bluuebunny/crossref_metadata_2025 huggingface dataset:
Agonistic behaviour in final-instar larvae of Episynlestes cristatus, Synlestes tropicus and Chorismagrion risi (Odonata : Synlestidae), and relationships within the 'Lestoidea'
Authors: Rowe R. J.
Published: June 2004

Larval agonistic displays are reported from three sympatric synlestid damselflies: Episynlestes cristatus, Synlestes tropicus and Chorismagrion risi. There were strong similarities between the species in the observed displays. Repertoires of all three species contained elements otherwise known only from larval Lestidae (conventionally interpreted as a member of the sister group to the Synlestidae). In night-time observations under infrared illumination different displays, some similar to those of coenagrionids, occurred. On the basis of similarities in larval displays I conclude that Chorismagrion risi, regarded on adult characters as an enigmatic form, is a member of the Synlestidae and that the Synlestidae and Lestidae are closely allied.
Activation of alternative NF-κB pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein (vFLIP)
Authors: Matta Hittu , Chaudhary Preet M.
Published: June 2004

The Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) has been linked to KS and primary effusion lymphoma (PEL) in immunocompromised individuals. We report that PEL cell lines have constitutive active alternative NF-κB pathway and demonstrate high-level expression of NF-κB2/p100 precursor and its processed subunit p52. To elucidate the mechanism of activation of the alternative NF-κB pathway in PEL cells, we have investigated the role of KSHV-encoded viral Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein (vFLIP) K13. We demonstrate that stable expression of K13, but not other FLIPs, in a variety of cell lines constitutively up-regulates p100/NF-κB2 expression and leads to its processing into the p52 subunit. K13-induced up-regulation and processing of p100 critically depends on the IκB kinase (IKK)α/IKK1 subunit of the IKK complex, whereas IKKβ/IKK2, receptor-interacting protein, and NF-κB-inducing kinase are dispensable for this process. Silencing of endogenous K13 expression by siRNA inhibits p100 processing and cellular proliferation. Our results demonstrate for the first time, to our knowledge, that KSHV vFLIP K13 is required for the growth and proliferation of PEL cells and alternative NF-κB pathway plays a key role in this process. Therapeutic agents targeting the alternative NF-κB pathway may have a role in the treatment of KSHV-associated lymphomas.
Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase
Authors: McClung James P. , Roneker Carol A. , Mu Weipeng , Lisk Donald J. , Langlais Paul , Liu Feng , Lei Xin Gen
Published: June 2004

Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H2O2)in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n= 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P< 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g,P< 0.001) and fatter (37% vs. 17% fat,P< 0.01) than the WT mice. At 30–60 min after an insulin challenge, the OE mice had 25% less (P< 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30–70% reduction (P< 0.05) in the insulin-stimulated phosphorylations of insulin receptor (β-subunit) in liver and Akt (Ser473and Thr308) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.
Involvement of Notch signaling in hippocampal synaptic plasticity
Authors: Wang Yue , Chan Sic L. , Miele Lucio , Yao Pamela J. , Mackes Jennifer , Ingram Donald K. , Mattson Mark P. , Furukawa Katsutoshi
Published: June 2004

During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-κB activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes.
Genome sequence of
Picrophilus torridus
and its implications for life around pH 0
Authors: Fütterer O. , Angelov A. , Liesegang H. , Gottschalk G. , Schleper C. , Schepers B. , Dock C. , Antranikian G. , Liebl W.
Published: June 2004

The euryarchaea
Picrophilus torridus
and
Picrophilus oshimae
are able to grow around pH 0 at up to 65°C, thus they represent the most thermoacidophilic organisms known. Several features that may contribute to the thermoacidophilic survival strategy of
P. torridus
were deduced from analysis of its 1.55-megabase genome.
P. torridus
has the smallest genome among nonparasitic aerobic microorganisms growing on organic substrates and simultaneously the highest coding density among thermoacidophiles. An exceptionally high ratio of secondary over ATP-consuming primary transport systems demonstrates that the high proton concentration in the surrounding medium is extensively used for transport processes. Certain genes that may be particularly supportive for the extreme lifestyle of
P. torridus
appear to have been internalized into the genome of the
Picrophilus
lineage by horizontal gene transfer from crenarchaea and bacteria. Finally, it is noteworthy that the thermoacidophiles from phylogenetically distant branches of the
Archaea
apparently share an unexpectedly large pool of genes.
Prediction of protein folding rates from the amino acid sequence-predicted secondary structure
Authors: Ivankov Dmitry N. , Finkelstein Alexei V.
Published: June 2004

We present a method for predicting folding rates of proteins from their amino acid sequences only, or rather, from their chain lengths and their helicity predicted from their sequences. The method achieves 82% correlation with experiment over all 64 “two-state” and “multistate” proteins (including two artificial peptides) studied up to now.
Genetic control of branching in foxtail millet
Authors: Doust Andrew N. , Devos Katrien M. , Gadberry Michael D. , Gale Mike D. , Kellogg Elizabeth A.
Published: June 2004

Reduction in vegetative branching is commonplace when crops are domesticated from their wild progenitors. We have identified genetic loci responsible for these changes in foxtail millet (
Setaria italica
), a crop closely related to maize but whose genetics are little known. Quantitative trait locus (QTL) analysis and comparative genomics reveal that basal branching (tillering) and axillary branching are partially controlled by separate loci, and that the orthologue of
teosinte branched1
, the major gene controlling branching phenotype in maize, has only a minor and variable effect. We identify other candidate genes for control of branching, including a number of hormone biosynthesis pathway genes. These results suggest that similar phenotypic effects may not be produced by orthologous loci, even in closely related species, and that results from well characterized model systems such as maize must be reviewed critically before being applied to other species.
The crystal structure of activated protein C-inactivated bovine factor Va: Implications for cofactor function
Authors: Adams Ty E. , Hockin Matthew F. , Mann Kenneth G. , Everse Stephen J.
Published: June 2004

In vertebrate hemostasis, factor Va serves as the cofactor in the prothrombinase complex that results in a 300,000-fold increase in the rate of thrombin generation compared with factor Xa alone. Structurally, little is known about the mechanism by which factor Va alters catalysis within this complex. Here, we report a crystal structure of protein C inactivated factor Va (A1·A3-C1-C2) that depicts a previously uncharacterized domain arrangement. This orientation has implications for binding to membranes essential for function. A high-affinity calcium-binding site and a copper-binding site have both been identified. Surprisingly, neither shows a direct involvement in chain association. This structure represents the largest physiologically relevant fragment of factor Va solved to date and provides a new scaffold for the future generation of models of coagulation cofactors.
Early events in speciation: Polymorphism for hybrid male sterility in
Drosophila
Authors: Reed Laura K. , Markow Therese A.
Published: June 2004

Capturing the process of speciation early enough to determine the initial genetic causes of reproductive isolation remains a major challenge in evolutionary biology. We have found, to our knowledge, the first example of substantial intraspecific polymorphism for genetic factors contributing to hybrid male sterility. Specifically, we show that the occurrence of hybrid male sterility in crosses between
Drosophila mojavensis
and its sister species,
Drosophila arizonae
, is controlled by factors present at different frequencies in different populations of
D. mojavensis
. In addition, we show that hybrid male sterility is a complex phenotype; some hybrid males with motile sperm still cannot sire offspring. Because male sterility factors in hybrids between these species are not yet fixed within
D. mojavensis
, this system provides an invaluable opportunity to characterize the genetics of reproductive isolation at an early stage.
Biochemical crypsis in the avoidance of natural enemies by an insect herbivore
Authors: De Moraes Consuelo M. , Mescher Mark C.
Published: June 2004

Plant-herbivore interactions provide well studied examples of coevolution, but little is known about how such interactions are influenced by the third trophic level. Here we show that larvae of the specialized lepidopteran herbivore
Heliothis subflexa
reduce their vulnerability to natural enemies through adaptation to a remarkable and previously unknown feature of their host plant,
Physalis angulata
: The fruits of this plant lack linolenic acid (LA), which is required for the development of most insects. By overcoming this nutritional deficiency,
H. subflexa
larvae achieve numerous advantages. First, they gain near-exclusive access to a food resource: we demonstrate that closely related
Heliothis virescens
larvae cannot develop on
P. angulata
fruit unless the fruit are treated with LA. Second, they reduce their vulnerability to enemies: LA is a key component of volicitin, an elicitor of plant-volatile-signaling defenses. We demonstrate that volicitin is absent in the oral secretions of fruit-feeding caterpillars, that the volatile profiles of plants induced by fruit feeding differ from those induced by leaf feeding or by feeding on LA-treated fruit, and that the former are far less attractive to female
Cardiochiles nigriceps
parasitoids. Finally, they render themselves nutritionally unsuitable as hosts for enemies that require LA for their own development: we show that
C. nigriceps
larvae fail to develop within the bodies of fruit-feeding caterpillars but do develop in caterpillars feeding on LA-treated fruit. Thus,
H. subflexa
larvae not only overcome a serious dietary deficiency but also reduce their vulnerability to natural enemies through a form of “biochemical crypsis.”
Carbon monoxide-induced suspended animation protects against hypoxic damage in
Caenorhabditis elegans
Authors: Nystul Todd G. , Roth Mark B.
Published: June 2004

Oxygen deprivation is a major cause of cellular damage and death. Here we demonstrate that
Caenorhabditis elegans
embryos, which can survive both in anoxia (<0.001 kPa O
2
) by entering into suspended animation and in mild hypoxia (0.25-1 kPa O
2
) through a hypoxia-inducible factor 1-mediated response, cannot survive in intermediate concentrations of oxygen, between 0.01 and 0.1 kPa O
2
. Moreover, we show that carbon monoxide can protect
C. elegans
embryos against hypoxic damage in this sensitive range. Carbon monoxide can also rescue the hypoxia-sensitive mutant
hif-1(ia04)
from lethality in hypoxia. This work defines the oxygen tensions over which hypoxic damage occurs in
C. elegans
embryos and demonstrates that carbon monoxide can prevent this damage by inducing suspended animation.
Multi-trophic level interactions in a cassava–maize mixed cropping system in the humid tropics of West Africa
Authors: Schulthess F. , Chabi-Olaye A. , Gounou S.
Published: June 2004

Multi-trophic level interactions in a mixed crop, involving cassava and maize, were studied in derived-savanna in Benin, West Africa. Two trials were planted, one during the short rainy season two months before onset of the dry season and one during the long rainy season in spring. Key pests under study on maize were the noctuidSesamia calamistisHampson and the pyralidsEldana saccharinaWalker andMussidia nigrivenellaRagonot, and on cassava, the exotic mealybug,Phenacoccus manihotiMatile-Ferrero and its encyrtid parasitoidApoanagyrus lopeziDe Santis. Both crops received insecticide treatments to assess the crop loss by a pest species. On maize, intercropping with cassava reduced egg and immature numbers ofS. calamistisby 67 and 83%, respectively, as a result of reduced host finding by the ovipositing adult moth and of higher egg parasitism byTelenomusspp. Both trials showed similar effects on maize yields: on insecticide-treated maize, intercropping with cassava reduced maize yields by 9–16%, while on untreated maize the net effect of reduced pest density and increased plant competition resulted in zero yield differences; yield losses were lower in inter- compared to monocropped maize. For cassava, cropping system had no effect on parasitism byA. lopezi. Yield differences between mono- and intercropped cassava depended on time of harvest: they were large at the beginning and zero at final harvest. Land equivalent ratios were mostly > 1.5 indicating that a maize/cassava mixed crop, protected or unprotected, considerably increased the productivity per unit area of land.
Biological and chemical assays of pyrethroids in cattle dung
Authors: Vale G.A. , Grant I.F. , Dewhurst C.F. , Aigreau D.
Published: June 2004

Bioassays were developed in Zimbabwe to measure pyrethroid in cattle dung. These and chemical assays then estimated concentrations in dung from treated oxen and elucidated risks to dung fauna. Laboratory bioassays with adult beetles (Histeridae and Scarabaeinae, including Copris, Digitonthophagus, Onitis and Sisyphus spp.) and muscoid larvae (Musca lusoria Wiedemann) indicated that the LC50 of pyrethroids, as ppm in the wet weight, averaged 0.04 for deltamethrin pour-on, 0.25 for deltamethrin dip, 0.22 for alphacypermthrin pour-on, 0.10 for cyfluthrin pour-on, 0.23 for cypermethrin dip and 0.63 for flumethrin dip. Field bioassays involved artificial dung pats of 800 g, deployed in woodland and inspected after 24 h to record insects dead and alive. Beetles were most abundant in the wet season. Muscoid larvae were less seasonal. The LC50 of insecticides in the field confirmed laboratory indications. Adult Diptera (muscoids and Sgifidae) were not repelled or killed until the deltamethrin concentration reached 10 ppm. Pat dispersal by dung fauna and termites (Microtermes spp.) was halved by deltamethrin at 0.1–1 ppm. Scavenging of dead beetles by ants was greatest with small beetles (< 15 mm long) uncontaminated with insecticide. Dips and pour-ons of deltamethrin on cattle gave residues of about 0.01–0.1 ppm in dung produced in the fortnight after application. About 1.6% of the deltamethrin applied was transferred to dung. Deltamethrin and alphacypermethrin in dung showed no detectable degradation in 64 days. Contamination levels threaten populations of slow-breeding beetles.
Like Phoenix from the Ashes? The Renewal of Clusters in Old Industrial Areas
Authors: Todtling Franz , Trippl Michaela
Published: June 2004

Many cluster studies have focused on growth regions and industries covering only the early phases of cluster development. Little attention, however, has been paid to the renewal of clusters in old industrial regions. The aim of the paper is to address the question of how clusters renew themselves in such regions and how they adjust to changes in their environment. After identifying relevant factors from the literature, a comparison is made of the renewal of the automotive and the metal clusters in the old industrial region of Styria. The paper investigates and analyses the different development paths. Critical factors of cluster renewal turn out to be a well developed regional innovation system, the establishment of new innovation networks and new and more indirect forms of policy approach.
Knowledge-based Clusters and Urban Location: The Clustering of Software Consultancy in Oslo
Authors: Isaksen Arne
Published: June 2004

The paper examines the reasons for the clustering of Norwegian software firms in Oslo. The analysis focuses on how software firms perform individual activities and how they interact with other players in performing the activities. The clustering of software firms in Oslo rests first of all on the need for very close interaction between consulting companies and important customers, and among software consulting companies themselves. The fact is that consulting activity is project-based and involves lots of coalition-building and face-to-face contact which is facilitated when players co-locate. Demand-side factors are important in explaining the concentration of software companies in Oslo, while important supply-side factors are the possibilities of meeting persons in other software firms and the gathering of information in formal and informal settings.
Life Sciences Clusters and Regional Science Policy
Authors: Cooke Philip
Published: June 2004

This paper focuses upon Life Sciences and the manner in which R&D-led clustering concentrates key resources such as basic research funding, research infrastructure and innovative businesses in a few clusters where even large pharmaceuticals firms are nowadays often learners (from academia) rather than research leaders, as in the past. Because Life Sciences and healthcare are strongly intertwined, and huge increases in healthcare R&D and general expenditure mean that some 20 per cent of GDP is accounted for by the broad sector, regions that have missed out on this future 'knowledge economy' bonanza are desperately seeking to remedy things. Examples are provided of new regional science policy instruments for redistribution of such knowledge economy advantages that moves beyond mere innovation support.
Innovation and Clustering in the Globalised International Economy
Authors: Simmie James
Published: June 2004

In this paper, it is argued that innovation is the key driver of competitiveness and productivity. Innovation is an internationally distributed system of activities and therefore geographically localised and clustered firms are likely to form only a limited set of the total actors engaged in such a system. Where Porter's concept of clusters is used to describe mainly localised economic interactions it is not therefore likely to contribute much to an understanding of the relationships between innovation and economic growth. On the other hand, when the concept is applied to trading nodes in the global economy it is more likely to incorporate the international linkages between suppliers, producers and customers that are a key characteristic of the most innovative firms. The paper focuses on Porter's main arguments concerning the relationships between innovation and clustering. The vagueness of his analysis of the geography of clusters is highlighted. Nevertheless, following his argument that trading clusters are the key to economic growth, the analysis focuses on the nature and extent of linkages and in particular their contribution to innovation. Evidence from previous studies is used to suggest that national and international linkages and networks are just as significant as their local counterparts for firms in the UK. Evidence from the third Community Innovation Survey is used to test four of Porter's six hypotheses concerning the contribution of clustering to innovation. All of them are shown to benefit from national and international linkages and collaboration.
Working through Knowledge Pools: Labour Market Dynamics, the Transference of Knowledge and Ideas, and Industrial Clusters
Authors: Power Dominic , Lundmark Mats
Published: June 2004

This article explores a prominent cluster in the Swedish capital Stockholm and its surrounding region: the ICT (information and communications technology) cluster. In particular, the article focuses on the issue of the extent to which labour market and labour mobility are the most likely channels for local and extra-local sources of knowledge and ideas. Thus the article positions itself against a growing literature that focuses on rather diffuse and vague notions that knowledge and innovation reside 'in the air' or in the 'buzz' of urban life. Instead, the underlying hypothesis is that in many sectors and industries such things as a cosmopolitan street life or accidental face-to-face encounters play relatively little part in the flow of experiences, knowledge and innovation. Rather, it is in the workplace that these exchanges and flows are located and it is thus through labour mobility that intracluster exchanges occur. The article tests such ideas in relation to the ICT cluster and the Stockholm region using a uniquely detailed time-series data-set. The data-set used is based on official taxation and civil registration records and contains complete details on everything from education to career changes to income levels for every individual resident in Sweden. The detail of the individual records and the complete nature of the data-set mean that it offers a unique possibility to examine, on a large scale, the micro dynamics of individuals in the labour market and in clusters. The data are used to examine whether there have existed over time higher levels of labour market mobility in clusters as opposed to the rest of the urban economy. The article empirically verifies the idea that labour market mobility is significantly higher in the cluster than in the rest of the urban economy.
Where Is the Value Added in the Cluster Approach? Hermeneutic Theorising, Economic Geography and Clusters as a Multiperspectival Approach
Authors: Benneworth Paul , Henry Nick
Published: June 2004

Barnes has argued that (new) economic geography has moved in to a phase of theory development that he describes as 'hermeneutic' theorising. This epistemological position is characterised by an interpretive, reflexive and open-ended mode of inquiry that recognises the diversity of sources available for theorising and the subsequent conversations that will ensue from such diversity. In a recent deconstruction of the clusters concept in economic geography, and especially that version (or brand) expounded by Michael Porter, Martin and Sunley ask the question as to what added value is delivered by the concept's gatecrashing of academic and policy debates. This paper argues that clusters should not be overendowed as a singular 'brand', but recognised as an emergent set of multiple perspectives in dialogue. From a position of hermeneutic theorising, 'clusters' have the potential to add value by allowing theoretical debate across a wide range of (overlapping and competing) perspectives whose partiality and situatedness are made explicit. The possibilities for theoretical, empirical and policy cross-fertilisation from the difficult act of holding together these threads is one potential drawn from the conversations engendered through hermeneutic theorising in economic geography. Nevertheless, this 'work in progress' must be deepened and extended if the potential of clusters is to be realised.
Visceral Leishmaniasis (Kala‐Azar) and Pregnancy
Authors: Figueiró-Filho Ernesto Antonio , Duarte Geraldo , El-Beitune Patrícia , Quintana Silvana Maria , Maia Tamara Lemos
Published: June 2004

Objective: The aim of the present review was to close the gap in the approach to pregnant women with
visceral leishmaniasis (kala‐azar) by providing up‐to‐date information to obstetricians about physiopathology,
epidemiology, vertical transmission, drugs and treatment during pregnancy.

Background: Infection with Leishmania chagasi during pregnancy is rare and deserves special attention since
little information is available regarding the occurrence of visceral leishmaniasis during gestational period and the
real possibility of vertical transmission of this disease. Because specific areas in the world are endemic for the
disease and considering the continuous growth of the population, cases of pregnant women with visceral
leishmaniasis are becoming more frequent. Unfortunately, textbooks on infectious diseases do not include this
specific group of patients, and studies in the literature on aspects related to pregnancy and visceral leishmaniasis
are scarce.

Conclusions: Vertical transmission of leishmaniasis is possible and the institution of treatment is imperative in
cases of pregnant women with kala‐azar. Amphotericin B is strongly recommended as the first choice drug due
to its fewer maternal‐fetal adverse effects.
Hepatitis C Virus (HCV): Prevalence in a Gynecological UrgentCare Clinic Population
Authors: Adusumalli J. , Bonney E. A. , Odenat L. , Jamieson D. J.
Published: June 2004

Objective: To determine the prevalence of hepatitis C virus (HCV) among women seeking urgent gynecological
care.

Methods: Women were asked to complete a short self‐assessment screening of HCV risk. Those answering yes
to any of the screening questions were offered HCV testing and were asked to complete a more detailed
questionnaire.

Results: Among the 125 women who completed the screening questionnaire, 80% (100) answered yes to one
or more of the screening questions. Of the 99 women who underwent testing, six (6.1%) were HCV
seropositive; a history of injection drug use was the only finding associated with HCV seropositivity (R.R 9.7:
95% CI 1.90–49.40).

Conclusions: Women seeking urgent outpatient gynecological care, particularly those who are injection drug
users, are at a substantial risk of HCV infection. A careful risk assessment should be completed in order to
identify women who should be offered HCV testing.
p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress
Authors: Charrier-Savournin Fabienne Baus , Château Marie-Thérèse , Gire Véronique , Sedivy John , Piette Jacques , Dulić Vjekoslav
Published: June 2004

G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their entry into mitosis, with the concomitant risks of oncogenic transformation. According to the current model, signals elicited by DNA damage prevent mitosis by inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic regulator. We now show that normal human fibroblasts use additional mechanisms to block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This nuclear retention, which strictly depends on association with endogenous p21, prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well as its recruitment to the centrosome. In p21-deficient normal human fibroblasts and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could be readily detected at the centrosome in response to DNA damage. Therefore, in normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21 directly prevents mitosis by inactivating and maintaining the inactive state of mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic cyclins, further contributes to the establishment of a permanent G2 arrest.
Does a Sentinel or a Subset of Short Telomeres Determine Replicative Senescence?
Authors: Zou Ying , Sfeir Agnel , Gryaznov Sergei M. , Shay Jerry W. , Wright Woodring E.
Published: June 2004

The proliferative life span of human cells is limited by telomere shortening, but the specific telomeres responsible for determining the onset of senescence have not been adequately determined. We here identify the shortest telomeres by the frequency of signal-free ends after in situ hybridization with telomeric probes and demonstrate that probes adjacent to the shortest ends colocalize with γH2AX-positive DNA damage foci in senescent cells. Normal BJ cells growth arrest at senescence before developing significant karyotypic abnormalities. We also identify all of the telomeres involved in end-associations in BJ fibroblasts whose cell-cycle arrest at the time of replicative senescence has been blocked and demonstrate that the 10% of the telomeres with the shortest ends are involved in >90% of all end-associations. The failure to find telomeric end-associations in near-senescent normal BJ metaphases, the presence of signal-free ends in 90% of near-senescent metaphases, and the colocalization of short telomeres with DNA damage foci in senescent interphase cells suggests that end-associations rather than damage signals from short telomeres per se may be the proximate cause of growth arrest. These results demonstrate that a specific group of chromosomes with the shortest telomeres rather than either all or only one or two sentinel telomeres is responsible for the induction of replicative senescence.
Transmembrane proteins in the Protein Data Bank: identification and classification
Authors: Tusnády Gábor E. , Dosztányi Zsuzsanna , Simon István
Published: June 2004

Motivation: Integral membrane proteins play important roles in living cells. Although these proteins are estimated to constitute 25% of proteins at a genomic scale, the Protein Data Bank (PDB) contains only a few hundred membrane proteins due to the difficulties with experimental techniques. The presence of transmembrane proteins in the structure data bank, however, is quite invisible, as the annotation of these entries is rather poor. Even if a protein is identified as a transmembrane one, the possible location of the lipid bilayer is not indicated in the PDB because these proteins are crystallized without their natural lipid bilayer, and currently no method is publicly available to detect the possible membrane plane using the atomic coordinates of membrane proteins.

Results: Here, we present a new geometrical approach to distinguish between transmembrane and globular proteins using structural information only and to locate the most likely position of the lipid bilayer. An automated algorithm (TMDET) is given to determine the membrane planes relative to the position of atomic coordinates, together with a discrimination function which is able to separate transmembrane and globular proteins even in cases of low resolution or incomplete structures such as fragments or parts of large multi chain complexes. This method can be used for the proper annotation of protein structures containing transmembrane segments and paves the way to an up-to-date database containing the structure of all known transmembrane proteins and fragments (PDB_TM) which can be automatically updated. The algorithm is equally important for the purpose of constructing databases purely of globular proteins.

Availability: The PDB_TM database is available for academic users on http://www.enzim.hu/PDB_TM.

Supplementary information: Data files used in this article can be found under the PDB_TM homepage (http://www.enzim.hu/PDB_TM/index.php?method=docs).
Supervised machine learning techniques for the classification of metabolic disorders in newborns
Authors: Baumgartner C. , Böhm C. , Baumgartner D. , Marini G. , Weinberger K. , Olgemöller B. , Liebl B. , Roscher A. A.
Published: June 2004

Motivation: During the Bavarian newborn screening programme all newborns have been tested for about 20 inherited metabolic disorders. Owing to the amount and complexity of the generated experimental data, machine learning techniques provide a promising approach to investigate novel patterns in high-dimensional metabolic data which form the source for constructing classification rules with high discriminatory power.

Results: Six machine learning techniques have been investigated for their classification accuracy focusing on two metabolic disorders, phenylketo nuria (PKU) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Logistic regression analysis led to superior classification rules (sensitivity >96.8%, specificity >99.98%) compared to all investigated algorithms. Including novel constellations of metabolites into the models, the positive predictive value could be strongly increased (PKU 71.9% versus 16.2%, MCADD 88.4% versus 54.6% compared to the established diagnostic markers). Our results clearly prove that the mined data confirm the known and indicate some novel metabolic patterns which may contribute to a better understanding of newborn metabolism.

Availability: WEKA machine learning package: www.cs.waikato.ac.nz/~ml/weka and statistical software package ADE-4: http://pbil.univ-lyon1.fr/ADE-4
Comparative analysis of protein unfoldedness in human housekeeping and non-housekeeping proteins
Authors: Pandey Neeraj , Ganapathi Mythily , Kumar Kaushal , Dasgupta Dipayan , Das Sutar Sushanta Kumar , Dash Debasis
Published: June 2004

Summary: Absence of any regular structure is increasingly being observed in structural studies of proteins. These disordered regions or random coils, which have been observed under physiological conditions, are indicators of protein plasticity. The wide variety of interactions possible due to the flexibility of these ‘natively disordered’ regions confers functional advantage to the protein and the organism in general. This concept is underscored by the increasing proportion of intrinsically unstructured proteins seen with the ascension in the complexity of the organisms.

The ‘natively unfolded/disordered’ state of the protein can be predicted utilizing Uversky's or Dunker's algorithm. We utilized Uversky's prediction scheme and based on the unique position of a protein in the charge–hydrophobicity plot, a derived net score was used to predict the overall disorder of the human housekeeping and non-housekeeping proteins. Substantial numbers of proteins in both the classes were predicted to be unfolded. However, comparative genomic analysis of predicted unfolded Homo sapiens proteins with homologues in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus revealed significant increase in unfoldedness in non-housekeeping proteins in comparison with housekeeping proteins. Our analysis in the evolutionary context suggests addition or substitution of amino acid residues which favour unfoldedness in non-housekeeping proteins compared to housekeeping proteins.

Supplementary information:  http://www.igib.res.in/data/pda/proteindisorderanalysis.html
Visualizations for taxonomic and phylogenetic trees
Authors: Parr Cynthia Sims , Lee Bongshin , Campbell Dana , Bederson Benjamin B.
Published: June 2004

Motivation: Despite substantial efforts to develop and populate the back-ends of biological databases, front-ends to these systems often rely on taxonomic expertise. This research applies techniques from human–computer interaction research to the biodiversity domain.

Results: We developed an interactive node-link tool, TaxonTree, illustrating the value of a carefully designed interaction model, animation, and integrated searching and browsing towards retrieval of biological names and other information. Users tested the tool using a new, large integrated dataset of animal names with phylogenetic-based and classification-based tree structures. These techniques also translated well for a tool, DoubleTree, to allow comparison of trees using coupled interaction. Our approaches will be useful not only for biological data but as general portal interfaces.

Availability: Working versions of TaxonTree and DoubleTree and video demonstrations of DoubleTree are available at http://www.cs.umd.edu/hcil/biodiversity

Supplementary information: All datasets and folk tree illustration are available at http://www.cs.umd.edu/hcil/biodiversity
Picky: oligo microarray design for large genomes
Authors: Chou Hui-Hsien , Hsia An-Ping , Mooney Denise L. , Schnable Patrick S.
Published: June 2004

Motivation: Many large genomes are getting sequenced nowadays. Biologists are eager to start microarray analysis taking advantage of all known genes of a species, but existing microarray design tools were very inefficient for large genomes. Also, many existing tools operate in a batch mode that does not assure best designs.

Results: Picky is an efficient oligo microarray design tool for large genomes. Picky integrates novel computer science techniques and the best known nearest-neighbor parameters to quickly identify sequence similarities and estimate their hybridization properties. Oligos designed by Picky are computationally optimized to guarantee the best specificity, sensitivity and uniformity under the given design constrains. Picky can be used to design arrays for whole genomes, or for only a subset of genes. The latter can still be screened against a whole genome to attain the same quality as a whole genome array, thereby permitting low budget, pathway-specific experiments to be conducted with large genomes. Picky is the fastest oligo array design tool currently available to the public, requiring only a few hours to process large gene sets from rice, maize or human.

Availability: Picky is independent of any external software to execute, is designed for non-programmers to easily operate through a graphical user interface, and is made available for all major computing platforms (e.g. Mac, Windows and Linux) at http://www.complex.iastate.edu.

Supplementary information: A short paper detailing the probability analysis for Picky, a program that implements functions mentioned in the paper, and the output of the program are available online from the Publisher's website.
lga972: a cross-platform application for optimizing LD studies using a genetic algorithm
Authors: Robles Jaime R. , van den Oord Edwin J. C. G.
Published: June 2004

Summary: lga972 is a user-friendly cross-platform application with a graphical interface for determining the design features of two-stage genetic linkage disequilibrium studies that minimize the genotyping burden.

Availability: lga972 is freely available at http://www.vipbg.vcu.edu/~edwin.

Supplementary information: Program instructions and more detailed technical information can be found in the manual that can also be downloaded from the aforementioned website.
Combination Effects of Herbs in a Multi‐herbal Formula: Expression of Juzen‐taiho‐to′s Immuno‐modulatory Activity on the Intestinal Immune System
Authors: Kiyohara Hiroaki , Matsumoto Tsukasa , Yamada Haruki
Published: June 2004

Herbal formulas of traditional Japanese (Kampo), Chinese and Korean medicines usually comprise multiple herbs in a single formula. These medicines are expected to show their clinical effects by chemical, pharmacological and pharmaceutical combination effects of multi‐herbs. However, little effort has been made so far to scientifically clarify the nature of such combination effects. Interestingly, for example, though a Kampo medicine Juzen‐taiho‐to (Shi‐Quan‐Da‐Bu‐Tang in Chinese) stimulates the immune functions of Peyer′s patch cells, none of its single component herbs shows such activity. We thus examined the combination effect of herbs in the Juzen‐taiho‐to formula for the expression of its immuno‐stimulating activity. Juzen‐taiho‐to, a composite formula of 10 herbs, has been generally considered to comprise two kinds of basic formula, each of which consists of four different herbs in addition to two others. The combinations of herbs based on these two basic formulas were evaluated for their stimulating activities on cytokine production from murine Peyer′s patch cells both in vitro and ex vivo. Combined decoction of six among 10 herbs in Juzen‐taiho‐to is crucial for the expression of its stimulating activity on Peyer′s patch cells. 3D‐HPLC analysis of the ingredients in the fractions from the combined decoctions indicated that, in addition to quantitative changes of ingredients, alterations occur in their chemical composition by decoction of different herbs. The stimulating activity of Juzen‐taiho‐to on Peyer′s patch cells results from the combination effect of its six essential component herbs. This combination effect is based on physicochemical interactions among the ingredients of the component herbs.
Ozone Therapy for Tumor Oxygenation: a Pilot Study
Authors: Clavo Bernardino , Pérez Juan L. , López Laura , Suárez Gerardo , Lloret Marta , Rodríguez Victor , Macías David , Santana Maite , Hernández María A. , Martín-Oliva Roberto , Robaina Francisco
Published: June 2004

Tumor hypoxia is an adverse factor for chemotherapy and radiotherapy. Ozone therapy is a non‐conventional form of medicine that has been used successfully in the treatment of ischemic disorders. This prospective study was designed to assess the effect of ozone therapy on tumor oxygenation. Eighteen subjects were recruited for the study. Systemic ozone therapy was administered by autohemotransfusion on three alternate days over one week. Tumor oxygenation levels were measured using polarographic needle probes before and after the first and the third ozone therapy session. Overall, no statistically significant change was observed in the tumor oxygenation in the 18 patients. However, a significant decrease was observed in hypoxic values ≤10 and ≤5 mmHg of pO2. When individually assessed, a significant and inverse non‐linear correlation was observed between increase in oxygenation and the initial tumor pO2 values at each measuring time‐point, thus indicating that the more poorly‐oxygenated tumors benefited most (rho = −0.725; P = 0.001). Additionally, the effect of ozone therapy was found to be lower in patients with higher hemoglobin concentrations (rho = −0.531; P < 0.034). Despite being administered over a very short period, ozone therapy improved oxygenation in the most hypoxic tumors. Ozone therapy as adjuvant in chemo‐radiotherapy warrants further research.
CAM and NK Cells
Authors: Takeda Kazuyoshi , Okumura Ko
Published: June 2004

It is believed that tumor development, outgrowth and metastasis are under the surveillance of the immune system. Although both innate and acquired immune systems play roles, innate immunity is the spearhead against tumors. Recent studies have revealed the critical role of natural killer (NK) cells in immune surveillance and that NK cell activity is considerably influenced by various agents, such as environmental factors, stress, foods and drugs. Some of these NK cell stimulants have been used in complementary and alternative medicine (CAM) since ancient times. Therefore, the value of CAM should be re‐evaluated from this point of view. In this review, we overview the intimate correlation between NK cell functions and CAM agents, and discuss possible underlying mechanisms mediating this. In particular, neuro‐immune crosstalk and receptors for CAM agents are the most important and interesting candidates for such mechanisms.
Phosphorylation of SMC1 is a critical downstream event in the ATM–NBS1–BRCA1 pathway
Authors: Kitagawa Risa , Bakkenist Christopher J. , McKinnon Peter J. , Kastan Michael B.
Published: June 2004

The ATM protein kinase is activated by intermolecular autophosphorylation in response to DNA damage and initiates cellular signaling pathways that facilitate cell survival and reduce chromosomal breakage. Here, we show that NBS1 and BRCA1 are required for the recruitment of previously activated ATM to the sites of DNA breaks after ionizing irradiation, and that this recruitment is required for the phosphorylation of SMC1 by ATM. To explore the functional importance of SMC1 phosphorylation, murine cells were generated, in which the two damage-induced phosphorylation sites in SMC1 are mutated. Although these cells demonstrate normal phosphorylation and focus formation of ATM, NBS1, and BRCA1 proteins after IR, they exhibit a defective S-phase checkpoint, decreased survival, and increased chromosomal aberrations after DNA damage. These observations suggest that many of the abnormal stress responses seen in cells lacking ATM, NBS1, or BRCA1 result from a failure of ATM migration to sites of DNA breaks and a resultant lack of SMC1 phosphorylation.
Preparation and characterisation of high performance anticorrosive paints based on novel corrosion inhibitive amide polymers
Authors: Youssef E.A.M.
Published: June 2004

New types of amide polymers have been prepared and evaluated as corrosion inhibitors for steel protection. Such polymers included o‐, m‐, and p‐ itaconyl phenylene amides, itaconyl o‐ tolidine amide and maleiyl phenylene amide polymers. The polymers were prepared by condensation of equimolar ratios of diamine with itaconic or maleic acids in non‐polar solvents of high boiling point (>135°C) using the Dean and Stark apparatus. The amide polymers obtained were characterised and their structures confirmed based on the micro‐analysis of C, H, and N, the estimated amount of water liberated from the condensation reaction, the IR spectrophotometric measurements and the molecular weight determined by gel permeation chromatography (GPC). The amide polymers obtained were incorporated into paint formulations as corrosion inhibitors for steel protection.
Introduction: On the Horizon special issue
Authors: Davidson Drew
Published: June 2004

This special issue of On the Horizon focuses on strategies for applying games, simulations and interactive experiences in learning contexts. A facet of this issue is the interactive and collaborative method in which it was created. Instead of separated individual articles, the authors and editors have orchestrated the articles together, reading and writing as a whole so that the concepts across the articles resonate with each other. It is the intention that this special issue will serve as the basis of many more discussions across conference panels, online forums and interactive media that in turn will engender more special collaborative issues.
The four slates of educational experiences
Authors: Aldrich Clark
Published: June 2004

Proposes that simulations teach timing and balance which is not possible to teach in a traditional manner through classrooms, books or films. States that these can be used to increase the power of the organization if they are used correctly. Proceeds to explain four stages, or slates of simulation deployment used today. Concludes that although simulations take more work, they result in exponentially better results.