bluuebunny/crossref_metadata_2025 huggingface dataset:
Palace Intrigue: Missiles, Treason, and the Rule of Law in Bolivia
Authors: Carey John M.
Published: May 2009

The Bolivian presidency is a precarious position, not only because so many presidents have left office under duress, but because former presidents are subject to legal jeopardy. The case of Eduardo Rodríguez Veltzé illustrates the weakness of the rule of law in Bolivia and the political motivations that sustain it. Rodríguez was a respected Chief Justice of Bolivia's Supreme Court. He reluctantly assumed the presidency during a political crisis and shepherded the country through peaceful elections in 2005 that brought Evo Morales to the presidency. He was subsequently charged with treason in a case that involved the transfer from the Bolivian military to the United States of some obsolete surface-to-air missiles. The Rodríguez case was politically important enough to be useful for the Morales Government, but only briefly, and the moment passed. Now, the case's obscurity and the fecklessness of the Bolivian courts have left Rodríguez in legal and professional limbo. Full disclosure from the U.S. government regarding its involvement in the missiles case might clear Rodríguez's name.
Response to Shane Hamilton's review of From the New Deal to the New Right: Race and the Southern Origins of Modern Conservatism
Authors: Lowndes Joseph E.
Published: May 2009

Let me first thank Jeffrey Isaac for choosing our books for this exchange, and Shane Hamilton for his review. I would like to draw on Hamilton's main criticisms to consider political change in two ways: first, as it relates to political actors; and second, to political orders.
Response to Jackie Smith's review of Beyond Citizenship American Identity After Globalization
Authors: Spiro Peter
Published: May 2009

My thanks to Jackie Smith for her thoughtful observations on Beyond Citizenship. My only point of disagreement goes to the nature of a world that, if not truly postnational, has witnessed the dramatic rise of nonstate forms of association. On the one hand, the ability of individuals to more fully actuate identities not anchored in the state advances autonomy values. On the other hand, these nonstate forms of association should not be romanticized. They, too, will implicate exclusion and conflict.
State Failure and Challenges to Democratization in Africa
Authors: Bratton Michael
Published: May 2009

This lean volume digs into the roots of African politics by exploring the foundations of political order. The author sees state formation as originating in rulers' political decisions about how to extract wealth from society. Specifically, do they use coercion—the defining attribute of state power—to protect their subjects or to prey on them? If rulers—whom he characterizes as “specialists in violence”—calculate that their own political and economic interests are best served by taxing production, they will establish the infrastructure of a bureaucratic state. If, however, they conclude that the costs of providing protection to society's producers outweigh the expected benefits, then they will be tempted to turn the state apparatus into an instrument of predation.
Regulation as the art of intuitive judgment: a critique of the economic approach to environmental regulation
Authors: Perez Oren
Published: May 2009

This article develops a general critique of the economic approach to environmental regulation, drawing on the insights of systems theory. It highlights, first, the problematic of subjugating the regulatory system to a single purpose – which in the context of environmental economics is interpreted as the utilitarian maximization of collective welfare. Second, it questions the teleological pretence of the regulatory project as it is configured in the economic literature. It highlights in this context the problem of trans-systemic incompatibilities, which impede the incorporation of economic ideas into the systems of law and politics. Environmental economics in both its normative and sociopolitical strands, fails to provide a convincing response to this dilemma. The article discusses two examples of the reconstruction of economic ideas within the legal and political domains, drawing on the EU and US regulatory experience. This twofold critique of the economic approach can be extended, it is argued, to every regulatory project with far-reaching teleological ambitions. The article applies this critique to some alternative regulatory visions, such as self-regulation, reflexive law and responsive regulation, noting in this context the limitations of systems theory itself. It concludes with a discussion of the role of intuition in regulatory decision-making.
Migration and access to health care in English medical law: a rhetorical critique
Authors: Harrington John
Published: May 2009

This paper develops a rhetorical critique of recent cases on migration and access to health care in Britain. It argues that the national territory, once a taken-for-granted starting point for reasoning in medical law, has lost its common-sense status as a result of neoliberal globalisation. This is evident in recent decisions involving on the one hand HIV-positive asylum seekers coming to the UK and on the other hand British ‘health tourists’ seeking funding for treatment elsewhere in the European Union. Courts are aware that many of these cases are likely to call forth the sympathy of audiences for the individual concerned, further undermining their privileging of the national scale. In curbing this ‘politics of pity’ they adopt a range of persuasive strategies.
Culture, power and the human animal: a reply
Authors: Cotterrell Roger
Published: May 2009

I am very grateful to Naomi Mezey, John Mikhail and Robin West for their thought-provoking comments on my paper. Since each of the comments has a different orientation, this reply will address them in turn, but picking up especially one theme – the place (or absence) of power in my picture of law’s engagement with multiculturalism – that recurs in all of them.
Opportunity trajectory reconstruction techniques for evaluation of ATC systems
Authors: Garcia Jesus , Besada Juan A. , Soto Andres , de Miguel Gonzalo
Published: May 2009

This paper describes some key points of a new tool being currently developed by Eurocontrol for the assessment of air traffic control (ATC) multisensor trackers performance. It summarizes the algorithmic foundations of the high-accuracy trajectory reconstruction process used to obtain reference trajectories from recorded measures. These trajectories will serve as a reference for the evaluation of the accuracy of ATC data processing centers. The performance of the system is illustrated with some reconstruction experiments on synthetic and real data.
Aleatoric and epistemic uncertainty in groundwater flow and transport simulation
Authors: Ross James L. , Ozbek Metin M. , Pinder George F.
Published: May 2009

The characterization of aleatory hydrogeological parameter uncertainty has traditionally been accomplished using probability theory. However, when consideration is given to epistemic as well as aleatory uncertainty, probability theory is not necessarily appropriate. This is especially the case where expert opinion is regarded as a suitable source of information. When experts opine upon the uncertainty of a parameter value, both aleatoric and epistemic uncertainties are introduced and must be modeled appropriately. A novel approach to expert‐provided parameter uncertainty characterization can be defined that bridges an historical gap between probability theory and fuzzy set theory. Herein, a random set, a generalization of a random variable is employed to formalize expert knowledge, and fuzzy sets are used to propagate this uncertainty to model estimates of contaminant transport. The resultant random set‐based concentration estimates are shown to be more general than the corresponding random variable estimates. In some cases, the random set‐based results are shown as upper and lower probabilities that bound the corresponding random variable's cumulative distribution function.
Dynasore inhibits removal of wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) from the plasma membrane
Authors: Young Andrew , Gentzsch Martina , Abban Cynthia Y. , Jia Ying , Meneses Patricio I. , Bridges Robert J. , Bradbury Neil A.
Published: May 2009

Dynasore, a small molecule inhibitor of dynamin, was used to probe the role of dynamin in the endocytosis of wild-type and mutant CFTR (cystic fibrosis transmembrane conductance regulator). Internalization of both wild-type and ‘temperature-corrected’ ΔF508 CFTR was markedly inhibited by a short exposure to dynasore, implicating dynamin as a key element in the endocytic internalization of both wild-type and mutant CFTR. The inhibitory effect of dynasore was readily reversible upon washout of dynasore from the growth media. Corr-4 ({2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]-bithiazolyl-2′-yl}-phenyl-methanonone), a pharmacological corrector of ΔF508 CFTR biosynthesis, caused a marked increase in the cell surface expression of mutant CFTR. Co-incubation of ΔF508 CFTR expressing cells with Corr-4 and dynasore caused a significantly greater level of cell surface CFTR than that observed in the presence of Corr-4 alone. These results argue that inhibiting the endocytic internalization of mutant CFTR provides a novel therapeutic target for augmenting the benefits of small molecule correctors of mutant CFTR biosynthesis.
Automated high-dimensional flow cytometric data analysis
Authors: Pyne Saumyadipta , Hu Xinli , Wang Kui , Rossin Elizabeth , Lin Tsung-I , Maier Lisa M. , Baecher-Allan Clare , McLachlan Geoffrey J. , Tamayo Pablo , Hafler David A. , De Jager Philip L. , Mesirov Jill P.
Published: May 2009

Flow cytometric analysis allows rapid single cell interrogation of surface and intracellular determinants by measuring fluorescence intensity of fluorophore-conjugated reagents. The availability of new platforms, allowing detection of increasing numbers of cell surface markers, has challenged the traditional technique of identifying cell populations by manual gating and resulted in a growing need for the development of automated, high-dimensional analytical methods. We present a direct multivariate finite mixture modeling approach, using skew and heavy-tailed distributions, to address the complexities of flow cytometric analysis and to deal with high-dimensional cytometric data without the need for projection or transformation. We demonstrate its ability to detect rare populations, to model robustly in the presence of outliers and skew, and to perform the critical task of matching cell populations across samples that enables downstream analysis. This advance will facilitate the application of flow cytometry to new, complex biological and clinical problems.
V-region mutation in vitro, in vivo, and in silico reveal the importance of the enzymatic properties of AID and the sequence environment
Authors: MacCarthy Thomas , Kalis Susan L. , Roa Sergio , Pham Phuong , Goodman Myron F. , Scharff Matthew D. , Bergman Aviv
Published: May 2009

The somatic hypermutation of Ig variable regions requires the activity of activation-induced cytidine deaminase (AID) which has previously been shown to preferentially deaminate WRC (W = A/T, R = A/G) motif hot spots in in vivo and in vitro assays. We compared mutation profiles of in vitro assays for the 3′ flanking intron of VhJ558-Jh4 region to previously reported in vivo profiles for the same region in the
Msh2
−/−
Ung
−/−
mice that lack base excision and mismatch repair. We found that the in vitro and in vivo mutation profiles were highly correlated for the top (nontranscribed) strand, while for the bottom (transcribed) strand the correlation is far lower. We used an
in silico
model of AID activity to elucidate the relative importance of motif targeting in vivo. We found that the mutation process entails substantial complexity beyond motif targeting, a large part of which is captured in vitro. To elucidate the contribution of the sequence environment to the observed differences between the top and bottom strands, we analyzed intermutational distances. The bottom strand shows an approximately exponential distribution of distances in vivo and in vitro, as expected from a null model. However, the top strand deviates strongly from this distribution in that mutations approximately 50 nucleotides apart are greatly reduced, again both in vivo and in vitro, illustrating an important strand asymmetry. While we have confirmed that AID targeting of hot and cold spots is a key part of the mutation process, our results suggest that the sequence environment plays an equally important role.
Specific targeting of breast tumor by octreotide-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 3.0-tesla magnetic resonance scanner
Authors: Li Xubin , Du Xiangke , Huo Tianlong , Liu Xia , Zhang Sen , Yuan Fei
Published: May 2009

Background: Targeted magnetic resonance contrast agents have enabled the imaging of biological processes in vivo, and current insights have opened up new perspectives for the monitoring and diagnosis of many diseases.

Purpose: To develop a contrast agent for targeting somatostatin receptors (SSTRs) expressed on breast cancer cells, and to evaluate the detection capabilities of a molecular probe using magnetic resonance (MR) imaging in an in vivo mouse model of breast carcinoma.

Material and Methods: Octreotide (OCT) was conjugated with polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles by an ethyl-3-(dimethylaminopropyl) carbodiimide (EDC)-mediated reaction. Prussian blue staining for intracellular iron, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and cellular MR imaging in vitro were performed on labeled MCF-7 breast cancer cells. Twenty-four mice bearing tumors were divided into two groups: 1) study group with injection of OCT-USPIOs ( n=12); 2) control group with injection of USPIOs ( n=12). Tumors were monitored in vivo using a 3.0-Tesla MR scanner before and after injection of contrast agents, and the findings were correlated with the histopathological findings.

Results: OCT-USPIOs were shown to specifically bind to MCF-7 cells and did not affect proliferation and viability of the cells labeled. T2 value of the cells labeled with OCT-USPIOs in vitro was 56.465±13.147 ms, while those of the cells cultured with USPIOs and gelatin/phosphate-buffered saline (PBS) gel alone were 75.435±16.171 ms and 85.950±22.352 ms, respectively ( P<0.05). Signal intensity of the tumor gradually decreased, and its T2 value reached a minimum of approximately 24.49% 6 hours after injection of OCT-USPIOs in vivo, compared to a minimum of 21.89% after 2 hours in the control group. Iron depositions were visualized as blue particles in tumor 6 hours after injection of OCT-USPIOs, while no blue particles were observed in the control group.

Conclusion: SSTR expression in vitro and in vivo can be selectively and directly imaged with an MR molecular probe. OCT-conjugated PEG-coated USPIO is potentially suitable to be used as a magnetic resonance contrast agent for MR imaging in vivo and increases the sensitivity for the early detection of breast carcinoma.
Risk factors and clinical course of portal and/or splenic vein thrombosis after partial splenic embolization
Authors: Matsumoto Tomohiro , Yamagami Takuji , Terayama Koshi , Kato Takeharu , Hirota Tatsuya , Yoshimatsu Rika , Miura Hiroshi , Ito Hirotoshi , Okanoue Takeshi , Nishimura Tsunehiko
Published: May 2009

Background: Although portal and/or splenic vein thrombosis after partial splenic embolization (PSE) is a well-known complication, few reports evaluating risk factors have been published.

Purpose: To investigate risk factors and clinical course of portal and/or splenic vein thrombosis after PSE.

Material and Methods: Sixteen patients with severe hypersplenism underwent PSE between March 2005 and April 2008. The correlation between portal and/or splenic vein thrombosis after PSE detected on multidetector row CT (MDCT) and various factors were retrospectively reviewed. Further, the clinical course of portal and/or splenic vein thrombosis after PSE was observed on follow-up MDCT.

Results: Splenic vein thrombosis was detected in eight patients (50%) on MDCT images taken within 9 days after PSE. In one, the thrombosis also involved the portal vein. The infarct volume was identified as a significant risk factor for portal and/or splenic vein thrombosis ( P=0.046). In all but one patient, splenic vein thrombosis resolved completely or improved without anticoagulation therapy. In this patient, both portal and splenic vein thrombosis developed after PSE, and anticoagulation therapy was necessary.

Conclusion: It is suggested that a large splenic infarct volume is a risk factor for portal and/or splenic vein thrombosis after PSE. Indications for treatment of thrombosis of the portal vein system after PSE may be limited to patients with portal vein thrombosis.
Signal intensity of myocardial scars at delayed-enhanced mri
Authors: Themudo Raquel Espregueira , Johansson Lars , Ebeling-Barbier Charlotte , Lind Lars , Ahlström Håkan , Bjerner Tomas
Published: May 2009

Background: Traditionally, unrecognized myocardial infarction (UMI) is defined as the appearance, in a non-acute setting, of a new diagnostic Q wave. In the recent past, delayed-enhanced magnetic resonance imaging (DE-MRI) has provided a new imaging method for evaluating myocardial viability and to detect myocardial scars.

Purpose: To investigate differences in tissue characteristics between UMI and recognized myocardial infarction (RMI) scars, by assessing the signal intensity (SI) detected by DE-MRI.

Material and Methods: A randomized subgroup of 259 subjects from the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) study was submitted to cardiac magnetic resonance imaging (MRI). DE-MRI-detected myocardial scars were divided in two groups, UMI and RMI, according to the hospital medical records. The scars detected by DE-MRI were analyzed by measuring SI ratio of scar tissue to normal myocardium.

Results: The mean SI ratio in the UMI group (4.5±3.0, mean±SD) was lower than in the RMI group 8.9±5.1 ( P-value = 0.001). This difference was still significant ( P<0.0001) after adjustment for gender, body mass index, time of image acquisition after gadolinium administration, scar transmurality, or total myocardial infarction mass.

Conclusion: The difference in the SI ratio of the scars between the two groups most likely reflects a different contrast distribution volume of the tissues, which might indicate that UMI and RMI tissues diverge in tissue composition.
Anterior dynamic ultrasound of the infant hip: evaluation of investigator dependence
Authors: Kaijser Magnus , Larsson Jonas , Rosenberg Lena , Josephson Thomas
Published: May 2009

Background: Anterior dynamic ultrasound of the infant hip has been shown to be a valuable tool for detection of developmental dysplasia of the infant hip, but to what extent the results from this method depends on the investigator is unknown.

Purpose: To study to what extent the proportion of positive findings at anterior dynamic ultrasound investigation of infant hips varies with the observer.

Material and Methods: Information on all ultrasound investigations of infant hips at a county hospital between January 2004 and August 2007 was evaluated. Proportion of findings for different investigators were calculated and in a multivariable logistic regression analysis, risk of treatment by investigating orthopedic surgeon and radiologist were adjusted for each other as well as for calendar period and infant sex.

Results: There was a striking variation in proportion of positive findings depending on the investigator. The proportion of infants treated varied with orthopedic surgeon from 4.2 to 53.9% (95% CI: 2.27 to 7.13 and 43.0 to 64.6, respectively) and the corresponding variation for radiologists ranged from 7.4 (95% CI: 4.29 to 11.8) to 23.9% (95% CI: 17.2 to 31.8). In the adjusted analysis, variation between different investigators remained essentially unaltered.

Conclusion: Although the true proportions of positive findings in our study are unknown, our findings are unlikely to be explained by selection bias or chance. Thus, our study suggests that anterior dynamic ultrasound of the infant hip is highly dependent on the investigator and further studies of the implications of our results are warranted.
The Role of theCucumber mosaic virus2b Protein in Viral Movement and Symptom Induction
Authors: Lewsey Mathew , Surette Monique , Robertson Fiona C. , Ziebell Heiko , Choi Sun Hee , Ryu Ki Hyun , Canto Tomas , Palukaitis Peter , Payne Tina , Walsh John A. , Carr John P.
Published: May 2009

The Cucumber mosaic virus (CMV) 2b protein is a counter-defense factor and symptom determinant. Conserved domains in the 2b protein sequence were mutated in the 2b gene of strain Fny-CMV. The effects of these mutations were assessed by infection of Nicotiana tabacum, N. benthamiana, and Arabidopsis thaliana (ecotype Col-0) with mutant viruses and by expression of mutant 2b transgenes in A. thaliana. We confirmed that two nuclear localization signals were required for symptom induction and found that the N-terminal domain was essential for symptom induction. The C-terminal domain and two serine residues within a putative phosphorylation domain modulated symptom severity. Further infection studies were conducted using Fny-CMVΔ2b, a mutant that cannot express the 2b protein and that induces no symptoms in N. tabacum, N. benthamiana, or A. thaliana ecotype Col-0. Surprisingly, in plants of A. thaliana ecotype C24, Fny-CMVΔ2b induced severe symptoms similar to those induced by the wild-type virus. However, C24 plants infected with the mutant virus recovered from disease while those infected with the wild-type virus did not. Expression of 2b transgenes from either Fny-CMV or from LS-CMV (a mild strain) in Col-0 plants enhanced systemic movement of Fny-CMVΔ2b and permitted symptom induction by Fny-CMVΔ2b. Taken together, the results indicate that the 2b protein itself is an important symptom determinant in certain hosts. However, they also suggest that the protein may somehow synergize symptom induction by other CMV-encoded factors.
The N-terminal Region of thePlantago asiatica mosaic virusCoat Protein Is Required for Cell-to-Cell Movement but Is Dispensable for Virion Assembly
Authors: Ozeki Johji , Hashimoto Masayoshi , Komatsu Ken , Maejima Kensaku , Himeno Misako , Senshu Hiroko , Kawanishi Takeshi , Kagiwada Satoshi , Yamaji Yasuyuki , Namba Shigetou
Published: May 2009

Potexvirus cell-to-cell movement requires coat protein (CP) and movement proteins. In this study, mutations in two conserved in-frame AUG codons in the 5′ region of the CP open reading frame of Plantago asiatica mosaic virus (PlAMV) were introduced, and virus accumulation of these mutants was analyzed in inoculated and upper noninoculated leaves. When CP was translated only from the second AUG codon, virus accumulation in inoculated leaves was lower than that of wild-type PlAMV, and the viral spread was impaired. Trans-complementation analysis showed that the leucine residue at the third position (Leu-3) of CP is important for cell-to-cell movement of PlAMV. The 14-amino-acid N-terminal region of CP was dispensable for virion formation. Immunoprecipitation assays conducted with an anti-TGBp1 antibody indicated that PlAMV CP interacts with TGBp1 in vivo and that this interaction is not affected by alanine substitution at Leu-3. These results support the concept that the N-terminal region of potexvirus CP can be separated into two distinct functional domains.
Interaction with a Host Ubiquitin-Conjugating Enzyme Is Required for the Pathogenicity of a Geminiviral DNA β Satellite
Authors: Eini Omid , Dogra Satish , Selth Luke A. , Dry Ian B. , Randles John W. , Rezaian M. Ali
Published: May 2009

DNA β is a single-stranded satellite DNA which encodes a single gene, βC1. To better understand the role of βC1 in the pathogenicity of DNA β, a yeast two-hybrid screen of a tomato cDNA library was carried out using βC1 from Cotton leaf curl Multan virus (CLCuMV) DNA β as the bait. A ubiquitin-conjugating enzyme, designated SlUBC3, which functionally complemented a yeast mutant deficient in ubiquitin-conjugating enzymes was identified. The authenticity and specificity of the interaction between βC1 and SlUBC3 was confirmed both in vivo, using a bimolecular fluorescence complementation assay, and in vitro, using a protein-binding assay. Analysis of deletion mutants of the βC1 protein showed that a myristoylation-like motif is required both for its interaction with SlUBC3 and the induction of DNA-β-specific symptoms in host plants. The level of polyubiquitinated proteins in transgenic tobacco plants expressing βC1 was found to be reduced compared with wild-type plants. These results are consistent with the hypothesis that interaction of βC1 with SlUBC3 is required for DNA-β-specific symptom induction, and that this is possibly due to downregulation of the host ubiquitin proteasome pathway.
MS-qFRET: A quantum dot-based method for analysis of DNA methylation
Authors: Bailey Vasudev J. , Easwaran Hariharan , Zhang Yi , Griffiths Elizabeth , Belinsky Steven A. , Herman James G. , Baylin Stephen B. , Carraway Hetty E. , Wang Tza-Huei
Published: May 2009

DNA methylation contributes to carcinogenesis by silencing key tumor suppressor genes. Here we report an ultrasensitive and reliable nanotechnology assay, MS-qFRET, for detection and quantification of DNA methylation. Bisulfite-modified DNA is subjected to PCR amplification with primers that would differentiate between methylated and unmethylated DNA. Quantum dots are then used to capture PCR amplicons and determine the methylation status via fluorescence resonance energy transfer (FRET). Key features of MS-qFRET include its low intrinsic background noise, high resolution, and high sensitivity. This approach detects as little as 15 pg of methylated DNA in the presence of a 10,000-fold excess of unmethylated alleles, enables reduced use of PCR (as low as eight cycles), and allows for multiplexed analyses. The high sensitivity of MS-qFRET enables one-step detection of methylation at PYCARD, CDKN2B, and CDKN2A genes in patient sputum samples that contain low concentrations of methylated DNA, which normally would require a nested PCR approach. The direct application of MS-qFRET on clinical samples offers great promise for its translational use in early cancer diagnosis, prognostic assessment of tumor behavior, as well as monitoring response to therapeutic agents.
Cytochrome b sequences of ancient cattle and wild ox support phylogenetic complexity in the ancient and modern bovine populations
Authors: Stock F. , Edwards C. J. , Bollongino R. , Finlay E. K. , Burger J. , Bradley D. G.
Published: May 2009

Mitochondrial DNA has been the traditional marker for the study of animal domestication, as its high mutation rate allows for the accumulation of molecular diversity within the time frame of domestic history. Additionally, it is exclusively maternally inherited and haplotypes become part of the domestic gene pool via actual capture of a female animal rather than by interbreeding with wild populations. Initial studies of British aurochs identified a haplogroup, designated P, which was found to be highly divergent from all known domestic haplotypes over the most variable portion of the D‐loop. Additional analysis of a large and geographically representative sample of aurochs from northern and central Europe found an additional, separate aurochs haplotype, E. Until recently, the European aurochs appeared to have no matrilinear descendants among the publicly available modern cattle control regions sequenced; if aurochs mtDNA was incorporated into the domestic population, aurochs either formed a very small proportion of modern diversity or had been subsequently lost. However, a haplogroup P sequence has recently been found in a modern sample, along with a new divergent haplogroup called Q. Here we confirm the outlying status of the novel Q and E haplogroups and the modern P haplogroup sequence as a descendent of European aurochs, by retrieval and analysis of cytochrome b sequence data from twenty ancient wild and domesticated cattle archaeological samples.
Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review
Authors: Staahl Camilla , Olesen Anne Estrup , Andresen Trine , Arendt‐Nielsen Lars , Drewes Asbjørn Mohr
Published: May 2009

AIM

Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed.

METHOD

A literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids.

RESULTS

Opioids with a strong affinity for the µ‐opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non‐painful sensations. The effects of opioids with weaker affinity for the µ‐opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive.

CONCLUSION

The way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials.
Assessment of QTc‐prolonging potential of BX471 in healthy volunteers. A ‘thorough QTc study’ following ICH E14 using various QT correction methods
Authors: Vandemeulebroecke Marc , Lembcke Jürgen , Wiesinger Herbert , Sittner Wolfgang , Lindemann Stefanie
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• A prolongation of the QT interval in the ECG is a sign of delayed cardiac repolarization, a condition that increases the risk of potentially fatal arrhythmias.

• Since the QT interval depends on heart rate, some correction is indicated to obtain a less heart rate dependent ‘QTc interval’.

• Building on the recently issued ICH E14 guideline, the most appropriate methods to evaluate the QT/QTc prolonging potential of novel drugs are yet to be found.

WHAT THIS STUDY ADDS

• This study gives a detailed account of different analysis strategies and QT correction methods consistent with ICH E14.

• Regression‐based QT correction methods, applied to average intervals of each ECG recording, yielded results comparable with those obtained by Fridericia's formula; using one representative of such methods may be sufficient in practice.

• BX471 does not cause meaningful QTc prolongation.

AIMS

Within the framework of the clinical development of BX471, this study was intended to provide experience in conducting ‘thorough QTc studies’ according to ICH E14. A broad range of QT correction methods and analysis strategies was employed.

METHODS

A double‐blind, placebo‐ and positive‐controlled, single‐centre, three‐way cross‐over study was conducted in 74 healthy volunteers. Electrocardiograms were read by blinded experts. QT correction methods included Bazett's (QTcB), Fridericia's (QTcF) and several regression‐based corrections.

RESULTS

There was a significant QTcF prolongation of 10.26 ms by the positive control compared with placebo [95% confidence interval (7.83, 12.70)]. BX471 at therapeutic doses did not cause substantial QTc prolongation [QTcF estimate 2.93 ms, 95% confidence interval (1.00, 4.86); QTcB estimate 3.30 ms, 95% confidence interval (0.85, 5.74)]. Regression‐based QT correction methods yielded similar results to Fridericia's correction [e.g. using a linear regression across the study population, QTc estimate 2.39 ms, 95% confidence interval (0.55, 4.23)]. Differences between the various regression‐based correction methods were small. Results were not affected by whether the QT corrections were performed per ECG or per beat.

CONCLUSIONS

BX471 does not cause meaningful QTc prolongation. Three QT correction methods may be sufficient in future studies: Bazett's (required by regulatory authorities), Fridericia's (as the most reliable fixed formula) and a regression‐based correction (individually or population‐based), each performed per ECG (i.e. applied to the means of several beats of one ECG recording).
Ex vivo expanded cord blood CD4 T lymphocytes exhibit a distinct expression profile of cytokine‐related genes from those of peripheral blood origin
Authors: Miyagawa Yoshitaka , Kiyokawa Nobutaka , Ochiai Nakaba , Imadome Ken‐Ichi , Horiuchi Yasuomi , Onda Keiko , Yajima Misako , Nakamura Hiroyuki , Katagiri Yohko U. , Okita Hajime , Morio Tomohiro , Shimizu Norio , Fujimoto Junichiro , Fujiwara Shigeyoshi
Published: May 2009

With an increase in the importance of umbilical cord blood (CB) as an alternative source of haematopoietic progenitors for allogenic transplantation, donor lymphocyte infusion (DLI) with donor CB‐derived activated CD4+ T cells in the unrelated CB transplantation setting is expected to be of increased usefulness as a direct approach for improving post‐transplant immune function. To clarify the characteristics of activated CD4+ T cells derived from CB, we investigated their mRNA expression profiles and compared them with those of peripheral blood (PB)‐derived activated CD4+ T cells. Based on the results of a DNA microarray analysis and quantitative real‐time reverse transcriptase–polymerase chain reaction (RT‐PCR), a relatively high level of forkhead box protein 3 (Foxp3) gene expression and a relatively low level of interleukin (IL)‐17 gene expression were revealed to be significant features of the gene expression profile of CB‐derived activated CD4+ T cells. Flow cytometric analysis further revealed protein expression of Foxp3 in a portion of CB‐derived activated CD4+ T cells. The low level of retinoic acid receptor‐related orphan receptor γ isoform t (RORγt) gene expression in CB‐derived activated CD4+ T cells was speculated to be responsible for the low level of IL‐17 gene expression. Our data indicate a difference in gene expression between CD4+ T cells from CB and those from PB. The findings of Foxp3 expression, a characteristic of regulatory T cells, and a low level of IL‐17 gene expression suggest that CB‐derived CD4+ T cells may be a more appropriate source for DLI.
Comparing senior executive and project manager perceptions of IT project risk: a Chinese Delphi study
Authors: Liu Shan , Zhang Jinlong , Keil Mark , Chen Tao
Published: May 2009

The success rate for information technology (IT) projects continues to be low. With an increasing number of IT projects in developing countries such as China, it is important to understand the risks they are experiencing on IT projects. To date, there has been little research documenting Asian perceptions of IT project risk. In this research, we examine the risks identified by Chinese senior executives (SEs) and project managers (PMs), and compare these two groups. The importance of top management support in IT projects is well documented. Prior research has shown that from the perspective of IT PMs, lack of support from SEs is the number one risk in IT projects. Surprisingly, senior executives' perceptions towards IT project risk have never been systematically examined. One reason why lack of support from senior executives continues to represent a major risk may be that senior executives themselves do not realize the critical role that they can play in helping to deliver successful projects. In this study, we use the Delphi method to compare the risk perceptions of senior executives and project managers. By comparing risk factors selected by each group, zones of concordance and discordance are identified. In terms of perceived importance ascribed to risk factors, PMs tend to focus on lower‐level risks with particular emphasis on risks associated with requirements and user involvement, whereas SEs tend to focus on higher‐level risks such as those risks involving politics, organization structure, process, and culture. Finally, approaches for dealing with risk factors that are seen as important by both SEs and PMs are provided.
A lepidopteran orthologue of reaper reveals functional conservation and evolution of IAP antagonists
Authors: Bryant B. , Zhang Y. , Zhang C. , Santos C. P. , Clem R. J. , Zhou L.
Published: May 2009

Genetic studies in Drosophila melanogaster have revealed that inhibitor of apoptosis (IAP) proteins and IAP antagonists such as reaper play a pivotal role in controlling cell death in insects. Interestingly, although the sequences and structures of IAPs are highly conserved, the sequence of IAP antagonists diverged very rapidly during evolution, making their identification difficult. Using a customized bioinformatics approach, we identified an IAP antagonist, IAP‐binding motif 1 (Ibm1), from the genome of the silkworm Bombyx mori. This is the first reaper/grim orthologue identified in a nondipteran insect. Previous analysis indicated that both Reaper and Grim induce cell death through their N‐terminal IBM as well as the Grim_helix3 (GH3) domain. Functional studies indicated that Ibm1 binds to an IAP protein from B. mori, BmIAP1, and induces apoptosis in insect cells via the IAP‐binding motif, a seven amino acid sequence that is highly conserved in all IAP antagonists. Interestingly, Ibm1 also contains a region that is a statistically significant match to the GH3 domain. Mutational analysis indicated that the GH3‐like motif in Ibm1 has an important supportive role in IAP‐antagonist function and can trigger cell death under certain conditions.
Cloning and characterization of a pyridoxine 5′‐phosphate oxidase from silkworm, Bombyx mori
Authors: Huang S‐H. , Shi R‐J. , Zhang J‐Y. , Wang Z. , Huang L‐Q.
Published: May 2009

A cDNA encoding Pyridoxine 5′‐phosphate oxidase (PNPO) from Bombyx mori was cloned and characterized (GenBank accession number: DQ452398). The cDNA encodes a polypeptide of 257 amino acid residues. The recombinant enzyme purified from Escherichia coli exhibited maximal activity at pH 9.0, and the Km values for the substrates of pyridoxine 5′‐phosphate and pyridoxamine 5′‐phosphate were determined as 0.65 and 1.15 µmol/l. It was found that B. mori PNPO shares 51.44% homology with humans, but several function‐related, key amino acid residues in B. mori PNPO are different from the human and E. Coli gene. B. mori has a single copy of the PNPO gene, which spans a 3.5 kb region and contains five exons and four introns. B. mori PNPO is a homodimer, with each monomer containing nine antiparallel β‐strands and five α‐helical segments. The secondary structure was deduced from computational study.
Electrophysiological characterization of electrolyte and nutrient transport across the small intestine in horses
Authors: Cehak A. , Burmester M. , Geburek F. , Feige K. , Breves G.
Published: May 2009

The aim of this study was to characterize the transport mechanisms of electrolytes and nutrients across the jejunum of nine healthy horses electrophysiologically. The stripped mucosa was mounted in Ussing chambers and tissue conductances (Gt) and short circuit currents (Isc) were continuously monitored. After blocking the sodium and potassium channels with amiloride, tetraethylammonium chloride (TEA) and barium, chloride secretion was stimulated by carbachol and forskolin. Subsequently, chloride channels were inhibited by 4,4′‐diisothiocyanato‐stilbene‐2,2′‐disulfonic acid, 5‐nitro‐2‐(3‐phenylpropylamino)benzoic acid, CFTRinh‐172, N‐(2‐naphtalenyl)‐(3.5‐dibromo‐2.4‐dihydroxyphenyl)methylene glycine hydrazide (GlyH‐101) and glibenclamide and their dose–response effect was investigated. The response to glucose, l‐alanine and glycyl‐l‐glutamine was determined at two different mucosal pH values (pH 7.4 and 5.4 respectively). Mean basal Isc was −0.47 ± 0.31 μEq/cm2h and mean Gt was 22.17 ± 1.78 mS/cm2. Amiloride and TEA did not alter the baseline Isc. Barium, carbachol and forskolin significantly increased Isc. Irrespective of the dose, none of the chloride inhibitors changed Isc. All nutrients induced a significant increase in Isc with the increase being significantly higher at pH 7.4 than at pH 5.4. In conclusion, there is evidence that chloride secretion in horses may be different from respective transport mechanisms in other species. The glucose absorption is suggestive of a sodium‐dependent glucose cotransporter 1. However, a decrease in luminal pH did not stimulate current response to peptides as shown for other mammals.
BEAUTY IN THE LIVING WORLD
Authors: Garcia‐Rivera Alejandro , Graves Mark , Neumann Carl
Published: May 2009

Almost all admit that there is beauty in the natural world. Many suspect that such beauty is more than an adornment of nature. Few in our contemporary world suggest that this beauty is an empirical principle of the natural world itself and instead relegate beauty to the eye and mind of the beholder. Guided by theological and scientific insight, the authors propose that such exclusion is no longer tenable, at least in the data of modern biology and in our view of the natural world in general. More important, we believe an empirical aesthetics exists that can help guide experimental design and development of computational models in biology. Moreover, because theology and science can both contribute toward and equally profit from such an aesthetics, we propose that this empirical aesthetics provides the foundation for a living synergy between theology and science.
THE MAGICIAN IN THE WORLD: BECOMING, CREATIVITY, AND TRANSVERSAL COMMUNICATION
Authors: Semetsky Inna
Published: May 2009

This essay interprets the meaning of one of the cards in aTarot deck, “The Magician,” in the context of process philosophy in the tradition of Alfred North Whitehead. It brings into the conversation the philosophical legacy of American semiotician Charles Sanders Peirce as well as French poststructuralist Gilles Deleuze. Some of their conceptualizations are explored herein for the purpose of explaining the symbolic function of the Magician in the world. From the perspective of the logic of explanation, the sign of the Magician is an index of nonmechanistic, mutualist or circular, causality that enables self‐organization embedded in coordination dynamics. Its action is such as to establish an unorthodox connection crossing over the dualistic gap between mind and matter, science and magic, process and structure, the world without and the world within, subject and object, and human experience and the natural world, thereby overcoming what Whitehead called the paradox of the connectedness of things. The Magician represents a certain quality that acts as a catalytic agent capable of eliciting transmutations, that is, the emergence of novelty. I present a model for process∼structure that uses mathematics on the complex plane and the rules of projective geometry. The corollary is such that the presence of the Magician in the world enables a particular organization of thought that makes pre‐cognition possible.
ABUNDANT NATURE'S LONG‐TERM OPENNESS TO HUMANE BIOCULTURAL DESIGNS
Authors: Glassman Robert B.
Published: May 2009

Not by Genes Alone excellently explains Peter J. Richerson and Robert Boyd's important ideas about human gene‐culture co‐evolution to a broader audience but remains short of a larger vision of civilization. Several decades ago Ralph Burhoe had seen that fertile possibility in Richerson and Boyd's work. I suggest getting past present reductionistic customs to a scientific perspective having an integral place for virtue. Subsystem agency is part of this view, as is the driving role of abundance, whose ultimate origins are in the mysterious, quintessentially energetic Big Bang. The free‐rider problem may not impede higher social organization as inexorably as Richerson and Boyd believe; “the tragedy” of enervating leakage from “the commons” may often be less influential than an invigorating flow of externalities to the commons. Eukaryotic origins mark the origin of inevitable wider sharing as higher living systems evolve. I use a metaphor of flesh and spirit in drawing a parallel between that turning point and the wide sharing that occurs in civilization. This helps solve the enigma of the demographic transition. Why do so many productive participants in first‐world societies severely restrict their selfish‐gene reproduction to below replacement birth rate? It is not because culture is maladaptive but because civilization's brain and womb have become partially differentiated in distinct populations. Considerations of social boundaries, myths of sacrifice, and human creativity help in understanding how human social evolution taps potentials present in reality. Human beings' diverse vigorous activities—the organized ones and the inadvertent ones, the wise and the foolish, the good and the bad, the carefully thoughtful and the merely playful—provide the ground of being, or primordial soup, for cultural entities that transcend our intentions. If we have it right for the most part and are fortunate, we will continue to emerge at higher levels.
Toward Farsightedly Stable International Environmental Agreements
Authors: OSMANI DRITAN , TOL RICHARD
Published: May 2009

The stability of International Environmental Agreements (IEA) is analyzed by using game theory. The integrated assessment model FUND provides the cost‐benefit payoff functions of pollution abatement for sixteen different world regions. The farsighted stability concept of Chwe (1994) is used and solved by combinatorial algorithms. Farsighted stability assumes perfect foresight of the players and predicts which coalitions can be formed when players are farsighted. All farsightedly stable coalitions are found, and their improvement to environment and welfare is considerable. The farsightedly stable coalitions are refined further to preferred farsightedly stable coalitions, which are coalitions where the majority of coalition members reach higher profits in comparison with any other farsightedly stable coalitions. Farsightedly stable coalitions contribute more to the improvement of environment and welfare in comparison to D'Aspremont et al.'s (1983) stable ones. Considering multiple farsighted stable coalitions, participation in coalitions for environmental protection is significantly increased, which is an optimistic result of our game theoretical model.
RE‐EXAMINING THE IMPLICATIONS OF THE NEW CONSENSUS: ENDOGENOUS MONEY AND TAYLOR RULES IN A SIMPLE NEOCLASSICAL MACRO MODEL
Authors: Docherty Peter
Published: May 2009

This paper re‐examines the impact of endogenous money in a neoclassical model with interest‐sensitive expenditures. It first outlines a benchmark model with exogenous money and the usual full employment and money growth‐determined inflation results. It then replaces exogenous money with endogenous money, which is shown to generate model indeterminacy. Two methods of resolving this indeterminacy are then explored: money illusion and a Taylor rule for monetary policy, a key feature of new consensus models. The paper concludes that endogenous money has negative implications for the behaviour and interpretation of neoclassical and new consensus models.
Neoliberalism and health care
Authors: McGregor Sue
Published: May 2009

Within the context of globalization, health care reform is occurring around the world. This paper explores the neoliberal mind set shaping health care reform in the UK, Canada, United States, Australia and New Zealand. Neoliberalism is comprised of three principles: individualism, free market via privatization and deregulation, and decentralization. After describing the nature of a health care system that is shaped by those embracing this mind set, an alternative approach is introduced that could bring dignity and a human face to health care. The basic premise of the paper is that we must broaden our analysis of health care by understanding and challenging the neoliberal mind set.