bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of two macrolide antibiotics on human leukocyte membrane receptors and functions
Authors: NÆSS ARE , SOLBERG CLAUS OLA
Published: October 2009

Polymorphonuclear granulocytes (PMNs) and lymphocytes from healthy persons were incubated in varying concentrations of erythromycin and RU 28965, a new macrolide antibiotic. Incubation in erythromycin — even in high dilutions — caused a significant increase in the percentage of PMNs bearing receptors for the Fc portion of IgG (FcγR) and for C3b (C3bR) as measured by rosette formation with EA (erythrocyte‐antibody) and EAC (erythrocyte‐antibody‐complement) indicator cells. This effect could not be removed by extended washing of the cells. Incubation in RU 28965 had a similar effect, except for a decrease in EA and EAC rosetting cells at high concentrations (200 mg/l). Phagocytosis, as measured by chemiluminescence, and random migration of PMNs were unaffected by erythromycin. Chemotaxis under agarose was decreased after incubation in erythromycin or RU 28965. Erythromycin incubation increased the percentage of lymphocytes bearing receptors for sheep erythrocytes (E), but had no effect on the proportion of lymphocytes rosetting with EA or EAC, or on lymphocyte responses to mitogens PHA, conA, or PWM.
Rapid diagnosis of Pneumocystis carinii using dark‐field microscopy on bronchoalveolar lavage
Authors: Olling Sante
Published: October 2009

20 lavages from patients with pulmonary infiltrates were microscopically studied by a rapid dark field assay and after methenamine silver staining. In 8 samples typical Pneumocystis carinii cysts were identified in the methenamine silver‐slides and in 7 of these clusters of round spawn‐like particles were also seen in the dark field microscope. One test was “false negative” in the dark field assay due to presence of too few pneumocystes. Another test was “false positive” due to presence of Candida albicans spores in the lavage. It is thus possible to give a Pneumocystis carinii diagnosis, with some reservation, within 15 minutes after obtaining the bronchoalveolar lavage.
In vitro susceptibility of diarrhoea producing Gram negative enteric bacteria to sulfasalazine, 5‐aminosalicylic acid, sulfapyridine and four quinolones
Authors: ANDREASEN JAN JESPER , ANDERSEN LEIF PERCIVAL , HARTZEN SUSANNE HARTVIG
Published: October 2009

The in vitro susceptibility of diarrhoea producing Gram negative enteric bacteria to sulfasalazine, 5‐aminosalicylic acid, sulfapyridine and four quinolones was investigated using an agar dilution method. All strains were resistant to 1600 μg/ml of sulfasalazine and 5‐aminosalicylic acid. MIC range of sulfapyridine for Y. enterocolitica was 3.1–25 μg/ml (median: 6.2) and for Salmonella 25–100 μg/ml (median: 100) Campylobacter jejuni/coli were less susceptible to sulfapyridine with MIC values ranging from 200 to 800 μg/ml. Shigella and three of five E. coli strains were resistant to 1600 μg/ml of sulfapyridine. Two strains of E. coli were inhibited by 25 μg/ml. All strains were fairly susceptible to enoxacin, ciprofloxacin, pefloxacin and ofloxacin. Cirpofloxacin was the most active drug on weight basis.
Association of a single nucleotide polymorphism in ribosomal protein L27a gene with marbling in Japanese Black beef cattle
Authors: YAMADA Takahisa , SASAKI Seiki , SUKEGAWA Shin , MIYAKE Takeshi , FUJITA Tatsuo , KOSE Hiroyuki , MORITA Mitsuo , TAKAHAGI Youichi , MURAKAMI Hiroshi , MORIMATSU Fumiki , SASAKI Yoshiyuki
Published: October 2009

Marbling, defined by the amount and distribution of intramuscular fat, is an economically important trait of beef cattle in Japan. The c2‐11#2 expressed sequence tag (EST) has been previously shown to possess expression difference in musculus longissimus muscle between low‐marbled and high‐marbled steer groups, and to be located within genomic region of a quantitative trait locus for marbling. Thus, the ribosomal protein L27a (RPL27A) gene containing the c2‐11#2 EST sequence was considered as a positional candidate for the gene responsible for marbling. In the present study, a single nucleotide polymorphism (SNP) in the promoter region of the RPL27A, referred to as g.3109537C>T, was detected between the 2 steer groups. The SNP was associated with the predicted breeding value for beef marbling standard number by the analyses using Japanese Black beef cattle population. The effect of genotypes of the SNP on the predicted breeding value for subcutaneous fat thickness was not statistically significant. These findings suggest that the RPL27A SNP may be useful for effective marker‐assisted selection to increase the levels of marbling in Japanese Black beef cattle.
Alternative Futures: Comment on Terry Moe's “The Revolution in Presidential Studies”
Authors: COHEN JEFFREY E.
Published: October 2009

In “The Revolution in Presidential Studies,” Terry Moe suggests that bounded rationality and computational and agent‐based modeling should become the core for future research on the presidency. I suggest other, perhaps complementary, directions for future research: (1) a greater integration of theories on the institutional presidency with those on the public presidency; (2) a broader and more comparative approach to studying political executives instead of the current parochial focus on the American presidency; and (3) a large‐scale, cooperative data collection effort that parallels such efforts in other subfields, which has reinvigorated those subfields, attracted students, and allowed for more ambitious research questions and designs.
Thoughts on “The Revolution in Presidential Studies”
Authors: MAYER KENNETH R.
Published: October 2009

Few scholars have done more than Terry Moe to propel the presidency studies literature into its current generation. He offered—or, it could be said, insisted on—an alternative theoretical foundation, based on rational choice and economic approaches on institutional organization and development. There is little doubt that the resulting reorientation constituted a historic shift, one that happens once in a generation. While Moe overstates the importance of rational choice to this shift, the current presidency literature is full of interesting questions, novel approaches, sophisticated methods, and, perhaps most importantly, empirical disagreements.
Does the Revolution in Presidential Studies Mean “Off With the President's Head”?
Authors: ROCKMAN BERT A.
Published: October 2009

Terry Moe's expansive yet incisive article extolling what he calls the “revolution” in presidential studies explicitly ties the progress of the presidency subfield to theoretical developments that have been critical to the mainstream of political science. This commentary shares Moe's positive view of these developments but departs from his negative view of other streams of work, especially Neustadt's contributions and the scientific empirical studies that he indirectly helped generate. Most particularly, Moe is attracted to theories of invariant behavior—that is, how any person should or would have behaved in the face of similar conditions. In studying the presidency, this is a necessary place to begin, but not always a sufficient place to end. Presidents remain important to the presidency because of their decision‐making role amid uncertainty and ambiguity—precisely where people make a difference. Although we have virtually no usable theory of individual difference, which is usually unexplained residual variance, we can make use of observations to assess the way presidents do make decisions.
Mission Accomplished
Authors: SKOWRONEK STEPHEN
Published: October 2009

Notwithstanding Terry Moe's claim, rational choice scholarship has been pursuing the least “revolutionary” of the possible lines of advance in presidential studies. This scholarship asks the same basic question that Richard Neustadt asked nearly a half century ago: how much can a president get done? It follows Neustadt as well in its strategic approach to presidential action and in thinking about the problem of presidential strategy systemically. The new rational choice scholarship has many real strengths. It has helped clarify system parameters and specify how they affect an incumbent's opportunities, incentives risks, and constraints. But this is a “rigor revolution” that does more to perpetuate the traditional preoccupations of presidential studies than to overthrow them. The real revolution will come when we start asking questions about the presidency that no one in 1960 would have thought to ask.
The 2008‐2009 Presidential Transition: Preparing Federal Agencies
Authors: JOHNSON CLAY
Published: October 2009

While scholars study the transitions into office of new presidents and their teams, there has been less interest in how sitting presidents and their administrations prepare to leave office. The 2008‐2009 transition is particularly important to study because the preparations made by the incumbent president began earlier than previously was the case and involved all agencies in the administration. Clay Johnson, former deputy director for management in the Office of Management and Budget, was charged in April 2008 with preparing federal agencies for the transition. In this essay, he explains how the administration did so. First, Johnson discussed responsibilities and timetables for the transition preparations with the 22 agency members of the President's Management Council. Then, in July, based on information generated in the council sessions, Johnson sent a letter to agencies with goals for the transition and guidelines for achieving them. He and Gail Lovelace, the transition official in the General Services Administration working with career employees, subsequently made certain that their goals were met.
Polls and Elections: Preelection Poll Accuracy in the 2008 General Elections
Authors: PANAGOPOULOS COSTAS
Published: October 2009

This report examines accuracy and bias in national and subnational preelection polls conducted during the 2008 presidential election cycle. The analyses indicate that, despite concerns about poll methodology voiced during the election cycle, polls across the board generally performed quite well in 2008. That said, concerns about poll methodologies should not be wholly and readily dismissed. While the evidence suggests that improvements in accuracy and declining bias in preelection polls as a whole, compared to previous election cycles, sources of inaccuracy and bias can also be detected using 2008 polls.
An Agent‐Based Model of Border Enforcement for Invasive Species Management
Authors: Ameden Holly A. , Boxall Peter C. , Cash Sean B. , Vickers D. Angele
Published: October 2009

This paper presents a model of border enforcement in order to address trade‐related invasive species risk. An agent‐based modeling (ABM) framework was developed based on a theoretical economic model that incorporates a spatially explicit damage function. The framework was applied to a representative commodity (broccoli), invasive species (crucifer flea beetle), ports‐of‐entry (Calexico and Otay Mesa U.S./Mexico land ports), and vulnerable location (California). The ABM evaluated the economic impacts of port‐specific and importer‐specific enforcement regimes, enabling regulators to improve both the allocation of scarce enforcement resources and the effectiveness of current enforcement policies. The analysis generated several policy relevant findings concerning importing firm behavior and suggests conditions under which increasing enforcement may or may not significantly reduce invasive species risk and associated crop damages. The analysis illustrates that with a more realistic parameterization, the ABM could be used to make real‐world policy decisions concerning allocation of limited resources across ports‐of‐entry.

Dans le présent article, nous présentons un modèle de renforcement des frontières pour examiner le risque d'introduction d'espèces envahissantes par le biais d'échanges commerciaux. Nous avons élaboré un modèle multiagent fondé sur un modèle économique théorique qui intègre une fonction de dommage spatiale. Nous avons appliqué ce modèle à une denrée représentative (le brocoli), à une espèce envahissante (l'altise des crucifères), à des points d'entrée (les points d'entrée terrestre de Calexico et d'Otay Mesa à la frontière des États−Unis et du Mexique) et à un endroit vulnérable (la Californie). Le modèle multiagent a évalué les répercussions économiques des régimes de renforcement spécifiques à un point d'entrée et à un importateur, permettant aux organismes de réglementation d'améliorer à la fois l'allocation des ressources de renforcement qui sont rares et l'efficacité des politiques de renforcement actuelles. L'analyse a généré plusieurs résultats quant aux politiques concernant le comportement des entreprises importatrices et indique des conditions dans lesquelles l'accroissement du renforcement pourrait diminuer considérablement ou pas le risque d'introduction d'espèces envahissantes pouvant causer des dommages aux cultures. L'analyse a montré que, à l'aide d'une paramétrisation plus réaliste, le modèle multiagent pourrait être utilisé pour prendre des décisions stratégiques du monde réel quant à l'allocation des ressources limitées dans les points d'entrée.
Using Numerical Dynamic Programming to Compare Passive and Active Learning in the Adaptive Management of Nutrients in Shallow Lakes
Authors: Bond Craig A. , Loomis John B.
Published: October 2009

This paper illustrates the use of dual/adaptive control methods to compare passive and active adaptive management decisions in the context of an ecosystem with a threshold effect. Using discrete‐time dynamic programming techniques, we model optimal phosphorus loadings under both uncertainty about natural loadings and uncertainty regarding the critical level of phosphorus concentrations beyond which nutrient recycling begins. Active management is modeled by including the anticipated value of information (or learning) in the structure of the problem, and thus the agent can perturb the system (experiment), update beliefs, and learn about the uncertain parameter. Using this formulation, we define and value optimal experimentation both ex ante and ex post. Our simulation results show that experimentation is optimal over a large range of phosphorus concentration and belief space, though ex ante benefits are small in our example. Furthermore, realized benefits may critically depend on the true underlying parameters of the problem.

Le présent article illustre l'utilisation des méthodes de contrôle adaptatif pour comparer les décisions de gestion adaptative active et passive dans le cas d'un écosystème ayant un effet de seuil. À l'aide des techniques de programmation dynamique en temps discret, nous avons conçu un modèle des charges optimales en polluants phosphorés en tenant compte, à la fois, de l'incertitude quant aux charges naturelles et de l'incertitude quant au niveau critique des concentrations en phosphore au‐delà desquelles le recyclage des éléments nutritifs débute. Nous avons modélisé la gestion active en incluant la valeur prévue de l'information (ou de l'apprentissage) dans la structure du problème; par conséquent, l'agent peut perturber le système (l’expérience), actualiser ses croyances et découvrir les paramètres incertains. À l'aide de ce modèle, nous avons caractérisé et évalué l'expérience optimale ex ante et ex poste. Les résultats de notre modèle de simulation ont montré que l'expérience est optimale pour un large éventail de concentrations en phosphore et de croyances, bien que les avantages ex ante soient faibles dans le cas de notre exemple. Les avantages réalisés pourraient dépendre des paramètres sous‐jacents réels du problème.
A Stochastic Dynamic Programming Analysis of Farmland Investment and Financial Management
Authors: Lohano Heman D. , King Robert P.
Published: October 2009

This paper develops a multiperiod investment portfolio model that includes risky farmland, risky and risk‐free nonfarm assets, and debt financing on farmland in the presence of transaction costs and credit constraints. The model is formulated as a stochastic continuous‐state dynamic programming problem, and is solved numerically for Southwestern Minnesota, USA. Results show that optimal investment decisions are dynamic and take into account the future decisions due to uncertainty, partial irreversibility, and the option to wait. The optimal policy includes ranges of inaction, states where the optimal policy in the current year is to wait. The risk‐averse farmer makes a lower investment in risky farmland reflecting risk‐avoiding behavior. We find that, in addition to risk aversion, the length of the planning horizon affects risk‐avoiding behavior in investment decisions. In contrast to a static model, changes in the riskiness of returns affect optimal investment decisions even when the decision maker is risk neutral. Finally, we find that higher debt financing on farmland is optimal when risky nonfarm assets can be included in the optimal investment portfolio and that the probability of exiting farming increases with the risky nonfarm investment.

Dans le présent article, nous avons élaboré un modèle de portefeuille multipériode composé d'actifs agricoles risqués (terres), d'actifs non agricoles risqués et sans risque ainsi que de financement par emprunt de terres comprenant des coûts de transaction et des contraintes de crédit. Le modèle a été formulé comme un problème de programmation dynamique stochastique en temps continu et a été résolu de façon numérique pour le sud‐ouest du Minnesota, aux États‐Unis. Les résultats ont montré que les décisions optimales d'investissement sont dynamiques et qu’elles tiennent compte des décisions futures en raison de l'incertitude, de l'irréversibilité partielle et du choix d'attendre. La politique optimale inclut des plages d'inaction et des situations où la politique optimale de l'année en cours doit attendre. L'agriculteur risquophobe investit peu dans des actifs fonciers risqués ce qui traduit un comportement d'évitement des risques. Nous sommes arrivés à la conclusion que la longueur de l'horizon de planification, en plus de l'aversion pour le risque, influe sur le comportement d'évitement des risques au moment de prendre des décisions d'investissement. Contrairement au modèle statique, les changements dans les risques de rendements influent sur les décisions optimales d'investissement même si le décideur est indifférent au risque. Finalement, nous avons trouvé que le financement par emprunt pour des terres agricoles est optimal lorsqu’il est possible d'inclure des actifs non agricoles risqués dans le portefeuille optimal et que la probabilité de quitter l'agriculture augmente en présence d'investissements non agricoles risqués.
‘It's a public, I reckon’: Publicness and a Suburban Shopping Mall in Sydney's Southwest
Authors: TYNDALL ADAM
Published: October 2009

Traditionally, public space has been perceived as an integral part of fully functioning liberal democracy. Yet much research argues that public space is in decline due to regimes of neoliberal governance paralleled with a growth in quasi‐public spaces such as shopping malls, casinos and gated communities. It is argued that these new spatial forms posit a commercialised, sanitised and ultimately exclusionary urban form in place of more egalitarian, engaging and ultimately democratic public spaces. Increasingly, however, urban research has questioned the veracity of the claims made about the nature of traditional public space as well as investigating the marginal and contingent nature of publicness as constituted by and enacted in a variety of places. Drawing on Foucault's concept of heterotopic space, this paper reports on a qualitative study based on focus group interviews conducted with users of a suburban shopping mall in Sydney's southwest. The research uncovers both a more complex and less overtly deterministic publicness than has previously been identified in such spaces. From these findings the paper argues for a conception of publicity which moves beyond the zero‐sum game approach endemic in much work in this area to one which analyses the qualitative effect quasi‐public spaces are having on the nature of publicness in the Australian context. The paper concludes by arguing that a rethinking of publicness allows room for the emergence of a more progressive public ethic.
Ligand‐based 3D‐QSAR Studies of Physostigmine Analogues as Acetylcholinesterase Inhibitors
Authors: Ul‐Haq Zaheer , Mahmood Uzma , Jehangir Bushra
Published: October 2009

Natural alkaloid Physostigmine is one of the most potent pseudo‐irreversible inhibitor of Acetylcholinesterase. It was found to accelerate long‐term memory process, but due to its short half life and variable bioavailability, has inconsistent clinical efficacy. 3D‐QSAR studies based on the comparative molecular field analysis and comparative molecular similarity indices analysis were applied to a set of 40 Physostigmine derivatives which are divided into two classes: A and B. The study was conducted to obtain a highly reliable and extensive dynamic QSAR model based on alignment procedure with co‐crystallized Ganstigmine as template. The strategy yielded significant 3D‐QSAR models with the cross‐validated q2 values 0.762 and 0.754 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Resulted models were validated by external set of eight compounds yielding high correlation coefficient r2 values of 0.730 and 0.720 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Furthermore, the analysis of comparative molecular field analysis and comparative molecular similarity indices analysis contour maps within the active site of AChE were conducted in order to understand the interactions between the receptor and the Physostigmine derivatives. This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease.
Activity Prediction and Structural Insights of Extracellular Signal‐Regulated Kinase 2 Inhibitors with Molecular Dynamics Simulations
Authors: Del Rio Alberto , Baldi Benedetta Frida , Rastelli Giulio
Published: October 2009

A computational application to predict, probe and interpret the activities of a series of congeneric compounds inhibiting extracellular signal‐regulated kinase 2 protein kinase is presented. The study shows that molecular dynamics coupled with molecular mechanics Poisson–Boltzmann solvent accessible surface area free energy estimation is a suitable tool for investigating the experimental binding activities of ligands to protein kinases. Computed and experimental binding activities were found to be significantly correlated. Moreover, the interpretation of the X‐ray co‐crystal structure in conjunction with computational results shows that the hinge region of the protein insure the principal binding site via multiple hydrogen bonding interactions, whereas fine‐modulation of biological activities along the series is accomplished through the combination of weak and strong interactions that compete with water. These are located in the substituent moieties of the ligands interfacing with the DFG motif, the sugar region and the hydrophobic pocket of extracellular signal‐regulated kinase 2. The study suggests that a wider interaction framework that is well beyond the hinge region is required to predict and rationalize at molecular level the experimental biological activities of congeneric compound series.
Impact of RNA Virus Infection on Plant Cell Function and Evolution
Authors: Niehl Annette , Heinlein Manfred
Published: October 2009

Viruses are obligate symbionts that tightly interact with their hosts to complete their life cycle. Each infected cell is confronted with the accumulation of viral products and activities that have evolved to support the replication and spread of the virus in the context of host cell functions and defense responses. Tobacco mosaic virus encodes replicase proteins and coat protein, to replicate and protect the RNA genome, and a movement protein (MP) that binds viral RNA and manipulates the size exclusion limit of plasmodesmata to facilitate the spread of the viral genomic RNA (vRNA). The MP and replicase also interfere with the cellular RNA silencing machinery that influences plant gene expression and development. Moreover, virus‐infected cells stimulate the production of a systemic signal ahead of the virus front that triggers genomic recombination leading to heritable genetic changes. Thus viruses can interact with their hosts through diverse molecular interactions. Given the high mutation rate of viruses, these interactions have implications for evolutionary processes and adaptations at the virus‐host interface that may contribute to eukaryotic evolution.
Evolution of Genes and Organisms
Authors: Olendzenski Lorraine , Gogarten J. Peter
Published: October 2009

Gene exchange necessitates expanding the model of the tree of life, impacts the notion of organismal and molecular most recent common ancestors, and provides examples of natural selection working at multiple levels. Gene exchange, whether by horizontal gene transfer (HGT), hybridization of species, or symbiosis, modifies the organismal tree of life into a web. Darwin suggested the tree of life was like a coral, where living surface branches were supported by masses of dead branches. In phylogenetic trees, organismal or molecular lineages coalesce back to a lucky universal ancestor whose descendents are found in current lineages and which coexisted with other, now‐extinct lineages. HGT complicates the reconstruction of a universal ancestor; genes in a genome can have different evolutionary histories, and even infrequent gene transfer will cause different molecular lineages to coalesce to molecular ancestors that existed in different organismal lineages and at different times. HGT, as well as symbiosis, provides a mechanism for integrating and expanding the organizational level on which natural selection acts, contributing to selection at the group and community level.
Natural Genetic Engineering of Hepatitis C Virus NS5A for Immune System Counterattack
Authors: El Hefnawi Mahmoud M. , El Behaidy Wessam H. , Youssif Aliaa A. , Ghalwash Atek Z. , El Housseiny Lamya A. , Zada Suher
Published: October 2009

The Hepatitis C virus nonstructural 5A (NS5A) protein is a hydrophilic phosphoprotein with diverse functions. The domain assignment of NS5A had been refined using a systematic in silico bioinformatics approach using DOMAC, the protein is divided into three domains and domain III is subdivided into two subdomains using ProDom and SSEP servers. The fold structure for domains II and III were predicted using the meta‐server 3D‐Jury. Scanning motif databases (SMART, BLOCKS, and PROSITE) gave new motifs. Two important motifs, the interleukins 1 and 8 interaction motifs, relating to NS5A function in inducing the interleukin 8 promoter, were discovered from the BLOCKS scan. Protein–protein interaction motifs were predicted as hot loops and disordered regions, corresponding to binding regions with the ds‐protein kinase R, viral polymerase, and Src homology 3 signaling proteins binding motif. Other hot loops were predicted in the V3 region and in the single‐stranded DNA‐binding protein motif. The different mechanisms by which the NS5A protein leads to immune system signaling dysfunction points to the natural genetic engineering of this protein.
Cellular Genes Derived from Gypsy/Ty3 Retrotransposons in Mammalian Genomes
Authors: Volff Jean‐Nicolas
Published: October 2009

Gypsy/Ty3 retrotransposons, a group of long terminal repeat retrotransposons related to vertebrate retroviruses, are found in the genome of many fungi, plants, and animals. Although multiple families of such retroelements are present in fish, active Gypsy/Ty3 retrotransposons have all been eliminated from the lineage leading to mammals at least 180 million years ago. However, over 50 cellular genes related to Gypsy/Ty3 retrotransposons have been identified in mammalian genomes, indicating recurrent “molecular domestication” of these elements by their host during evolution. Most retrotransposon‐derived proteins are conserved in divergent mammalian species and show sequence similarity to Gag proteins, major structural proteins for retroelement particle formation. Among the proposed and demonstrated biological functions for gag‐derived genes, placenta formation in the mouse requires two gag‐derived genes from the same family. Some forms of epigenetic regulation of gag‐related genes might derive from host genome defense mechanisms that repelled retrotransposon ancestors. Together, such observations support a major role for transposable elements as a source of new coding sequences allowing important genetic innovations during evolution.
Conceptual and Methodological Biases in Network Models
Authors: Lamm Ehud
Published: October 2009

Many natural and biological phenomena can be depicted as networks. Theoretical and empirical analyses of networks have become prevalent. I discuss theoretical biases involved in the delineation of biological networks. The network perspective is shown to dissolve the distinction between regulatory architecture and regulatory state, consistent with the theoretical impossibility of distinguishing a priori between “program” and “data.” The evolutionary significance of the dynamics of trans‐generational and interorganism regulatory networks is explored and implications are presented for understanding the evolution of the biological categories development‐heredity, plasticity‐evolvability, and epigenetic‐genetic.
The Source of Self
Authors: Villarreal Luis P.
Published: October 2009

Stable colonization of the host by viruses (genetic parasites) can alter the systems of host identity and provide immunity against related viruses. To attain the needed stability, some viruses of prokaryotes (P1 phage) use a strategy called an addiction module. The linked protective and destructive gene functions of an addiction module insures both virus persistence but will also destroy cells that interrupt this module and thereby prevent infection by competitors. Previously, I have generalized this concept to also include persistent and lytic states of virus infection, which can be considered as a virus addiction module.1Such states often involve defective viruses. In this report, I examine the origin of the adaptive immune system from the perspective of a virus addiction module. The likely role of both endogenous and exogenous retroviruses, DNA viruses, and their defective elements is considered in the origin of all the basal components of adaptive immunity (T‐cell receptor, RAG‐mediated gene rearrangement, clonal lymphocyte proliferation, antigen surface presentation, apoptosis, and education of immune cells). It is concluded that colonization by viruses and their defectives provides a more coherent explanation for the origin of adaptive immunity.
The Natural Genetic Engineering of Polydnaviruses
Authors: Webb Bruce , Fisher Tonja , Nusawardani Tyasning
Published: October 2009

The polydnaviruses represent an unusual example of a highly evolved symbiosis between some parasitic wasps, DNA containing particles or viruses, and lepidopteran larval hosts of the wasp. The viruses can no longer replicate independently, as genes that encode viral structural proteins are restricted to the wasp genome and are not encapsidated. Interestingly, the DNA that is encapsidated is more similar in terms of gene identity and gene density to eukaryotic genomes than viral genomes. We compare and relate this unusual example of natural genetic engineering to the well‐known system of viral lysogeny. The similarities in the two systems may prove useful in understanding the replication strategy and genomic organization of polydnaviruses and provide some insight into how this unusual virus system may have evolved.
Enzyme‐Linked Oxygen Sensing by Potassium Channels
Authors: Kemp Paul J. , Telezhkin Vsevolod , Wilkinson William J. , Mears Ruth , Hanmer Stuart B. , Gadeberg Hanne C. , Müller Carsten T. , Riccardi Daniela , Brazier Stephen P.
Published: October 2009

The ability of ion channels to respond to an acute perturbation in oxygen tension is a widespread phenomenon, which encompasses many of the major ion channel families. Integral to the ability of several ion channels to respond to acute hypoxic challenge is modulation by upstream enzymatic reactions, suggesting that many ion channels sense oxygen via enzyme‐linked processes. Several enzyme‐linked oxygen sensing systems have been proposed, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase‐dependent production of hydrogen peroxide, hemoxygenase‐dependent generation of carbon monoxide, adenosine monophosphate (AMP) kinase‐dependent channel phosphorylation, and src‐Lck protein tyrosine kinase, via a currently undetermined mechanism. Each of these enzymes has been shown to endow specific ion channels with the ability to respond to changes in oxygen, with hypoxia exclusively evoking channel inhibition. This article reviews these proposed mechanisms and presents new insights into how one system, hemeoxygenase‐2, confers oxygen sensitivity to large conductance, voltage‐ and calcium‐activated potassium channels.
Role of Hypoxia‐Inducible Factors in Epigenetic Regulation via Histone Demethylases
Authors: Yang Jun , Ledaki Ioanna , Turley Helen , Gatter Kevin C. , Montero Juan‐Carlos Martinez , Li Ji‐Liang , Harris Adrian L.
Published: October 2009

Eukaryotic chromatin is subject to multiple posttranslational histone modifications such as acetylation, methylation, phosphorylation, and ubiquitination. These various covalent modifications have been proposed to constitute a “histone code,” playing important roles in the establishment of global chromatin environments, transcription, DNA repair, and DNA replication. Among these modifications, histone methylation specifies regulatory marks that delineate transcriptionally active and inactive chromatin. These histone methyl marks were considered irreversible; however, recent identification of site‐specific histone demethylases demonstrates that histone methylation is dynamically regulated, which may allow cells to rapidly change chromatin conformation to adapt to environmental stresses or intrinsic stimuli. Of major interest is the observation that these histone demethylase enzymes, which are in the Jumonji gene family, require oxygen to function and, in some cases, are induced by hypoxia in an HIFα‐dependent manner. This provides a new mechanism for regulation of the response to hypoxia.
The Neuronal Control of Hypoxic Ventilation
Authors: Gassmann Max , Tissot van Patot Martha , Soliz Jorge
Published: October 2009

Using mice, we demonstrated that when oxygen supply is lowered, erythropoietin (Epo), the main regulator of red blood cell production, modulates the ventilatory response by interacting with central (brainstem) and peripheral (carotid bodies) respiratory centers. We showed that enhanced Epo levels in the brainstem increased the hypoxic ventilatory response, and that intracerebroventricular injection of an Epo antagonist (soluble Epo receptor) abolished the ventilatory acclimatization to hypoxia. More recently, we have found that the impact of Epo on ventilation occurs in a sex‐dependent manner. Keeping in mind that women are less susceptible to several respiratory sicknesses and syndromes than men, we suggest that Epo plays a key role in sexually‐dimorphic hypoxic ventilation. Accordingly, we foresee that Epo has a potential therapeutic use as treatment for hypoxia‐associated ventilatory diseases.
Regulation of Oxygen Sensitivity in Adrenal Chromaffin Cells
Authors: Nurse Colin A. , Buttigieg Josef , Brown Stephen , Holloway Alison C.
Published: October 2009

Adrenomedullary chromaffin cells (AMC) possess a direct hypoxia‐sensing mechanism that promotes a vital catecholamine surge at birth. This mitochondria‐dependent adaptive mechanism is suppressed postnatally as AMC acquire cholinergic innervation, and it is mediated by K+ channel inhibition, membrane depolarization, and voltage‐gated Ca2+ entry. We hypothesized that nicotinic ACh receptor (AChR) activation might contribute to this postnatal loss of O2 sensitivity. Following in utero nicotinic AChR activation, via maternal administration of nicotine bitartrate, hypoxic sensitivity was suppressed in neonatal AMC. Similarly, when neonatal AMC or immortalized chromaffin (MAH) cells were cultured for ∼7 d with nicotine base (50 μM), hypoxic sensitivity was suppressed. This effect required α7 nAChR stimulation, and involved upregulation of KATP channels, which are activated during hypoxia. Thus, nicotinic AChR activation may contribute to the suppression of hypoxic sensitivity in AMC, and this pathway could provide the basis for the loss of hypoxia tolerance in the offspring of smoking mothers.
Intermittent Hypoxia‐Mediated Plasticity of Acute O2 Sensing Requires Altered Red‐Ox Regulation by HIF‐1 and HIF‐2
Authors: Prabhakar Nanduri R. , Kumar Ganesh K. , Nanduri Jayasri
Published: October 2009

This article provides a brief review of recent studies addressing the effects of chronic intermittent hypoxia (IH) on acute O2 sensing in carotid bodies (CBs) and adrenal medullary chromaffin cells (AMCs) and the underlying mechanisms. Chronic IH upregulates hypoxic sensing ability of CBs and AMCs in adults and neonates. The effects of IH were reversible in adult rats, whereas that of neonatal IH persist into adult life. Reactive oxygen species (ROS) mediate IH‐induced changes in O2 sensing. Differential regulation of hypoxia‐inducible factors 1 and 2 (HIF‐1 and 2) contribute to IH‐evoked oxidative stress. HIF‐1 activation by IH appears to be linked to increased pro‐oxidant(s), whereas downregulation of HIF‐2 by IH is coupled to transcriptional downregulation of antioxidant enzyme(s). Thus, the studies with chronic IH suggest novel, hitherto uncharacterized, roles for HIF‐1 and HIF‐2 in regulating red‐ox status leading to plasticity of O2 sensing in CBs and AMCs.
Mitochondrial Metabolism and Cancer
Authors: Weinberg Frank , Chandel Navdeep S.
Published: October 2009

Historically, it has been assumed that glycolytic metabolism, not mitochondrial metabolism, is essential for tumor cell proliferation. However, most tumor cells have functional mitochondria, and recent studies suggest that the citric acid cycle (TCA) cycle intermediates are precursors for synthesis of nucleotides, lipids, and amino acids. Here we review the accumulating evidence that mitochondrial metabolism plays an essential role in tumor cell proliferation.
Ion Channel Regulation by AMPK
Authors: Evans A. Mark , Hardie D. Grahame , Peers Chris , Wyatt Christopher N. , Viollet Benoit , Kumar Prem , Dallas Mark L. , Ross Fiona , Ikematsu Naoko , Jordan Heidi L. , Barr Barbara L. , Rafferty J. Nicole , Ogunbayo Oluseye
Published: October 2009

Vital homeostatic mechanisms monitor O2 supply and adjust respiratory and circulatory function to meet demand. The pulmonary arteries and carotid bodies are key systems in this respect. Hypoxic pulmonary vasoconstriction (HPV) aids ventilation−perfusion matching in the lung by diverting blood flow from areas with an O2 deficit to those rich in O2, while a fall in arterial pO2 increases sensory afferent discharge from the carotid body to elicit corrective changes in breathing patterns. We discuss here the new concept that hypoxia, by inhibiting oxidative phosphorylation, activates AMP‐activated protein kinase (AMPK) leading to consequent phosphorylation of target proteins, such as ion channels, which initiate pulmonary artery constriction and carotid body activation. Consistent with this view, AMPK knockout mice exhibit an impaired ventilatory response to hypoxia. Thus, AMPK may be sufficient and necessary for hypoxia‐response coupling and may regulate O2 and thereby energy (ATP) supply at the whole body as well as the cellular level.
FIH‐Dependent Asparaginyl Hydroxylation of Ankyrin Repeat Domain‐Containing Proteins
Authors: Cockman Matthew E. , Webb James D. , Ratcliffe Peter J.
Published: October 2009

Studies on hypoxia‐sensitive pathways have identified a series of Fe(II)‐dependent dioxygenases that regulate hypoxia‐inducible factor (HIF) by prolyl and asparaginyl hydroxylation. The asparaginyl hydroxylase factor inhibiting HIF (FIH) targets a conserved asparaginyl residue in the C‐terminal transactivation domain of HIF‐α. This modification suppresses HIF transcriptional activity by inhibiting co‐activator recruitment. Recent work has demonstrated that FIH targets an alternative class of substrate. Proteins containing a common interaction motif known as the ankyrin repeat domain (ARD) have been shown to be efficiently hydroxylated by FIH. This review aims to summarize what is currently known regarding ARD hydroxylation, including the kinetics and determinants of FIH‐mediated ARD hydroxylation, the structural and functional consequences of ARD hydroxylation, and the potential for cross‐talk between ARD proteins and HIF signaling.
Survival in Acute and Severe Low O2 Environment
Authors: Azad Priti , Haddad Gabriel G.
Published: October 2009

Hypoxia whether present during physiologic states (e.g., embryogenesis) or during pathologic states (e.g., obstructive sleep apnea and sickle cell anemia), challenges the vertebrate or invertebrate organism. Clearly, hypoxia can lead to sublethal cell injury or death and consequently organ or systemic injury and failure, depending on severity. We discovered that the adult Drosophila melanogaster is tolerant to a low O2 environment, withstanding ∼3‐4 hours of total O2 deprivation or anoxia without showing any evidence of cell injury. This opened major avenues for us since the Drosophila has been used so effectively in so many relevant research areas. We investigated the changes in gene expression in D. melanogaster after severe (1% O2) intermittent or constant hypoxia treatment for 2.5 hours. Our microarray analysis has identified multiple gene families that are up‐ or downregulated in response to acute constant (CH) and intermittent hypoxia (IH). We observed that even for short‐term the gene expression response to IH and CH varied not only in the number of genes but also type of gene families. Furthermore, by utilizing powerful Drosophila genetic tools we studied the role of single genes (up‐ or downregulated in arrays) in survival under either paradigm in adult flies. We observed significant increased adult survival (as compared to controls) of P‐element lines for Hsp70 and Hsp23 genes during CH and Mdr49 and l (2)08717 genes during IH. This suggests that the increased transcript levels as observed in array data after either paradigm play an important role under severe hypoxia. Indeed, we found for example that over‐expressing Hsp70 in vivo in specific fly organs (such as heart) significantly increased adult survival during CH as compared to controls. These data provide further clues about the mechanisms by which intermittent and constant hypoxia lead to cell injury and morbidity or adaptation and survival.
Cardiovascular Chronobiology: Do You Know What Time It Is?
Authors: Bridges Elizabeth J. , Woods Susan L.
Published: October 2009

Cardiovascular indices, such as blood pressure, heart rate, cardiac output, and fibrinolytic factors, vary over a 24‐hour period. For example, nocturnal blood pressure may decrease to 30–50 mm Hg and heart rate to 25 beats per minute. In addition, these cardiovascular rhythms interact and may trigger a cardiovascular catastrophe, such as a myocardial infarction, sudden cardiac arrest, or stroke, with the highest risk during the first 6 hours after awakening and arising. Understanding the fluctuations in cardiovascular indices and the rhythmic increase in risk is crucial in assessing patients and developing a protective plan of care. This article discusses the cardiovascular rhythms and the rhythmic increase in risk for cardiovascular catastrophes. A framework demonstrating the interaction of these rhythms provides the basis for the development and exploration of interventions, including modification of activity and medications, and nursing actions to protect patients during periods of high cardiovascular risk.
A genome‐wide set of 106 microsatellite markers for the blue tit (Cyanistes caeruleus)
Authors: OLANO‐MARIN JUANITA , DAWSON DEBORAH A. , GIRG ALEXANDER , HANSSON BENGT , LJUNGQVIST MARCUS , KEMPENAERS BART , MUELLER JAKOB C.
Published: October 2009

We have characterized a set of 106 microsatellite markers in 26–127 individual blue tits (Cyanistes caeruleus), and assigned their location on the zebra finch (Taeniopygia guttata) and on the chicken (Gallus gallus) genome on the basis of sequence homology. Thirty‐one markers are newly designed from zebra finch EST (expressed sequence tags) sequences, 22 markers were developed by others from EST sequences using different methods and the remaining 53 loci were previously designed or modified passerine markers. The 106 microsatellite markers are distributed over 26 and 24 chromosomes in the zebra finch and in the chicken genome respectively and the number of alleles varies between 2 and 49. Eight loci deviate significantly from Hardy–Weinberg equilibrium and show a high frequency of null alleles, and three pairs of markers located in the same chromosome appear to be in linkage disequilibrium. With the exception of these few loci, the polymorphic microsatellite markers presented here provide a useful genome‐wide resource for population and evolutionary genetic studies of the blue tit, in addition to their potential utility in other passerine birds.
An RFLP assay to determine if Mytilus galloprovincialis Lmk. (Mytilidae; Bivalvia) is of Northern or Southern hemisphere origin
Authors: WESTFALL K. M. , WIMBERGER P. H. , GARDNER J. P. A.
Published: October 2009

Mytilus galloprovincialis is one of three smooth shelled blue mussel species belonging to the Mytilus edulis species complex. Naturally occurring and introduced populations of M. galloprovincialis are widely distributed throughout many regions of the globe. Mytilus galloprovincialis includes morphologically indistinguishable Northern and Southern hemisphere mtDNA lineages that have been separated for ∼1 my. To distinguish recently introduced Northern M. galloprovincialis from resident Southern M. galloprovincialis in New Zealand, we developed a 16s rRNA RFLP assay. We compared RFLP assignments of 178 mussels with those generated from a 16s rRNA sequence‐estimated phylogeny. All mussels were correctly assigned by the RFLP to their sequence‐based phylogenetic placement. This assay allows the rapid identification of Northern and Southern hemisphere M. galloprovincialis and will provide an important tool for monitoring human mediated introductions of otherwise cryptic lineages.
A program to compare genetic differentiation statistics across loci using resampling of individuals and loci
Authors: NEFF BRYAN D. , FRASER BONNIE A.
Published: October 2009

Comparisons of genetic differentiation across populations based on different loci can provide insight into the evolutionary patterns acting on various regions of genomes. Here, we develop a program to statistically compare population genetic differentiation statistics (FST or G′ST) calculated from different loci. The program employs a routine that resamples either or both of individuals and loci and calculates a bootstrap confidence interval in the statistics. Resampling individuals is important when fewer than 25 individuals are sampled per population and when confidence intervals are required for individual loci. Resampling loci provides confidence intervals for sets of loci, such as a set presumed to be neutral, but can be anticonservative if fewer than 20 loci are analysed. We demonstrate the program using previously published data on the genetic differentiation at a major histocompatibility complex locus and at microsatellite loci across 10 populations of the guppy (Poecilia reticulata).