bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes
Authors: Evans Hayley G. , Suddason Tesha , Jackson Ian , Taams Leonie S. , Lord Graham M.
Published: October 2007

Recently, a new lineage of CD4
+
T cells has been described in the mouse that specifically secretes IL-17 [T helper (Th) 17]. This discovery has led to a revision of the hypothesis that many autoimmune diseases are predominantly a Th1 phenomenon and may instead be critically dependent on the presence of Th17 cells. Murine Th17 cells differentiate from naïve T cell precursors in the presence of TGF-β and IL-6 or IL-21. However, given their putative importance in human autoimmunity, very little is known about the pathways that control the expression of IL-17 in humans. Here we show that the factors that determine the expression of IL-17 in human CD4
+
T cells are completely different from mice. IL-6 and IL-21 were unable to induce IL-17 expression in either naïve or effector T cells, and TGF-β actually inhibited IL-17 expression. The expression of IL-17 was maximally induced from precommitted precursors present in human peripheral blood by cell–cell contact with Toll-like receptor-activated monocytes in the context of T cell receptor ligation. Furthermore, unlike IFN-γ, IL-17 expression was not suppressed by the presence of FOXP3
+
regulatory CD4
+
T cells. Taken together, these data indicate that human and mouse Th17 cells have important biological differences that may be of critical importance in the development of therapeutic interventions in diseases characterized by aberrant T cell polarization.
Conventional dendritic cells regulate the outcome of colonic inflammation independently of T cells
Authors: Abe Kazumichi , Nguyen Kim Phung , Fine Sean D. , Mo Ji-Hun , Shen Carol , Shenouda Steve , Corr Maripat , Jung Steffen , Lee Jongdae , Eckmann Lars , Raz Eyal
Published: October 2007

We explored the physiological role of conventional dendritic cells (cDCs) in acute colitis induced by a single cycle of dextran sodium sulfate administration. Depending on their mode of activation and independently of T cells, cDCs can enhance or attenuate the severity of dextran sodium sulfate-induced colitis. The latter beneficial effect was achieved, in part, by IFN-1 induced by Toll-like receptor 9-activated cDCs. IFN-1 inhibits colonic inflammation by regulating neutrophil and monocyte trafficking to the inflamed colon and restraining the inflammatory products of tissue macrophages. These data highlight a novel role of cDCs in the regulation of other innate immune cells and position them as major players in acute colonic inflammation.
Variation in HIV-1 set-point viral load: Epidemiological analysis and an evolutionary hypothesis
Authors: Fraser Christophe , Hollingsworth T. Déirdre , Chapman Ruth , de Wolf Frank , Hanage William P.
Published: October 2007

The natural course of HIV-1 infection is characterized by a high degree of heterogeneity in viral load, not just within patients over time, but also between patients, especially during the asymptomatic stage of infection. Asymptomatic, or set-point, viral load has been shown to correlate with both decreased time to AIDS and increased infectiousness. The aim of this study is to characterize the epidemiological impact of heterogeneity in set-point viral load. By analyzing two cohorts of untreated patients, we quantify the relationships between both viral load and infectiousness and the duration of the asymptomatic infectious period. We find that, because both the duration of infection and infectiousness determine the opportunities for the virus to be transmitted, this suggests a trade-off between these contributions to the overall transmission potential. Some public health implications of variation in set-point viral load are discussed. We observe that set-point viral loads are clustered around those that maximize the transmission potential, and this leads us to hypothesize that HIV-1 could have evolved to optimize its transmissibility, a form of adaptation to the human host population. We discuss how this evolutionary hypothesis can be tested, review the evidence available to date, and highlight directions for future research.
The Estonian SSR Language Law (1989): Background and Implementation
Authors: Raun Toivo U.
Published: October 2007

The Estonian Language Law, passed by the Estonian SSR Supreme Soviet on 18 January 1989, was the first of its kind in the Soviet Union. It helped launch a wave of similar legislation in other union republics and symbolized a new level of assertion of republican rights against Moscow and the tradition of centralized control. It is no coincidence that the Language Law was drafted and became available for public discussion at virtually the same time as Estonia's declaration on sovereignty (16 November 1988), also a first in Gorbachev's USSR. Indeed in late 1988 and early 1989 Estonia was leading the way in the movement for decentralization in the Soviet empire as the major political goal began to shift from autonomy to independence. This article will assess the origins and nature of the law itself as well as its implementation and impact over a nearly five-year period to late 1993.
Problems of Language Law Implementation in Uzbekistan
Authors: Fierman William
Published: October 2007

In October 1989, Uzbekistan's Supreme Soviet adopted the law “On the State Language of the Uzbek SSR.” At that time, Uzbekistan was still one of the 15 constituent republics of the USSR. The law was an important symbol of Uzbekistan's changing relation to Russia and the assertion of the preeminence of Uzbek culture in Uzbekistan.
Zusammenarbeit and Spoluprace: Sudeten German-Czech Cooperation in Interwar Czechoslovakia
Authors: Kopecek Herman
Published: October 2007

On 22 December 1918 Tomáš G. Masaryk delivered his first political message as president of the fledgling Czechoslovakia. Addressing the Constituent Assembly at Hradčany in Prague, he vowed that the frontier districts of Bohemia, Moravia, and Silesia, which contained a predominantly German-speaking population (and which German nationalists eventually designated collectively as the Sudetenland) would remain in the new Republic. Inimical toward and unwilling to live in a state dedicated to the sovereignty of Czechs and Slovaks, virtually all German leaders at the time of Masaryk's address were working to separate German districts from Czechoslovakia and link them with Austria.
The Empire Strikes Back: How Right-Wing Nationalists Tried to Recapture Russian Literature
Authors: Parthe Kathleen
Published: October 2007

This article attempts to reconstruct thekhod myshleniia(thought process) of the ultra-nationalist, ultra-conservative camp, not just because it is interesting in and of itself but also because of the way that some of their ideas, concerns, and ways of seeing Russia and the world are shared by a growing number of people in the middle of the political spectrum. The extremists' ideas aboutrussifikatsiiamay not spread very far, butrusskost'is a powerful and attractive concept.
The Politics of the Conquest of the Caucasus, 1855-1864
Authors: Brooks Willis
Published: October 2007

The study of politics is popular in Russian history; the examination of Russian politics in its regions is not, at least, not yet. The spectrum of interpretations about autocratic politics includes the parading of litanies of imperial arbitrariness and/or manipulation of interest groups against each other, incidents of ministerial incapacity to restrain the autocrat, examples of the inordinate power of favorites, the failure to establish regularizing institutions that would restrain autocrats, and a series of interesting categories including such wonderfully suggestive terms as “free floaters” proposed in Alfred Rieber's important article on the subject. Whether one is wedded to the notion that tsars decided all in the nineteenth century, or advocate some scheme that emphasizes the plurality of conflicting interests at play in decisionmaking, however, the pattern of scholarly production suggests that regional politics has been of secondary importance, and that in any event documentation often is lacking; in short, such approaches are not seen as ideal lines of inquiry. This article seeks to make a contribution to the debate about the politics of autocrats by examining a localized question where documentation is rather complete and where ministerial/bureaucratic lines may be traced fairly closely, in an attempt to shed added light on Russia's leadership in a time of great crisis, specifically the aftermath of the humiliating defeat in the Crimean War and the tension surrounding the preparations and implementation of the Emancipation and other reforms. To be specific as well as anticipatory, it is argued that there are regional questions of great national, indeed international, importance to autocrats, that the Caucasus was so recognized in the post-Crimean War period, and that those involved in the region affected policy decisions in ways that rivaled, as well as displaced, senior officials in the capital.
The Pomaks: A Religious Minority in the Balkans
Authors: Apostolov Mario
Published: October 2007

A religious minority of Bulgarian-speaking Muslims, the Pomaks now live dispersed in five Balkan countries: Bulgaria, Macedonia, Greece, Albania and Turkey. A living legacy of the complexities of Balkan history, the Pomaks represent a perfect case to study interstate political intricacies around the unsettled identity of small inter-communal groups. An examination of this community should enrich the knowledge about the nature of Balkan Islam that stands on the periphery of the Arab-Iranian-Turkic Islamic heartland, the three peoples who carried the major burden of Islamic history.
Writing Off Slovakia to “The East”? Examining Charges of Bias in British Press Reporting of Slovakia, 1993–1994
Authors: Burgess Adam
Published: October 2007

Along with her better known Czech neighbour, Slovakia is one of Europe's newest states. Born over the new year of 1993, it is the latest product of the unravelling of the post-communist order. A small nation—although at 5,269,000, it has a larger population than Norway, Denmark or Finland—Slovakia has yet to make a significant impact on European consciousness. This is illustrated by the repeated reply of a Slovak woman, living in London, to the question of the whereabouts of the strange land of her origin. Honolulu was the capital of this island she told Londoners in jest. To her amazement, rarely did anyone question her geography. When it comes to Britain, it would appear the sense of Slovakia can be aptly summarized by the infamous phrase with which interwar Czechoslovakia was dismissed by P.M. Neville Chamberlin—as a “faraway country of which we know nothing …” It still comes as a surprise, even to those who consider themselves familiar with the contours of contemporary Europe, that Bratislava, the new capital of this “faraway country's” eastern half (Slovakia), is only 60 kilometres from Vienna.
Jewish Identity and Russian Culture: The Case of M. O. Gershenzon*
Authors: Horowitz Brian
Published: October 2007

In late tsarist Russia, when a Russian historian writes about Russia he need not justify his activity; his work is naturally understood as an example of cultural self-expression. When a Jew, however, writes about Russia for an intended Russian audience, he has to explain and defend his work before himself, before his fellow Jews and before hostile Russians. His work inevitably elicits questions, and coming from a repressed ethnic minority, the assimilated Jew appears suspect. Why does he so love the nation which treats his people so badly?
Migrations in Kazakhstan: Past and Present
Authors: Kendirbaeva Gulnar
Published: October 2007

Kazakhstan has experienced more powerful pressures of migration unlike any other republic of the former Soviet Union. An especially great number of immigrants came to Kazakhstan during the Soviet period. Many peoples of the former Soviet Union, often against their wishes, took up residence in the republic. The recent situation in Kazakhstan is characterized by a further intensification of migratory processes. Their complicated character, both in the past and today, has, in many aspects, influenced the present-day problems of the republic.
Introduction
Authors: Hamm Michael F.
Published: October 2007

In June 1990, following the example set by Boris Yeltsin and the Russian Republic, the Supreme Soviet in Chişinău declared Moldova sovereign. Henceforth, Moldovans would recognize only those laws approved by their own parliament and maintain relations with the other republics only within “an association of sovereign states.” Formal independence came a year later, on 27 August 1991, following the failure of the Moscow coup that sought to unseat Mikhail Gorbachev and preserve the Soviet Union. In the heady times that followed, Moldovans debated basic questions of political organization and, inevitably, the difficult issue of Moldova's relationship with neighboring Romania.
Kishinev: The Character and Development of a Tsarist Frontier Town*
Authors: Hamm Michael F.
Published: October 2007

At the Treaty of Bucharest in 1812, Russia annexed the eastern half of Moldavia, the territory between the Dnestr and Prut Rivers, which it called “Bessarabia.” One historian argues that this was an effort to circumvent the Tilsit agreement with Napoleon in which Russia had agreed to vacate both Romanian principalities. Since Tilsit “did not mention ‘Bessarabia’ the Russian troops could remain there.”
Early Warning, Ethnopolitical Conflicts, and the United Nations: Assessing the Violence in Georgia/Abkhazia*
Authors: Alexseev Mikhail A.
Published: October 2007

The collapse of communism in the former Soviet Union and Eastern Europe was accompanied by ethnopolitical conflicts that erupted “with unusual cruelty and violence” but without much warning and were soon recognized as a major threat to peace, security, and development in the post-Cold War era. Can one be alerted to the Nagorno-Karabakhs, Bosnias, Rwandas, and Tajikistans of the world—in time to take decisive preventive action?
After the Fall: Attitudes Towards Jews in Post-1989 Poland
Authors: Ambrosewicz-Jacobs Jolanta , Orla-Bukowska Annamaria
Published: October 2007

The Enlightenment instilled European and European-rooted societies with certain fundamental principles which are generally taken for granted; among the most important are democracy, education, and human equality. Not all of mankind experienced this period of cultural history, but in those areas that the Enlightenment touched, a tautology functions in the collective subconscious that where there is democracy and where there is an educated people, there will be equality. Western nations—their politicians, scholars, and common folk alike—believe that a preordained consequence of the system of democratic rule in a developed country is open-mindedness and tolerance; in contrast, it is generally maintained that non-democratic governments where knowledge is evidently censored and controlled, such as those of the former Soviet Bloc, produce narrow-mindedness and intolerance.
Constitutional Reform and Regional Politics in Kazakstan
Authors: Kusainova Azhar , Gleason Gregory
Published: October 2007

The fate of democracy in Kazakstan may well depend less upon decisions taken in Kazakstan's capital, Almaty (the capital is now Aqmola), than upon what takes place in Kazakstan's far-flung and disparate regions. This should come as no surprise to anyone who appreciates the history and complexities of democratic development. The history of democracy is a history of bottom-up initiative. The democratic institutions that are the most successful and enduring are those that originate from the common and everyday interests and concerns of citizens. Even in historical cases where the political institutions of democracy were adopted consciously and deliberately to break with authoritarian tradition, democracy has been closely associated with local control, self-governance, public participation, and citizen empowerment. The fate of Kazakstan's constitutional order, on the other hand, depends almost exclusively upon decisions taken at the “center” of the new Kazakstan government. The establishment of a constitutional order is a highly conscious and deliberate process. It is also a highly political undertaking. To what extent has the democratic process in Kazakstan corresponded to the process of the establishment of a constitutional order in Kazakstan? To what extent has constitutional development supported limited, accountable government based on popular sovereignty? To what extent can democratic process and constitutional development be expected to mutually reinforce one another in Kazakstan's future? The answers to these questions have great importance for the development of democracy in Kazakstan. They have great importance for the efforts of the international community to encourage democratic development in Kazakstan. These are the key questions of this article.
Kazakstan and the Rest of Central Asia: Fifteen Shades of Difference
Authors: Rywkin Michael
Published: October 2007

Kazakstan is both part of former Soviet Central Asia and yet stands apart in many respects. Its geographic position, past history and present development are unique for the area. It is significant that Soviet-era writings treated Kazakstan distinctly from the other four Central Asian republics. This essay is devoted to these differences.
Mappings of finite distortion: Formation of cusps II
Authors: Takkinen Juhani
Published: October 2007

Fors>0s>0given, we consider a planar domain Ωs\Omega _swith a rectifiable boundary but containing a cusp of degree ss, and show that there is no homeomorphismf:R2→R2f\colon \mathbb {R}^2\to \mathbb {R}^2of finite distortion withexp⁡(λK)∈Lloc1(R2)\exp (\lambda K)\in L^1_{\mathrm {loc}}(\mathbb {R}^2)so thatf(B)=Ωsf(B)=\Omega _swhenλ>4/s\lambda >4/sand BBis the unit disc. On the other hand, forλ>2/s\lambda >2/ssuch an ffexists. The critical value forλ\lambdaremains open.
Dual Mechanism of a Natural CaMKII Inhibitor
Authors: Vest Rebekah S. , Davies Kurtis D. , O'Leary Heather , Port J. David , Bayer K. Ulrich
Published: October 2007

Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of cellular Ca2+signaling. Several inhibitors are commonly used to study CaMKII function, but these inhibitors all lack specificity. CaM-KIIN is a natural, specific CaMKII inhibitor protein. CN21 (derived from CaM-KIIN amino acids 43–63) showed full specificity and potency of CaMKII inhibition. CNs completely blocked Ca2+-stimulated and autonomous substrate phosphorylation by CaMKII and autophosphorylation at T305. However, T286 autophosphorylation (the autophosphorylation generating autonomous activity) was only mildly affected. Two mechanisms can explain this unusual differential inhibitor effect. First, CNs inhibited activity by interacting with the CaMKII T-site (and thereby also interfered with NMDA-type glutamate receptor binding to the T-site). Because of this, the CaMKII region surrounding T286 competed with CNs for T-site interaction, whereas other substrates did not. Second, the intersubunit T286 autophosphorylation requires CaM binding both to the “kinase” and the “substrate” subunit. CNs dramatically decreased CaM dissociation, thus facilitating the ability of CaM to make T286 accessible for phosphorylation. Tat-fusion made CN21 cell penetrating, as demonstrated by a strong inhibition of filopodia motility in neurons and insulin secrection from isolated Langerhans' islets. These results reveal the inhibitory mechanism of CaM-KIIN and establish a powerful new tool for dissecting CaMKII function.
Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin
Authors: Panaretakis Theocharis , Hjortsberg Linn , Tamm Katja Pokrovskaja , Björklund Ann-Charlotte , Joseph Bertrand , Grandér Dan
Published: October 2007

Interferon (IFN)α induces apoptosis via Bak and Bax and the mitochondrial pathway. Here, we investigated the role of known IFNα-induced signaling cascades upstream of Bak activation. By pharmacological and genetic inhibition of the kinases protein kinase C (PKC)δ, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) in U266-1984 and RHEK-1 cells, we could demonstrate that all three enzymes are critical for the apoptosis-associated mitochondrial events and apoptotic cell death induced by IFNα, at a step downstream of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Furthermore, the activation of JNK was found to occur in a PKCδ/ERK-dependent manner. Inhibition of these kinases did not affect the canonical IFNα-stimulated Janus tyrosine kinase-signal transducer and activator of transcription signaling or expression of IFN-responsive genes. Therefore, enucleated cells (cytoplasts) were examined for IFNα-induced apoptosis, to test directly whether this process depends on gene transcription. Cytoplasts were found to undergo apoptosis after IFNα treatment, as analyzed by several apoptosis markers by using flow cytometry, live cell imaging, and biochemical analysis of flow-sorted cytoplasts. Furthermore, inhibition of mTOR, ERK, and JNK blocked IFNα-induced apoptosis in cytoplasts. In conclusion, IFNα-induced apoptosis requires activation of ERK1/2, PKCδ, and JNK downstream of PI3K and mTOR, and it can occur in a nucleus-independent manner, thus demonstrating for the first time that IFNα induces apoptosis in the absence of de novo transcription.
Novel Functions of Ect2 in Polar Lamellipodia Formation and Polarity Maintenance during “Contractile Ring-Independent” Cytokinesis in Adherent Cells
Authors: Kanada Masamitsu , Nagasaki Akira , Uyeda Taro Q.P.
Published: October 2007

Some mammalian cells are able to divide via both the classic contractile ring-dependent method (cytokinesis A) and a contractile ring-independent, adhesion-dependent method (cytokinesis B). Cytokinesis A is triggered by RhoA, which, in HeLa cells, is activated by the guanine nucleotide-exchange factor Ect2 localized at the central spindle and equatorial cortex. Here, we show that in HT1080 cells undergoing cytokinesis A, Ect2 does not localize in the equatorial cortex, though RhoA accumulates there. Moreover, Ect2 depletion resulted in only modest multinucleation of HT1080 cells, enabling us to establish cell lines in which Ect2 was constitutively depleted. Thus, RhoA is activated via an Ect2-independent pathway during cytokinesis A in HT1080 cells. During cytokinesis B, Ect2-depleted cells showed narrower accumulation of RhoA at the equatorial cortex, accompanied by compromised pole-to-equator polarity, formation of ectopic lamellipodia in regions where RhoA normally would be distributed, and delayed formation of polar lamellipodia. Furthermore, C3 exoenzyme inhibited equatorial RhoA activation and polar lamellipodia formation. Conversely, expression of dominant active Ect2 in interphase HT1080 cells enhanced RhoA activity and suppressed lamellipodia formation. These results suggest that equatorial Ect2 locally suppresses lamellipodia formation via RhoA activation, which indirectly contributes to restricting lamellipodia formation to polar regions during cytokinesis B.
Caenorhabditis elegansIntersectin: A Synaptic Protein Regulating Neurotransmission
Authors: Rose Simon , Malabarba Maria Grazia , Krag Claudia , Schultz Anna , Tsushima Hanako , Di Fiore Pier Paolo , Salcini Anna Elisabetta
Published: October 2007

Intersectin is a multifunctional protein that interacts with components of the endocytic and exocytic pathways, and it is also involved in the control of actin dynamics. Drosophila intersectin is required for viability, synaptic development, and synaptic vesicle recycling. Here, we report the characterization of intersectin function in Caenorhabditis elegans. Nematode intersectin (ITSN-1) is expressed in the nervous system, and it is enriched in presynaptic regions. The C. elegans intersectin gene (itsn-1) is nonessential for viability. In addition, itsn-1-null worms do not display any evident phenotype, under physiological conditions. However, they display aldicarb-hypersensitivity, compatible with a negative regulatory role of ITSN-1 on neurotransmission. ITSN-1 physically interacts with dynamin and EHS-1, two proteins involved in synaptic vesicle recycling. We have previously shown that EHS-1 is a positive modulator of synaptic vesicle recycling in the nematode, likely through modulation of dynamin or dynamin-controlled pathways. Here, we show that ITSN-1 and EHS-1 have opposite effects on aldicarb sensitivity, and on dynamin-dependent phenotypes. Thus, the sum of our results identifies dynamin, or a dynamin-controlled pathway, as a potential target for the negative regulatory role of ITSN-1.
The Uni2 Phosphoprotein is a Cell Cycle–regulated Component of the Basal Body Maturation Pathway inChlamydomonas reinhardtii
Authors: Piasecki Brian P. , LaVoie Matthew , Tam Lai-Wa , Lefebvre Paul A. , Silflow Carolyn D.
Published: October 2007

Mutations in the UNI2 locus in Chlamydomonas reinhardtii result in a “uniflagellar” phenotype in which flagellar assembly occurs preferentially from the older basal body and ultrastructural defects reside in the transition zones. The UNI2 gene encodes a protein of 134 kDa that shares 20.5% homology with a human protein. Immunofluorescence microscopy localized the protein on both basal bodies and probasal bodies. The protein is present as at least two molecular-weight variants that can be converted to a single form with phosphatase treatment. Synthesis of Uni2 protein is induced during cell division cycles; accumulation of the phosphorylated form coincides with assembly of transition zones and flagella at the end of the division cycle. Using the Uni2 protein as a cell cycle marker of basal bodies, we observed migration of basal bodies before flagellar resorption in some cells, indicating that flagellar resorption is not required for mitotic progression. We observed the sequential assembly of new probasal bodies beginning at prophase. The uni2 mutants may be defective in the pathways leading to flagellar assembly and to basal body maturation.
Optimization of HAART with genetic algorithms and agent-based models of HIV infection
Authors: Castiglione F. , Pappalardo F. , Bernaschi M. , Motta S.
Published: October 2007

Motivation: Highly Active AntiRetroviral Therapies (HAART) can prolong life significantly to people infected by HIV since, although unable to eradicate the virus, they are quite effective in maintaining control of the infection. However, since HAART have several undesirable side effects, it is considered useful to suspend the therapy according to a suitable schedule of Structured Therapeutic Interruptions (STI).

In the present article we describe an application of genetic algorithms (GA) aimed at finding the optimal schedule for a HAART simulated with an agent-based model (ABM) of the immune system that reproduces the most significant features of the response of an organism to the HIV-1 infection.

Results: The genetic algorithm helps in finding an optimal therapeutic schedule that maximizes immune restoration, minimizes the viral count and, through appropriate interruptions of the therapy, minimizes the dose of drug administered to the simulated patient.

To validate the efficacy of the therapy that the genetic algorithm indicates as optimal, we ran simulations of opportunistic diseases and found that the selected therapy shows the best survival curve among the different simulated control groups.

Availability: A version of the C-ImmSim simulator is available at http://www.iac.cnr.it/~filippo/c-ImmSim.html

Contact:  f.castiglione@iac.cnr.it
PFRES: protein fold classification by using evolutionary information and predicted secondary structure
Authors: Chen Ke , Kurgan Lukasz
Published: October 2007

Motivation: The number of protein families has been estimated to be as small as 1000. Recent study shows that the growth in discovery of novel structures that are deposited into PDB and the related rate of increase of SCOP categories are slowing down. This indicates that the protein structure space will be soon covered and thus we may be able to derive most of remaining structures by using the known folding patterns. Present tertiary structure prediction methods behave well when a homologous structure is predicted, but give poorer results when no homologous templates are available. At the same time, some proteins that share twilight-zone sequence identity can form similar folds. Therefore, determination of structural similarity without sequence similarity would be beneficial for prediction of tertiary structures.

Results: The proposed PFRES method for automated protein fold classification from low identity (<35%) sequences obtains 66.4% and 68.4% accuracy for two test sets, respectively. PFRES obtains 6.3–12.4% higher accuracy than the existing methods. The prediction accuracy of PFRES is shown to be statistically significantly better than the accuracy of competing methods. Our method adopts a carefully designed, ensemble-based classifier, and a novel, compact and custom-designed feature representation that includes nearly 90% less features than the representation of the most accurate competing method (36 versus 283). The proposed representation combines evolutionary information by using the PSI-BLAST profile-based composition vector and information extracted from the secondary structure predicted with PSI-PRED.

Availability: The method is freely available from the authors upon request.

Contact:  lkurgan@ece.ualberta.ca

Supplementary information: Supplementary data are available at Bioinformatics online.
Mining experimental evidence of molecular function claims from the literature
Authors: Crangle Colleen E. , Cherry J. Michael , Hong Eurie L. , Zbyslaw Alex
Published: October 2007

Motivation: The rate at which gene-related findings appear in the scientific literature makes it difficult if not impossible for biomedical scientists to keep fully informed and up to date. The importance of these findings argues for the development of automated methods that can find, extract and summarize this information. This article reports on methods for determining the molecular function claims that are being made in a scientific article, specifically those that are backed by experimental evidence.

Results: The most significant result is that for molecular function claims based on direct assays, our methods achieved recall of 70.7% and precision of 65.7%. Furthermore, our methods correctly identified in the text 44.6% of the specific molecular function claims backed up by direct assays, but with a precision of only 0.92%, a disappointing outcome that led to an examination of the different kinds of errors. These results were based on an analysis of 1823 articles from the literature of Saccharomyces cerevisiae (budding yeast).

Availability: The annotation files for S.cerevisiae are available from ftp://genome-ftp.stanford.edu/pub/yeast/data_download/literature_curation/gene_association.sgd.gz. The draft protocol vocabulary is available by request from the first author.

Contact:  crangle@converspeech.com
Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G
Authors: Iwatani Yasumasa , Chan Denise S.B. , Wang F. , Stewart-Maynard Kristen , Sugiura Wataru , Gronenborn Angela M. , Rouzina Ioulia , Williams Mark C. , Musier-Forsyth Karin , Levin Judith G.
Published: October 2007

APOBEC3G (A3G), a host protein that inhibits HIV-1 reverse transcription and replication in the absence of Vif, displays cytidine deaminase and single-stranded (ss) nucleic acid binding activities. HIV-1 nucleocapsid protein (NC) also binds nucleic acids and has a unique property, nucleic acid chaperone activity, which is crucial for efficient reverse transcription. Here we report the interplay between A3G, NC and reverse transcriptase (RT) and the effect of highly purified A3G on individual reactions that occur during reverse transcription. We find that A3G did not affect the kinetics of NC-mediated annealing reactions, nor did it inhibit RNase H cleavage. In sharp contrast, A3G significantly inhibited all RT-catalyzed DNA elongation reactions with or without NC. In the case of ( − ) strong-stop DNA synthesis, the inhibition was independent of A3G's catalytic activity. Fluorescence anisotropy and single molecule DNA stretching analyses indicated that NC has a higher nucleic acid binding affinity than A3G, but more importantly, displays faster association/disassociation kinetics. RT binds to ssDNA with a much lower affinity than either NC or A3G. These data support a novel mechanism for deaminase-independent inhibition of reverse transcription that is determined by critical differences in the nucleic acid binding properties of A3G, NC and RT.
Internal initiation of translation from the human rhinovirus-2 internal ribosome entry site requires the binding of Unr to two distinct sites on the 5′ untranslated region
Authors: Anderson Emma C. , Hunt Sarah L. , Jackson Richard J.
Published: October 2007

Internal initiation of translation from the human rhinovirus-2 (HRV-2) internal ribosome entry site (IRES) is dependent upon host cell trans-acting factors. The multiple cold shock domain protein Unr and the polypyrimidine tract-binding protein have been identified as synergistic activators of HRV-2 IRES-driven translation. In order to investigate the mechanism by which Unr acts in this process, we have mapped the binding sites of Unr to two distinct secondary structure domains of the HRV-2 IRES, and have identified specific nucleotides that are involved in the binding of Unr to the IRES. The data suggest that Unr acts as an RNA chaperone to maintain a complex tertiary IRES structure required for translational competency.
Endogenous low-level expression of the coxsackievirus and adenovirus receptor enables coxsackievirus B3 infection of RD cells
Authors: Carson Steven D. , Kim Kyung-Soo , Pirruccello Samuel J. , Tracy Steven , Chapman Nora M.
Published: October 2007

Cells in which the appropriate viral receptor cannot be detected may paradoxically act as a host to the virus. For example, RD cells are often considered to be non-permissive for infection with coxsackievirus and adenovirus receptor (CAR)-dependent group B coxsackieviruses (CVB), insofar as inoculated cell monolayers show little or no cytopathic effect (CPE) and immunohistological assays for CAR have been consistently negative. Supernatants recovered from RD cells exposed to CVB, however, contained more virus than was added in the initial inoculum, indicating that productive virus replication occurred in the monolayer. When infected with a recombinant CVB type 3 (CVB3) chimeric strain expressing S-Tag within the viral polyprotein, 4–11 % of RD cells expressed S-Tag over 48 h. CAR mRNA was detected in RD cells by RT-PCR, and CAR protein was detected on Western blots of RD lysates; both were detected at much lower levels than in HeLa cells. Receptor blockade by an anti-CAR antibody confirmed that CVB3 infection of RD cells was mediated by CAR. These results show that some RD cells in the culture population express CAR and can thereby be infected by CVB, which explains the replication of CAR-dependent CVB in cell types that show little or no CPE and in which CAR has not previously been detected. Cells within cultures of cell types that have been considered non-permissive may express receptor transiently, leading to persistent replication of virus within the cultured population.
Knockdown of hDaxx in normally non-permissive undifferentiated cells does not permit human cytomegalovirus immediate-early gene expression
Authors: Groves Ian J. , Sinclair John H.
Published: October 2007

The cellular protein human Daxx (hDaxx), a component of nuclear domain 10 structures, is known to mediate transcriptional repression of human cytomegalovirus immediate-early (IE) gene expression upon infection of permissive cell types, at least in part, by regulation of chromatin structure around the major IE promoter (MIEP). As it is now clear that differentiation-dependent regulation of the MIEP also plays a pivotal role in the control of latency and reactivation, we asked whether hDaxx-mediated repression is involved in differentiation-dependent MIEP regulation. We show that downregulation of hDaxx by using small interfering RNA technology in undifferentiated NT2D1 cells does not permit expression of viral IE genes, nor does it result in changes in chromatin structure around the MIEP. Viral IE gene expression is only observed upon cellular differentiation, suggesting little involvement of hDaxx in the regulation of the viral MIEP in undifferentiated cells.
Bayesian coalescent inference of hepatitis A virus populations: evolutionary rates and patterns
Authors: Moratorio Gonzalo , Costa-Mattioli Mauro , Piovani Rosina , Romero Héctor , Musto Héctor , Cristina Juan
Published: October 2007

Hepatitis A virus (HAV) is a hepatotropic member of the family Picornaviridae. Previous studies suggested that HAV may evolve more slowly than other members of the family. To estimate HAV substitution rates precisely, we used a Bayesian Markov chain Monte Carlo (MCMC) approach on temporally sampled HAV VP1 full-length sequences from strains isolated in France. A mean rate of evolutionary change of 9.76×10−4 nucleotide substitution per site per year was found. The results also revealed that the synonymous rate found for HAV is lower than that of other members of the family. Bayesian skyline plots revealed a sharp decline in the effective number of infections in 1996, coinciding with the introduction of HAV vaccine.
Classical swine fever virus inhibits nitric oxide production in infected macrophages
Authors: Zaffuto K. M. , Piccone M. E. , Burrage T. G. , Balinsky C. A. , Risatti G. R. , Borca M. V. , Holinka L. G. , Rock D. L. , Afonso C. L.
Published: October 2007

Classical swine fever virus (CSFV)–macrophage interactions during infection were analysed by examining macrophage transcriptional responses via microarray. Eleven genes had increased mRNA levels (>2.5-fold, P<0.05) in infected cell cultures, including arginase-1, an inhibitor of nitric oxide production, phosphoinositide 3-kinase, chemokine receptor 4 and interleukin-1β. Lower levels of nitric oxide and increased arginase activity were found in CSFV-infected macrophages. These changes in gene expression in macrophages suggest viral modulation of host expression to suppress nitric oxide production.
Determination of the human antibody response to the epitope defined by the hepatitis C virus-neutralizing monoclonal antibody AP33
Authors: Tarr Alexander W. , Owsianka Ania M. , Jayaraj Dhanya , Brown Richard J. P. , Hickling Timothy P. , Irving William L. , Patel Arvind H. , Ball Jonathan K.
Published: October 2007

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and there is a pressing need for the development of a preventative vaccine as well as new treatments. It was recently demonstrated that the mouse monoclonal antibody (mAb) AP33 potently neutralizes infectivity of HCV pseudoparticles (HCVpp) carrying E1E2 envelopes representative of all of the major genotypes of HCV. This study determined the prevalence of human serum antibodies reactive to the region of HCV E2 recognized by AP33. Antibodies recognizing this region were present in less than 2.5 % of sera obtained from individuals with chronic HCV infection. A similar prevalence was found in a smaller cohort of individuals who had experienced an acute infection, suggesting that AP33-like antibodies do not play a major role in natural clearance of HCV infection. Sera exhibited different patterns of reactivity to a panel of peptides representing circulating variants, highlighting the presence of distinct epitopes in this region. Only two sera contained antibodies that could recognize a specific AP33-reactive peptide mimotope. AP33-like antibodies made a measurable contribution to the ability of these sera to inhibit E2–CD81 interaction, but not to the overall neutralization of cell entry. Together, these data show that antibodies to the AP33 epitope are not commonly generated during natural infection and that generation of such antibodies via vaccination may require modified immunogens to focus the generation of specific antibodies. Importantly, individuals harbouring AP33-like antibodies are an important potential source of human mAbs for future therapeutic development.
Response of tomato and its wild relatives in the genus Solanum to cucumber mosaic virus and satellite RNA combinations
Authors: Cillo F. , Pasciuto M. M. , De Giovanni C. , Finetti-Sialer M. M. , Ricciardi L. , Gallitelli D.
Published: October 2007

The differential response of 29 genotypes of tomato and wild tomato relatives (Solanum section Lycopersicon species) to cucumber mosaic virus strain Fny (CMV-Fny), alone or in combination with three different satellite RNA (satRNA) variants, allowed the identification of four disease phenotype patterns, each including plants that developed very severe symptoms (leaf malformations, top stunting and lethal necrosis) and plants that remained asymptomatic. No resistance or tolerance to CMV-Fny was observed, whilst individual host genotypes displayed latent infection upon inoculation with one (CMV-Fny/Tfn-satRNA, phenotype patterns 1 and 4), two (CMV-Fny/Tfn-satRNA and CMV-Fny/TTS-satRNA, phenotype pattern 2) or all three (the former two plus CMV-Fny/77-satRNA, phenotype pattern 3) CMV/satRNA combinations. RNA gel-blot analyses showed that latent infection generally correlated with a strong downregulation of CMV RNA accumulation levels. Introgression lines derived from a cross between Solanum habrochaites LA1777, which displayed disease phenotype pattern 2, and Solanum lycopersicum were screened for tolerance to the stunting phenotype induced by CMV-Fny/TTS-satRNA, and only one line, carrying an introgression on chromosome 6, was identified as being partially tolerant. Solanum chilense LA1932×S. lycopersicum back-cross introgression lines were screened for tolerance to lethal necrosis induced by CMV-Fny/77-satRNA (phenotype pattern 3); the tolerant phenotype was observed in 33 % of plants of the BC1F2 progeny and <1 % of plants of the BC1F3 progeny. Thus, potentially useful sources of tolerance to CMV/satRNA-induced diseases were identified, although the tolerant phenotypes appeared to be controlled by complex quantitative trait loci.
Origin of highly pathogenic H5N1 avian influenza virus in China and genetic characterization of donor and recipient viruses
Authors: Mukhtar Muhammad Mahmood , Rasool Sahibzada T. , Song Degui , Zhu Chengliang , Hao Qian , Zhu Ying , Wu Jianguo
Published: October 2007

Genetic analysis of all eight genes of two Nanchang avian influenza viruses, A/Duck/Nanchang/1681/92 (H3N8-1681) and A/Duck/Nanchang/1904/92 (H7N1-1904), isolated from Jiangxi province, China, in 1992, showed that six internal genes of H3N8-1681 virus and five internal (except NS gene) genes of H7N1-1904 virus were closely similar to A/Goose/Guangdong/1/96 (H5N1) virus, the first highly pathogenic avian influenza (HPAI) virus of subtype H5N1 isolated in Asia. The neuraminidase (NA) gene of Gs/Gd/1/96 had the highest genetic similarity with A/Duck/Hokkaido/55/96 (H1N1-55) virus. The haemagglutinin (HA) gene of Gs/Gd/1/96 virus might have originated as a result of mutation of H5 HA gene from A/Swan/Hokkaido/51/96 (H5N3-51)-like viruses. The PA gene of H5N3-51 virus had the highest similarity with Gs/Gd/1/96. This study explains the origin of first Asian HPAI H5N1 virus in Guangdong by the reassortment of Nanchang (close to Guangdong) and Hokkaido (Japan) (H1N1-55 and H5N3-51) viruses. Genetic characteristics of donor and recipient viruses were also studied.
Murine cytomegalovirus open reading frame m29.1 augments virus replication both in vitro and in vivo
Authors: Ahasan Mohammad M. , Sweet Clive
Published: October 2007

Murine cytomegalovirus mutant Rc29, with a premature stop codon mutation in the m29 open reading frame (ORF), produced no apparent phenotype in cell culture or following infection of BALB/c mice. In contrast, a similar mutant virus, Rc29.1, with a premature stop codon mutation in its m29.1 ORF, showed reduced virus yields (2–3 log10 p.f.u. ml−1) in tissue culture. Mutant virus yields in BALB/c mice were delayed, reduced (∼1 log10 p.f.u. per tissue) and persisted less well in salivary glands compared with wild-type (wt) and revertant (Rv29.1) virus. In severe combined immunodeficiency mice, Rc29.1 virus showed delayed and reduced replication initially in all tissues (liver, spleen, kidneys, heart, lung and salivary glands). This delayed death until 31 days post-infection (p.i.) compared with wt (23 days p.i.) but at death virus yields were similar to wt. m29 gene transcription was initiated at early times post-infection, while production of a transcript from ORF m29.1 in the presence of cycloheximide indicated that it was an immediate-early gene. ORFs m29.1 and M28 are expressed from a bicistronic message, which is spliced infrequently. However, it is likely that each ORF expresses its own protein, as antiserum derived in rabbits to the m29.1 protein expressed in bacteria from the m29.1 ORF detected only one protein in Western blot analysis of the size predicted for the m29.1 protein. Our results suggest that neither ORF is essential for virus replication but m29.1 is important for optimal viral growth in vitro and in vivo.
Genetic analysis of maize streak virus isolates from Uganda reveals widespread distribution of a recombinant variant
Authors: Owor Betty E. , Martin Darren P. , Shepherd Dionne N. , Edema Richard , Monjane Adérito L. , Rybicki Edward P. , Thomson Jennifer A. , Varsani Arvind
Published: October 2007

Maize streak virus (MSV) contributes significantly to the problem of extremely low African maize yields. Whilst a diverse range of MSV and MSV-like viruses are endemic in sub-Saharan Africa and neighbouring islands, only a single group of maize-adapted variants – MSV subtypes A1–A6– causes severe enough disease in maize to influence yields substantially. In order to assist in designing effective strategies to control MSV in maize, a large survey covering 155 locations was conducted to assess the diversity, distribution and genetic characteristics of the Ugandan MSV-A population. PCR–restriction fragment-length polymorphism analyses of 391 virus isolates identified 49 genetic variants. Sixty-two full-genome sequences were determined, 52 of which were detectably recombinant. All but two recombinants contained predominantly MSV-A1-like sequences. Of the ten distinct recombination events observed, seven involved inter-MSV-A subtype recombination and three involved intra-MSV-A1recombination. One of the intra-MSV-A1recombinants, designated MSV-A1UgIII, accounted for >60 % of all MSV infections sampled throughout Uganda. Although recombination may be an important factor in the emergence of novel geminivirus variants, it is demonstrated that its characteristics in MSV are quite different from those observed in related African cassava-infecting geminivirus species.