bluuebunny/crossref_metadata_2025 huggingface dataset:
Damage Detection with Parallel Genetic Algorithms and Operational Modes
Authors: Meruane V. , Heylen W.
Published: March 2010

The detection of damage with model-based methods is a constrained nonlinear optimization problem. Conventional optimization approaches usually lead to local minima. Furthermore, they are highly sensitive to experimental noise or numerical errors. Genetic algorithms (GAs) provide an attractive alternative since they can potentially explore the entire solution space and reach the global optimum. However, GAs are inherently slow when they work with complicated or time consuming objective functions. To overcome this problem parallel GAs are proposed, and they are particularly easy to implement and provide a superior numerical performance. In this study, a real-coded parallel GA is implemented to detect structural damage. The objective function is based on operational modal data; it considers the initial errors in the numerical model. False damage detection is avoided by using damage penalization. The algorithm is verified with two experimental cases. First, a test structure of an airplane subjected to three increasing levels of damage. Second, a multiple cracked reinforced concrete beam that is subjected to a nonsymmetrical increasing static load to introduce cracks. In both cases, the detected damage has a good correspondence with the experimental damage.
Estimating Operating Load Conditions on Reinforced Concrete Highway Bridges with b-value Analysis from Acoustic Emission Monitoring
Authors: Schumacher Thomas , Higgins Christopher C. , Lovejoy Steven C.
Published: March 2010

Transportation agencies commonly have conventionally steel reinforced concrete deck girder (RCDG) bridges in their inventory that were built in the mid-twentieth century. These bridges have been in service beyond their intended design lives and tools are needed to permit freight mobility and maintain operational safety. The practical applicability of AE monitoring techniques were investigated to help estimate the condition of diagonally cracked RCDG bridges. Experiments on two full-scale girder specimens representative of Oregon’s RCDG bridges were built and tested under realistic service conditions. Overloading conditions were imposed to increase the level of deterioration. It was found that characterizing the current health condition of a monitored bridge component or element based on short term in service loading is difficult and the proximity of a potential bridge failure not easily predictable until it is impending. However, it was observed that the current operating load level of a bridge component can be estimated using a newly proposed method called minimum b-value analysis. The influence of factors that can affect b-value estimations such as stage of deterioration or external sources was studied and is introduced. The experiment as well as data from the two laboratory specimens are presented and interpreted.
Energy Harvesting and Wireless Energy Transmission for Embedded SHM Sensor Nodes
Authors: Farinholt Kevin M. , Miller Nathan , Sifuentes Wilfredo , MacDonald Jason , Park Gyuhae , Farrar Charles R.
Published: March 2010

In this article, we present experimental investigations using energy harvesting and wireless energy transmission to power wireless structural health monitoring sensor nodes. The goal of this study is to develop sensing systems that can be permanently embedded within a host structure without the need for an on-board power source. With this approach the required energy will be harvested from the ambient environment, or periodically delivered by a radio-frequency energy source to supplement conventional harvesting approaches. This approach combines several transducer types to harvest energy from multiple sources, providing a more robust solution that does not rely on a single energy source. Both piezoelectric and thermoelectric transducers are considered as energy harvesters to extract the ambient energy commonly available on civil structures such as bridges. Methods of increasing the efficiency, energy storage medium, target applications and the integrated use of energy harvesting sources with wireless energy transmission will be presented.
The Forgotten Role of the Global Newsreel Industry in the Long Transition from Text to Television
Authors: Althaus Scott L.
Published: March 2010

Political communication scholars often mark the increasing popularity of electronically broadcast news film as a dividing line between a text-based information culture that survived through World War II and a visually oriented electronic information culture that was in place by the late 1960s.Yet this standard view is incomplete, for it neglects a forgotten but extremely popular worldwide system of visual news reporting based on documentary film shorts. A global system for distributing twice-weekly newsreels was already in place before the First World War, nearly half a century before television news would begin to attract large national audiences and seven decades before CNN would begin distributing news footage once again to all corners of the world. This article aims to reorient political communication scholarship to the historical importance of the newsreel medium and to direct political communication scholars to the rich trove of newsreel film stock that recently became available for analysis.
Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B
Authors: Arruda Valder R. , Stedman Hansell H. , Haurigot Virginia , Buchlis George , Baila Stefano , Favaro Patricia , Chen Yifeng , Franck Helen G. , Zhou Shangzhen , Wright J. Fraser , Couto Linda B. , Jiang Haiyan , Pierce Glenn F. , Bellinger Dwight A. , Mingozzi Federico , Nichols Timothy C. , High Katherine A.
Published: March 2010

Muscle represents an important tissue target for adeno-associated viral (AAV) vector-mediated gene transfer of the factor IX (FIX) gene in hemophilia B (HB) subjects with advanced liver disease. Previous studies of direct intramuscular administration of an AAV-FIX vector in humans showed limited efficacy. Here we adapted an intravascular delivery system of AAV vectors encoding the FIX transgene to skeletal muscle of HB dogs. The procedure, performed under transient immunosuppression (IS), resulted in widespread transduction of muscle and sustained, dose-dependent therapeutic levels of canine FIX transgene up to 10-fold higher than those obtained by intramuscular delivery. Correction of bleeding time correlated clinically with a dramatic reduction of spontaneous bleeding episodes. None of the dogs (n = 14) receiving the AAV vector under transient IS developed inhibitory antibodies to canine FIX; transient inhibitor was detected after vector delivery without IS. The use of AAV serotypes with high tropism for muscle and low susceptibility to anti-AAV2 antibodies allowed for efficient vector administration in naive dogs and in the presence of low- but not high-titer anti-AAV2 antibodies. Collectively, these results demonstrate the feasibility of this approach for treatment of HB and highlight the importance of IS to prevent immune responses to the FIX transgene product.
Alignment and clustering of phylogenetic markers - implications for microbial diversity studies
Authors: White James R , Navlakha Saket , Nagarajan Niranjan , Ghodsi Mohammad-Reza , Kingsford Carl , Pop Mihai
Published: March 2010

Background

Molecular studies of microbial diversity have provided many insights into the bacterial communities inhabiting the human body and the environment. A common first step in such studies is a survey of conserved marker genes (primarily 16S rRNA) to characterize the taxonomic composition and diversity of these communities. To date, however, there exists significant variability in analysis methods employed in these studies.

Results

Here we provide a critical assessment of current analysis methodologies that cluster sequences into operational taxonomic units (OTUs) and demonstrate that small changes in algorithm parameters can lead to significantly varying results. Our analysis provides strong evidence that the species-level diversity estimates produced using common OTU methodologies are inflated due to overly stringent parameter choices. We further describe an example of how semi-supervised clustering can produce OTUs that are more robust to changes in algorithm parameters.

Conclusions

Our results highlight the need for systematic and open evaluation of data analysis methodologies, especially as targeted 16S rRNA diversity studies are increasingly relying on high-throughput sequencing technologies. All data and results from our study are available through the JGI FAMeS website http://fames.jgi-psf.org/.
Genetic diversity, molecular phylogeny and selection evidence of the silkworm mitochondria implicated by complete resequencing of 41 genomes
Authors: Li Dong , Guo Yiran , Shao Haojing , Tellier Laurent C , Wang Jun , Xiang Zhonghuai , Xia Qingyou
Published: March 2010

Background

Mitochondria are a valuable resource for studying the evolutionary process and deducing phylogeny. A few mitochondria genomes have been sequenced, but a comprehensive picture of the domestication event for silkworm mitochondria remains to be established. In this study, we integrate the extant data, and perform a whole genome resequencing of Japanese wild silkworm to obtain breakthrough results in silkworm mitochondrial (mt) population, and finally use these to deduce a more comprehensive phylogeny of the Bombycidae.

Results

We identified 347 single nucleotide polymorphisms (SNPs) in the mt genome, but found no past recombination event to have occurred in the silkworm progenitor. A phylogeny inferred from these whole genome SNPs resulted in a well-classified tree, confirming that the domesticated silkworm, Bombyx mori, most recently diverged from the Chinese wild silkworm, rather than from the Japanese wild silkworm. We showed that the population sizes of the domesticated and Chinese wild silkworms both experience neither expansion nor contraction. We also discovered that one mt gene, named cytochrome b, shows a strong signal of positive selection in the domesticated clade. This gene is related to energy metabolism, and may have played an important role during silkworm domestication.

Conclusions

We present a comparative analysis on 41 mt genomes of B. mori and B. mandarina from China and Japan. With these, we obtain a much clearer picture of the evolution history of the silkworm. The data and analyses presented here aid our understanding of the silkworm in general, and provide a crucial insight into silkworm phylogeny.
Use of a liquid nicotine delivery product to promote smoking cessation
Authors: Geimer Nicholas , Olson Carl E , Baumgarten Deborah , Kepner James L , Mahoney Martin C
Published: March 2010

Background

Despite access to various pharmacotherapies and counseling support to aid cessation, smokers typically demonstrate quit rates below 50%. This report describes the results of a Phase 2a study exploring the efficacy of a liquid nicotine delivery system as an aid to smoking cessation assessed after 12 weeks of therapy.

Methods

A single-arm Phase 2a study was conducted. Community-based smokers (ages 18+ years, smoking at least 10 cigarettes daily for the past year and interested in making a quit attempt) were recruited and completed clinic visits at 2 week intervals over the 12 week study period where carbon monoxide levels were assessed and the Smoke-Break product was rated on taste and overall satisfaction. Participants were provided with a supply of liquid nicotine cigarettes (e.g., Smoke-Break) at each clinic visit. A total of 69 smokers were enrolled and received the intervention product (intention to treat group, ITT) and 52 smokers verified participation (according to protocol group, ATP).

Results

The cessation rate at 12 weeks after the baseline visit, assessed as the bioverified point prevalence of abstinence, was 71.1% (95% confidence interval [CI] 58.8%-83.5%) in the ATP group and 53.6% (41.8%-65.4%) in the ITT group. Participants rated the liquid nicotine delivery system highly and also expressed general satisfaction. Few adverse events were identified with no serious adverse events.

Conclusions

These results support the efficacy of the liquid nicotine delivery system in smoking cessation. If this nicotine delivery product proves to be effective in larger trials, it could represent an inexpensive, readily accessible and well-tolerated agent to promote smoking cessation.

Trial Registration

This trial is registered at clinicaltrials.gov as study NCT00715871.
Postprandial endothelial dysfunction in subjects with new-onset type 2 diabetes: an acarbose and nateglinide comparative study
Authors: Kato Toru , Inoue Teruo , Node Koichi
Published: March 2010

Background

Postprandial hyperglycemia is believed to affect vascular endothelial function. The aim of our study was to compare the effects of acarbose and nateglinide on postprandial endothelial dysfunction.

Methods

We recruited a total of 30 patients with newly diagnosed type 2 diabetes (19 men and 11 women, age 67.8 ± 7.3 years). Patients were randomly assigned to 3 groups receiving either 300 mg/day acarbose, 270 mg/day nateglinide, or no medication. A cookie test (consisting of 75 g carbohydrate, 25 g butter fat, and 7 g protein for a total of 553 kcal) was performed as dietary tolerance testing. During the cookie test, glucose and insulin levels were determined at 0, 30, 60, and 120 min after load. In addition, endothelial function was assessed by % flow-mediated dilation (FMD) of the brachial artery at 0 and 120 min after cookie load.

Results

Postprandial glucose and insulin levels were similar in the 3 groups. Postprandial endothelial dysfunction was similar in the 3 groups before treatment. After 12 weeks of intervention, postprandial FMD was significantly improved in the acarbose group compared with the control group (6.8 ± 1.3% vs 5.2 ± 1.1%, p = 0.0022). Area under the curve (AUC) for insulin response was significantly increased in the nateglinide and control groups; however, no significant change was observed in the acarbose group.

Conclusions

Our results suggest that acarbose improves postprandial endothelial function by improvement of postprandial hyperglycemia, independent of postprandial hyperinsulinemia. Acarbose may thus have more beneficial effects on postprandial endothelial function in patients with type 2 diabetes than nateglinide.
Mouse Rad1 deletion enhances susceptibility for skin tumor development
Authors: Han Lu , Hu Zhishang , Liu Yuheng , Wang Xiangyuan , Hopkins Kevin M. , Lieberman Howard B. , Hang Haiying
Published: March 2010

Background

Cells are constantly exposed to stresses from cellular metabolites as well as environmental genotoxins. DNA damage caused by these genotoxins can be efficiently fixed by DNA repair in cooperation with cell cycle checkpoints. Unrepaired DNA lesions can lead to cell death, gene mutation and cancer. The Rad1 protein, evolutionarily conserved from yeast to humans, exists in cells as monomer as well as a component in the 9-1-1 protein complex. Rad1 plays crucial roles in DNA repair and cell cycle checkpoint control, but its contribution to carcinogenesis is unknown.

Results

To address this question, we constructed mice with a deletion ofMrad1. Matings between heterozygousMrad1mutant mice producedMrad1+/+andMrad1+/-but noMrad1-/-progeny, suggesting theMrad1null is embryonic lethal.Mrad1+/-mice demonstrated no overt abnormalities up to one and half years of age. DMBA-TPA combinational treatment was used to induce tumors on mouse skin. Tumors were larger, more numerous, and appeared earlier on the skin ofMrad1+/-mice compared toMrad1+/+animals. Keratinocytes isolated fromMrad1+/-mice had significantly more spontaneous DNA double strand breaks, proliferated slower and had slightly enhanced spontaneous apoptosis thanMrad1+/+control cells.

Conclusion

These data suggest thatMrad1is important for preventing tumor development, probably through maintaining genomic integrity. The effects of heterozygous deletion ofMrad1on proliferation and apoptosis of keratinocytes is different from those resulted fromMrad9heterozygous deletion (from our previous study), suggesting thatMrad1also functions independent ofMrad9besides its role in the Mrad9-Mrad1-Mhus1 complex in mouse cells.
Microglia in the aging brain: relevance to neurodegeneration
Authors: Luo Xiao-Guang , Ding Jian-Qing , Chen Sheng-Di
Published: March 2010

Microglia cells are the brain counterpart of macrophages and function as the first defense in the brain. Although they are neuroprotective in the young brain, microglia cells may be primed to react abnormally to stimuli in the aged brain and to become neurotoxic and destructive during neurodegeneration. Aging-induced immune senescence occurs in the brain as age-associated microglia senescence, which renders microglia to function abnormally and may eventually promote neurodegeneration. Microglia senescence is manifested by both morphological changes and alterations in immunophenotypic expression and inflammatory profile. These changes are likely caused by microinvironmental factors, but intrinsic factors cannot yet be completely excluded. Microglia senescence appears to underlie the switching of microglia from neuroprotective in the young brain to neurotoxic in the aged brain. The hypothesis of microglia senescence during aging offers a novel perspective on their roles in aging-related neurodegeneration. In Parkinson's disease and Alzheimer's disease, over-activation of microglia may play an active role in the pathogenesis because microglia senescence primes them to be neurotoxic during the development of the diseases.
Automated characterization of cell shape changes during amoeboid motility by skeletonization
Authors: Xiong Yuan , Kabacoff Cathryn , Franca-Koh Jonathan , Devreotes Peter N , Robinson Douglas N , Iglesias Pablo A
Published: March 2010

Background

The ability of a cell to change shape is crucial for the proper function of many cellular processes, including cell migration. One type of cell migration, referred to as amoeboid motility, involves alternating cycles of morphological expansion and retraction. Traditionally, this process has been characterized by a number of parameters providing global information about shape changes, which are insufficient to distinguish phenotypes based on local pseudopodial activities that typify amoeboid motility.

Results

We developed a method that automatically detects and characterizes pseudopodial behavior of cells. The method uses skeletonization, a technique from morphological image processing to reduce a shape into a series of connected lines. It involves a series of automatic algorithms including image segmentation, boundary smoothing, skeletonization and branch pruning, and takes into account the cell shape changes between successive frames to detect protrusion and retraction activities. In addition, the activities are clustered into different groups, each representing the protruding and retracting history of an individual pseudopod.

Conclusions

We illustrate the algorithms on movies of chemotaxing Dictyostelium cells and show that our method makes it possible to capture the spatial and temporal dynamics as well as the stochastic features of the pseudopodial behavior. Thus, the method provides a powerful tool for investigating amoeboid motility.
A paucity of heterochromatin at functional human neocentromeres
Authors: Alonso Alicia , Hasson Dan , Cheung Fanny , Warburton Peter E
Published: March 2010

Background

Centromeres are responsible for the proper segregation of replicated chromatids during cell division. Neocentromeres are fully functional ectopic human centromeres that form on low-copy DNA sequences and permit analysis of centromere structure in relation to the underlying DNA sequence. Such structural analysis is not possible at endogenous centromeres because of the large amounts of repetitive alpha satellite DNA present.

Results

High-resolution chromatin immunoprecipitation (ChIP) on CHIP (microarray) analysis of three independent neocentromeres from chromosome 13q revealed that each neocentromere contained ~100 kb of centromere protein (CENP)-A in a two-domain organization. Additional CENP-A domains were observed in the vicinity of neocentromeres, coinciding with CpG islands at the 5' end of genes. Analysis of histone H3 dimethylated at lysine 4 (H3K4me2) revealed small domains at each neocentromere. However, these domains of H3K4me2 were also found in the equivalent non-neocentric chromosomes. A surprisingly minimal (~15 kb) heterochromatin domain was observed at one of the neocentromeres, which formed in an unusual transposon-free region distal to the CENP-A domains. Another neocentromere showed a distinct absence of nearby significant domains of heterochromatin. A subtle defect in centromere cohesion detected at these neocentromeres may be due to the paucity of heterochromatin domains.

Conclusions

This high-resolution mapping suggests that H3K4me2 does not seem sufficiently abundant to play a structural role at neocentromeres, as proposed for endogenous centromeres. Large domains of heterochromatin also do not appear necessary for centromere function. Thus, this study provides important insight into the structural requirements of human centromere function.
Quantity and clinical relevance of circulating endothelial progenitor cells in human ovarian cancer
Authors: Su Yajuan , Zheng Lei , Wang Qian , Li Weiqi , Cai Zhen , Xiong Shilong , Bao Jie
Published: March 2010

Background

Circulating bone marrow-derived endothelial progenitor cells (EPCs) have been reported to participate in tumor angiogenesis and growth; however, the role of circulating EPCs in tumor progression is controversial. The role of circulating EPCs in ovarian cancer progression and angiogenesis has not yet been investigated.

Methods

The number of circulating EPCs in the peripheral blood in 25 healthy volunteers and 42 patients with ovarian cancer was determined by flow cytometry. EPCs were defined by co-expression of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2). In addition, we determined CD34 and VEGFR2 mRNA levels by real-time reverse transcription-polymerase chain reaction. Plasma levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were determined by enzyme-linked immunosorbent assay.

Results

Circulating levels of EPCs were significantly increased in ovarian cancer patients, correlating with tumor stage and residual tumor size. Higher levels of EPCs were detected in patients with stage III and IV ovarian cancer than in patients with stage I and II disease. After excision of the tumor, EPCs levels rapidly declined. Residual tumor size greater than 2 cm was associated with significantly higher levels of EPCs. In addition, high circulating EPCs correlated with poor overall survival. Pretreatment CD34 mRNA levels were not significantly increased in ovarian cancer patients compared with healthy controls; however, VEGFR2 expression was increased, and plasma levels of VEGF and MMP-9 were also elevated.

Conclusions

Our results demonstrate the clinical relevance of circulating EPCs in ovarian cancer. EPCs may be a potential biomarker to monitor ovarian cancer progression and angiogenesis and treatment response.
Bisphosphonates and risk of atrial fibrillation: a meta-analysis
Authors: Kim Seo Young , Kim Min Jung , Cadarette Suzanne M , Solomon Daniel H
Published: March 2010

Introduction

Bisphosphonates are the most commonly used drugs for the prevention and treatment of osteoporosis. Although a recent FDA review of the results of clinical trials reported no clear link between bisphosphonates and serious or non-serious atrial fibrillation (AF), some epidemiologic studies have suggested an association between AF and bisphosphonates.

Methods

We conducted a meta-analysis of non-experimental studies to evaluate the risk of AF associated with bisphosphonates. Studies were identified by searching MEDLINE and EMBASE using a combination of the Medical Subject Headings and keywords. Our search was limited to English language articles. The pooled estimates of odds ratios (OR) as a measure of effect size were calculated using a random effects model.

Results

Seven eligible studies with 266,761 patients were identified: three cohort, three case-control, and one self-controlled case series. Bisphosphonate exposure was not associated with an increased risk of AF [pooled multivariate OR 1.04, 95% confidence interval (CI) 0.92-1.16] after adjusting for known risk factors. Moderate heterogeneity was noted (I-squared score = 62.8%). Stratified analyses by study design, cohort versus case-control studies, yielded similar results. Egger's and Begg's tests did not suggest an evidence of publication bias (P = 0.90, 1.00 respectively). No clear asymmetry was observed in the funnel plot analysis. Few studies compared risk between bisphosphonates or by dosing.

Conclusions

Our study did not find an association between bisphosphonate exposure and AF. This finding is consistent with the FDA's statement.
Prediction of hospital outcome in septic shock: a prospective comparison of tissue Doppler and cardiac biomarkers
Authors: Sturgess David J , Marwick Thomas H , Joyce Chris , Jenkins Carly , Jones Mark , Masci Paul , Stewart David , Venkatesh Bala
Published: March 2010

Introduction

Diastolic dysfunction as demonstrated by tissue Doppler imaging (TDI), particularly E/e' (peak early diastolic transmitral/peak early diastolic mitral annular velocity) is common in critical illness. In septic shock, the prognostic value of TDI is undefined. This study sought to evaluate and compare the prognostic significance of TDI and cardiac biomarkers (B-type natriuretic peptide (BNP); N-terminal proBNP (NTproBNP); troponin T (TnT)) in septic shock. The contribution of fluid management and diastolic dysfunction to elevation of BNP was also evaluated.

Methods

Twenty-one consecutive adult patients from a multidisciplinary intensive care unit underwent transthoracic echocardiography and blood collection within 72 hours of developing septic shock.

Results

Mean ± SD APACHE III score was 80.1 ± 23.8. Hospital mortality was 29%. E/e' was significantly higher in hospital non-survivors (15.32 ± 2.74, survivors 9.05 ± 2.75; P = 0.0002). Area under ROC curves were E/e' 0.94, TnT 0.86, BNP 0.78 and NTproBNP 0.67. An E/e' threshold of 14.5 offered 100% sensitivity and 83% specificity. Adjustment for APACHE III, cardiac disease, fluid balance and grade of diastolic function, demonstrated E/e' as an independent predictor of hospital mortality (P = 0.019). Multiple linear regression incorporating APACHE III, gender, cardiac disease, fluid balance, noradrenaline dose, C reactive protein, ejection fraction and diastolic dysfunction yielded APACHE III (P = 0.033), fluid balance (P = 0.001) and diastolic dysfunction (P = 0.009) as independent predictors of BNP concentration.

Conclusions

E/e' is an independent predictor of hospital survival in septic shock. It offers better discrimination between survivors and non-survivors than cardiac biomarkers. Fluid balance and diastolic dysfunction were independent predictors of BNP concentration in septic shock.
XOMA 052, an Anti-IL-1β Monoclonal Antibody, Improves Glucose Control and β-Cell Function in the Diet-Induced Obesity Mouse Model
Authors: Owyang Alexander M. , Maedler Kathrin , Gross Lisa , Yin Johnny , Esposito Lin , Shu Luan , Jadhav Jaaee , Domsgen Erna , Bergemann Jennifer , Lee Steve , Kantak Seema
Published: March 2010

Recent evidence suggests that IL-1β-mediated glucotoxicity plays a critical role in type 2 diabetes mellitus. Although previous work has shown that inhibiting IL-1β can lead to improvements in glucose control and β-cell function, we hypothesized that more efficient targeting of IL-1β with a novel monoclonal antibody, XOMA 052, would reveal an effect on additional parameters affecting metabolic disease. In the diet-induced obesity model, XOMA 052 was administered to mice fed either normal or high-fat diet (HFD) for up to 19 wk. XOMA 052 was administered as a prophylactic treatment or as a therapy. Mice were analyzed for glucose tolerance, insulin tolerance, insulin secretion, and lipid profile. In addition, the pancreata were analyzed for β-cell apoptosis, proliferation, and β-cell mass. Mice on HFD exhibited elevated glucose and glycated hemoglobin levels, impaired glucose tolerance and insulin secretion, and elevated lipid profile, which were prevented by XOMA 052. XOMA 052 also reduced β-cell apoptosis and increased β-cell proliferation. XOMA 052 maintained the HFD-induced compensatory increase in β-cell mass, while also preventing the loss in β-cell mass seen with extended HFD feeding. Analysis of fasting insulin and glucose levels suggests that XOMA 052 prevented HFD-induced insulin resistance. These studies provide new evidence that targeting IL-1β in vivo could improve insulin sensitivity and lead to β-cell sparing. This is in addition to previously reported benefits on glycemic control. Taken together, the data presented suggest that XOMA 052 could be effective for treating many aspects of type 2 diabetes mellitus.
TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood
Authors: Gianetti Elena , Tusset Cintia , Noel Sekoni D. , Au Margaret G. , Dwyer Andrew A. , Hughes Virginia A. , Abreu Ana Paula , Carroll Jessica , Trarbach Ericka , Silveira Leticia F. G. , Costa Elaine M. F. , de Mendonça Berenice Bilharinho , de Castro Margaret , Lofrano Adriana , Hall Janet E. , Bolu Erol , Ozata Metin , Quinton Richard , Amory John K. , Stewart Susan E. , Arlt Wiebke , Cole Trevor R. , Crowley William F. , Kaiser Ursula B. , Latronico Ana Claudia , Seminara Stephanie B.
Published: March 2010

Context: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established.

Objective: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships.

Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide.

Patients or Other Participants: 345 probands, 18 family members, and 292 controls were studied.

Intervention: Reproductive phenotypes throughout reproductive life and before and after therapy were examined.

Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected.

Results: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism.

Conclusions: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
Borderlines: An Interview with Robert Lepage and Le Théâtre Repère
Authors: Salter Denis
Published: March 2010

Le Théâtre Repère was founded by the director Jacques Lessard in 1980 in Québec City. A theater of research, not a permanent acting troupe, Repère creates a special company of actors for each project it undertakes. Robert Lepage joined Lessard and Repère in 1983 and stayed until 1990 when he became, for three years, the Artistic Director of French Theater at the National Arts Centre in Ottawa. His major projects with Repère have included The Dragons' Trilogy (1985), Polygraph (1988), Tectonic Plates (1990), and now The Shakespeare Cycle, consisting of Michel Garneau's tradaptations (translation-adaptations) of Coriolan/Coriolanus, Macbeth, and La tempête/The Tempest. After its premiere in Maubeuge, France, in October 1992, The Shakespeare Cycle toured to Paris, Frankfurt, Montréal, Amsterdam, Zurich, and Bremen; in autumn, 1993, it toured to France, Japan, and England. The scores were composed by Guy Laramée and interpreted by Louise Simard. Marie Brassard played Lady Macbeth, Ariel, and Virgilia; Anne-Marie Cadieux a Witch and a Lady in Macbeth, Caliban, and Volumnia.
The Character of the University
Authors: Aravamudan Srinivas
Published: March 2010

This essay argues that the university ought to encourage the flourishing of multiple languages and metalanguages. Opposing recent Habermasian universalism and Victorianist virtue talk (e.g., Amanda Anderson's The Way We Argue Now), it queries why critics turn to character as a trope for stability, sincerity, and competence while in full flight from the supposed poststructuralist evils of undecidability, authenticity, and performance. However, this aspiration for a guaranteed and individuated meaning comes at a price, which is that of refusing to comprehend deconstructive insights about language. While the jargon of authenticity bedevils identity politics and multiculturalism today, deconstruction dismantles both authenticity and sincerity through a deployment of metasincerity. The essay investigates the character of critique as it arose in the early debates around the Enlightenment. Philosophical critique can be rejuvenated by paying attention to the texture of the “university in the world,” whereas the “globalizing university” subsumes difference and multiplicity under late capitalist managerialism. Defending the Derridean vision of “the university without condition” as achievable by welcoming multiple metalanguages, the article connects the older Kantian commitments to critique with the newer transcultural commitments to hospitality. Derrida's reflections in The Monolingualism of the Other explain the pathologies of the language politics of the university. By allowing a rich interplay of languages, the university can function as a site of openness wherein new epistemologies and a democratic future for the world can be crafted.
“We Asians”? Modernity, Visual Art Exhibitions, and East Asia
Authors: Wee C. J. W.-L.
Published: March 2010

Rapid economic development in East Asia in the 1980s–1990s saw a revivification of the idea of “Asia,” a region no longer regarded as backward. This article examines the East Asian visual arts scene, one of the most visible sites of cultural interaction in which the idea of contemporary New Asia was curated into “being” in Japanese, Australian, and Singapore museums. A key goal was the attempt to imagine a cosmopolitan-multicultural Asia able to transcend national boundaries, even as there was the awareness that the region's cultural diversity and history of political fractures—primarily between China and Japan—made this endeavor difficult. The “contemporary” in this context is simultaneously a critical (or postcolonial) modernity that embraces notions of multiculturalism for “rethinking” Asia and a fractured modernity that does not quite manage to be a break from modern East Asian history. Two significant moments in the exhibitions of Asia are examined. The first is the Fukuoka Art Museum's First Asian Artists Exhibition (1979–1980); the second is the Japan Foundation's and the Tokyo City Opera Art Gallery's Under Construction: New Dimensions of Asian Art (2000–2002). A “global-regional” curatorial framework, as opposed to the “international-regional” framework of 1979–1980, stood for that attempt to think of the potentialities of a critical modernity in the light of a more economically integrated regionalism.
Edward W. Said and Zionism: Rethinking the Exodus Story
Authors: Spanos William V.
Published: March 2010

In The Question of Palestine and elsewhere, Edward Said locates the “justificatory regime” that Zionism has developed to interpose between its Palestinian victims and itself in the discourse of nineteenth-century British imperialism, by which he means the representation of the land occupied by empire as “terra nullius.” This essay retrieves Said's “Canaanite” reading of Michael Waltzer's Exodus and Revolution, in which the latter invokes, above all, the English Puritan revolution to demonstrate the emancipatory politics of the Old Testament story and reconstellates it into the American context, in which, according to Sacvan Bercovitch in The American Jeremiad, the Puritan founders' figural reenactment of the Exodus story is, in fact, one of conquest and occupation rather than emancipation. Such a retrieval and reconstellation will show that Said's genealogy of the Zionist justificatory regime undergoes a significant modification when, in the 1950s, the United States takes over the sponsorship of the Israeli state from the Old World empires. It will show, specifically, the imperial ideology of the Old World that was the original model of the Zionist justificatory regime vis-à-vis Palestine was displaced by the far more politically “effective” exceptionalist jeremiadic ideology of the “pioneering” New World.
Lucid/Ludic
Authors: Pound Scott
Published: March 2010

This article examines the mythologies and materialities informing the ludic performance of sophism and lucid practice of scholarship to show that after two and a half millennia of standing in sharp opposition to one another the two are starting to converge. The article documents the return of rhetoric and poetics and argues that, far from simply reflecting changes in academic fashion, this event signals a complete reorientation of the scholarly apparatus. The argument calls attention to the material and historical alignment of scholarship with the medium of literacy and suggests that challenges to the literate apparatus from new media are also challenges to the scholarly apparatus and its inbuilt antipathy for rhetoric and poetics. In what amounts to a reversal of the inaugural gesture of the very first academy, scholars are rediscovering the value of rhetorical and poetic play as functional elements of their craft. With this change a new scholarly myth begins to emerge, giving us a new scholar-hero: a sophist with close ties to the world of poetry and poetics.
The Future Continuous: Ashbery's Lyric Mediacy
Authors: Lerner Ben
Published: March 2010

It is a commonplace that John Ashbery's poetry is, in some important sense, “about time,” but we lack an account of the specific experience of temporality it enables. Part of the bizarre power of Ashbery's best poetry is that it seems to narrate what it is like to read Ashbery's best poetry. When his work manages to describe the time of its own reading in the time of its own reading, we experience mediacy immediately. This review of John Ashbery's Collected Poems, 1956–1987 (Library of America, No. 187) explores what I call the “lyric mediacy” of Ashbery's work and considers how his poems' complicated play with temporality interacts with his rapid canonization.
A Limited Constitution: Publius, the State of Emergency, and “One Supreme Tribunal”
Authors: Lozano Benjamin
Published: March 2010

What is the nature of republican power in a state of emergency? This question has shadowed much of the legal and political discourse in the United States in the aftermath of the traumatic event of 9/11 and subsequent prosecution of the war on terror. Eric Posner and Adrian Vermeule's Terror in the Balance: Security, Liberty, and the Courts argues that far from it being the case that judicial oversight of government-imposed security measures should be heightened in states of emergency, on the contrary, it is precisely at such times that they should be given the broadest latitude—even when legally suspect. This essay asks the simple question of how Publius of The Federalist Papers would have regarded the argument of Terror in the Balance.
Functional specialization of cellulose synthase genes of prokaryotic origin in chordate larvaceans
Authors: Sagane Yoshimasa , Zech Karin , Bouquet Jean-Marie , Schmid Martina , Bal Ugur , Thompson Eric M.
Published: March 2010

Extracellular matrices play important, but poorly investigated, roles in morphogenesis. Extracellular cellulose is central to regulation of pattern formation in plants, but among metazoans only tunicates are capable of cellulose biosynthesis. Cellulose synthase (CesA) gene products are present in filter-feeding structures of all tunicates and also regulate metamorphosis in the ascidian Ciona. Ciona CesA is proposed to have been acquired by lateral gene transfer from a prokaryote. We identified two CesA genes in the sister-class larvacean Oikopleura dioica. Each has a mosaic structure of a glycoslyltransferase 2 domain upstream of a glycosyl hydrolase family 6 cellulase-like domain, a signature thus far unique to tunicates. Spatial-temporal expression analysis revealed that Od-CesA1 produces long cellulose fibrils along the larval tail, whereas Od-CesA2 is responsible for the cellulose scaffold of the post-metamorphic filter-feeding house. Knockdown of Od-CesA1 inhibited cellulose production in the extracellular matrix of the larval tail. Notochord cells either failed to align or were misaligned, the tail did not elongate properly and tailbud embryos also exhibited a failure to hatch. Knockdown of Od-CesA2 did not elicit any of these phenotypes and instead caused a mild delay in pre-house formation. Phylogenetic analyses including Od-CesAs indicate that a single lateral gene transfer event from a prokaryote at the base of the lineage conferred biosynthetic capacity in all tunicates. Ascidians possess one CesA gene, whereas duplicated larvacean genes have evolved distinct temporal and functional specializations. Extracellular cellulose microfibrils produced by the pre-metamorphic Od-CesA1 duplicate have a role in notochord and tail morphogenesis.
ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells
Authors: Haenssen Keneshia K. , Caldwell Sarah A. , Shahriari Kristina S. , Jackson S. RaElle , Whelan Kelly A. , Klein-Szanto Andres J. , Reginato Mauricio J.
Published: March 2010

ErbB2, a receptor tyrosine kinase highly expressed in many tumors, is known to inhibit apoptotic signals. Overexpression of ErbB2 causes anoikis resistance that contributes to luminal filling in three-dimensional mammary epithelial acinar structures in vitro. Given that integrins and growth factor receptors are highly interdependent for function, we examined the role of integrin subunits in ErbB2-mediated survival signaling. Here, we show that MCF-10A cells overexpressing ErbB2 upregulate integrin α5 via the MAP-kinase pathway in three-dimensional acini and found elevated integrin α5 levels associated with ErbB2 status in human breast cancer. Integrin α5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis as depletion of integrin α5 reverses anoikis resistance and Bim inhibition. Integrin α5 is required for full activation of ErbB2 tyrosine phosphorylation on Y877 and ErbB2 phosphorylation is associated with increased activity of Src in the absence of adhesion. Indeed, we show that blocking elevated Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Thus, integrin α5 serves as a key mediator of Src and ErbB2-survival signaling in low adhesion states, which are necessary to block the pro-anoikis mediator Bim, and we suggest that this pathway represents a potential novel therapeutic target in ErbB2-positive tumors.
Dishevelled-KSRP complex regulates Wnt signaling through post-transcriptional stabilization of β-catenin mRNA
Authors: Bikkavilli Rama Kamesh , Malbon Craig C.
Published: March 2010

Canonical Wnt/β-catenin signaling is crucial during embryonic development. Upon Wnt stimulation, Dishevelled proteins relay the signal from upstream Frizzled receptors to downstream effectors. By using affinity purification followed by ion-trap mass spectrometry we identified K-homology splicing regulator protein (KSRP) as a novel Dishevelled-interacting protein. We show that KSRP negatively regulates Wnt/β-catenin signaling at the level of post-transcriptional CTNNB1 (β-catenin) mRNA stability. Thus, Dishevelled-KSRP complex operates in Wnt regulation of β-catenin, functioning post-transcriptionally upon CTNNB1 mRNA stability.
Dimerization of adiponectin receptor 1 is inhibited by adiponectin
Authors: Kosel David , Heiker John T. , Juhl Cathleen , Wottawah Cornelia M. , Blüher Matthias , Mörl Karin , Beck-Sickinger Annette G.
Published: March 2010

AdipoR1 and AdipoR2 are newly discovered members of the huge family of seven-transmembrane receptors, but both receptors are structurally and functionally different from G-protein-coupled receptors. Little is known about the oligomerization of the AdipoRs. Here, we show the presence of endogenous AdipoR1 dimers in various cell lines and human muscle tissue. To directly follow and localize the dimerization, we applied bimolecular fluorescence complementation (BiFC) in combination with flow cytometry. We visualized and quantified AdipoR1 homodimers in HEK293 cells. Moreover, we identified a GxxxG dimerization motif in the fifth transmembrane domain of the AdipoR1. By mutating both glycine residues to phenylalanine or glutamic acid, we were able to modulate the dimerization of AdipoR1, implicating a role for the GxxxG motif in AdipoR1 dimerization. Furthermore, we tested whether the AdipoR1 ligand adiponectin had any influence on receptor dimerization. Interestingly, we found that adiponectin decreases the receptor dimerization in a concentration-dependent manner. This effect is mainly mediated by segments of the collagen-like domain of full-length adiponectin. Accordingly, this is the first direct read-out signal of adiponectin at the AdipoR1 receptor, which revealed the involvement of specific amino acids of both the receptor and the ligand to modulate the quaternary structure of the AdipoR1.
Phosphatidylinositol- and phosphatidylcholine-transfer activity of PITPβ is essential for COPI-mediated retrograde transport from the Golgi to the endoplasmic reticulum
Authors: Carvou Nicolas , Holic Roman , Li Michelle , Futter Clare , Skippen Alison , Cockcroft Shamshad
Published: March 2010

Vesicles formed by the COPI complex function in retrograde transport from the Golgi to the endoplasmic reticulum (ER). Phosphatidylinositol transfer protein β (PITPβ), an essential protein that possesses phosphatidylinositol (PtdIns) and phosphatidylcholine (PtdCho) lipid transfer activity is known to localise to the Golgi and ER but its role in these membrane systems is not clear. To examine the function of PITPβ at the Golgi-ER interface, RNA interference (RNAi) was used to knockdown PITPβ protein expression in HeLa cells. Depletion of PITPβ leads to a decrease in PtdIns(4)P levels, compaction of the Golgi complex and protection from brefeldin-A-mediated dispersal to the ER. Using specific transport assays, we show that anterograde traffic is unaffected but that KDEL-receptor-dependent retrograde traffic is inhibited. This phenotype can be rescued by expression of wild-type PITPβ but not by mutants defective in docking, PtdIns transfer and PtdCho transfer. These data demonstrate that the PtdIns and PtdCho exchange activity of PITPβ is essential for COPI-mediated retrograde transport from the Golgi to the ER.