bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.