bluuebunny/crossref_metadata_2025 huggingface dataset:
Social aspects of location-monitoring systems: the case of Guide Me and of My-SOS
Authors: Joore Peter
Published: September 2008

What are the social implications of the new geo-information systems and location based services (LBS) that are becoming more and more widely used in modern society, and how are these aspects incorporated into the current development process of these products? Based on his experience as an industrial design engineer closely involved in the development of several LBS in the area of safety and security, and care and sports, the author describes the development of two LBS in which the Dutch research organization TNO has been involved. He analyzes the positive social implications of the systems, designed to improve the safety and independence of their users, as well as the potentially less positive rebound effects that they could bring about. The author finds that developers focus primarily on the positive effects to be gained from their new LBS, but don't pay conscious attention to the potential negative rebound effects of their inventions. Although many stakeholders are involved in the development and implementation of the LBS, none of these actors seems to be responsible for the deliberate monitoring of the social effects the new products will have. This leaves space for one of the present parties involved, or for a new organization not yet involved at this stage, to claim this responsibility for monitoring the social consequences of new LBS to be introduced on the market.
Spatial Proximity to the U.S.—Mexico Border and Newspaper Coverage of Immigration Issues
Authors: Branton Regina P. , Dunaway Johanna
Published: September 2008

This article examines how geographic proximity to the U.S.—Mexico border influences newspaper coverage of immigration issues. The authors investigate two questions: Do media organizations spatially proximate to the border offer more frequent coverage of Latino immigration than media organizations farther removed from the border? Do media organizations spatially proximate to the border offer more frequent coverage of the negative aspects of immigration than media organizations farther removed from the border? We find that news organizations closer to the border generate a higher volume of articles about Latino immigration, articles featuring the negative aspects of immigration, and articles regarding illegal immigration.
Using Nonmedically Trained Interviewers to Collect Biomeasures in a National In-home Survey
Authors: Jaszczak Angela , Lundeen Katie , Smith Stephen
Published: September 2008

A key operational component of the National Social Life, Health, and Aging Project (NSHAP) is the use of nonmedically trained interviewers to collect biomeasures in a national in-home survey of health and aging. Few studies have integrated in-home biomeasure collection using nonmedically trained interviewers on a large scale. In this article, the authors discuss their approach to using nonmedically trained interviewers to collect biomeasures in the home. The article focuses on activities that impact the ability to integrate biomeasures into survey research, including developing field methods, recruiting and training interviewers, and monitoring data collection activities. In addition, cooperation rates and measures of interviewer productivity and data quality are provided to evaluate the authors' approach.
Studies on macrosegregation and double diffusive convection during directional solidification of binary mixture
Authors: Barman N. , Dutta P.
Published: September 2008

Experimental and numerical studies on macrosegregation during directional solidification of an aqueous ammonium chloride solution in a rectangular cavity are presented. Depending on the initial concentration and boundary temperature conditions, three distinct situations in the liquid during the solidification process are studied: mass diffusion only, solutal convection and double diffusive convection. The time dependent concentration of the solution inside the cavity is measured online for the above three situations using a laser based technique. This technique measures refractive index of the solution, which indirectly gives the concentration variation at a point in the solution during solidification. The interface growth is photographed using a shadowgraph technique, and the flow is visualised using a sheet of laser light scattered by neutrally buoyant, hollow glass spheres seeded in the fluid. Corresponding numerical studies are performed using a macroscopic model based on a fixed grid, enthalpy based, control volume approach. A good agreement between the experimental and computational results is observed.
Influence of grain size fluctuations on ductility of superplastic magnesium alloys processed by severe plastic deformation
Authors: del Valle J. A. , Ruano O. A.
Published: September 2008

The influence of fluctuations in the grain size along the gauge length on ductility is analysed in the superplastic regime. It is demonstrated that these fluctuations produce a similar effect to that produced by variations in the initial uniformity of the sample, leading to premature necking. To reach superplastic elongations of 400%, fluctuations in grain size of <0·5% between two zones of the gauge length are required. As an example, the superplastic behaviour of an AZ61 alloy, processed by severe plastic deformation (SPD), with a heterogeneous microstructure is analysed when the grain boundary sliding mechanism controls deformation. It is found that neck formation is related to bands of fine grains that are formed during SPD processing by the mechanism of recrystallisation by rotation. Under these circumstances, grain refinement is rendered unsuccessful. The present investigation emphasises the importance of the microstructure homogeneity in developing grain refinement processing routes.
Comparison of fatigue performance of HVOF spray coated and conventional roll bonded aluminium bearing alloys
Authors: Ali M. S. , Reed P. A. S. , Syngellakis S.
Published: September 2008

A comparative study on fatigue resistance of thin aluminium bearing linings (supported by harder backing steel layers) produced by high velocity oxyfuel (HVOF) spray coating and conventional roll bonding (RB) processes has shown that the former is superior to the latter with similar lining composition (Al–20%Sn–1%Cu–0·25%Mn) when compared on the basis of oscillating lining surface strains under a three point bend test condition. In terms of the integrity of the multilayered bearing system under oscillating stresses, HVOF lining appeared to show worse fatigue resistance, due to poor/brittle bond between the lining and the backing steel layer resulting in the detachment of the lining from the backing layer. The newly developed RB alloy with reduced Sn content (Al–6·5Sn–2·5Si–1Ni–1Cu–0·25Mn) and scattered intermetallics showed higher fatigue resistance than the HVOF and previous RB systems. This was linked to delayed initiation of short cracks leading to a longer overall lifetime compared to all other systems.
Effects of strain rate and temperature on dynamic mechanical behaviour and microstructural evolution in aluminium–scandium (Al–Sc) alloy
Authors: Lee W.-S. , Chen T.-H.
Published: September 2008

The present study applies a compressive split Hopkinson bar to investigate the mechanical response, microstructural evolution and fracture characteristics of an aluminium–scandium (Al–Sc) alloy at temperatures ranging from − 100 to 300°C and strain rates of 1·2 × 103, 3·2×103 and 5·8 × 103 s−1. The relationship between the dynamic mechanical behaviour of the Al–Sc alloy and its microstructural characteristics is explored. The fracture features and microstructural evolution are observed using scanning and transmission electron microscopy techniques. The stress–strain relationships indicate that the flow stress, work hardening rate and strain rate sensitivity increase with increasing strain rate, but decrease with increasing temperature. Conversely, the activation volume and activation energy increase as the temperature increases or the strain rate decreases. Additionally, the fracture strain reduces with increasing strain rate and decreasing temperature. The Zerilli–Armstrong fcc constitutive model is used to describe the plastic deformation behaviour of the Al–Sc alloy, and the error between the predicted flow stress and the measured stress is found to be less than 5%. The fracture analysis results reveal that cracks initiate and propagate in the shear bands of the Al–Sc alloy specimens and are responsible for their ultimate failure. However, at room temperature, under a low strain rate of 1·2 × 103 s−1 and at a high experimental temperature of 300°C under all three tested strain rates, the specimens do not fracture, even under large strain deformations. Scanning electron microscopy observations show that the surfaces of the fractured specimens are characterised by transgranular dimpled features, which are indicative of ductile fracture. The depth and density of these dimples are significantly influenced by the strain rate and temperature. The transmission electron microscopy structural observations show the precipitation of Al3Sc particles in the matrix and at the grain boundaries. These particles suppress dislocation motion and result in a strengthening effect. The transmission electron microscopy analysis also reveals that the dislocation density increases, but the dislocation cell size decreases, with increasing strain rate for a constant level of strain. However, a higher temperature causes the dislocation density to decrease, thereby increasing the dislocation cell size.
Investigation of tin penetration at bottom surface of float borosilicate glasses
Authors: Liu S. M. , Zhao G. L. , Lin X. H. , Ying H. , Liu J. B. , Wang J. X. , Han G. R.
Published: September 2008

Tin penetration at the bottom surface of float borosilicate glasses was studied. The changes of tin penetration depth with different reaction temperatures and times were studied by field emission scanning electron microscopy and energy dispersive X-ray spectroscopy. The results showed that tin penetration layer could not be observed until 850°C. The tin penetration depth increased with increasing reaction temperature from 850 to 950°C, while it decreased with further increasing temperature from 950 to 1050°C. X-ray photoelectron spectroscopy (XPS) was employed to study the mechanism of the decrease occurred from 950 to 1050°C. The coexistence of Sn0 and Sn2+ ions and the changes of relative concentration ratio between them in the tin penetration layer were investigated by XPS.
G6PD deficiency, absence of α-thalassemia, and hemolytic rate at baseline are significant independent risk factors for abnormally high cerebral velocities in patients with sickle cell anemia
Authors: Bernaudin Françoise , Verlhac Suzanne , Chevret Sylvie , Torres Martine , Coic Lena , Arnaud Cécile , Kamdem Annie , Hau Isabelle , Grazia Neonato Maria , Delacourt Christophe
Published: September 2008

Stroke is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). This study aimed at defining predictive factors for abnormally high velocities (≥ 2 m/sec) based on the Créteil pediatric sickle cell anemia (SCA) cohort composed of 373 stroke-free SCA children. α genes and β-globin haplotypes were determined. Biologic parameters were obtained at baseline. α-thalassemia was present in 155 of 325 and G6PD deficiency in 36 of 325 evaluated patients. TCD was abnormal in 62 of 373 patients. Multivariate logistic regression analysis showed that G6PD deficiency (odds ratio [OR] = 3.36, 95% confidence interval [CI] 1.10-10.33; P = .034), absence of alpha-thalassemia (OR = 6.45, 95% CI 2.21-18.87; P = .001), hemoglobin (OR per g/dL = 0.63, 95% CI 0.41-0.97; P = .038), and lactate dehydrogenase (LDH) levels (OR per IU/L = 1.001, 95% CI 1.000-1.002; P = .047) were independent risk factors for abnormally high velocities. This study confirms the protective effect of alpha-thalassemia and shows for the first time that G6PD deficiency and hemolysis independently increase the risk of cerebral vasculopathy.
Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation
Authors: Cutler Corey , Stevenson Kristen , Kim Haesook T. , Richardson Paul , Ho Vincent T. , Linden Erica , Revta Carolyn , Ebert Ruth , Warren Diane , Choi Sung , Koreth John , Armand Philippe , Alyea Edwin , Carter Shelly , Horowitz Mary , Antin Joseph H. , Soiffer Robert
Published: September 2008

Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.
Diversity in genomic organisation, developmental regulation and distribution of the murine PR72/B" subunits of protein phosphatase 2A
Authors: Zwaenepoel Karen , Louis Justin V , Goris Jozef , Janssens Veerle
Published: September 2008

Background

Protein phosphatase 2A (PP2A) is a serine/threonine-specific phosphatase displaying vital functions in growth and development through its role in various signalling pathways. PP2A holoenzymes comprise a core dimer composed of a catalytic C and a structural A subunit, which can associate with a variable B-type subunit. The importance of the B-type subunits for PP2A regulation cannot be overestimated as they determine holoenzyme localisation, activity and substrate specificity. Three B-type subunit families have been identified: PR55/B, PR61/B' and PR72/B", of which the latter is currently the least characterised.

Results

We deduced the sequences and genomic organisation of the different murine PR72/B" isoforms: three genes encode nine isoforms, five of which are abundantly expressed and give rise to genuine PP2A subunits. Thereby, one novel subunit was identified. Using Northern blotting, we examined the tissue-specific and developmental expression of these subunits. All subunits are highly expressed in heart, suggesting an important cardiac function. Immunohistochemical analysis revealed a striated expression pattern of PR72 and PR130 in heart and skeletal muscle, but not in bladder smooth muscle. The subcellular localisation and cell cycle regulatory ability of several PR72/B" isoforms were determined, demonstrating differences as well as similarities.

Conclusion

In contrast to PR55/B and PR61/B', the PR72/B" family seems evolutionary more divergent, as only two of the murine genes have a human orthologue. We have integrated these results in a more consistent nomenclature of both human and murine PR72/B" genes and their transcripts/proteins. Our results provide a platform for the future generation of PR72/B" knockout mice.
S100A4 overexpression proves to be independent marker for breast cancer progression
Authors: Ismail Nawfal I , Kaur Gurjeet , Hashim Hasnah , Hassan Mohammed S
Published: September 2008

Background

Breast cancer is the most common cancer and cause of deaths in women around the world. Oncogene amplification usually occurs late in tumor progression and correlates well with aggressiveness of tumor. In fact the function of the S100A4 protein and its role in metastasis is unclear at present. The purpose of the study was to determine the expression of S100A4 protein in the invasion status and metastatic potential of breast cancer by using tissue microarray and to determine its role in breast cancer based on the expression of S100A4 gene product.

Methods

S100A4 protein expression was examined by immunohistochemistry (IHC) using commercially available tissue microarray containing malignant and normal breast tissue cores from 216 patients.

Results

S100A4 was absent in normal breast tissues while positive in 45.1% of infiltrating ductal carcinoma (IDC) node negative and 48.8% of infiltrating lobular carcinoma node negative. In paired samples, S100A4 protein was expressed in 13.5% of IDC node positive cases and 35.1% of matched lymph node metastasis.

Conclusion

S100A4 protein expression appears widely expressed in early and advanced breast cancer stages compared with normal breast. Our study suggests S100A4 may play a role in breast cancer progression and may prove to be an independent marker of breast cancer which appears to be down regulated in more advanced stages of breast cancer.
The identification of disease-induced biomarkers in the urine of BSE infected cattle
Authors: Simon Sharon LR , Lamoureux Lise , Plews Margot , Stobart Michael , LeMaistre Jillian , Ziegler Ute , Graham Catherine , Czub Stefanie , Groschup Martin , Knox J David
Published: September 2008

Background

The bovine spongiform encephalopathy (BSE) epidemic and the emergence of a new human variant of Creutzfeldt-Jakob Disease (vCJD) have led to profound changes in the production and trade of agricultural goods. The rapid tests currently approved for BSE monitoring in slaughtered cattle are all based on the detection of the disease related isoform of the prion protein, PrPd, in brain tissue and consequently are only suitable for post-mortem diagnosis. Objectives: In instances such as assessing the health of breeding stock for export purposes where post-mortem testing is not an option, there is a demand for an ante-mortem test based on a matrix or body fluid that would permit easy access and repeated sampling. Urine and urine based analyses would meet these requirements.

Results

Two dimensional differential gel eletrophoresis (2D-DIGE) and mass spectrometry analyses were used to identify proteins exhibiting differential abundance in the urine of BSE infected cattle and age matched controls over the course of the disease. Multivariate analyses of protein expression data identified a single protein able to discriminate, with 100% accuracy, control from infected samples. In addition, a subset of proteins were able to predict with 85% ± 13.2 accuracy the time post infection that the samples were collected.

Conclusion

These results suggest that in principle it is possible to identify biomarkers in urine useful in the diagnosis, prognosis and monitoring of disease progression of transmissible spongiform encephalopathy diseases (TSEs).
Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: a prospective study
Authors: Courvoisier Natacha , Dougados Maxime , Cantagrel Alain , Goupille Philippe , Meyer Olivier , Sibilia Jean , Daures Jean Pierre , Combe Bernard
Published: September 2008

Introduction

The objectives of this study were to determine the predictive factors of long-term radiographic outcome of rheumatoid arthritis (RA) and to describe the relationship between joint damage and disability over the course of the disease.

Methods

A cohort of 191 patients with early RA referred from primary care physicians were prospectively followed for 10 years. To determine the predictive factors of radiographic outcome, univariate analysis of the relationship between baseline values and outcome measures was undertaken using a chi-squared or Fisher's exact test. Stepwise multiple logistic regression was also performed to select independent prognostic factors.

Results

From data available for 112 patients, univariate analysis revealed a total Sharp score at 10 years that was significantly correlated with erythrocyte sedimentation rate (ESR), presence and level of IgA rheumatoid factor, presence of an anti-citrullinated protein antibody (ACPA), serum level of matrix metalloproteinase-3 and radiographic score at baseline. Logistic regression identified the baseline erosion score to be the most important baseline parameter as an independent prognostic factor of total radiographic score at 10 years (odds ratio = 5.64; 95% confidence interval = 1.78 to 17.86). After excluding radiographic scores from the entry parameters, the presence of ACPA and ESR were also predictive of the final total Sharp score. The Health Assessment Questionnaire (HAQ) score was strongly correlated with disease activity parameters, such as disease activity score and pain, at baseline and at three, five and 10 years. No correlation was found between total radiographic Sharp score and HAQ score throughout the study.

Conclusions

In this prospective study, baseline radiographic score, ESR and ACPA were the best predictive factors of 10-year radiographic outcome in early RA. HAQ disability was associated with disease activity throughout the 10-year follow-up but not with joint damage. This discrepancy with previous reports may be due in part to the early start of therapy with disease-modifying anti-rheumatic drugs.
The Homeodomain-Interacting Protein Kinase 2 Regulates Insulin Promoter Factor-1/Pancreatic Duodenal Homeobox-1 Transcriptional Activity
Authors: Boucher Marie-Josée , Simoneau Mélanie , Edlund Helena
Published: September 2008

The homeodomain transcription factor insulin promoter factor (IPF)-1/pancreatic duodenal homeobox (PDX)-1 plays a crucial role in both pancreas development and maintenance of β-cell function. Targeted disruption of the Ipf1/Pdx1 gene in β-cells of mice leads to overt diabetes and reduced Ipf1/Pdx1 gene expression results in decreased insulin expression and secretion. In humans, mutations in the IPF1 gene have been linked to diabetes. Hence, the identification of molecular mechanisms regulating the transcriptional activity of this key transcription factor is of great interest. Herein we analyzed homeodomain-interacting protein kinase (Hipk) 2 expression in the embryonic and adult pancreas by in situ hybridization and RT-PCR. Moreover, we functionally characterized the role of HIPK2 in regulating IPF1/PDX1 transcriptional activity by performing transient transfection experiments and RNA interference. We show that Hipk2 is expressed in the developing pancreatic epithelium from embryonic d 12–15 but that the expression becomes preferentially confined to pancreatic endocrine cells at later developmental stages. Moreover, we show that HIPK2 positively influences IPF1/PDX1 transcriptional activity and that the kinase activity of HIPK2 is required for this effect. We also demonstrate that HIPK2 directly phosphorylates the C-terminal portion of IPF1/PDX1. Taken together, our data provide evidence for a new mechanism by which IPF1/PDX1 transcriptional activity, and thus possibly pancreas development and/or β-cell function, is regulated.

Homeodomain-interacting protein kinase 2 phosphorylates the C-terminal portion of IPF1/PDX1 as well as positively regulating IPF1/PDX1 transcriptional activity.
Antiandrogen Exposure in Utero Disrupts Expression of Desert Hedgehog and Insulin-Like Factor 3 in the Developing Fetal Rat Testis
Authors: Brokken Leon J. S. , Adamsson Annika , Paranko Jorma , Toppari Jorma
Published: September 2008

Testicular development is an androgen-dependent process, and fetal exposure to antiandrogens disrupts male sexual differentiation. A variety of testicular disorders may result from impaired development of fetal Leydig and Sertoli cells. We hypothesized that antiandrogenic exposure during fetal development interferes with desert hedgehog (Dhh) signaling in the testis and results in impaired Leydig cell differentiation. Fetal rats were exposed in utero to the antiandrogen flutamide from 10.5 d post conception (dpc) until they were killed or delivery. Fetal testes were isolated at different time points during gestation and gene expression levels of Dhh, patched-1 (Ptc1), steroidogenic factor 1 (Sf1), cytochrome P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (Hsd3b1), and insulin-like factor 3 (Insl3) were analyzed. To study direct effects of hedgehog signaling on testicular development, testes from 14.5 dpc fetuses were cultured for 3 d in the presence of cyclopamine, sonic hedgehog, or vehicle, and gene expression levels and testosterone secretion were analyzed. Organ cultures were also analyzed histologically, and cleaved-caspase 3 immunohistochemistry was performed to assess apoptosis. In utero exposure to flutamide decreased expression levels of Dhh, Ptc1, Sf1, P450scc, Hsd3b1, and Insl3, particularly from 17.5 dpc onward. Inhibition of hedgehog signaling in testis cultures resulted in similar effects on gene expression levels. Apoptosis in Wolffian ducts was increased by cyclopamine compared with sonic hedgehog- or vehicle-treated cultures. We conclude that exposure to the antiandrogen flutamide interferes with Dhh signaling resulting in an impaired differentiation of the fetal Leydig cells and subsequently leading to abnormal testicular development and sexual differentiation.

Antiandrogenic exposure of rat fetuses in utero affects genes that are involved in sexual differentiation of the testis and suppresses sexual maturation.
Superoxide and Respiratory Coupling in Mitochondria of Insulin-Deficient Diabetic Rats
Authors: Herlein Judith A. , Fink Brian D. , O'Malley Yunxia , Sivitz William I.
Published: September 2008

Mitochondrial reactive oxygen species have been implicated in both diabetic complications and the progression of the underlying diabetic state. However, it is not clear whether mitochondria of diabetic origin are intrinsically altered to generate excess reactive oxygen species independent of the surrounding diabetic milieu. Mitochondria were isolated from gastrocnemius, heart, and liver of 2-wk and 2-month streptozotocin diabetic rats and controls. We rigidly quantified mitochondrial superoxide, respiration and ATP production, respiratory coupling, the expression of several proteins with antioxidant properties, and the redox state of glutathione. Both fluorescent assessment and electron paramagnetic spectroscopy revealed that superoxide production was unchanged or reduced in the 2-month diabetic mitochondria compared with controls. Kinetic analysis of the proton leak showed that diabetic heart and muscle mitochondria were actually more coupled compared with control despite an approximate 2- to 4-fold increase in uncoupling protein-3 content. Adenine nucleotide translocator type 1 expression was reduced by approximately 50% in diabetic muscle mitochondria. Catalase was significantly up-regulated in muscle and heart tissue and in heart mitochondria, whereas glutathione peroxidase expression was increased in liver mitochondria of diabetic rats. We conclude that gastrocnemius, heart, and liver mitochondria of streptozotocin diabetic rats are not irrevocably altered toward excess superoxide production either by complex I or complex III. Moreover, gastrocnemius and heart mitochondria demonstrate increased, not decreased, respiratory coupling. Mitochondria of insulin-deficient diabetic rats do show signs of adaptation to antecedent oxidative stress manifested as tissue-specific enzyme and uncoupling protein expression but remain remarkably robust with respect to superoxide production.

Mitochondria of streptozotocin-diabetic rats do not generate excess superoxide, manifest decreased or unchanged respiratory coupling, and show adaptation to antecedent in vivo oxidative stress.
Aldose Reductase Regulates High Glucose-Induced Ectodomain Shedding of Tumor Necrosis Factor (TNF)-α via Protein Kinase C-δ and TNF-α Converting Enzyme in Vascular Smooth Muscle Cells
Authors: Reddy Aramati B. M. , Ramana Kota V. , Srivastava Sanjay , Bhatnagar Aruni , Srivastava Satish K.
Published: September 2008

Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes, however, the mechanisms by which diabetes increases inflammation remain poorly understood. Here, we report that exposure to high glucose (HG) stimulates ectodomain shedding of TNF-α from rat aortic smooth muscle cells in culture. Our results show that exposure to HG decreases membrane-associated TNF-α. This decrease in unprocessed TNF-α was prevented by the aldose reductase (AR) inhibitor sorbinil and AR small interference RNA. Treatment with HG, but not equimolar mannitol or 3-O-methyl glucose, resulted in phosphorylation and activation of TNF-α converting enzyme (TACE) (ADAM17), which were attenuated by sorbinil or AR-specific small interference RNA. HG-induced TACE phosphorylation and TNF-α processing were also prevented by TNF-α protease inhibitor-1, an inhibitor of TACE. Inhibition of protein kinase C (PKC)-δ by rottlerin prevented HG-induced TACE activation and the accumulation of unprocessed TNF-α. Treatment with sorbinil decreased elevated levels of circulating TNF-α in streptozotocin-treated diabetic rats. Sorbinil treatment also decreased the expression of TNF-α, matrix metalloproteinase-2, matrix metalloproteinase-9, and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats. These results indicate that HG-induced TNF-α shedding could be attributed to TACE activation, which is regulated, in part, by PKC-δ and AR. Therefore, inhibition of TACE by TNF-α protease inhibitor-1, or pharmacological inhibition of PKC-δ or AR may represent useful strategies for treating vascular inflammation associated with diabetes.

In adrenocortical cells high versus low levels of steroidogenic factor 1 (SF-1) differentially regulates the expression of aldosterone synthase and aldosterone production.
Lysophosphatidic Acid Signaling during Embryo Development in Sheep: Involvement in Prostaglandin Synthesis
Authors: Liszewska Ewa , Reinaud Pierrette , Billon-Denis Emmanuelle , Dubois Olivier , Robin Philippe , Charpigny Gilles
Published: September 2008

We investigated the lysophosphatidic acid (LPA) pathway during early pregnancy in sheep. LPA was detected in the uteri of early-stage pregnant ewes. Using quantitative RT-PCR, the expression of autotaxin, the LPA-generating enzyme, was found in the endometrium and conceptus. In the latter autotaxin, transcript levels were low on d 12–14 and increased on d 15–16, in parallel with the level of LPA. Autotaxin was localized in the luminal epithelium and superficial glands of the endometrium and in trophectoderm cells of the conceptus. The expression of G protein-coupled receptors for LPA was also examined in the ovine conceptus. LPA receptor LPAR1 and LPAR3 transcripts were expressed during early pregnancy and displayed a peak on d 14, whereas the highest level of protein for both receptors was observed at d 17. LPAR1 was localized in cellular membranes and nuclear compartments of the trophectoderm cells, whereas LPAR3 was revealed only in membranes. LPA activated phosphorylation of the MAPK ERK1/2 in ovine trophectoderm-derived cells. Moreover, the bioactive lipid increased the proliferation of trophectoderm cells in culture, as shown by thymidine and bromodeoxyuridine incorporation. Furthermore, LPA induced changes to the organization of β-actin and α-tubulin, suggesting a role for it in rearrangement of trophectoderm cells cytoskeleton. Because a link had previously been established between prostaglandin and LPA pathways, we analyzed the effect of LPA on prostaglandin synthesis. LPA induced an increase in the release of prostaglandin F2α and prostaglandin E2, with no significant modifications to cytosolic phospholipase A2α and prostaglandin synthase-2 expression. Taken together, our results suggest a new role for LPA-mediated signaling in the ovine conceptus at the time of implantation.

Lysophosphatidic acid (LPA) receptor 1 (R1) and LPAR3 mediate signaling of lysophosphatidic acid produced by autotaxin and induce prostaglandin biosynthesis and cytoskeleton changes in ovine trophectoderm cells at implantation time.
Identification of Novel Biphenyl Carboxylic Acid Derivatives as Novel Antiresorptive Agents that Do Not Impair Parathyroid Hormone-Induced Bone Formation
Authors: Idris Aymen I. , Greig Iain R. , Bassonga-Landao Euphemie , Ralston Stuart H. , van 't Hof Rob J.
Published: September 2008

Bisphosphonates are widely used in the treatment of osteoporosis, but they inhibit bone formation and blunt the anabolic effect of PTH. Here we describe a novel series of compounds that have potent antiresorptive effects in vitro and in vivo that do not adversely affect osteoblast function. The effects of the compounds on osteoclast formation and survival were studied on mouse osteoclasts generated from bone marrow macrophages and on osteoblast function using primary mouse calvarial osteoblast cultures and bone nodule cultures. Studies were performed in vivo using sham-operated or ovariectomized mice. The most potent compound tested was ABD350, a halogen-substituted derivative of the parent compound ABD56 in which the labile ester bond was replaced by a reduced ketone link, with IC50 osteoclast formation at a concentration of 1.3 μm. All compounds inhibited receptor activator of nuclear factor-κB ligand-induced inhibitor of nuclear factor κB phosphorylation and caused osteoclast apoptosis but no inhibitory effects on osteoblast function were observed at concentrations of up to 20μm. ABD350 prevented ovariectomy-induced bone loss when given ip (5 mg/kg · d), whereas ABD56 was only partially effective at this dose. In contrast to the bisphosphonate alendronate, ABD350 had no inhibitory effect on PTH-induced bone formation in ovariectomized mice. In conclusion, the biphenyl carboxylic acid derivatives like ABD350 represent a new class of antiresorptive drugs that inhibit osteoclast activity but have no significant inhibitory effects on osteoblast activity in vitro or PTH-induced bone formation in vivo.

The biphenyl-carboxylate ABD350 inhibits osteoclast formation in vitro and in vivo and, unlike the bisphosphonate Alendronate, does not inhibit the bone anabolic effects of PTH.
Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development
Authors: ten Berge Derk , Brugmann Samantha A. , Helms Jill A. , Nusse Roel
Published: September 2008

A fundamental question in developmental biology is how does an undifferentiated field of cells acquire spatial pattern and undergo coordinated differentiation? The development of the vertebrate limb is an important paradigm for understanding these processes. The skeletal and connective tissues of the developing limb all derive from a population of multipotent progenitor cells located in its distal tip. During limb outgrowth,these progenitors segregate into a chondrogenic lineage, located in the center of the limb bud, and soft connective tissue lineages located in its periphery. We report that the interplay of two families of signaling proteins, fibroblast growth factors (FGFs) and Wnts, coordinate the growth of the multipotent progenitor cells with their simultaneous segregation into these lineages. FGF and Wnt signals act together to synergistically promote proliferation while maintaining the cells in an undifferentiated, multipotent state, but act separately to determine cell lineage specification. Withdrawal of both signals results in cell cycle withdrawal and chondrogenic differentiation. Continued exposure to Wnt, however, maintains proliferation and re-specifies the cells towards the soft connective tissue lineages. We have identified target genes that are synergistically regulated by Wnts and FGFs, and show how these factors actively suppress differentiation and promote growth. Finally, we show how the spatial restriction of Wnt and FGF signals to the limb ectoderm, and to a specialized region of it, the apical ectodermal ridge, controls the distribution of cell behaviors within the growing limb, and guides the proper spatial organization of the differentiating tissues.
Luteinizing hormone causes MAP kinase-dependent phosphorylation and closure of connexin 43 gap junctions in mouse ovarian follicles: one of two paths to meiotic resumption
Authors: Norris Rachael P. , Freudzon Marina , Mehlmann Lisa M. , Cowan Ann E. , Simon Alexander M. , Paul David L. , Lampe Paul D. , Jaffe Laurinda A.
Published: September 2008

Luteinizing hormone (LH) acts on ovarian follicles to reinitiate meiosis in prophase-arrested mammalian oocytes, and this has been proposed to occur by interruption of a meioisis-inhibitory signal that is transmitted through gap junctions into the oocyte from the somatic cells that surround it. To investigate this idea, we microinjected fluorescent tracers into live antral follicle-enclosed mouse oocytes, and we demonstrate for the first time that LH causes a decrease in the gap junction permeability between the somatic cells,prior to nuclear envelope breakdown (NEBD). The decreased permeability results from the MAP kinase-dependent phosphorylation of connexin 43 on serines 255,262 and 279/282. We then tested whether the inhibition of gap junction communication was sufficient and necessary for the reinitiation of meiosis. Inhibitors that reduced gap junction permeability caused NEBD, but an inhibitor of MAP kinase activation that blocked gap junction closure in response to LH did not prevent NEBD. Thus, both MAP kinase-dependent gap junction closure and another redundant pathway function in parallel to ensure that meiosis resumes in response to LH.
Hematological changes associated with egg production: direct evidence for changes in erythropoiesis but a lack of resource dependence?
Authors: Wagner Emily C. , Stables Christine A. , Williams Tony D.
Published: September 2008

Reductions in hematological parameters among laying birds are well reported, but the cause of this anemia is not known. We tested specific predictions generated from several, non-mutually exclusive hypotheses for mechanisms underlying reproductive anemia associated with egg production(hemodilution, transient suppression of erythropoiesis, resource dependence)in relation to (1) the time-course of development and recovery from anemia,(2) changes in specific hematological traits, and (3) the effect of diet quality, in female zebra finches (Taeniopygia guttata). Female zebra finches showed marked decreases in hematocrit (∼6%), red blood cell counts(∼8%), and plasma hemoglobin concentration (∼9%) during egg production, even on a high-quality ad libitum diet, consistent with an effect of hemodilution associated with yolk precursor production. However,our results provide strong support for the hypothesis that erythropoiesis is transiently suppressed during egg-laying and that the recovery from anemia is relatively long-lasting, extending through incubation and hatching periods. Decreased hematocrit, red blood cell counts, and hemoglobin concentration did not recover at clutch completion, but showed evidence of recovery to baseline pre-breeding levels at hatching. More importantly, there was significant time-dependent variation in the proportion of reticulocytes, which increased at clutch completion but peaked at hatching 10–12 days after clutch completion, and in mean red blood cell volume, which showed a significant increase at clutch completion; consistent with enhanced production and release of larger immature cells into the circulation following suppression of erythropoiesis. Finally, we found no evidence for resource dependence of anemia associated with egg production in relation to diet quality, i.e. exogenous lipid and protein resources available to the laying female. This study demonstrates that transient suppression of erythropoiesis and,subsequently, increased reticulocytosis, are key components of reproductive anemia in egg-laying females.
The near and far wake of Pallas' long tongued bat (Glossophaga soricina)
Authors: Johansson L. Christoffer , Wolf Marta , von Busse Rhea , Winter York , Spedding Geoffrey R. , Hedenström Anders
Published: September 2008

The wake structures of a bat in flight have a number of characteristics not associated with any of the bird species studied to this point. Unique features include discrete vortex rings generating negative lift at the end of the upstroke at medium and high speeds, each wing generating its own vortex loop,and a systematic variation in the circulation of the start and stop vortices along the wingspan, with increasing strength towards the wing tips. Here we analyse in further detail some previously published data from quantitative measurements of the wake behind a small bat species flying at speeds ranging from 1.5 to 7 m s–1 in a wind tunnel. The data are extended to include both near- and far-wake measurements. The near-/far-wake comparisons show that although the measured peak vorticity of the start and stop vortices decreases with increasing downstream distance from the wing, the total circulation remains approximately constant. As the wake evolves, the diffuse stop vortex shed at the inner wing forms a more concentrated vortex in the far wake. Taken together, the results show that studying the far wake,which has been the standard procedure, nevertheless risks missing details of the wake. Although study of the far wake alone can lead to the misinterpretation of the wake topology, the net, overall circulation of the main wake vortices can be preserved so that approximate momentum balance calculations are not unreasonable within the inevitably large experimental uncertainties.
Fish and chips: functional genomics of social plasticity in an African cichlid fish
Authors: Renn Susan C. P. , Aubin-Horth Nadia , Hofmann Hans A.
Published: September 2008

Behavior and physiology are regulated by both environment and social context. A central goal in the study of the social control of behavior is to determine the underlying physiological, cellular and molecular mechanisms in the brain. The African cichlid fish Astatotilapia burtoni has long been used as a model system to study how social interactions regulate neural and behavioral plasticity. In this species, males are either socially dominant and reproductively active or subordinate and reproductively suppressed. This phenotypic difference is reversible. Using an integrative approach that combines quantitative behavioral measurements, functional genomics and bioinformatic analyses, we examine neural gene expression in dominant and subordinate males as well as in brooding females. We confirm the role of numerous candidate genes that are part of neuroendocrine pathways and show that specific co-regulated gene sets (modules), as well as specific functional gene ontology categories, are significantly associated with either dominance or reproductive state. Finally, even though the dominant and subordinate phenotypes are robustly defined, we find a surprisingly high degree of individual variation in the transcript levels of the very genes that are differentially regulated between these phenotypes. The results of the present study demonstrate the molecular complexity in the brain underlying social behavior, identify novel targets for future studies, validate many candidate genes and exploit individual variation in order to gain biological insights.
Urea loading enhances freezing survival and postfreeze recovery in a terrestrially hibernating frog
Authors: Costanzo Jon P. , Lee Richard E.
Published: September 2008

We tested the hypothesis that urea, an osmolyte accumulated early in hibernation, functions as a cryoprotectant in the freeze-tolerant wood frog, Rana sylvatica. Relative to saline-treated, normouremic (10 μmol ml–1) frogs, individuals rendered hyperuremic (70 μmol ml–1) by administration of an aqueous urea solution exhibited significantly higher survival (100% versus 64%) following freezing at–4°C, a potentially lethal temperature. Hyperuremic frogs also had lower plasma levels of intracellular proteins (lactate dehydrogenase, creatine kinase, hemoglobin), which presumably escaped from damaged cells, and more quickly recovered neurobehavioral functions following thawing. Experimental freezing–thawing did not alter tissue urea concentrations, but did elevate glucose levels in the blood and organs of all frogs. When measured 24 h after thawing commenced, glucose concentrations were markedly higher in urea-loaded frogs as compared to saline-treated ones, possibly because elevated urea retarded glucose clearance. Like other low-molecular-mass cryoprotectants, urea colligatively reduces both the amount of ice forming within the body and the osmotic dehydration of cells. In addition, by virtue of certain non-colligative properties, it may bestow additional protection from freeze–thaw damage not afforded by glucose.
In-flight corrections in free-flying barn owls (Tyto alba)during sound localization tasks
Authors: Hausmann Laura , Plachta Dennis T. T. , Singheiser Martin , Brill Sandra , Wagner Hermann
Published: September 2008

Barn owls localize a stationary auditory target with high accuracy. They might also be able to hit a target that is intermittently moving while the owl is approaching. If so, there should be a critical delay before strike initiation, up to which the owl can adapt its flight path to a new stimulus position. In this study, this critical stimulus delay was determined in a three-dimensional free-flight paradigm. Barn owls localized a pulsed broadband noise while sitting on a perch in total darkness. This initial signal stopped with the owl's take-off and an in-flight stimulus (target sound), lasting 200 ms, was introduced at variable time delays (300–1200 ms) during the approximate flight time of 1300 ms. The owls responded to the in-flight signal with a corrective head and body turn. The percentage of trials in which correction turns occurred (40–80%) depended upon the individual bird,but was independent of the stimulus delay within a range of 800 ms after take-off. Correction turns strongly decreased at delays ≥800 ms. The landing precision of the owls, defined as their distance to the in-flight speaker, did not decrease with increasing stimulus delay, but decreased if the owl failed to perform a correction turn towards that speaker. Landing precision was higher for a short (50 cm) than for a large (100 cm) distance between the initial and the new target. Thus, the ability of barn owls to adapt their flight path to a new sound target depends on the in-flight stimulus delay, as well as on the distance between initial and novel targets.