bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic, context-specific generation of Gene Ontology slims
Authors: Davis Melissa J , Sehgal Muhammad Shoaib B , Ragan Mark A
Published: October 2010

Background

The use of ontologies to control vocabulary and structure annotation has added value to genome-scale data, and contributed to the capture and re-use of knowledge across research domains. Gene Ontology (GO) is widely used to capture detailed expert knowledge in genomic-scale datasets and as a consequence has grown to contain many terms, making it unwieldy for many applications. To increase its ease of manipulation and efficiency of use, subsets calledGO slimsare often created by collapsing terms upward into more general, high-level terms relevant to a particular context. Creation of a GO slim currently requires manipulation and editing of GO by an expert (or community) familiar with both the ontology and the biological context. Decisions about which terms to include are necessarily subjective, and the creation process itself and subsequent curation are time-consuming and largely manual.

Results

Here we present an objective framework for generating customised ontology slims for specific annotated datasets, exploiting information latent in the structure of the ontology graph and in the annotation data. This framework combines ontology engineering approaches, and a data-driven algorithm that draws on graph and information theory. We illustrate this method by application to GO, generating GO slims at different information thresholds, characterising their depth of semantics and demonstrating the resulting gains in statistical power.

Conclusions

Our GO slim creation pipeline is available for use in conjunction with any GO-annotated dataset, and creates dataset-specific, objectively defined slims. This method is fast and scalable for application to other biomedical ontologies.
Dynamic, mating-induced gene expression changes in female head and brain tissues of Drosophila melanogaster
Authors: Dalton Justin E , Kacheria Tanvi S , Knott Simon RV , Lebo Matthew S , Nishitani Allison , Sanders Laura E , Stirling Emma J , Winbush Ari , Arbeitman Michelle N
Published: October 2010

Background

Drosophila melanogaster females show changes in behavior and physiology after mating that are thought to maximize the number of progeny resulting from the most recent copulation. Sperm and seminal fluid proteins induce post-mating changes in females, however, very little is known about the resulting gene expression changes in female head and central nervous system tissues that contribute to the post-mating response.

Results

We determined the temporal gene expression changes in female head tissues 0-2, 24, 48 and 72 hours after mating. Females from each time point had a unique post-mating gene expression response, with 72 hours post-mating having the largest number of genes with significant changes in expression. At most time points, genes expressed in the head fat body that encode products involved in metabolism showed a marked change in expression. Additional analysis of gene expression changes in dissected brain tissues 24 hours post-mating revealed changes in transcript abundance of many genes, notably, the reduced transcript abundance of genes that encode ion channels.

Conclusions

Substantial changes occur in the regulation of many genes in female head tissues after mating, which might underlie aspects of the female post-mating response. These results provide new insights into the physiological and metabolic changes that accompany changes in female behaviors.
Genome analysis and comparative genomics of a Giardia intestinalis assemblage E isolate
Authors: Jerlström-Hultqvist Jon , Franzén Oscar , Ankarklev Johan , Xu Feifei , Nohýnková Eva , Andersson Jan O , Svärd Staffan G , Andersson Björn
Published: October 2010

Background

Giardia intestinalis is a protozoan parasite that causes diarrhea in a wide range of mammalian species. To further understand the genetic diversity between the Giardia intestinalis species, we have performed genome sequencing and analysis of a wild-type Giardia intestinalis sample from the assemblage E group, isolated from a pig.

Results

We identified 5012 protein coding genes, the majority of which are conserved compared to the previously sequenced genomes of the WB and GS strains in terms of microsynteny and sequence identity. Despite this, there is an unexpectedly large number of chromosomal rearrangements and several smaller structural changes that are present in all chromosomes. Novel members of the VSP, NEK Kinase and HCMP gene families were identified, which may reveal possible mechanisms for host specificity and new avenues for antigenic variation. We used comparative genomics of the three diverse Giardia intestinalis isolates P15, GS and WB to define a core proteome for this species complex and to identify lineage-specific genes. Extensive analyses of polymorphisms in the core proteome of Giardia revealed differential rates of divergence among cellular processes.

Conclusions

Our results indicate that despite a well conserved core of genes there is significant genome variation between Giardia isolates, both in terms of gene content, gene polymorphisms, structural chromosomal variations and surface molecule repertoires. This study improves the annotation of the Giardia genomes and enables the identification of functionally important variation.
Coxiella burnetii Nine Mile II proteins modulate gene expression of monocytic host cells during infection
Authors: Mahapatra Saugata , Ayoubi Patricia , Shaw Edward I
Published: October 2010

Background

Coxiella burnetii is an intracellular bacterial pathogen that causes acute and chronic disease in humans. Bacterial replication occurs within enlarged parasitophorous vacuoles (PV) of eukaryotic cells, the biogenesis and maintenance of which is dependent on C. burnetii protein synthesis. These observations suggest that C. burnetii actively subverts host cell processes, however little is known about the cellular biology mechanisms manipulated by the pathogen during infection. Here, we examined host cell gene expression changes specifically induced by C. burnetii proteins during infection.

Results

We have identified 36 host cell genes that are specifically regulated when de novo
C. burnetii protein synthesis occurs during infection using comparative microarray analysis. Two parallel sets of infected and uninfected THP-1 cells were grown for 48 h followed by the addition of chloramphenicol (CAM) to 10 μg/ml in one set. Total RNA was harvested at 72 hpi from all conditions, and microarrays performed using Phalanx Human OneArray™ slides. A total of 784 (mock treated) and 901 (CAM treated) THP-1 genes were up or down regulated ≥2 fold in the C. burnetii infected vs. uninfected cell sets, respectively. Comparisons between the complementary data sets (using >0 fold), eliminated the common gene expression changes. A stringent comparison (≥2 fold) between the separate microarrays revealed 36 host cell genes modulated by C. burnetii protein synthesis. Ontological analysis of these genes identified the innate immune response, cell death and proliferation, vesicle trafficking and development, lipid homeostasis, and cytoskeletal organization as predominant cellular functions modulated by C. burnetii protein synthesis.

Conclusions

Collectively, these data indicate that C. burnetii proteins actively regulate the expression of specific host cell genes and pathways. This is in addition to host cell genes that respond to the presence of the pathogen whether or not it is actively synthesizing proteins. These findings indicate that C. burnetii modulates the host cell gene expression to avoid the immune response, preserve the host cell from death, and direct the development and maintenance of a replicative PV by controlling vesicle formation and trafficking within the host cell during infection.
Application of tumor-node-metastasis staging 2002 version in locally advanced hepatocellular carcinoma: is it predictive of surgical outcome?
Authors: Li Binkui , Yuan Yunfei , Chen Guihua , He Liru , Zhang Yaqi , Li Jinqing , Li Guohui , Lau Wan Yee
Published: October 2010

Background

Locally advanced (pT3-4N0M0) hepatocellular carcinoma (HCC) is a heterogeneous group of tumors, which consists of four different categories, including HCC with "multiple tumors more than 5 cm", "major vascular invasion", "invasion of adjacent organs", and "perforation of visceral peritoneum". The aim of our study was to verify whether the 2002 version of the Tumor-Node-Metastasis staging system could predict surgical outcomes in patients with locally advanced HCC.

Methods

We retrospectively reviewed 298 patients with pT3-4N0M0 HCC who underwent hepatic resection from 1993 to 2000 in an academic tertiary hospital. Overall survival (OS) and cumulative recurrence rate (CRR) of the four categories of locally advanced HCC patients were compared.

Results

In multivariate analysis, major vascular invasion was identified as the most significant factor (HR = 3.291, 95% CI 2.362-4.584, P < 0.001) followed by cirrhosis status on OS, and was found to be the only independent factor of CRR (HR = 2.242, 95% CI 1.811-3.358, P < 0.001) in patients with locally advanced HCC. Among the four categories of locally advanced HCC, OS was significantly worse, and CRR was significantly higher in patients with HCC with major vascular invasion (pT3) than with multiple tumors more than 5 cm (pT3); or tumor invasion of adjacent organs (pT4); or perforation of visceral peritoneum (pT4). No significant differences were observed in OS or CRR between the latter three groups of patients.

Conclusions

HCC with major vascular invasion, which are classified as pT3 under the current TNM staging, have the worst prognosis when compared with the other categories of pT3-4 disease. There is a need to redefine the T classification and to stratify locally advanced HCC.
Association of FcγRIIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression
Authors: Bournazos Stylianos , Grinfeld Jacob , Alexander Karen M , Murchison John T , Wallace William A , McFarlane Pauline , Hirani Nikhil , Simpson A John , Dransfield Ian , Hart Simon P
Published: October 2010

Background

A significant genetic component has been described for idiopathic pulmonary fibrosis (IPF). The R131H (rs1801274) polymorphism of the IgG receptor FcγRIIa determines receptor affinity for IgG subclasses and is associated with several chronic inflammatory diseases. We investigated whether this polymorphism is associated with IPF susceptibility or progression.

Methods

In a case-control study, we compared the distribution of FcγRIIa R131H genotypes in 142 patients with IPF and in 218 controls using allele-specific PCR amplification.

Results

No differences in the frequency of FcγRIIa genotypes were evident between IPF patients and control subjects. However, significantly impaired pulmonary function at diagnosis was observed in HH compared to RR homozygotes, with evidence of more severe restriction (reduced forced vital capacity (FVC)) and lower diffusing capacity for carbon monoxide (DLCO). Similarly, increased frequency of the H131 allele was observed in patients with severe disease (DLCO< 40% predicted) (0.53 vs. 0.38; p = 0.03). Furthermore, the H131 allele was associated with progressive pulmonary fibrosis as determined by > 10% drop in FVC and/or > 15% fall in DLCOat 12 months after baseline (0.48 vs. 0.33; p = 0.023).

Conclusions

These findings support an association between the FcγRIIa R131H polymorphism and IPF severity and progression, supporting the involvement of immunological mechanisms in IPF pathogenesis.
Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model
Authors: Westerweel Peter E , van Velthoven Cindy TJ , Nguyen Tri Q , den Ouden Krista , de Kleijn Dominique PV , Goumans Marie Jose , Goldschmeding Roel , Verhaar Marianne C
Published: October 2010

Background

Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. Recently it has been shown that circulating smooth muscle progenitor cells (SPC) contribute to intimal hyperplasia. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-β/BMP-6 signaling as potential underlying mechanism.

Methods

We isolated SPC from C57Bl/6 mice with streptozotocin-induced diabetes and controls. SPC differentiation was evaluated by immunofluorescent staining for αSMA and collagen Type I. SPC mRNA expression of TGF-β and BMP-6 was quantified using real-time PCR. Intima formation was assessed in cuffed femoral arteries. Homing of bone marrow derived cells to cuffed arterial segments was evaluated in animals transplanted with bone marrow from GFP-transgenic mice.

Results

We observed that SPC differentiation was accelerated and numeric outgrowth increased in diabetic animals (24.6 ± 8.8 vs 8.3 ± 1.9 per HPF after 10 days, p < 0.05). Quantitative real-time PCR showed increased expression of TGF-β and decreased expression of the BMP-6 in diabetic SPC. SPC were MAC-3 positive, indicative of monocytic lineage. Intima formation in cuffed arterial segments was increased in diabetic mice (intima/media ratio 0.68 ± 0.15 vs 0.29 ± 0.06, p < 0.05). In GFP-chimeric mice, bone marrow derived cells were observed in the neointima (4.4 ± 3.3 cells per section) and particularly in the adventitia (43.6 ± 9.3 cells per section). GFP-positive cells were in part MAC-3 positive, but rarely expressed α-SMA.

Conclusions

In conclusion, in a diabetic mouse model, SPC levels are increased and SPC TGF-β/BMP-6 expression is modulated. Altered TGF-β/BMP-6 expression is known to regulate smooth muscle cell differentiation and may facilitate SPC differentiation. This may contribute to exaggerated intimal hyperplasia in diabetes as bone marrow derived cells home to sites of neointima formation.
Lineage divergence detected in the malaria vector Anopheles marajoara (Diptera: Culicidae) in Amazonian Brazil
Authors: McKeon Sascha N , Lehr Margaret A , Wilkerson Richard C , Ruiz John F , Sallum Maria A , Lima Jose BP , Povoa Marinete M , Conn Jan E
Published: October 2010

Background

Cryptic species complexes are common among anophelines. Previous phylogenetic analysis based on the complete mtDNA COI gene sequences detected paraphyly in the Neotropical malaria vector Anopheles marajoara. The "Folmer region" detects a single taxon using a 3% divergence threshold.

Methods

To test the paraphyletic hypothesis and examine the utility of the Folmer region, genealogical trees based on a concatenated (white + 3' COI sequences) dataset and pairwise differentiation of COI fragments were examined. The population structure and demographic history were based on partial COI sequences for 294 individuals from 14 localities in Amazonian Brazil. 109 individuals from 12 localities were sequenced for the nDNA white gene, and 57 individuals from 11 localities were sequenced for the ribosomal DNA (rDNA) internal transcribed spacer 2 (ITS2).

Results

Distinct A. marajoara lineages were detected by combined genealogical analysis and were also supported among COI haplotypes using a median joining network and AMOVA, with time since divergence during the Pleistocene (<100,000 ya). COI sequences at the 3' end were more variable, demonstrating significant pairwise differentiation (3.82%) compared to the more moderate 2.92% detected by the Folmer region. Lineage 1 was present in all localities, whereas lineage 2 was restricted mainly to the west. Mismatch distributions for both lineages were bimodal, likely due to multiple colonization events and spatial expansion (~798 - 81,045 ya). There appears to be gene flow within, not between lineages, and a partial barrier was detected near Rio Jari in Amapá state, separating western and eastern populations. In contrast, both nDNA data sets (white gene sequences with or without the retention of the 4th intron, and ITS2 sequences and length) detected a single A. marajoara lineage.

Conclusions

Strong support for combined data with significant differentiation detected in the COI and absent in the nDNA suggest that the divergence is recent, and detectable only by the faster evolving mtDNA. A within subgenus threshold of >2% may be more appropriate among sister taxa in cryptic anopheline complexes than the standard 3%. Differences in demographic history and climatic changes may have contributed to mtDNA lineage divergence in A. marajoara.
The assessment of population exposure to chlorination by-products: a study on the influence of the water distribution system
Authors: Legay Christelle , Rodriguez Manuel J , Sérodes Jean Baptiste , Levallois Patrick
Published: October 2010

Background

The relationship between chlorination by-products (CBPs) in drinking water and human health outcomes has been investigated in many epidemiological studies. In these studies, population exposure assessment to CBPs in drinking water is generally based on available CBP data (e.g., from regulatory monitoring, sampling campaigns specific to study area). Since trihalomethanes (THMs) and haloacetic acids (HAAs) are the most documented CBP classes in drinking water, they are generally used as indicators of CBP exposure.

Methods

In this paper, different approaches to spatially assign available THM and HAA concentrations in drinking water for population exposure assessment purposes are investigated. Six approaches integrating different considerations for spatial variability of CBP occurrence within different distribution systems are compared. For this purpose, a robust CBP database (i.e., high number of sampling locations selected according to system characteristics) corresponding to nine distribution systems was generated.

Results and conclusion

The results demonstrate the high impact of the structure of the distribution system (e.g., presence of intermediary water infrastructures such as re-chlorination stations or reservoirs) and the spatial variability of CBPs in the assigned levels for exposure assessment. Recommendations for improving the exposure assessment to CBPs in epidemiological studies using available CBP data from water utilities are also presented.
Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer
Authors: King Judy A , Tan Fang , Mbeunkui Flaubert , Chambers Zachariah , Cantrell Sarah , Chen Hairu , Alvarez Diego , Shevde Lalita A , Ofori-Acquah Solomon F
Published: October 2010

Background

Activated leukocyte cell adhesion molecule (ALCAM) is implicated in the prognosis of multiple cancers with low level expression associated with metastasis and early death in breast cancer. Despite this significance, mechanisms that regulate ALCAM gene expression and ALCAM's role in adhesion of pre-metastatic circulating tumor cells have not been defined. We studied ALCAM expression in 20 tumor cell lines by real-time PCR, western blot and immunochemistry. Epigenetic alterations of the ALCAM promoter were assessed using methylation-specific PCR and bisulfite sequencing. ALCAM's role in adhesion of tumor cells to the vascular wall was studied in isolated perfused lungs.

Results

A common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiplecis-active elements including a functional p65 NF-κB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters.

Conclusion

Our data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer.
Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells
Authors: Mathews Lesley A , Hurt Elaine M , Zhang Xiaohu , Farrar William L
Published: October 2010

Background

Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes includingOct3/4andNanogand are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation.

Results

Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of bothStat3andSox1.

Conclusions

Using this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis.
Imperforate anus with a rectovestibular fistula and pseudotail: a case report
Authors: Raines Miranda D , Wills Marcia L , Jackson Gretchen P
Published: October 2010

Introduction

Human tails and pseudotails are rare sacrococcygeal lesions that are associated with a wide variety of anomalies and syndromes. Anorectal malformations are also relatively uncommon congenital defects that often occur in conjunction with syndromes or other congenital abnormalities. The anomalies associated with both disorders determine the timing and approach to surgical correction. We present an unusual case of a patient with both imperforate anus and a pseudotail in the absence of a syndrome or other associated anomalies and we emphasize the necessity of a thorough preoperative evaluation.

Case presentation

A Caucasian girl was born at term after an uncomplicated pregnancy and was noted at birth to have a skin-covered posterior midline mass and imperforate anus with a fistula to the vaginal vestibule. Ultrasound and magnetic resonance imaging revealed a predominately fatty lesion without presacral extension and ruled out associated spinal and cord abnormalities. The patient underwent diversion with colostomy and a mucous fistula in the newborn period as a fistulogram demonstrated a long fistulous tract to normal rectum and it was anticipated that anoplasty and resection of the mass would require extensive posterior dissection. The sacrococcygeal mass was removed during posterior sagittal anorectoplasty at the age of six weeks which was determined to be a pseudotail because of the composition of brown fat and cartilage. The patient is now 14 months old with normal bowel function after a colostomy takedown.

Conclusion

A comprehensive preoperative assessment and thoughtful operative plan were necessary in this unusual case because of the extensive differential diagnosis for sacrococcygeal masses in the newborn and the frequency of anomalies and syndromes associated with tail variants and imperforate anus. The pediatricians and neonatologists who initially evaluate such patients and the surgeons who correct these disorders must be aware of the potential pitfalls in their management.
A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes
Authors: Haimovich Beatrice , Reddell Michael T , Calvano Jacqueline E , Calvano Steve E , Macor Marie A , Coyle Susette M , Lowry Stephen F
Published: October 2010

Introduction

An endotoxin challenge, sepsis, and injury/trauma, trigger significant changes in human peripheral blood leukocytes (PBL) gene expression. In this study, we have sought to test the hypothesis that the Toll-like receptor 4 (TLR4) induced transcription patterns elicited in humans exposed to in vivo endotoxin would parallel gene expression patterns observed in trauma patients with initial non-infectious injury. In addition, we sought to identify functional modules that are commonly affected by these two insults of differing magnitude and duration.

Methods

PBL were obtained from seven adult human subject experimental groups. The groups included a group of healthy, hospitalized volunteers (n = 15), that comprised four study groups of subjects challenged with intravenous endotoxin, without or with cortisol, and two serial samplings of trauma patients (n = 5). The PBL were analyzed for gene expression using a 8,793 probe microarray platform (Gene Chip® Focus, Affymetrix). The expression of a subset of genes was determined using qPCR.

Results

We describe sequential selection criteria of gene expression data that identifies 445 genes that are significantly differentially expressed (both P ≤ 0.05 and >1.2 fold-change) in PBL derived from human subjects during the peak of systemic inflammatory responses induced by in vivo endotoxin, as well as in PBL obtained from trauma patients at 1 to 12 days after admission. We identified two functional modules that are commonly represented by this analysis. The first module includes more than 50 suppressed genes that encode ribosomal proteins or translation regulators. The second module includes up-regulated genes encoding key enzymes associated with glycolysis. Finally, we show that several circadian clock genes are also suppressed in PBL of surgical ICU patients.

Conclusions

We identified a group of >400 genes that exhibit similar expression trends in PBL derived from either endotoxin-challenged subjects or trauma patients. The suppressed translational and circadian clock modules, and the upregulated glycolytic module, constitute a robust and long lasting PBL gene expression signature that may provide a tool for monitoring systemic inflammation and injury.
Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults
Authors: Adamzik Michael , Eggmann Martin , Frey Ulrich H , Görlinger Klaus , Bröcker-Preuß Martina , Marggraf Günter , Saner Fuat , Eggebrecht Holger , Peters Jürgen , Hartmann Matthias
Published: October 2010

Introduction

Established biomarkers for the diagnosis of sepsis are procalcitonin, interleukin 6, and C-reactive protein. Although sepsis evokes changes of coagulation and fibrinolysis, it is unknown whether thromboelastometry can detect these alterations. We investigated whether thromboelastometry variables are suitable as biomarkers for severe sepsis in critically ill adults.

Methods

In the observational cohort study, blood samples were obtained from patients on the day of diagnosis of severe sepsis (n = 56) and from postoperative patients (n = 52), and clotting time, clot formation time, maximum clot firmness, alpha angle, and lysis index were measured with thromboelastometry. In addition, procalcitonin, interleukin 6, and C-reactive protein levels were determined. For comparison of biomarkers, receiver operating characteristic (ROC) curves were used, and the optimal cut-offs and odds ratios were calculated.

Results

In comparison with postoperative controls, patients with sepsis showed an increase in lysis index (97% ± 0.3 versus 92 ± 0.5; P < 0.001; mean and SEM) and procalcitonin (2.5 ng/ml ± 0.5 versus 30.6 ± 8.7; P < 0.001). Clot-formation time, alpha angle, maximum clot firmness, as well as interleukin 6 and C-reactive protein concentrations were not different between groups; clotting time was slightly prolonged. ROC analysis demonstrated an area under the curve (AUC) of 0.901 (CI 0.838 - 0.964) for the lysis index, and 0.756 (CI 0.666 - 0.846) for procalcitonin. The calculated cut-off for the lysis index was > 96.5%, resulting in a sensitivity of 84.2%, and a specificity of 94.2%, with an odds ratio of 85.3 (CI 21.7 - 334.5).

Conclusions

The thromboelastometry lysis index proved to be a more reliable biomarker of severe sepsis in critically ill adults than were procalcitonin, interleukin 6, and C-reactive protein. The results also demonstrate that early involvement of the hemostatic system is a common event in severe sepsis.
Joint PP-PS angle-stack analysis and AVA inversion in Grane Field, offshore Norway
Authors: Jenkinson Tim , Bansal Rishi , Martinez Alex , Matheney Mike , Khare Vijay , Cornaglia Vincent
Published: October 2010

Eleven years ago, publication of the UK North Sea Alba Field OBC converted-wave (PS) image examples by MacLeod et al. caused quite a stir. The authors provided convincing evidence that “the Alba survey is the first 3D OBC survey in which successful converted-wave imaging of the reservoir has created significant economic benefit.” Most of us with an interest in multicomponent seismology know it well, as Alba has become one of the classic examples of a “stealth” reservoir (Rape et al., 2005), having low P- but high S-impedance contrast. The Alba reservoir and others like it are difficult to recognize on conventional P-wave images, but they stand out quite nicely when viewed on their PS equivalents.
S-wave velocity and statics from ground-roll inversion
Authors: Roy Soumya , Stewart Robert R. , Al Dulaijan Khaled
Published: October 2010

We are interested in the near surface for many reasons including the need to see through it to resolve geology and resources at depth. The near-surface often consists of unconsolidated, low-velocity material which can cause time delays in passing seismic waves, especially S-waves. Hence, it is necessary to obtain a detailed near-surface S-wave velocity structure to correct for these delays. Multichannel analysis of surface waves (MASW) (Park et al., 1998 and 1999; Xia et al., 1999) is an effective and increasingly popular method to obtain a near-surface S-wave velocity. MASW uses Rayleigh waves (or ground roll) to create dispersion curves (phase velocity versus frequency plots). Then, the inversion of these dispersion curves for the fundamental mode provides the near-surface S-wave velocity. These velocities can be used to infer the S-wave receiver statics.
The ups and downs of ocean-bottom seismic processing: Applications of wavefield separation and up-down deconvolution
Authors: Wang Yi , Bale Richard , Grion Sergio , Holden Julian
Published: October 2010

A key advantage of acquiring multicomponent data using ocean-bottom sensors, whether using cables or nodes, is the ability to separate the wavefield into up- and downgoing parts. This opens up a host of attractive possibilities such as mirror imaging using the downgoing wave, attenuating receiver-side multiples using the upgoing wave only, or combining both up- and downgoing waves to completely remove the free-surface effect using up-down deconvolution. We focus here on the latter.
Shear-wave splitting in compliant rocks
Authors: Cary Peter , Li Xinxiang , Popov Gulia , Zhang Changjun
Published: October 2010

Shear-wave splitting is a phenomenon that has received a lot of attention primarily because of its connection with vertically aligned cracks or fractures within reservoirs. However, in most cases the largest amount of shear-wave splitting is observed to occur in the near-surface layers where the rocks are the least consolidated, and so are least likely to be stiff enough to support cracks. Ironically, we have observed during the processing of many multicomponent data sets in western Canada that the largest amounts of shear-wave splitting occur in an area where we least expect to see it— in the highly unconsolidated sediments that comprise the heavy oil plays in the northwestern part of Alberta. At first we thought that the rocks in this area were surely too soft to support cracks and therefore that shear-wave splitting would be smaller than observed elsewhere. The data have taught us that the opposite is true.
GEOPHYSICS BRIGHT SPOTS
Authors: Mahrer Ken
Published: October 2010

This is GEOPHYSICS' 75th year. In celebration, Vladimir Grechka, Tamas Nemeth, Enders Robinson, Sven Treitel, and Kees Wapenaar coordinated and compiled a commemorative special section in GEOPHYSICS. They asked each associate editor to write an overview, or suggest an expert or experts to write the overview, covering the associate editor's discipline within GEOPHYSICS. The response was wonderful. Seventeen papers were accepted; some are historical and others are tutorial. Since Kees worked so hard he deserves the credit: he wrote this month's Bright Spots column. In his words, “What follows is a discussion of … some bright spots between the bright spots.”
NOD2 Activation Induces Muscle Cell-Autonomous Innate Immune Responses and Insulin Resistance
Authors: Tamrakar Akhilesh K. , Schertzer Jonathan D. , Chiu Tim T. , Foley Kevin P. , Bilan Philip J. , Philpott Dana J. , Klip Amira
Published: October 2010

Insulin resistance is associated with chronic low-grade inflammation in vivo, largely mediated by activated innate immune cells. Cytokines and pathogen-derived ligands of surface toll-like receptors can directly cause insulin resistance in muscle cells. However, it is not known if intracellular pathogen sensors can, on their own, provoke insulin resistance. Here, we show that the cytosolic pattern recognition receptors nucleotide-binding oligomerization domain-containing protein (NOD)1 and NOD2 are expressed in immune and metabolic tissues and hypothesize that their activation in muscle cells would result in cell-autonomous responses leading to insulin resistance. Bacterial peptidoglycan motifs that selectively activate NOD2 were directly administered to L6- GLUT4myc myotubes in culture. Within 3 h, insulin resistance arose, characterized by reductions in each insulin-stimulated glucose uptake, GLUT4 translocation, Akt Ser473 phosphorylation, and insulin receptor substrate 1 tyrosine phosphorylation. Muscle cell-autonomous responses to NOD2 ligand included activation of the stress/inflammation markers c-Jun N-terminal kinase, ERK1/2, p38 MAPK, degradation of inhibitor of κBα, and production of proinflammatory cytokines. These results show that NOD2 alone is capable of acutely inducing insulin resistance within muscle cells, possibly by activating endogenous inflammatory signals and/or through cytokine production, curbing upstream insulin signals. NOD2 is hence a new inflammation target connected to insulin resistance, and this link occurs without the need of additional contributing cell types. This study provides supporting evidence for the integration of innate immune and metabolic responses through the involvement of NOD proteins and suggests the possible participation of cell autonomous immune responses in the development of insulin resistance in skeletal muscle, the major depot for postprandial glucose utilization.
Kisspeptin-10 Inhibits Angiogenesis in Human Placental Vessels ex Vivo and Endothelial Cells in Vitro
Authors: Ramaesh Thayalini , Logie James J. , Roseweir Antonia K. , Millar Robert P. , Walker Brian R. , Hadoke Patrick W. F. , Reynolds Rebecca M.
Published: October 2010

Recent studies suggest that kisspeptin (a neuropeptide central to the regulation of gonadotrophin secretion) has diverse roles in human physiology, including a putative role in implantation and placental function. Kisspeptin and its receptor are present in human blood vessels, where they mediate vasoconstriction, and kisspeptin is known to inhibit tumor metastasis and trophoblast invasion, both processes involving angiogenesis. We hypothesized that kisspeptin contributes to the regulation of angiogenesis in the reproductive system. The presence of the kisspeptin receptor was confirmed in human placental blood vessels and human umbilical vein endothelial cells (HUVEC) using immunochemistry. The ability of kisspeptin-10 (KP-10) (a shorter biologically active processed peptide) to inhibit angiogenesis was tested in explanted human placental arteries and HUVEC using complementary ex vivo and in vitro assays. KP-10 inhibited new vessel sprouting from placental arteries embedded in Matrigel and tube-like structure formation by HUVEC, in a concentration-dependent manner. KP-10 had no effect on HUVEC viability or apoptosis but induced concentration-dependent inhibition of proliferation and migration. In conclusion, KP-10 has antiangiogenic effects and, given its high expression in the placenta, may contribute to the regulation of angiogenesis in this tissue.
Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation
Authors: Yamada P. M. , Mehta H. H. , Hwang D. , Roos K. P. , Hevener A. L. , Lee K. W.
Published: October 2010

IGF-binding protein (IGFBP)-3 is a metabolic regulator that has been shown to inhibit insulin-stimulated glucose uptake in murine models. This finding contrasts with epidemiological evidence of decreased serum IGFBP-3 in patients with type 2 diabetes. The purpose of this study was to clarify the role of IGFBP-3 in metabolism. Four-week-old male IGFBP-3−/− and control mice were subjected to a high-fat diet (HFD) for 12 wk. IGFBP-3−/− mice were heavier before the initiation of HFD and at the end of the study period. Resting metabolic rate was significantly decreased in knockout mice; however, respiratory exchange ratio was not significantly different. Fasting blood glucose and insulin levels were significantly elevated in IGFBP-3−/− mice. However, IGFBP-3−/− mice had relatively normal glucose tolerance because the relative glucose excursion over time was not different between the groups. During hyperinsulinemic clamps, IGFBP-3−/− mice had increased basal hepatic glucose production, but after insulin stimulation, no differences in hepatic glucose production were observed. A second cohort of older IGFBP-3−/− mice on HFD displayed unexpected evidence of hepatic steatosis. In summary, glucose tolerance and clamp testing indicate that IGFBP-3−/− mice preserve insulin sensitivity despite evidence of increased basal glucose turnover and hepatic steatosis. We provide evidence that genetic deletion of IGFBP-3 modulates hepatic carbohydrate and lipid metabolism.
hCG-Induced Down-Regulation of PPARγ and Liver X Receptors Promotes Periovulatory Progesterone Synthesis by Macaque Granulosa Cells
Authors: Puttabyatappa Muraly , VandeVoort Catharine A. , Chaffin Charles L.
Published: October 2010

An ovulatory stimulus induces the rapid and dramatic increase in progesterone synthesis by the primate ovarian follicle. However, little is known about the early events leading to the shift from estrogen to progesterone production. Because steroidogenesis represents an aspect of cholesterol metabolism, it was hypothesized that transcription factors regulating cholesterol balance would be among the earliest to change in response to an ovulatory stimulus. Granulosa cells were isolated from rhesus monkey follicles following controlled ovarian stimulation protocols before or up to 24 hr after an ovulatory human chorionic gonadotropin (hCG) bolus. The peroxisome proliferator-activated receptor-γ (PPARG) and the liver X receptors [nuclear receptor (NR)1H2, NR1H3] decreased within 3 hr of hCG, as did the reverse cholesterol transporters ATP-binding cassette (ABC)A1 and ABCG1. Treatment of granulosa cells isolated before an ovulatory stimulus with hCG and rosiglitizone resulted in an increase in NR1H3 and ABCG1, and decreased steroidogenic acute regulatory (STAR) protein and scavenger receptor-BI (SCARB1). A liver X receptor agonist attenuated hCG-induced progesterone synthesis in vitro and increased the expression of ABCA1 and ABCG1, and suppressed STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B, and SCARB1. These data suggest that an initial action of LH/CG on the primate preovulatory follicle is to rapidly reduce the expression of PPARG, resulting in reduced NR1H3 with the consequence shifting the balance from cholesterol efflux via ABCA1 and ABCG1 to cholesterol uptake (SCARB1) and metabolism (STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B). That the regulation of PPARG and the liver X receptors occurs within 3 hr strongly indicates that early events in the primate luteinizing follicle are critical to successful ovulation and luteal formation.
Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
Authors: Finkielstain Gabriela P. , Chen Wuyan , Mehta Sneha P. , Fujimura Frank K. , Hanna Reem M. , Van Ryzin Carol , McDonnell Nazli B. , Merke Deborah P.
Published: October 2010

Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients.

Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype.

Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively.

Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.
Commentary: The Year in Circadian Rhythms
Authors: Sassone-Corsi Paolo
Published: October 2010

The circadian clock orchestrates intrinsic timing in most organisms and controls a large variety of physiological and metabolic programs. In my presentation “The Year in Circadian Rhythms” at the Endocrine Society meeting (San Diego, June 2010) I reviewed some of the recent spectacular developments of the field. The exceptional interest that circadian rhythms have suscitated during the past two decades has caused a remarkable increase in the number of researchers and of committed resources dedicated to the field. This has also generated the promise of potentially novel pharmacological strategies. Indeed, specific molecular pathways of circadian regulation have been recently linked to endocrine and metabolic control, as well as cell cycle and proliferation. Importantly, circadian gene expression involves an important proportion of cellular genes, underscoring the role played by dynamic mechanisms of chromatin remodeling. This suggests that the circadian machinery could have evolved as a privileged molecular interface between cellular metabolism and epigenetic control.
Efca, Alas, Is Not the Answer
Authors: Adams Roy J.
Published: October 2010

The presumptive theory underlying the Employee Free Choice Act (EFCA) is that American labor policy is basically sound and only needs a bit of tweaking to stimulate a new round of union growth. An estimate, attributed to Andy Stern, claims that upon EFCA's passage union membership would increase by 1.5 million members per year for ten to fifteen years.1 That prognosis flies in the face of the Canadian experience, where legislation incorporating card-check provisions and first contract arbitration, EFCA's key features, has been in effect for some time.
Despite Efca's Limitations, Its Demise Is a Profound Defeat for U.s. Labor
Authors: Lichtenstein Nelson
Published: October 2010

There are two ways to think about the Employee Free Choice Act (EFCA) and the political and ideological conditions that have led to its near-certain demise. The first way examines the law itself and its efficacy for creating conditions in which workers could join trade unions without overcoming obstacles usually found only in authoritarian, one-party regimes. The second way considers the status of American labor during the past few decades; it explores why every recent effort to reform the labor law has failed and why opposition to even the most incremental changes in the employer-employee relationship has been so militant and steadfast.
Towards a quantitative understanding of mitotic spindle assembly and mechanics
Authors: Mogilner Alex , Craig Erin
Published: October 2010

The ‘simple’ view of the mitotic spindle is that it self-assembles as a result of microtubules (MTs) randomly searching for chromosomes, after which the spindle length is maintained by a balance of outward tension exerted by molecular motors on the MTs connecting centrosomes and chromosomes, and compression generated by other motors on the MTs connecting the spindle poles. This picture is being challenged now by mounting evidence indicating that spindle assembly and maintenance rely on much more complex interconnected networks of microtubules, molecular motors, chromosomes and regulatory proteins. From an engineering point of view, three design principles of this molecular machine are especially important: the spindle assembles quickly, it assembles accurately, and it is mechanically robust – yet malleable. How is this design achieved with randomly interacting and impermanent molecular parts? Here, we review recent interdisciplinary studies that have started to shed light on this question. We discuss cooperative mechanisms of spindle self-assembly, error correction and maintenance of its mechanical properties, speculate on analogy between spindle and lamellipodial dynamics, and highlight the role of quantitative approaches in understanding the mitotic spindle design.