and preserve the phenotypic information. The extracted gene combinations are then employed as covariates in a predictive survival model formulation. We apply the proposed method to a large diffuse large-B-cell lymphoma dataset, which consists of 240 patients and 7399 genes, and build a Cox proportional hazards model based on the derived gene expression components. The proposed method is shown to provide a good predictive performance for patient survival, as demonstrated by both the significant survival difference between the predicted risk groups and the receiver operator characteristics analysis.

Availability: R programs are available upon request from the authors.

Supplementary information:  http://dna.ucdavis.edu/~hli/bioinfo-surv-supp.pdf.
Limited agreement among three global gene expression methods highlights the requirement for non-global validation
Authors: Haverty Peter M. , Hsiao Li-Li , Gullans Steven R. , Hansen Ulla , Weng Zhiping
Published: July 2004

Motivation: DNA microarrays have revolutionized biological research, but their reliability and accuracy have not been extensively evaluated. Thorough testing of microarrays through comparison to dissimilar gene expression methods is necessary in order to determine their accuracy.

Results: We have systematically compared three global gene expression methods on all available histologically normal samples from five human organ types. The data included 25 Affymetrix high-density oligonucleotide array experiments, 23 expressed sequence tag based expression (EBE) experiments and 5 SAGE experiments. The reported gene-by-gene expression patterns showed a wide range of correlations between pairs of methods. This level of agreement was sufficient for accurate clustering of datasets from the same tissue and dissimilar methods, but highlights the need for thorough validation of individual gene expression measurements by alternate, non-global methods. Furthermore, analyses of mRNA abundance distributions indicate limitations in the EBE and SAGE methods at both high- and low-expression levels.
CBS Genome Atlas Database: a dynamic storage for bioinformatic results and sequence data
Authors: Hallin Peter F. , Ussery David W.
Published: July 2004

Summary: Currently, new bacterial genomes are being published on a monthly basis. With the growing amount of genome sequence data, there is a demand for a flexible and easy-to-maintain structure for storing sequence data and results from bioinformatic analysis. More than 150 sequenced bacterial genomes are now available, and comparisons of properties for taxonomically similar organisms are not readily available to many biologists. In addition to the most basic information, such as AT content, chromosome length, tRNA count and rRNA count, a large number of more complex calculations are needed to perform detailed comparative genomics. DNA structural calculations like curvature and stacking energy, DNA compositions like base skews, oligo skews and repeats at the local and global level are just a few of the analysis that are presented on the CBS Genome Atlas Web page. Complex analysis, changing methods and frequent addition of new models are factors that require a dynamic database layout. Using basic tools like the GNU Make system, csh, Perl and MySQL, we have created a flexible database environment for storing and maintaining such results for a collection of complete microbial genomes. Currently, these results counts to more than 220 pieces of information. The backbone of this solution consists of a program package written in Perl, which enables administrators to synchronize and update the database content. The MySQL database has been connected to the CBS web-server via PHP4, to present a dynamic web content for users outside the center. This solution is tightly fitted to existing server infrastructure and the solutions proposed here can perhaps serve as a template for other research groups to solve database issues.

Availability: A web based user interface which is dynamically linked to the Genome Atlas Database can be accessed via www.cbs.dtu.dk/services/GenomeAtlas/

Supplementary information: This paper has a supplemental information page which links to the examples presented: www.cbs.dtu.dk/services/GenomeAtlas/suppl/bioinfdatabase