bluuebunny/crossref_metadata_2025 huggingface dataset:
'Fat mass and obesity associated' gene (FTO): No significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents
Authors: Müller Timo D , Hinney Anke , Scherag André , Nguyen Thuy T , Schreiner Felix , Schäfer Helmut , Hebebrand Johannes , Roth Christian L , Reinehr Thomas
Published: September 2008

Background

We have previously identified strong association of six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) to early onset extreme obesity within the first genome wide association study (GWA) for this phenotype. The aim of this study was to investigate whether the obesity risk allele of one of these SNPs (rs9939609) is associated with weight loss in a lifestyle intervention program. Additionally, we tested for association of rs9939609 alleles with fasting blood parameters indicative of glucose and lipid metabolism.

Methods

We initially analysed rs9939609 in a case-control study comprising 519 German overweight and obese children and adolescents and 178 normal weight adults. In 207 of the obese individuals who took part in the outpatient obesity intervention program 'Obeldicks' we further analysed whether carrier status of the obesity risk A-allele of rs9939609 has a differential influence on weight loss after the intervention program. Additionally, we investigated in 480 of the overweight and obese patients whether rs9939609 is associated with fasting blood levels of glucose, triglycerides and HDL and LDL-cholesterol. Genotyping was performed using allele specific polymerase chain reaction (ARMS-PCR). For the association study (case-control approach), the Cochran-Armitage trend test was applied. Blood parameters were analysed using commercially available test kits and the log10-transformed blood parameters and changes in BMI-standard deviation scores (BMI-SDS) were analysed by linear regression with sex and age as covariates under an additive mode of inheritance with the rs9939609 A-allele as risk allele.

Results

We confirmed the association of the risk A-allele of rs9939609 with overweight and early onset obesity (one sided p = 0.036). However, we observed no association of rs9939609 alleles with weight loss or fasting levels of blood glucose, triglycerides and cholesterol.

Conclusion

We confirmed the rs9939609 A-allele as a risk factor for early onset obesity whereas its impact on weight loss or on serum levels of glucose, triglycerides and cholesterol could not be detected in our samples.

Trial Registration

This study is registered at clinicaltrials.gov (NCT00435734).
Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2mutations
Authors: Zhang Xianqin , Chen Shenghan , Zhang Li , Liu Mugen , Redfearn Sharon , Bryant Randall M , Oberti Carlos , Vincent G Michael , Wang Qing K
Published: September 2008

Background

KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.

Methods

In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.

Results

LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).

Conclusion

Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.
Keratin 8 expression in head and neck epithelia
Authors: Matthias Christoph , Mack Brigitte , Berghaus Alexander , Gires Olivier
Published: September 2008

Background

The intermediate filament forming protein keratin 8 (K8) is a tumour-associated antigen, which was shown to be over-expressed in a variety of malignancies. Here, we present a study of K8 expression in squamous epithelia of the head and neck area, including normal mucosa, hyperplastic and dysplastic leukoplakia, carcinomas of different sub-localisations, and lymph node metastases.

Methods

K8 expression was assessed upon immunohistochemistry with specific antibodies in cryosections of primary tumours of the head and neck area.

Results

K8 expression was characteristic of transformed tissue and marked early stages of disease, i.e. dysplastic oral leukoplakia, but not normal or hyperplastic epithelium. With the exception of carcinomas of the larynx and the tongue, K8 expression also strictly differentiated carcinomas from normal epithelium of the same origin. Furthermore, K8high was characteristic of cells, which had detached from the sites of primary tumours and had been invading the surrounding tissue at the time point of surgery.

Conclusion

K8 is an excellent marker for head and neck malignancies, which allows for early detection as well as for visualisation of potentially disseminating tumour cells in vivo.
Secular changes in height, weight and body mass index in Hong Kong Children
Authors: So Hung-Kwan , Nelson Edmund AS , Li Albert M , Wong Eric MC , Lau Joseph TF , Guldan Georgia S , Mak Kwok-Hang , Wang Youfa , Fok Tai-Fai , Sung Rita YT
Published: September 2008

Background

Large population growth surveys of children and adolescents aged 6 to 18 y were undertaken in Hong Kong in 1963 and 1993. The global epidemic of obesity is a major public health concern. To monitor the impact of this epidemic in Hong Kong children and to identify secular changes in growth, a further growth survey was undertaken in 2005/6.

Methods

Cross-sectional height and weight measurements of 14,842 children and adolescents aged 6 to 18 y from Hong Kong's 18 districts were obtained during the 2005/6 school year. Percentile curves were constructed using LMS method and sex-specific percentile values of weight-for-age, height-for-age, and BMI-for-age were compared with those data from 1963 and 1993.

Results

Secular changes in height, weight and BMI were noted between 1963 and 1993 and between 1993 and 2005/6. In the latter period, greater changes were observed at younger ages, and particularly in boys. On an annual basis, the 1993–2005/6 changes were less than those during 1963–1993. Using the International Obesity Task Force cut-offs, 16.7% of children were overweight or obese in 2005/6, which was a 5.1% increase since 1993.

Conclusion

These data provide policy-makers with further evidence of the secular changes in child growth and the increasing obesity epidemic among Hong Kong children.
Low wintertime vitamin D levels in a sample of healthy young adults of diverse ancestry living in the Toronto area: associations with vitamin D intake and skin pigmentation
Authors: Gozdzik Agnes , Barta Jodi Lynn , Wu Hongyu , Wagner Dennis , Cole David E , Vieth Reinhold , Whiting Susan , Parra Esteban J
Published: September 2008

Background

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes. Recent research indicates that concentrations of serum 25-hydroxyvitamin D [25(OH)D], the main indicator of vitamin D status, should be in excess of 75 nmol/L. Low levels of 25(OH)D have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, those of non-European ancestry are at a higher risk of having low vitamin D levels. The main goal of this study was to examine the vitamin D status and vitamin D intake of young Canadian adults of diverse ancestry during the winter months.

Methods

One hundred and seven (107) healthy young adults self-reporting their ancestry were recruited for this study. Each participant was tested for serum 25(OH)D concentrations and related biochemistry, skin pigmentation indices and basic anthropometric measures. A seven-day food diary was used to assess their vitamin D intake. An ANOVA was used to test for significant differences in the variables among groups of different ancestry. Linear regression was employed to assess the impact of relevant variables on serum 25(OH)D concentrations.

Results

More than 93% of the total sample had concentrations below 75 nmol/L. Almost three-quarters of the subjects had concentrations below 50 nmol/L. There were significant differences in serum 25(OH)D levels (p < 0.001) and vitamin D intake (p = 0.034) between population groups. Only the European group had a mean vitamin D intake exceeding the current Recommended Adequate Intake (RAI = 200 IU/day). Total vitamin D intake (from diet and supplements) was significantly associated with 25(OH)D levels (p < 0.001). Skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D (p = 0.033).

Conclusion

We observe that low vitamin D levels are more prevalent in our sample of young healthy adults than previously reported, particularly amongst those of non-European ancestry. Major factors influencing 25(OH)D levels were vitamin D intake and skin pigmentation. These data suggest a need to increase vitamin D intake either through improved fortification and/or supplementation.
RASSF1A protein expression and correlation with clinicopathological parameters in renal cell carcinoma
Authors: Tezval Hossein , Merseburger Axel S , Matuschek Ira , Machtens Stefan , Kuczyk Markus A , Serth Jürgen
Published: September 2008

Background

Epigenetic silencing of RAS association family 1A (RASSF1A) tumor suppressor gene occurs in various histological subtypes of renal cell carcinoma (RCC) but RASSF1A protein expression in clear cell RCC as well as a possible correlation with clinicopathological parameters of patients has not been analyzed at yet.

Methods

318 primary clear cell carcinomas were analyzed using tissue microarray analysis and immunohistochemistry. Survival analysis was carried out for 187 patients considering a follow-up period of 2–240 month.

Results

Expression of RASSF1A was found to be significantly decreased in tumoral cells when compared to normal tubular epithelial cells. RASSF1A immunopositivity was significantly associated with pT stage, group stage and histological grade of tumors and showed a tendency for impaired survival in Kaplan-Meier analysis.

Conclusion

While most tumors demonstrate a loss of RASSF1A protein, a subset of tumors was identified to exhibit substantial RASSF1A protein expression and show increased tumor progression. Thus RCC tumorigenesis without depletion of RASSF1A may be associated with an adverse clinical outcome.
beta-estradiol attenuates the anti-HIV-1 efficacy of Stavudine (D4T) in primary PBL
Authors: Zhang Mingjie , Huang Qingsheng , Huang Yong , Wood Owen , Yuan Weishi , Chancey Caren , Daniel Sylvester , Rios Maria , Hewlett Indira , Clouse Kathleen A , Dayton Andrew I
Published: September 2008

Background

Female hormones are known to play an important role in predisposition for many infectious diseases. Recent work suggests there are gender effects in HIV/AIDS progression. Here we ask whether the sex steroid hormone β-estradiol affects the replication of HIV-1 or the efficacy of a common anti-retroviral drug, Stavudine (D4T).

Results

Human PBL were infected with HIV-1 in the presence or absence of combinations of sex steroid hormones and the anti-retroviral drug, D4T. After seven days in culture, viral supernatants were assayed for HIV-1 p24 protein. β-estradiol resulted in a modest inhibition of HIV-1 replication of ~26%. However, 2 nM β-estradiol increased the amount of HIV-1 replication in the presence of 50 nM D4T from a baseline of 33% (+/- SE = 5.4) to 74% (+/- SE = 5.4) of control virus levels in the absence of drug. Both results were statistically highly significant (p < 0.001). β-estradiol did not increase the replication of a D4T-resistant strain of HIV in the presence of D4T. The effects were unlikely to be due to general cell inhibition or toxicity because these concentrations of drug and hormone cause no cytotoxicity in PBL as measured by trypan blue exclusion.

Conclusion

β-estradiol inhibited both HIV-1 replication in primary human PBL and the antiretroviral efficacy of D4T in PBL cultures. To optimize antiretroviral drug therapy, it may be necessary to monitor patient hormonal status.
Homonuclear 1H NMR and circular dichroism study of the HIV-1 Tat Eli variant
Authors: Watkins Jennifer D , Campbell Grant R , Halimi Hubert , Loret Erwann P
Published: September 2008

Background

The HIV-1 Tat protein is a promising target to develop AIDS therapies, particularly vaccines, due to its extracellular role that protects HIV-1-infected cells from the immune system. Tat exists in two different lengths, 86 or 87 residues and 99 or 101 residues, with the long form being predominant in clinical isolates. We report here a structural study of the 99 residue Tat Eli variant using 2D liquid-state NMR, molecular modeling and circular dichroism.

Results

Tat Eli was obtained from solid-phase peptide synthesis and the purified protein was proven biologically active in a trans-activation assay. Circular dichroism spectra at different temperatures up to 70°C showed that Tat Eli is not a random coil at 20°C. Homonuclear 1H NMR spectra allowed us to identify 1639 NMR distance constraints out of which 264 were interresidual. Molecular modeling satisfying at least 1474 NMR constraints revealed the same folding for different model structures. The Tat Eli model has a core region composed of a part of the N-terminus including the highly conserved Trp 11. The extra residues in the Tat Eli C-terminus protrude from a groove between the basic region and the cysteine-rich region and are well exposed to the solvent.

Conclusion

We show that active Tat variants share a similar folding pattern whatever their size, but mutations induce local structural changes.
Effect of Excitatory and Inhibitory Agents and a Glial Inhibitor on Optically-Recorded Primary-Afferent Excitation
Authors: Ikeda Hiroshi , Kiritoshi Takaki , Murase Kazuyuki
Published: September 2008

The effects of GABA, excitatory amino-acid receptors antagonists and a glial metabolism inhibitor on primary-afferent excitation in the spinal dorsal horn were studied by imaging the presynaptic excitation of high-threshold afferents in cord slices from young rats with a voltage-sensitive dye. Primary afferent fibers and terminals were anterogradely labeled with a voltage-sensitive dye from the dorsal root attached to the spinal cord slice. Single-pulse stimulation of C fiber-activating strength to the dorsal root elicited compound action potential-like optical responses in the superficial dorsal horn. The evoked presynaptic excitation was increased by the GABAA receptor antagonists picrotoxin and bicuculline, by glutamate receptor antagonists D-AP5 and CNQX, and by the glial metabolism inhibitor mono-fluoroacetic acid (MFA). The increase in presynaptic excitation by picrotoxin was inhibited in the presence of D-AP5, CNQX and MFA. Presynaptic modulation in the central terminal of fine primary afferents by excitatory and inhibitory amino acids may represent a mechanism that regulates the transmission of pain.
Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood
Authors: Aspler Anne L , Bolshin Carly , Vernon Suzanne D , Broderick Gordon
Published: September 2008

Background

Genomic profiling of peripheral blood reveals altered immunity in chronic fatigue syndrome (CFS) however interpretation remains challenging without immune demographic context. The object of this work is to identify modulation of specific immune functional components and restructuring of co-expression networks characteristic of CFS using the quantitative genomics of peripheral blood.

Methods

Gene sets were constructed a priori for CD4+ T cells, CD8+ T cells, CD19+ B cells, CD14+ monocytes and CD16+ neutrophils from published data. A group of 111 women were classified using empiric case definition (U.S. Centers for Disease Control and Prevention) and unsupervised latent cluster analysis (LCA). Microarray profiles of peripheral blood were analyzed for expression of leukocyte-specific gene sets and characteristic changes in co-expression identified from topological evaluation of linear correlation networks.

Results

Median expression for a set of 6 genes preferentially up-regulated in CD19+ B cells was significantly lower in CFS (p = 0.01) due mainly to PTPRK and TSPAN3 expression. Although no other gene set was differentially expressed at p < 0.05, patterns of co-expression in each group differed markedly. Significant co-expression of CD14+ monocyte with CD16+ neutrophil (p = 0.01) and CD19+ B cell sets (p = 0.00) characterized CFS and fatigue phenotype groups. Also in CFS was a significant negative correlation between CD8+ and both CD19+ up-regulated (p = 0.02) and NK gene sets (p = 0.08). These patterns were absent in controls.

Conclusion

Dissection of blood microarray profiles points to B cell dysfunction with coordinated immune activation supporting persistent inflammation and antibody-mediated NK cell modulation of T cell activity. This has clinical implications as the CD19+ genes identified could provide robust and biologically meaningful basis for the early detection and unambiguous phenotyping of CFS.
A phase I radiation dose-escalation study to determine the maximal dose of radiotherapy in combination with weekly gemcitabine in patients with locally advanced pancreatic adenocarcinoma
Authors: Budiharto Tom , Haustermans Karin , Van Cutsem Eric , Van Steenbergen Werner , Topal Baki , Aerts Raymond , Ectors Nadine , Bielen Didier , Vanbeckevoort Dirk , Goethals Laurence , Verslype Chris
Published: September 2008

Background

The primary objective of this study was to determine the maximum tolerated dose (MTD) of escalating doses of radiotherapy (RT) concomitantly with a fixed dose of gemcitabine (300 mg/m2/week) within the same overall treatment time.

Methods

Thirteen patients were included. Gemcitabine 300 mg/m2/week was administered prior to RT. The initial dose of RT was 45 Gy in 1.8 Gy fractions, escalated by adding 5 fractions of 1.8 Gy (one/week) to a dose of 54 Gy with a total duration kept at 5 weeks. All patients received a dynamic MRI to assess the pancreatic respiratory related movements. Toxicity was scored using the RTOG-EORTC toxicity criteria.

Results

Three of six patients experienced an acute dose limiting toxicity (DLT) at the 54 Gy dose level. For these patients a grade III gastro-intestinal toxicity (GI) was noted. Patients treated at the 45 Gy dose level tolerated therapy without DLT. The 54 Gy dose level was designated as the MTD and was deemed not suitable for further investigation.

Between both dose levels, there was a significant difference in percentage weight loss (p = 0.006) and also in cumulative GI toxicity (p = 0.027). There was no grade 3 toxicity in the 45 Gy cohort versus 4 grade 3 toxicity events in the 54 Gy cohort. The mean dose to the duodenum was significantly higher in the 54 Gy cohort (38.45 Gy vs. 51.82 Gy; p = 0.001).

Conclusion

Accelerated dose escalation to a total dose of 54 Gy with 300 mg/m2/week gemcitabine was not feasible. GI toxicity was the DLT. Retrospectively, the dose escalation of 9 Gy by accelerated radiotherapy might have been to large. A dose of 45 Gy is recommended. Considering the good patient outcomes, there might be a role for the investigation of a fixed dose of gemcitabine and concurrent RT with small fractions (1.8 Gy/day) in borderline resectable or unresectable non-metastatic locally advanced pancreatic cancer.
Role of Smac/DIABLO in cancer progression
Authors: Martinez-Ruiz Gustavo , Maldonado Vilma , Ceballos-Cancino Gisela , Grajeda Juan P Reyes , Melendez-Zajgla Jorge
Published: September 2008

Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) is a proapoptogenic mitochondrial protein that is released to the cytosol in response to diverse apoptotic stimuli, including commonly used chemotherapeutic drugs. In the cytosol, Smac/DIABLO interacts and antagonizes inhibitors of apoptosis proteins (IAPs), thus allowing the activation of caspases and apoptosis. This activity has prompted the synthesis of peptidomimetics that could potentially be used in cancer therapy. For these reasons, several authors have analyzed the expression levels of Smac/DIABLO in samples of patients from different tumors. Although dissimilar results have been found, a tissue-specific role of this protein emerges from the data. The objective of this review is to present the current knowledge of the Smac/DIABLO role in cancer and its possible use as a marker or therapeutic target for drug design.
Ischemic volvulus of the transverse colon: A case report and review of literature
Authors: Sparks Dorothy A , Dawood Murtaza Y , Chase Daniel M , Thomas David J
Published: September 2008

A 75-year old male presented to the emergency room with worsening abdominal pain and distension. Plain radiographs were suggestive of a large bowel obstruction due to volvulus. An attempt to detorse the volvulus and decompress the colon endoscopically failed, after which the patient was taken for an exploratory laparotomy. A transverse colon volvulus was found, and an extended right hemicolectomy and ileostomy was performed. We discuss the diagnosis and management of transverse colon volvulus and review the pertinent literature.
Journal of the International AIDS Society: an important step forward
Authors: Wainberg Mark A , Katabira Elly , Heidari Shirin
Published: September 2008

This editorial welcomes readers to the launch of Journal of the International AIDS society.
Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer
Authors: Borgquist Signe , Jögi Annika , Pontén Fredrik , Rydén Lisa , Brennan Donal J , Jirström Karin
Published: September 2008

Introduction

We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up.

Methods

The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS).

Results

In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours.

Conclusions

HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.
Model-driven analysis of experimentally determined growth phenotypes for 465 yeast gene deletion mutants under 16 different conditions
Authors: Snitkin Evan S , Dudley Aimée M , Janse Daniel M , Wong Kaisheen , Church George M , Segrè Daniel
Published: September 2008

Background

Understanding the response of complex biochemical networks to genetic perturbations and environmental variability is a fundamental challenge in biology. Integration of high-throughput experimental assays and genome-scale computational methods is likely to produce insight otherwise unreachable, but specific examples of such integration have only begun to be explored.

Results

In this study, we measured growth phenotypes of 465 Saccharomyces cerevisiae gene deletion mutants under 16 metabolically relevant conditions and integrated them with the corresponding flux balance model predictions. We first used discordance between experimental results and model predictions to guide a stage of experimental refinement, which resulted in a significant improvement in the quality of the experimental data. Next, we used discordance still present in the refined experimental data to assess the reliability of yeast metabolism models under different conditions. In addition to estimating predictive capacity based on growth phenotypes, we sought to explain these discordances by examining predicted flux distributions visualized through a new, freely available platform. This analysis led to insight into the glycerol utilization pathway and the potential effects of metabolic shortcuts on model results. Finally, we used model predictions and experimental data to discriminate between alternative raffinose catabolism routes.

Conclusions

Our study demonstrates how a new level of integration between high throughput measurements and flux balance model predictions can improve understanding of both experimental and computational results. The added value of a joint analysis is a more reliable platform for specific testing of biological hypotheses, such as the catabolic routes of different carbon sources.
The extracellular matrix protein mindin regulates trafficking of murine eosinophils into the airspace
Authors: Li Zhuowei , Garantziotis Stavros , Jia Wei , Potts Erin N , Lalani Sikander , Liu Zhi , He You-Wen , Foster W Michael , Hollingsworth John W
Published: September 2008

Asthma remains a major cause of morbidity and hospitalizations in developed nations. Despite the widespread prevalence of this disease, the genetic and environmental factors that mediate development and progression of allergic airways disease remain poorly understood. Pulmonary recruitment of eosinophils is believed to contribute to many cardinal features of allergic airways disease. Therefore, it is paramount to understand host factors that contribute to pulmonary eosinophil recruitment into the lungs. Mindin is a component of pulmonary extracellular matrix, which can regulate inflammatory cell recruitment. We characterized the role of mindin in the severity of allergic airways disease using established murine models. There were no baseline differences in wild-type and mindin-deficient animals in cell counts or airway physiology. Using the OVA murine model of allergic airways disease, we observed that mindin-deficient animals have less-severe allergic airways disease with fewer airspace eosinophils and lower lung-lavage levels of inflammatory Th2 cytokines such as IL-13 and IL-4. Furthermore, mindin-deficient animals have reduced airway hyper-responsiveness after methacholine challenge. To determine the role of mindin in eosinophil trafficking, independent of antigen immunization or T lymphocyte activation, we instilled IL-13 directly into the lungs of mice. In this model, mindin regulates eosinophil recruitment into the airspace. In vitro experiments demonstrate that mindin can enhance eotaxin-mediated eosinophil adhesion and migration, which are dependent on the expression of integrins αMβ2 and α4β1. In conclusion, these data suggest that mindin participates in integrin-dependent trafficking of eosinophils and can contribute to the severity of allergic airways disease.
Modulation of dendritic cell function by persistent viruses
Authors: Liu Bisheng , Woltman Andrea M , Janssen Harry L A , Boonstra Andre
Published: September 2008

Worldwide, chronic viral infections cause major health problems with severe morbidity and mortality. HIV and hepatitis C virus (HCV) manifest themselves as persistent infections, but they are entirely distinct viruses with distinct replication mechanisms, tropism, and kinetics. Coinfections with HCV among people with HIV are emerging as a growing problem. Cellular immune responses play an important role in viral clearance and disease pathogenesis. However, cellular immunity to HIV and HCV is affected severely in chronic patients. Various hypotheses have been proposed to explain the dysfunctional T cell response, including viral escape mutations, exhaustion of the T cell compartment, and the activity of regulatory T cells. Also, modulation of the function of dendritic cells (DC) has been suggested as one of the mechanisms used by persistent viruses to evade the immune system. In this review, we will focus on DC interactions with one murine persistent virus (lymphocytic choriomeningitis virus clone 13) and two human persistent viruses (HIV-1 and HCV), intending to examine if general strategies are used by persistent viruses to modulate the function of DC to improve our understanding of the mechanisms underlying the development and maintenance of viral persistence.
Locating water-filled karst caverns and estimating their volume using magnetic resonance soundings
Authors: Legchenko A. , Ezersky M. , Camerlynck C. , Al-Zoubi A. , Chalikakis K. , Girard J-F.
Published: September 2008

Magnetic resonance sounding (MRS) is a geophysical technique developed for groundwater exploration. This technique can be used for investigating karst aquifers. Generally, the study of a karst requires a 3D field setup and corresponding multichannel data-acquisition instruments. Now only single-channel MRS equipment is available; i.e., the time needed for a 3D MRS field survey is multiplied by a factor of four or five. Where karst caverns are natural hazards, as in the Dead Sea coastal area at Nahal Hever, Israel, even an approximate localization of potentially dangerous zones and a corresponding estimation of the hazard dimensions are useful. We studied numerically the accuracy of MRS estimations of the volume of different 3D targets aroundNahal Hever, shifting a 3D target inside the MRS loop and calculating the volume-estimation errors for each target position. The calculations covered targets of different sizes. The size and position of a target being unknown factors in a field survey, the numerical data were considered as random values to be analyzed statistically. Using a 1D approximation of the MRS solution and assuming a [Formula: see text] MRS loop, the volume of a 3D target under Nahal Hever conditions is estimated within a [Formula: see text] error when the target is smaller than the MRS loop, and within a [Formula: see text] error when the target size is about the same as the MRS loop. The lower threshold of karst-cavity detection with MRS is about [Formula: see text]. For such estimation, only one sounding is required.
Beamlet migration using local cosine basis
Authors: Wu Ru-Shan , Wang Yongzhong , Luo Mingqiu
Published: September 2008

We have developed the theoretical foundation and technical details of a migration method using a local-cosine-bases (LCB) beamlet propagator. A beamlet propagator for heterogeneous media based on local perturbation theory is derived, and a fast implementation method is constructed. The use of local background velocities and local perturbations results in a two-scale decomposition of beamlet propagators: a background propagator for large-scale structures and a local phase-screen correction for small-scale local perturbations. Because of its locally adaptive nature, the beamlet propagator can handle strong lateral velocity variations with improved accuracy. For high-efficiency migration, we use a table-driven method and apply some techniques of sparse matrix operations. Compared with the Fourier finite-dif-ference and generalized screen propagator methods, the image quality and computational efficiency are similar. In some cases, we see fewer migration artifacts around and inside salt bodies with our method. We attribute this to the better high-angle accuracy of beamlet propagators in strong-contrast media. Numerical tests using synthetic data sets of the SEG-EAGE 2D salt model, Marmousi model, and Sigsbee 2A model demonstrate its high accuracy and reasonable efficiency. Another special feature of LCB beamlet migration is the availability of information in the local wavenumber domain during migration, which can be used to correct acquisition aperture effect and for other processing. Compared to beamlet migration using the Gabor-Daubechies frame (GDF) propagator, LCB migration is much more efficient because LCB is an orthonormal basis, whereas GDF has redundancy (usually greater than two) in the decomposition.
Seismic signal penetration beneath postrift sills on the Newfoundland rifted margin
Authors: Shillington Donna J. , Hopper John R. , Steven Holbrook W.
Published: September 2008

Analysis of averaged, smoothed instantaneous frequency and amplitude of seismic-reflection data collected on the Newfoundland magma-starved rifted margin along the Ocean Drilling Program (ODP) leg 210 transect demonstrate that the transparency of “transitional” crust arises from poor signal penetration. In principle, the high-frequency spectral content and amplitude of seismic reflection data should decrease with increasing traveltime as a result of absorption, geometric spreading, and scattering so long as seismic energy continues to return from deeper levels of the subsurface. As a result, if average frequency and amplitude cease to decrease with depth, background noise, rather than returning seismic energy, likely dominates the record. Average frequency increases and average amplitude remains comparatively constant below bright reflections overlying transitional crust on the Newfoundland margin. Similar patterns are not observed at the sediment-basement contact farther seaward in oceanic crust where intracrustal reflections are apparent. In thoserecords, both amplitude and frequency continue to decrease steadily for at least [Formula: see text] below the top of basement. We interpret these observations as evidence that signal penetration is comparatively poor beneath bright reflections overlying transitional basement. Consequently, the featureless appearance of transitional crust on the Newfoundland margin in seismic-reflection profiles cannot be used to make inferences about its physical properties; instead, only seismic characteristics observed in rare basement highs that rise above bright reflections in the lowermost sedimentary section can provide meaningful information. Weak signal penetration in this crustal domain is consistent with the results from site 1276 during ODP leg 210, where interlayered diabase sills and sediments were recovered above basement, which would be expected to result in high reflection coefficients and low signal penetration. The apparent lack of seismic penetration throughout the transition zone off Newfoundland also implies interlayered sills and sediments might be widespread over this crustal domain.
Suppression of Notch Signaling in the Neonatal Mouse Ovary Decreases Primordial Follicle Formation
Authors: Trombly Daniel J. , Woodruff Teresa K. , Mayo Kelly E.
Published: September 2008

Notch signaling directs cell fate during embryogenesis by influencing cell proliferation, differentiation, and apoptosis. Notch genes are expressed in the adult mouse ovary, and roles for Notch in regulating folliculogenesis are beginning to emerge from mouse genetic models. We investigated how Notch signaling might influence the formation of primordial follicles. Follicle assembly takes place when germ cell syncytia within the ovary break down and germ cells are encapsulated by pregranulosa cells. In the mouse, this occurs during the first 4–5 d of postnatal life. The expression of Notch family genes in the neonatal mouse ovary was determined through RT-PCR measurements. Jagged1, Notch2, and Hes1 transcripts were the most abundantly expressed ligand, receptor, and target gene, respectively. Jagged1 and Hey2 mRNAs were up-regulated over the period of follicle formation. Localization studies demonstrated that JAGGED1 is expressed in germ cells prior to follicle assembly and in the oocytes of primordial follicles. Pregranulosa cells that surround germ cell nests express HES1. In addition, pregranulosa cells of primordial follicles expressed NOTCH2 and Hey2 mRNA. We used an ex vivo ovary culture system to assess the requirement for Notch signaling during early follicle development. Newborn ovaries cultured in the presence of γ-secretase inhibitors, compounds that attenuate Notch signaling, had a marked reduction in primordial follicles compared with vehicle-treated ovaries, and there was a corresponding increase in germ cells that remained within nests. These data support a functional role for Notch signaling in regulating primordial follicle formation.

Gamma secretase inhibitor treatment suppresses germ cell nest breakdown in the neonatal mouse ovary, supporting a role for Notch signaling in promoting primordial follicle formation.
Induction of Heparanase in Bovine Granulosa Cells by Luteinizing Hormone: Possible Role during the Ovulatory Process
Authors: Klipper Eyal , Tatz Ehud , Kisliouk Tatiana , Vlodavsky Israel , Moallem Uzi , Schams Dieter , Lavon Yaniv , Wolfenson David , Meidan Rina
Published: September 2008

Follicular development, follicular rupture, and corpus luteum (CL) formation are accompanied by extensive tissue remodeling. We examined whether heparanase (HPSE), which cleaves heparan sulfate glycosaminoglycans, is induced during these processes. Prostaglandin F2α injection, which initiated luteolysis and the development of a preovulatory follicle, moderately increased HPSE mRNA in bovine granulosa cells (GCs). GnRH, used to induce gonadotropin surge, markedly augmented HPSE mRNA levels 12 h after its injection. The temporal pattern of HPSE gene expression in follicular-luteal transition was further examined in follicles collected before, and 4, 10, 20, 25, and 60 h after GnRH injection. HPSE mRNA increased transiently 10–20 h after GnRH injection to levels 10-fold higher than in untreated heifers. HPSE protein levels were similarly elevated 20 h after GnRH injection in GCs, but not in the theca layer. Cyclooxygenase-2 (PTGS2) mRNA peaked before ovulation when HPSE levels returned to baseline levels. HPSE mRNA abundance also remained low in the CLs. The antiprogesterone, RU-486, elevated HPSE levels in GC culture, suggesting that progesterone secreted by CLs may inhibit HPSE. HPSE immunostaining was more abundant in GCs than thecae. In cultured GCs, LH induced a transient increase in HPSE mRNA 3–6 h after its addition, but not at 24 h. However, PTGS2 mRNA was clearly induced at this time. These findings suggest that: 1) HPSE may play a role in ovulation but much less so during CL development, and 2) GC-derived HSPE may be a novel member of the LH-induced extracellular matrix-degrading enzyme family and may contribute to follicular rupture.

Granulosa-derived heparanase is a novel member of the luteinizing hormone-induced extracellular matrix-degrading enzymes contributing to follicular rupture and ovulation.
Identification and Characterization of Nesfatin-1 Immunoreactivity in Endocrine Cell Types of the Rat Gastric Oxyntic Mucosa
Authors: Stengel Andreas , Goebel Miriam , Yakubov Iskandar , Wang Lixin , Witcher Derrick , Coskun Tamer , Taché Yvette , Sachs George , Lambrecht Nils W. G.
Published: September 2008

Hypothalamic nesfatin-1, derived from the nucleobindin2 (NUCB2) precursor, inhibits nocturnal food intake and body weight gain in rats. Nesfatin-1 is able to cross the blood-brain barrier, suggesting a peripheral source of nesfatin-1. Many centrally acting food intake regulatory neuropeptides are also produced in the periphery, especially in the gastrointestinal tract. Therefore, we investigated the gene expression of NUCB2 and distribution of nesfatin-1-immunoreactive cells in the stomach. Microarray mRNA expression profiles in purified small endocrine cells of the gastric mucosa substantiated by quantitative RT-PCR showed significantly higher NUCB2 mRNA expression compared with brain and heart. Western blot confirmed the expression of NUCB2 protein and its transport into a secretory soluble fraction of gastric mucosal endocrine cell homogenates. Immunohistochemical colabeling for nesfatin-1 and ghrelin, histidine decarboxylase, or somatostatin revealed two subtypes of nesfatin-1-positive endocrine cells. Cells in the midportion of the glands coexpressed nesfatin-1 and ghrelin, whereas few cells in the glandular base coexpressed nesfatin-1 and somatostatin or histidine decarboxylase. High-resolution three-dimensional volume imaging revealed two separate populations of intracytoplasmic vesicles in these cells, one containing nesfatin-1 and the other ghrelin immunoreactivity. Microarray rat genome expression data of NUCB2 in small gastric endocrine cells confirmed by quantitative RT-PCR showed significant down-regulation of NUCB2 after 24 h fasting. In summary, NUCB2 mRNA expression as well as protein content is present in a specific subset of gastric endocrine cells, most of which coexpress ghrelin. NUCB2 gene expression is significantly regulated by nutritional status, suggesting a regulatory role of peripheral nesfatin-1 in energy homeostasis.

Nesfatin-1/nucleobindin 2 is co-expressed in gastric ghrelin-containing X/A-like cells, suggesting the release of orexigenic and anorexigenic peptides from the same endocrine cells regulating food intake.
Developmental and Diurnal Dynamics of Pax4 Expression in the Mammalian Pineal Gland: Nocturnal Down-Regulation Is Mediated by Adrenergic-Cyclic Adenosine 3′,5′-Monophosphate Signaling
Authors: Rath Martin F. , Bailey Michael J. , Kim Jong-So , Ho Anthony K. , Gaildrat Pascaline , Coon Steven L. , Møller Morten , Klein David C.
Published: September 2008

Pax4 is a homeobox gene that is known to be involved in embryonic development of the endocrine pancreas. In this tissue, Pax4 counters the effects of the related protein, Pax6. Pax6 is essential for development of the pineal gland. In this study we report that Pax4 is strongly expressed in the pineal gland and retina of the rat. Pineal Pax4 transcripts are low in the fetus and increase postnatally; Pax6 exhibits an inverse pattern of expression, being more strongly expressed in the fetus. In the adult the abundance of Pax4 mRNA exhibits a diurnal rhythm in the pineal gland with maximal levels occurring late during the light period. Sympathetic denervation of the pineal gland by superior cervical ganglionectomy prevents the nocturnal decrease in pineal Pax4 mRNA. At night the pineal gland is adrenergically stimulated by release of norepinephrine from the sympathetic innervation; here, we found that treatment with adrenergic agonists suppresses pineal Pax4 expression in vivo and in vitro. This suppression appears to be mediated by cAMP, a second messenger of norepinephrine in the pineal gland, based on the observation that treatment with a cAMP mimic reduces pineal Pax4 mRNA levels. These findings suggest that the nocturnal decrease in pineal Pax4 mRNA is controlled by the sympathetic neural pathway that controls pineal function acting via an adrenergic-cAMP mechanism. The daily changes in Pax4 expression may influence gene expression in the pineal gland.

The Pax4 homeobox gene is expressed in the postnatal pineal gland and exhibits a diurnal rhythm driven by adrenergic signaling, which suppresses nocturnal transcript levels.
Distinct Melanocortin 2 Receptor Accessory Protein Domains Are Required for Melanocortin 2 Receptor Interaction and Promotion of Receptor Trafficking
Authors: Webb Tom R. , Chan Li , Cooray Sadani N. , Cheetham Michael E. , Chapple J. Paul , Clark Adrian J. L.
Published: September 2008

Melanocortin 2 receptor (MC2R) is the receptor for the pituitary hormone ACTH. When activated, MC2R stimulates cAMP production and adrenal steroidogenesis. The functional expression of the receptor requires melanocortin 2 receptor accessory protein (MRAP), a single-transmembrane domain protein involved in the trafficking of MC2R from the endoplasmic reticulum to the cell surface. Mutations in both MC2R and MRAP cause the inherited disease familial glucocorticoid deficiency. At present, little is known regarding the mechanism of MRAP in MC2R functional expression. Here we report the characterization of MRAP in the trafficking of MC2R to the cell surface and the formation of a functional receptor. We identify the transmembrane domain of MRAP as the MC2R interaction domain and a conserved N-terminal tyrosine-rich domain of MRAP that is required for trafficking MC2R to the cell surface.

Melanocortin 2 receptor accessory protein interacts with the melanocortin 2 receptor (MC2R) via its transmembrane domain and requires a tyrosine-rich element for trafficking of the MC2R to the cell surface.
Severe Preeclampsia-Related Changes in Gene Expression at the Maternal-Fetal Interface Include Sialic Acid-Binding Immunoglobulin-Like Lectin-6 and Pappalysin-2
Authors: Winn Virginia D. , Gormley Matthew , Paquet Agnes C. , Kjaer-Sorensen Kasper , Kramer Anita , Rumer Kristen K. , Haimov-Kochman Ronit , Yeh Ru-Fang , Overgaard Michael T. , Varki Ajit , Oxvig Claus , Fisher Susan J.
Published: September 2008

Preeclampsia (PE), which affects 4–8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24–36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24–36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.

Gene expression analysis of placental basal plates from severe preeclamptic pregnancies and controls revealed differential expression of 55 genes, including Siglec-6 and pappalysin-2.