bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure and Causes of the Pulsation Mode in the Antarctic Circumpolar Current South of Australia
Authors: Dufour C. O. , Le Sommer J. , Penduff T. , Barnier B. , England M. H.
Published: September 2010

The subsurface variability of potential temperature and salinity south of Australia along 130°E is studied over a 25-yr period (1980–2004). The study is done with fields provided by a global eddy-permitting model of the DRAKKAR project forced by atmospheric reanalysis. The analysis performed by C. Sun and D. R. Watts with in situ hydrographic data is repeated. Sun and Watts have investigated the EOF modes in streamfunction space along the World Ocean Circulation Experiment (WOCE) SR3 section. In particular, they found that an EOF mode, which they called the “pulsation mode,” strongly dominates subsurface thermohaline variations. Here, it is found that, in the model, an EOF mode with spatial structure similar to the Sun and Watts pulsation mode dominates subsurface thermohaline variations in streamfunction space. The mode displays a maximum of variability at the Subantarctic Front (SAF) between Subantarctic Mode Water (SAMW) and Antarctic Intermediate Water (AAIW). The associated time series exhibits an intermittent interseasonal frequency (3–6 months), especially during three periods (1983–84, 1990, and 1994–96). Some energy is also found with a 4-yr period.

Further analyses reveal that the pulsation mode can also be observed in physical space. The pulsation mode is found to be related to movements of the SAF constrained by the bathymetry of the Southeast Indian Ridge. The pulsation mode displays many similarities with cold-core eddy events rather than being related to variations of the westerly wind stress, as previously proposed. The impact of those events on SAMW properties remains unclear.
A New Low-Cost, Stand-Alone Sensor System for Snow Monitoring
Authors: Varhola Andrés , Wawerla Jens , Weiler Markus , Coops Nicholas C. , Bewley Daniel , Alila Younes
Published: September 2010

Monitoring continuous changes in snowpack dynamics and its meteorological drivers is critical for understanding key aspects of water resources, climate variability, and ecology. While manual snow surveys have traditionally been used to evaluate snow processes, their high costs and discrete measurements can lead to biased estimations of accumulation and ablation rates. Ultrasonic range sensors offer an alternative to continuously monitor snow depth but their widespread employment has been limited because of high prices. This paper describes the development of an inexpensive prototype ultrasonic sensor suite characterized by a ready-to-use stand-alone design and flexibility to incorporate additional meteorological instruments. The performance of 48 units was tested during a winter season in central British Columbia, recording snow depth and air temperature data consistent with those from nearby weather stations and manual measurements. Despite a relatively small underestimation of snow depth due to known, repairable reasons, the sensor system demonstrated reliability for research and operations.
Exploring the Changing Meaning of Work for American High School Seniors From 1976 to 2005
Authors: Wray-Lake Laura , Syvertsen Amy K. , Briddell Laine , Osgood D. Wayne , Flanagan Constance A.
Published: September 2010

Using data from the Monitoring the Future study, this article presents historical trends in U.S. high school seniors’ work values across 30 years (1976-2005). Adolescents across three decades highly valued most aspects of work examined. Recent cohorts showed declines in the importance of work, values for job security, and various potential intrinsic rewards of work. After increasing until 1990, adolescents remained stable in their values for extrinsic and materialistic aspects of work until 2005. The value of work that allows for leisure time has steadily increased. Stable level differences in work values emerged for adolescents by gender, race, parents’ education, and college aspirations. Findings have implications for understanding the changing meaning of work for the future workforce.
Outbreak of Ataxia in Pigs Associated With Consumption of Piquillín (Condalia microphylla)
Authors: Delgado F. , Burtre C. , Capellino F. , Salvat A. , Blanco Viera F. J.
Published: September 2010

The plant piquillín ( Condalia microphylla) grows in arid regions of Argentina and is the cause of mal del piquillín in cattle. The salient histologic features of this leukomyelopathy are vacuolation of white matter and axonal degeneration in the spinal cord. The histologic lesions can be experimentally reproduced in cattle and pigs by feeding milled bark of the plant, but naturally occurring piquillín toxicosis has not been reported previously in pigs. The authors report an outbreak of progressive ataxia on an Argentine hog farm, where partially consumed piquillín plants were found in the pens of affected pigs. Histologic lesions included vacuolation of white matter, edema, and mild axonal degeneration in lumbosacral segments of the cord. The diagnosis of mal del piquillín was based on the history, clinical signs, histologic changes, and elimination of other potential causes of leukomyelopathy. No new outbreaks developed after elimination of piquillín from the hog lots. Results of this investigation indicate that C microphylla toxicosis can affect pigs under natural conditions and should be included in the differential diagnosis for porcine ataxia and leukomyelopathy in regions where the plant grows.
Effects of Angiotensin III on Protein, DNA, and Collagen Synthesis of Neonatal Cardiomyocytes and Cardiac Fibroblasts In Vitro
Authors: Wang Hong Xia , Zhang Qiu Fan , Zeng Xiang Jun , Wang Wen , Tang Chao Shu , Zhang Li Ke
Published: September 2010

This study compared angiotensin II (Ang II) and angiotensin III (Ang III) for their effects on rat neonatal cardiomyocytes and cardiac fibroblasts in vitro and discussed the possible role of Ang III in the pathogenesis of cardiac remodeling. To do so, protein synthesis, cardiac fibroblast proliferation, collagen synthesis, and secretion in response to treatment with Ang III and Ang II were investigated. Protein synthesis rate was assessed by3H-Leucine (3H-Leu) incorporation; the content of DNA was defined by3H-thymidine (3H-TdR) incorporation; and collagen synthesis and secretion were assessed by3H-proline (3H-Pro) incorporation. In neonatal cardiomyocytes, Ang III stimulated protein synthesis in a concentration-dependent manner, whereas in neonatal cardiac fibroblasts, DNA synthesis as well as collagen synthesis and secretion were increased in a concentration-dependent manner. Treatment with captopril, selective aminopeptidase A (APA) inhibitor (EC33), or selective aminopeptidase N inhibitor (PC18) had no effect on these outcomes. Treatment with losartan significantly decreased the effects of Ang III, except for cardiomyocyte protein synthesis. Compared with Ang II, Ang III could stimulate cardiomyocyte protein synthesis, cardiac fibroblast proliferation, and collagen synthesis and secretion. Furthermore, 10-7mol/L Ang II but not Ang III significantly increased APA activity in both cardiomyocytes and fibroblasts. All these results show the bioactive effects of Ang III on myocardial cells and suggest that Ang III could be an important independent factor besides Ang II in the regulation of cardiac function and may affect the pathogenesis of cardiac remodeling.
Migrant Male Domestic Workers in Comparative Perspective: Four Case Studies from Italy, India, Ivory Coast, and Congo
Authors: Bartolomei Maria Rita
Published: September 2010

This article is a contribution, from an anthropological perspective, to the understanding of how the current phase of globalization is transforming and shaping the meaning and the significance of paid domestic work, especially as far as the role of immigrant men as domestic workers is concerned. Drawing on literature about migration processes, gender relations, and domestic service, the article illustrates four case studies, set in Italy, Kerala, the Ivory Coast, and the Congo, respectively, from a comparative perspective. The research work adopted qualitative methodologies such as ethnographic interviews (355) and participant observation. The goal of the article is on one hand to show how, in all considered contexts, we witness a so-called racialization of paid domestic labor. On the other hand, the author’s fieldwork aims at raising attention to the fact that male domestic workers do not think of themselves as ‘‘failed patriarchs.’’ Migration processes, indeed, can affect gender relations and, consequently, the sexual division of labor in the domestic sphere in societies that both import and export labor.
Multiple sclerosis and epileptic seizures
Authors: Catenoix H , Marignier R , Ritleng C , Dufour M , Mauguière F , Confavreux C , Vukusic S
Published: September 2010

Background: The association between epilepsy and multiple sclerosis (MS) is not a coincidence.

Objective: Our objective was to compare MS patients with or without history of seizures.

Methods: In a population of 5041 MS patients, we identified 102 (2%) patients with epileptic seizures. In 67 patients (1.3%), epileptic seizure could not be explained by any cause other than MS.

Results: In these 67 patients, the median age at occurrence of the first epileptic seizure was 33 years. Epilepsy was the initial clinical manifestation of MS in seven patients. In total, 62 patients (92.5%) presented only one or a few seizures, and 18 patients (27%) presented at least one episode of status epilepticus, fatal in two. Compared with MS patients without epilepsy, there was no difference in gender, type of MS course and time from onset of MS to the progressive phase. Conversely, the median age at MS onset was earlier (25.0 years vs. 30, p < 0.0001) and there was a trend for a shorter time from MS onset to non-reversible disability.

Conclusions: Our study confirms an increased risk of epileptic seizures in MS patients. It underlines that seizures may be the first observable symptom in MS and the frequency and seriousness of status epilepticus.
From bumps in the road to the edge of chaos: The nature of change in adults
Authors: King Keenan Elizabeth
Published: September 2010

• Summary: This article explores the question of how human beings change, how change is constrained, and how change emerges out of and subsequently creates new forms of stability with adults. The emergence of Dynamic Systems Theories (DST) from developmental biology and neuroscience provide the tools to engage in such an understanding by attending to the issues of time, balance, influencing parameters (within person and sociocultural and material environments), and multiple adaptive and maladaptive pathways. DST provides the framework to understand the dynamic processes of bio-psychosocial factors that provide human beings with the stability and the flexibility to navigate the challenges and stressors of living. Complexity, the ability to experience inner continuity as one is changing, is a fluid balance that supports effective functioning.

• Findings: Key principles and concepts of DST describe multiple pathways of stability and change. A case example illustrates how DST helps social workers understand client experiences and responses to stressors, formulate initial and ongoing assessments, and monitor clients’ participation in change activities.

• Application: Social workers seek to help people who experience an imbalance due to an inability to effectively respond to the negative impact of a stressor. By understanding the various pathways of balance and imbalance along the continuum of continuity to change, social workers can better understand how stressors are impacting specific clients, and subsequently the kinds of change that would best assist each client.
The Benefits of Believing in Chance or Fate
Authors: Specht Jule , Egloff Boris , Schmukle Stefan C.
Published: September 2010

The death of a spouse is an extremely stressful life event that consequently causes a large drop in life satisfaction. Reactivity to the loss, however, varies markedly, a phenomenon that is currently not well understood. Because lack of controllability essentially contributes to the stressful nature of this incident, the authors analyzed whether individual differences in belief in external control influence the coping process. To examine this issue, widowed individuals ( N = 414) from a large-scaled panel study were followed for the 4 years before and after the loss by using a latent growth model. Results showed that belief in external control led to a considerably smaller decline in life satisfaction and higher scores in the year of the loss. Thus, although usually regarded as a risk factor, belief in external control seems to act as a protective factor for coping with the death of a spouse.
Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients
Authors: Leahy Michael F. , Turner J. Harvey
Published: September 2010

Radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of 131I-rituximab radioimmunotherapy and compares favorably with those reported for 131I-tositumomab or 90Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with 131I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse.
High-definition mapping of retroviral integration sites identifies active regulatory elements in human multipotent hematopoietic progenitors
Authors: Cattoglio Claudia , Pellin Danilo , Rizzi Ermanno , Maruggi Giulietta , Corti Giorgio , Miselli Francesca , Sartori Daniela , Guffanti Alessandro , Di Serio Clelia , Ambrosi Alessandro , De Bellis Gianluca , Mavilio Fulvio
Published: September 2010

Integration of retroviral vectors in the human genome follows nonrandom patterns that favor insertional deregulation of gene expression and increase the risk of their use in clinical gene therapy. The molecular basis of retroviral target site selection is still poorly understood. We used deep sequencing technology to build genomewide, high-definition maps of > 60 000 integration sites of Moloney murine leukemia virus (MLV)– and HIV-based retroviral vectors in the genome of human CD34+ multipotent hematopoietic progenitor cells (HPCs) and used gene expression profiling, chromatin immunoprecipitation, and bioinformatics to associate integration to genetic and epigenetic features of the HPC genome. Clusters of recurrent MLV integrations identify regulatory elements (alternative promoters, enhancers, evolutionarily conserved noncoding regions) within or around protein-coding genes and microRNAs with crucial functions in HPC growth and differentiation, bearing epigenetic marks of active or poised transcription (H3K4me1, H3K4me2, H3K4me3, H3K9Ac, Pol II) and specialized chromatin configurations (H2A.Z). Overall, we mapped 3500 high-frequency integration clusters, which represent a new resource for the identification of transcriptionally active regulatory elements. High-definition MLV integration maps provide a rational basis for predicting genotoxic risks in gene therapy and a new tool for genomewide identification of promoters and regulatory elements controlling hematopoietic stem and progenitor cell functions.
Lyn- and PLC-β3–dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease
Authors: Xiao Wenbin , Ando Tomoaki , Wang Huan-You , Kawakami Yuko , Kawakami Toshiaki
Published: September 2010

Hyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)–β3-dependent manner. Thus, PLC-β3–deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)– deficient mice. Here we show that Lyn/PLC-β3 doubly deficient lyn−/−;PLC-β3−/− mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn−/−;PLC-β3−/− mice that cause the CMML-like disease, phosphorylation of SHP-1 at Tyr536 and Tyr564 is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr564 by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr536 in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-β3–mediated regulatory mechanism of SHP-1 and Stat5 activities.
Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development
Authors: Schaffner Florence , Versteeg Henri H. , Schillert Anja , Yokota Naho , Petersen Lars C. , Mueller Barbara M. , Ruf Wolfram
Published: September 2010

Constitutive expression of tissue factor (TF) by cancer cells triggers local activation of the coagulation cascade and promotes breast cancer progression through cell signaling involving protease activated receptor (PAR)2. In human breast cancer, TF and PAR2 are up-regulated and TF cytoplasmic domain phosphorylation is correlated with relapse. Here we show that cancer cell PAR2 signaling promotes angiogenesis independent of PAR2 phosphorylation at the recognized β-arrestin recruitment site. Similar to PAR2−/− mice, TF cytoplasmic domain–deleted (TFΔCT) mice have delayed spontaneous breast cancer development in the polyoma middle T model. Simultaneous deletion of PAR2 in TFΔCT mice did not further delay tumor appearance, consistent with overlapping roles of TF and PAR2 in promoting the angiogenic switch in early stages of breast cancer. In advanced carcinomas, tumor-associated macrophages were reduced in TFΔCT and TFΔCT/PAR2−/− mice, and increased tumor vessel diameters of TFΔCT mice were partially reversed by PAR2-deficiency, indicating that the TF cytoplasmic domain has additional roles that are interdependent with PAR2 signaling in regulating host angiogenic responses. These experiments demonstrate a crosstalk of tumor cell TF cytoplasmic domain and PAR2 signaling and provide a possible mechanism for the close correlation between TF phosphorylation and cancer recurrence of TF and PAR2-positive clinical breast cancer.
Beta-arrestin inhibits CAMKKbeta-dependent AMPK activation downstream of protease-activated-receptor-2
Authors: Wang Ping , Jiang Yong , Wang Yinsheng , Shyy John Y , DeFea Kathryn A
Published: September 2010

Background

Proteinase-activated-receptor-2 (PAR2) is a seven transmembrane receptor that can activate two separate signaling arms: one through Gαq and Ca2+ mobilization, and a second through recruitment of β-arrestin scaffolds. In some cases downstream targets of the Gαq/Ca2+ signaling arm are directly inhibited by β-arrestins, while in other cases the two pathways are synergistic; thus β-arrestins act as molecular switches capable of modifying the signal generated by the receptor.

Results

Here we demonstrate that PAR2 can activate adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy balance, through Ca2+-dependent Kinase Kinase β (CAMKKβ), while inhibiting AMPK through interaction with β-arrestins. The ultimate outcome of PAR2 activation depended on the cell type studied; in cultured fibroblasts with low endogenous β-arrestins, PAR2 activated AMPK; however, in primary fat and liver, PAR2 only activated AMPK in β-arrestin-2-/- mice. β-arrestin-2 could be co-immunoprecipitated with AMPK and CAMKKβ under baseline conditions from both cultured fibroblasts and primary fat, and its association with both proteins was increased by PAR2 activation. Addition of recombinant β-arrestin-2 to in vitro kinase assays directly inhibited phosphorylation of AMPK by CAMKKβ on Thr172.

Conclusions

Studies have shown that decreased AMPK activity is associated with obesity and Type II Diabetes, while AMPK activity is increased with metabolically favorable conditions and cholesterol lowering drugs. These results suggest a role for β-arrestin in the inhibition of AMPK signaling, raising the possibility that β-arrestin-dependent PAR2 signaling may act as a molecular switch turning a positive signal to AMPK into an inhibitory one.
Sex-different hepatic glycogen content and glucose output in rats
Authors: Gustavsson Carolina , Yassin Kamal , Wahlström Erik , Cheung Louisa , Lindberg Johan , Brismar Kerstin , Östenson Claes-Göran , Norstedt Gunnar , Tollet-Egnell Petra
Published: September 2010

Background

Genes involved in hepatic metabolism have a sex-different expression in rodents. To test whether male and female rat livers differ regarding lipid and carbohydrate metabolism, whole-genome transcript profiles were generated and these were complemented by measurements of hepatic lipid and glycogen content, fatty acid (FA) oxidation rates and hepatic glucose output (HGO). The latter was determined in perfusates from in situ perfusion of male and female rat livers. These perfusates were also analysed using nuclear magnetic resonance (NMR) spectroscopy to identify putative sex-differences in other liver-derived metabolites. Effects of insulin were monitored by analysis of Akt-phosphorylation, gene expression and HGO after s.c. insulin injections.

Results

Out of approximately 3 500 gene products being detected in liver, 11% were significantly higher in females, and 11% were higher in males. Many transcripts for the production of triglycerides (TG), cholesterol and VLDL particles were female-predominant, whereas genes for FA oxidation, gluconeogenesis and glycogen synthesis were male-predominant. Sex-differences in mRNA levels related to metabolism were more pronounced during mild starvation (12 h fasting), as compared to the postabsorptive state (4 h fasting). No sex-differences were observed regarding hepatic TG content, FA oxidation rates or blood levels of ketone bodies or glucose. However, males had higher hepatic glycogen content and higher HGO, as well as higher ratios of insulin to glucagon levels. Based on NMR spectroscopy, liver-derived lactate was also higher in males. HGO was inhibited by insulin in parallel with increased phosphorylation of Akt, without any sex-differences in insulin sensitivity. However, the degree of Thr172-phosphorylated AMP kinase (AMPK) was higher in females, indicating a higher degree of AMPK-dependent actions.

Conclusions

Taken together, males had higher ratios of insulin to glucagon levels, higher levels of glycogen, lower degree of AMPK phosphorylation, higher expression of gluconeogenic genes and higher hepatic glucose output. Possibly these sex-differences reflect a higher ability for the healthy male rat liver to respond to increased energy demands.
ModuleOrganizer: detecting modules in families of transposable elements
Authors: Tempel Sebastien , Rousseau Christine , Tahi Fariza , Nicolas Jacques
Published: September 2010

Background

Most known eukaryotic genomes contain mobile copied elements called transposable elements. In some species, these elements account for the majority of the genome sequence. They have been subject to many mutations and other genomic events (copies, deletions, captures) during transposition. The identification of these transformations remains a difficult issue. The study of families of transposable elements is generally founded on a multiple alignment of their sequences, a critical step that is adapted to transposons containing mostly localized nucleotide mutations. Many transposons that have lost their protein-coding capacity have undergone more complex rearrangements, needing the development of more complex methods in order to characterize the architecture of sequence variations.

Results

In this study, we introduce the concept of a transposable element module, a flexible motif present in at least two sequences of a family of transposable elements and built on a succession of maximal repeats. The paper proposes an assembly method working on a set of exact maximal repeats of a set of sequences to create such modules. It results in a graphical view of sequences segmented into modules, a representation that allows a flexible analysis of the transformations that have occurred between them. We have chosen as a demonstration data set in depth analysis of the transposable element Foldback in Drosophila melanogaster. Comparison with multiple alignment methods shows that our method is more sensitive for highly variable sequences. The study of this family and the two other families AtREP21 and SIDER2 reveals new copies of very different sizes and various combinations of modules which show the potential of our method.

Conclusions

ModuleOrganizer is available on the Genouest bioinformatics center at http://moduleorganizer.genouest.org
Computational analysis and modeling of cleavage by the immunoproteasome and the constitutive proteasome
Authors: Diez-Rivero Carmen M , Lafuente Esther M , Reche Pedro A
Published: September 2010

Background

Proteasomes play a central role in the major histocompatibility class I (MHCI) antigen processing pathway. They conduct the proteolytic degradation of proteins in the cytosol, generating the C-terminus of CD8 T cell epitopes and MHCI-peptide ligands (P1 residue of cleavage site). There are two types of proteasomes, the constitutive form, expressed in most cell types, and the immunoproteasome, which is constitutively expressed in mature dendritic cells. Protective CD8 T cell epitopes are likely generated by the immunoproteasome and the constitutive proteasome, and here we have modeled and analyzed the cleavage by these two proteases.

Results

We have modeled the immunoproteasome and proteasome cleavage sites upon two non-overlapping sets of peptides consisting of 553 CD8 T cell epitopes, naturally processed and restricted by human MHCI molecules, and 382 peptides eluted from human MHCI molecules, respectively, using N-grams. Cleavage models were generated considering different epitope and MHCI-eluted fragment lengths and the same number of C-terminal flanking residues. Models were evaluated in 5-fold cross-validation. Judging by the Mathew's Correlation Coefficient (MCC), optimal cleavage models for the proteasome (MCC = 0.43 ± 0.07) and the immunoproteasome (MCC = 0.36 ± 0.06) were obtained from 12-residue peptide fragments. Using an independent dataset consisting of 137 HIV1-specific CD8 T cell epitopes, the immunoproteasome and proteasome cleavage models achieved MCC values of 0.30 and 0.18, respectively, comparatively better than those achieved by related methods. Using ROC analyses, we have also shown that, combined with MHCI-peptide binding predictions, cleavage predictions by the immunoproteasome and proteasome models significantly increase the discovery rate of CD8 T cell epitopes restricted by different MHCI molecules, including A*0201, A*0301, A*2402, B*0702, B*2705.

Conclusions

We have developed models that are specific to predict cleavage by the proteasome and the immunoproteasome. These models ought to be instrumental to identify protective CD8 T cell epitopes and are readily available for free public use at http://imed.med.ucm.es/Tools/PCPS/.
Natural selection retains overrepresented out-of-frame stop codons against frameshift peptides in prokaryotes
Authors: Tse Herman , Cai James J , Tsoi Hoi-Wah , Lam Esther PT , Yuen Kwok-Yung
Published: September 2010

Background

Out-of-frame stop codons (OSCs) occur naturally in coding sequences of all organisms, providing a mechanism of early termination of translation in incorrect reading frame so that the metabolic cost associated with frameshift events can be reduced. Given such a functional significance, we expect statistically overrepresented OSCs in coding sequences as a result of a widespread selection. Accordingly, we examined available prokaryotic genomes to look for evidence of this selection.

Results

The complete genome sequences of 990 prokaryotes were obtained from NCBI GenBank. We found that low G+C content coding sequences contain significantly more OSCs and G+C content at specific codon positions were the principal determinants of OSC usage bias in the different reading frames. To investigate if there is overrepresentation of OSCs, we modeled the trinucleotide and hexanucleotide biases of the coding sequences using Markov models, and calculated the expected OSC frequencies for each organism using a Monte Carlo approach. More than 93% of 342 phylogenetically representative prokaryotic genomes contain excess OSCs. Interestingly the degree of OSC overrepresentation correlates positively with G+C content, which may represent a compensatory mechanism for the negative correlation of OSC frequency with G+C content. We extended the analysis using additional compositional bias models and showed that lower-order bias like codon usage and dipeptide bias could not explain the OSC overrepresentation. The degree of OSC overrepresentation was found to correlate negatively with the optimal growth temperature of the organism after correcting for the G+C% and AT skew of the coding sequence.

Conclusions

The present study uses approaches with statistical rigor to show that OSC overrepresentation is a widespread phenomenon among prokaryotes. Our results support the hypothesis that OSCs carry functional significance and have been selected in the course of genome evolution to act against unintended frameshift occurrences. Some results also hint that OSC overrepresentation being a compensatory mechanism to make up for the decrease in OSCs in high G+C organisms, thus revealing the interplay between two different determinants of OSC frequency.
MicroRNA signature of the human developing pancreas
Authors: Rosero Samuel , Bravo-Egana Valia , Jiang Zhijie , Khuri Sawsan , Tsinoremas Nicholas , Klein Dagmar , Sabates Eduardo , Correa-Medina Mayrin , Ricordi Camillo , Domínguez-Bendala Juan , Diez Juan , Pastori Ricardo L
Published: September 2010

Background

MicroRNAs are non-coding RNAs that regulate gene expression including differentiation and development by either inhibiting translation or inducing target degradation. The aim of this study is to determine the microRNA expression signature during human pancreatic development and to identify potential microRNA gene targets calculating correlations between the signature microRNAs and their corresponding mRNA targets, predicted by bioinformatics, in genome-wide RNA microarray study.

Results

The microRNA signature of human fetal pancreatic samples 10-22 weeks of gestational age (wga), was obtained by PCR-based high throughput screening with Taqman Low Density Arrays. This method led to identification of 212 microRNAs. The microRNAs were classified in 3 groups: Group number I contains 4 microRNAs with the increasing profile; II, 35 microRNAs with decreasing profile and III with 173 microRNAs, which remain unchanged. We calculated Pearson correlations between the expression profile of microRNAs and target mRNAs, predicted by TargetScan 5.1 and miRBase altgorithms, using genome-wide mRNA expression data. Group I correlated with the decreasing expression of 142 target mRNAs and Group II with the increasing expression of 876 target mRNAs. Most microRNAs correlate with multiple targets, just as mRNAs are targeted by multiple microRNAs. Among the identified targets are the genes and transcription factors known to play an essential role in pancreatic development.

Conclusions

We have determined specific groups of microRNAs in human fetal pancreas that change the degree of their expression throughout the development. A negative correlative analysis suggests an intertwined network of microRNAs and mRNAs collaborating with each other. This study provides information leading to potential two-way level of combinatorial control regulating gene expression through microRNAs targeting multiple mRNAs and, conversely, target mRNAs regulated in parallel by other microRNAs as well. This study may further the understanding of gene expression regulation in the human developing pancreas.
Cross-approximate entropy of cortical local field potentials quantifies effects of anesthesia - a pilot study in rats
Authors: Kreuzer Matthias , Hentschke Harald , Antkowiak Bernd , Schwarz Cornelius , Kochs Eberhard F , Schneider Gerhard
Published: September 2010

Background

Anesthetics dose-dependently shift electroencephalographic (EEG) activity towards high-amplitude, slow rhythms, indicative of a synchronization of neuronal activity in thalamocortical networks. Additionally, they uncouple brain areas in higher (gamma) frequency ranges possibly underlying conscious perception. It is currently thought that both effects may impair brain function by impeding proper information exchange between cortical areas. But what happens at the local network level? Local networks with strong excitatory interconnections may be more resilient towards global changes in brain rhythms, but depend heavily on locally projecting, inhibitory interneurons. As anesthetics bias cortical networks towards inhibition, we hypothesized that they may cause excessive synchrony and compromise information processing already on a small spatial scale. Using a recently introduced measure of signal independence, cross-approximate entropy (XApEn), we investigated to what degree anesthetics synchronized local cortical network activity. We recorded local field potentials (LFP) from the somatosensory cortex of three rats chronically implanted with multielectrode arrays and compared activity patterns under control (awake state) with those at increasing concentrations of isoflurane, enflurane and halothane.

Results

Cortical LFP signals were more synchronous, as expressed by XApEn, in the presence of anesthetics. Specifically, XApEn was a monotonously declining function of anesthetic concentration. Isoflurane and enflurane were indistinguishable; at a concentration of 1 MAC (the minimum alveolar concentration required to suppress movement in response to noxious stimuli in 50% of subjects) both volatile agents reduced XApEn by about 70%, whereas halothane was less potent (50% reduction).

Conclusions

The results suggest that anesthetics strongly diminish the independence of operation of local cortical neuronal populations, and that the quantification of these effects in terms of XApEn has a similar discriminatory power as changes of spontaneous action potential rates. Thus, XApEn of field potentials recorded from local cortical networks provides valuable information on the anesthetic state of the brain.
Cost-effectiveness analysis of malaria chemoprophylaxis for travellers to West-Africa
Authors: Widmer Lukas L , Blank Patricia R , Van Herck Koen , Hatz Christoph , Schlagenhauf Patricia
Published: September 2010

Background

The importation of malaria to non-endemic countries remains a major cause of travel-related morbidity and a leading cause of travel-related hospitalizations. Currently they are three priority medications for malaria prophylaxis to West Africa: mefloquine, atovaquone/proguanil and doxycycline. We investigate the cost effectiveness of a partial reimbursement of the cheapest effective malaria chemoprophylaxis (mefloquine) for travellers to high risk areas of malaria transmission compared with the current situation of no reimbursement.

Methods

This study is a cost-effectiveness analysis based on malaria cases imported from West Africa to Switzerland from the perspective of the Swiss health system. We used a decision tree model and made a literature research on the components of travel related malaria. The main outcome measure was the cost effectiveness of malaria chemoprophylaxis reimbursement based on malaria and deaths averted.

Results

Using a program where travellers would be reimbursed for 80% of the cost of the cheapest malaria chemoprophylaxis is dominant (i.e. cost saving and more effective than the current situation) using the assumption that currently 68.7% of travellers to West Africa use malaria chemoprophylaxis. If the current usage of malaria chemoprophylaxis would be higher, 82.4%, the incremental cost per malaria case averted is € 2'302. The incremental cost of malaria death averted is € 191'833.

The most important factors influencing the model were: the proportion of travellers using malaria chemoprophylaxis, the probability of contracting malaria without malaria chemoprophylaxis, the cost of the mefloquine regimen, the decrease in the number of travellers without malaria chemoprophylaxis in the reimbursement strategy.

Conclusions

This study suggests that a reimbursement of 80% of the cost of the cheapest effective malaria chemoprophylaxis (mefloquine) for travellers from Switzerland to West Africa is highly effective in terms of malaria cases averted and is cost effective to the Swiss health system. These data are relevant to discussions about the cost effectiveness of malaria chemoprophylaxis reimbursement for vulnerable groups such as those visiting friends and relatives who have the highest risk of malaria, who are least likely to use chemoprophylaxis.
The influence of elastic orthotic belt on sagittal profile in adolescent idiopathic thoracic scoliosis: a comparative radiographic study with Milwaukee brace
Authors: Jiang Jun , Qiu Yong , Mao Saihu , Zhao Qinghua , Qian Bangping , Zhu Feng
Published: September 2010

Background

The effectiveness of bracing on preventing curve progression in coronal plane for mild and moderate adolescent idiopathic scoliosis (AIS) patients has been confirmed by previous radiographic researches. However, a hypokyphotic effect on the sagittal plane has been reported by a few studies. A relatively increasing number of AIS patients were noticed to wear a new kind of elastic orthotic belt for the treatments of scoliosis without doctors' instructions. We postulate the correcting mechanism of this new appliance may cause flattening of the spine. To our knowledge, no study has investigated the effects of this new orthosis on the sagittal profile of AIS patients. The aim of this study was to evaluate and compare the effects of elastic orthotic belt and Milwaukee brace on the sagittal alignment in AIS patients.

Methods

Twenty-eight female AIS patients with mild or moderate thoracic curves were included in this study. Standing full-length lateral radiographs were obtained in three conditions: natural standing posture without any treatment, with elastic orthotic belt and with Milwaukee brace. Thoracic kyphosis (TK), lumber lordosis (LL) and pelvic incidence (PI) were measured and compared between the above three conditions.

Results

Both elastic orthotic belt and Milwaukee brace can lead to significant decrease of TK, however, the decrease of TK after wearing elastic orthotic belt is significantly larger than that after wearing Milwaukee brace. Compared with no treatment, LL was found to be significantly smaller after wearing Milwaukee brace, however, such significant decrease was not noted after wearing elastic orthotic belt. No significant changes were observed for the PI between 3 conditions.

Conclusions

The elastic orthotic belt could lead to more severe thoracic hypokyphosis when compared with Milwaukee brace. This belt may not be a suitable conservative method for the treatment of mild and moderate AIS patients.
A systematic investigation of Escherichia coli central carbon metabolism in response to superoxide stress
Authors: Rui Bin , Shen Tie , Zhou Hong , Liu Jianping , Chen Jiusheng , Pan Xiaosong , Liu Haiyan , Wu Jihui , Zheng Haoran , Shi Yunyu
Published: September 2010

Background

The cellular responses of bacteria to superoxide stress can be used to model adaptation to severe environmental changes. Superoxide stress promotes the excessive production of reactive oxygen species (ROS) that have detrimental effects on cell metabolic and other physiological activities. To antagonize such effects, the cell needs to regulate a range of metabolic reactions in a coordinated way, so that coherent metabolic responses are generated by the cellular metabolic reaction network as a whole. In the present study, we have used a quantitative metabolic flux analysis approach, together with measurement of gene expression and activity of key enzymes, to investigate changes in central carbon metabolism that occur in Escherichia coli in response to paraquat-induced superoxide stress. The cellular regulatory mechanisms involved in the observed global flux changes are discussed.

Results

Flux analysis based on nuclear magnetic resonance (NMR) and mass spectroscopy (MS) measurements and computation provided quantitative results on the metabolic fluxes redistribution of the E. coli central carbon network under paraquat-induced oxidative stress. The metabolic fluxes of the glycolytic pathway were redirected to the pentose phosphate pathway (PP pathway). The production of acetate increased significantly, the fluxes associated with the TCA cycle decreased, and the fluxes in the glyoxylate shunt increased in response to oxidative stress. These global flux changes resulted in an increased ratio of NADPH:NADH and in the accumulation of α-ketoglutarate.

Conclusions

Metabolic flux analysis provided a quantitative and global picture of responses of the E. coli central carbon metabolic network to oxidative stress. Systematic adjustments of cellular physiological state clearly occurred in response to changes in metabolic fluxes induced by oxidative stress. Quantitative flux analysis therefore could reveal the physiological state of the cell at the systems level and is a useful complement to molecular systems approaches, such as proteomics and transcription analyses.
Autoimmune hepatitis triggered by nitrofurantoin: a case series
Authors: Appleyard Sally , Saraswati Ruma , Gorard David A
Published: September 2010

Introduction

Drugs can occasionally trigger the onset of autoimmune liver disease.

Case presentation

Three Caucasian women (aged 65, 42 and 74 years old) who were receiving long-term nitrofurantoin as prophylaxis against recurrent urinary tract infections developed hepatitic liver disease. Serological auto-antibody profiles and liver histology appearances were consistent with autoimmune hepatitis. Two of the patients presented with jaundice, and one required a prolonged hospital admission for liver failure. In all three patients nitrofurantoin was withdrawn, and long-term immunosuppressive therapy with prednisolone and azathioprine or mycophenolate was given. The patients responded well, with liver biochemistry returning to normal within a few months.

Conclusions

Although nitrofurantoin rarely causes autoimmune hepatitis, this antimicrobial is increasingly used as long-term prophylaxis against recurrent urinary tract infection. General practitioners and urologists who prescribe long-term nitrofurantoin therapy should be aware of this adverse effect.
Development of a neural network model for predicting glucose levels in a surgical critical care setting
Authors: Pappada Scott M , Borst Marilyn J , Cameron Brent D , Bourey Raymond E , Lather Jason D , Shipp Desmond , Chiricolo Antonio , Papadimos Thomas J
Published: September 2010

Development of neural network models for the prediction of glucose levels in critically ill patients through the application of continuous glucose monitoring may provide enhanced patient outcomes. Here we demonstrate the utilization of a predictive model in real-time bedside monitoring. Such modeling may provide intelligent/directed therapy recommendations, guidance, and ultimately automation, in the near future as a means of providing optimal patient safety and care in the provision of insulin drips to prevent hyperglycemia and hypoglycemia.
P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis
Authors: McHenry Peter R , Sears James C , Herrick Matthew P , Chang Peggy , Heckman-Stoddard Brandy M , Rybarczyk Megan , Chodosh Lewis A , Gunther Edward J , Hilsenbeck Susan G , Rosen Jeffrey M , Vargo-Gogola Tracy
Published: September 2010

Introduction

Rho GTPases are overexpressed and hyperactivated in human breast cancers. Deficiency of p190B RhoGAP, a major inhibitor of the Rho GTPases, inhibits mouse mammary tumor virus long terminal repeat (MMTV)-Neu/ErbB2 mammary tumor formation and progression in part through effects within the stromal environment, suggesting that p190B function is pro-tumorigenic. To further investigate the potential pro-tumorigenic actions of p190B, we examined the effects of exogenous p190B expression within the mammary epithelium on MMTV-Neu tumor formation and progression.

Methods

Tetracycline (tet)-regulatable p190B transgenic mice were bred to MMTV-Neu mice, and the effects of exogenous p190B expression on tumor latency, multiplicity, growth rates, angiogenesis, and metastasis were examined. The effects of exogenous p190B expression on cell-matrix adhesion and invasion were tested using non-transformed primary mammary epithelial cells (MECs). Rho GTPase activity, oxidative stress as an indicator of reactive oxygen species (ROS) production, and downstream signaling pathways were analyzed.

Results

Altered p190B expression resulted in a two-fold increase in tumor multiplicity and a three-fold increase in metastases compared to control mice indicating that exogenous p190B expression in the mammary epithelium promotes MMTV-Neu mammary tumor formation and progression. Interestingly, non-transformed primary MECs expressing exogenous p190B displayed increased adhesion to laminin and type IV collagen and formed invasive structures in a three-dimensional culture assay. Ras related C3 botulinum toxin 1 (Rac1)-GTP levels were elevated in p190B transgenic tumors whereas Ras homologous A (RhoA) and cell division cycle 42 (Cdc42)-GTP levels were not significantly altered. Rac1 activity affects production of ROS, which regulate transformation, metastasis, and oxidative stress. Protein carbonylation, which is indicative of oxidative stress, was elevated 1.75-fold in p190B transgenic tumors as compared to control tumors suggesting that exogenous p190B expression may affect Rac1-dependent ROS production.

Conclusions

These studies indicate that paradoxically, p190B RhoGAP, a major inhibitor of the Rho GTPases in vitro, has pro-tumorigenic functions that enhance MMTV-Neu induced mammary tumor formation and metastasis. Furthermore, exogenous p190B expression enhances cell adhesion and invasion, which may facilitate metastasis. Rac1 activity and oxidative stress are elevated in tumors expressing exogenous p190B suggesting that p190B may promote tumorigenesis through a Rac1/ROS dependent mechanism.