bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chapter 63 The Neoproterozoic glaciogenic deposits of Scotland and Ireland
Authors: Prave A. R. , Fallick A. E. 
Published: December 2011

Abstract

Of the three major Neoproterozoic supracrustal units in the Scottish and Irish Highlands (the Torridonian, Moine and Dalradian Supergroups), only the latter contains evidence of Neoproterozoic glaciations. The Dalradian is siliciclastic-dominated and constitutes much of the Scottish–Irish Highlands between the Great Glen and Highland Boundary Fault Zones, and their correlatives in Ireland. At the time of writing, three stratigraphically distinct glacial intervals in the Dalradian have been documented in the literature. The oldest is the Port Askaig Formation (Fm.) at the base of the Argyll Group (see
Arnaud & Fairchild 2011
). It ranges from several tens to many hundreds of metres in thickness and occurs in numerous localities in Scotland and the north of Ireland. A second glacial is recorded in the middle part of the Argyll Group (Easdale Subgroup) and consists of localised sedimentary breccias as well as pelites and schists containing dropstone/lonestone units inferred to be ice-rafted debris; these rocks are patchily preserved and typically a few metres or less in thickness. It is sharply overlain by a variably developed carbonate unit that is marked by a 1–7-m-thick, light-coloured, basal dolostone or dolomitic limestone interpreted as a cap carbonate. This succession is best preserved in Donegal, Ireland, as the Stralinchy–Reelan glacial and Cranford cap-carbonate sequence. A correlative cap carbonate, the Whiteness Limestone, has been identified in the Shetland Islands. The third and youngest glacial is represented by locally preserved dropstone and polymict diamictite beds ranging in thickness from several to a few tens of metres in thickness in the lower Southern Highland Group. These include the MacDuff and Loch na Cille Boulder Beds in, respectively, NE and SW Scotland, and the Inishowen Beds in Donegal, Ireland.
Coexistence of PIK3CA and Other Oncogene Mutations in Lung Adenocarcinoma–Rationale for Comprehensive Mutation Profiling
Authors: Chaft Jamie E. , Arcila Maria E. , Paik Paul K. , Lau Christopher , Riely Gregory J. , Pietanza M. Catherine , Zakowski Maureen F. , Rusch Valerie , Sima Camelia S. , Ladanyi Marc , Kris Mark G. 
Published: December 2011

Abstract
Phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) encodes the p110α subunit of the mitogenic signaling protein phosphoinositide 3-kinase (PI3K). PIK3CA mutations in the helical binding domain and the catalytic subunit of the protein have been associated with tumorigenesis and treatment resistance in various malignancies. Characteristics of patients with PIK3CA-mutant lung adenocarcinomas have not been reported. We examined epidermal growth factor receptor (EGFR), Kirsten rate sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), human epidermal growth factor receptor 2 (HER2), PIK3CA, v-akt murine thymoma vial oncogene homolog 1 (AKT1), v-ras neuroblastoma viral oncogene homolog (NRAS), dual specificity mitogen-activated protein kinase kinase 1 (MEK1), and anaplastic lymphoma kinase (ALK) in patients with adenocarcinoma of the lung to identify driver mutations. Clinical data were obtained from the medical records of individuals with mutations in PIK3CA. Twenty-three of 1,125 (2%, 95% CI: 1–3) patients had a mutation in PIK3CA, 12 in exon 9 (10 E545K and 2 E542K), and 11 in exon 20 (3 H1047L and 8 H1047R). The patients (57% women) had a median age of 66 at diagnosis (range: 34–78). Eight patients (35%) were never smokers. Sixteen of 23 (70%, 95% CI: 49–86) had coexisting mutations in other oncogenes—10 KRAS, 1 MEK1, 1 BRAF, 1 ALK rearrangement, and 3 EGFR exon 19 deletions. We conclude that PIK3CA mutations occur in lung adenocarcinomas, usually concurrently with EGFR, KRAS, and ALK. The impact of PIK3CA mutations on the efficacy of targeted therapies such as erlotinib and crizotinib is unknown. Given the high frequency of overlapping mutations, comprehensive genotyping should be carried out on tumor specimens from patients enrolling in clinical trials of PI3K and other targeted therapies. Mol Cancer Ther; 11(2); 485–91. ©2011 AACR.
Akt1–Mediated Skeletal Muscle Growth Attenuates Cardiac Dysfunction and Remodeling After Experimental Myocardial Infarction
Authors: Araki Satoshi , Izumiya Yasuhiro , Hanatani Shinsuke , Rokutanda Taku , Usuku Hiroki , Akasaki Yuichi , Takeo Toru , Nakagata Naomi , Walsh Kenneth , Ogawa Hisao 
Published: December 2011

Background—
It is appreciated that aerobic endurance exercise can attenuate unfavorable myocardial remodeling following myocardial infarction. In contrast, little is known about the effects of increasing skeletal muscle mass, typically achieved through resistance training, on this process. Here, we utilized transgenic (TG) mice that can induce the growth of functional skeletal muscle by switching Akt1 signaling in muscle fibers to assess the impact of glycolytic muscle growth on post-myocardial infarction cardiac remodeling.

Methods and Results—

Male-noninduced TG mice and their nontransgenic littermates (control) were subjected to left anterior coronary artery ligation. Two days after surgery, mice were provided doxycycline in their drinking water to activate Akt1 transgene expression in a skeletal muscle-specific manner. Myogenic Akt1 activation led to diminished left ventricular dilation and reduced contractile dysfunction compared with control mice. Improved cardiac function in Akt1 TG mice was coupled to diminished myocyte hypertrophy, decreased interstitial fibrosis, and increased capillary density. ELISA and protein array analyses demonstrated that serum levels of proangiogenic growth factors were upregulated in Akt1 TG mice compared with control mice. Cardiac eNOS was activated in Akt1 TG mice after myocardial infarction. The protective effect of skeletal muscle Akt activation on cardiac remodeling and systolic function was abolished by treatment with the eNOS inhibitor
l
-NAME.

Conclusions—
Akt1–mediated skeletal muscle growth attenuates cardiac remodeling after myocardial infarction and is associated with an increased capillary density in the heart. This improvement appears to be mediated by skeletal muscle to cardiac communication, leading to activation of eNOS-signaling in the heart.
Expansion of functionally defined mouse hematopoietic stem and progenitor cells by a short isoform of RUNX1/AML1
Authors: Tsuzuki Shinobu , Seto Masao 
Published: December 2011

Abstract
Self-renewal activity is essential for the maintenance and regeneration of the hematopoietic system. The search for molecules capable of promoting self-renewal and expanding hematopoietic stem cells (HSCs) has met with limited success. Here, we show that a short isoform (AML1a) of RUNX1/AML1 has such activities. Enforced AML1a expression expanded functionally defined HSCs, with an efficiency that was at least 20 times greater than that of the control in vivo and by 18-fold within 7 days ex vivo. The ex vivo–expanded HSCs could repopulate hosts after secondary transplantations. Moreover, AML1a expression resulted in vigorous and long-term (> 106-fold at 4 weeks) ex vivo expansion of progenitor cell populations capable of differentiating into multilineages. Gene expression analysis revealed that AML1a expression was associated with up-regulation of genes, including Hoxa9, Meis1, Stat1, and Ski. shRNA-mediated silencing of these genes attenuated AML1a-mediated activities. Overall, these findings establish AML1a as an isoform-specific molecule that can influence several transcriptional regulators associated with HSCs, leading to enhanced self-renewal activity and hematopoietic stem/progenitor cell expansion ex vivo and in vivo. Therefore, the abilities of AML1a may have implications for HSC transplantation and transfusion medicine, given that the effects also can be obtained by cell-penetrating AML1a protein.
Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement
Authors: Moreau Caroline , Bajolle Fanny , Siguret Virginie , Lasne Dominique , Golmard Jean-Louis , Elie Caroline , Beaune Philippe , Cheurfi Radhia , Bonnet Damien , Loriot Marie-Anne 
Published: December 2011

Abstract
Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.
Moxifloxacinversusamoxicillin/clavulanic acid in outpatient acute exacerbations of COPD: MAESTRAL results
Authors: Wilson Robert , Anzueto Antonio , Miravitlles Marc , Arvis Pierre , Alder Jeff , Haverstock Daniel , Trajanovic Mila , Sethi Sanjay 
Published: December 2011

Bacterial infections causing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) frequently require antibacterial treatment. More evidence is needed to guide antibiotic choice.The Moxifloxacin in Acute Exacerbations of Chronic Bronchitis TriaL (MAESTRAL) was a multiregional, randomised, double-blind non-inferiority outpatient study. Patients were aged ≥60 yrs, with an Anthonisen type I exacerbation, a forced expiratory volume in 1 s <60% predicted and two or more exacerbations in the last year. Following stratification by steroid use patients received moxifloxacin 400 mgp.o. q.d.(5 days) or amoxicillin/clavulanic acid 875/125 mgp.o. b.i.d.(7 days). The primary end-point was clinical failure 8 weeks post-therapy in the per protocol population.Moxifloxacin was noninferior to amoxicillin/clavulanic acid at the primary end-point (111 (20.6%) out of 538,versus114 (22.0%) out of 518, respectively; 95% CI -5.89–3.83%). In patients with confirmed bacterial AECOPD, moxifloxacin led to significantly lower clinical failure rates than amoxicillin/clavulanic acid (in the intent-to-treat with pathogens, 62 (19.0%) out of 327versus85 (25.4%) out of 335, respectively; p=0.016). Confirmed bacterial eradication at end of therapy was associated with higher clinical cure rates at 8 weeks post-therapy overall (p=0.0014) and for moxifloxacin (p=0.003). Patients treated with oral corticosteroids had more severe disease and higher failure rates.The MAESTRAL study showed that moxifloxacin was as effective as amoxicillin/clavulanic acid in the treatment of outpatients with AECOPD. Both therapies were well tolerated.
Building gene expression profile classifiers with a simple and efficient rejection option in R
Authors: Benso Alfredo , Di Carlo Stefano , Politano Gianfranco , Savino Alessandro , Hafeezurrehman Hafeez 
Published: December 2011

Abstract

Background
The collection of gene expression profiles from DNA microarrays and their analysis with pattern recognition algorithms is a powerful technology applied to several biological problems. Common pattern recognition systems classify samples assigning them to a set of known classes. However, in a clinical diagnostics setup, novel and unknown classes (new pathologies) may appear and one must be able to reject those samples that do not fit the trained model. The problem of implementing a rejection option in a multi-class classifier has not been widely addressed in the statistical literature. Gene expression profiles represent a critical case study since they suffer from the curse of dimensionality problem that negatively reflects on the reliability of both traditional rejection models and also more recent approaches such as one-class classifiers.

Results
This paper presents a set of empirical decision rules that can be used to implement a rejection option in a set of multi-class classifiers widely used for the analysis of gene expression profiles. In particular, we focus on the classifiers implemented in the R Language and Environment for Statistical Computing (R for short in the remaining of this paper). The main contribution of the proposed rules is their simplicity, which enables an easy integration with available data analysis environments. Since in the definition of a rejection model tuning of the involved parameters is often a complex and delicate task, in this paper we exploit an evolutionary strategy to automate this process. This allows the final user to maximize the rejection accuracy with minimum manual intervention.

Conclusions
This paper shows how the use of simple decision rules can be used to help the use of complex machine learning algorithms in real experimental setups. The proposed approach is almost completely automated and therefore a good candidate for being integrated in data analysis flows in labs where the machine learning expertise required to tune traditional classifiers might not be available.
Prediction of dinucleotide-specific RNA-binding sites in proteins
Authors: Fernandez Michael , Kumagai Yutaro , Standley Daron M , Sarai Akinori , Mizuguchi Kenji , Ahmad Shandar 
Published: December 2011

Abstract

Background
Regulation of gene expression, protein synthesis, replication and assembly of many viruses involve RNA–protein interactions. Although some successful computational tools have been reported to recognize RNA binding sites in proteins, the problem of specificity remains poorly investigated. After the nucleotide base composition, the dinucleotide is the smallest unit of RNA sequence information and many RNA-binding proteins simply bind to regions enriched in one dinucleotide. Interaction preferences of protein subsequences and dinucleotides can be inferred from protein-RNA complex structures, enabling a training-based prediction approach.

Results
We analyzed basic statistics of amino acid-dinucleotide contacts in protein-RNA complexes and found their pairing preferences could be identified. Using a standard approach to represent protein subsequences by their evolutionary profile, we trained neural networks to predict multiclass target vectors corresponding to 16 possible contacting dinucleotide subsequences. In the cross-validation experiments, the accuracies of the optimum network, measured as areas under the curve (AUC) of the receiver operating characteristic (ROC) graphs, were in the range of 65-80%.

Conclusions
Dinucleotide-specific contact predictions have also been extended to the prediction of interacting protein and RNA fragment pairs, which shows the applicability of this method to predict targets of RNA-binding proteins. A web server predicting the 16-dimensional contact probability matrix directly from a user-defined protein sequence was implemented and made available at: http://tardis.nibio.go.jp/netasa/srcpred.
Genetic copy number variants in myocardial infarction patients with hyperlipidemia
Authors: Shia Wei-Chung , Ku Tien-Hsiung , Tsao Yu-Ming , Hsia Chien-Hsun , Chang Yung-Ming , Huang Ching-Hui , Chung Yeh-Ching , Hsu Shih-Lan , Liang Kae-Woei , Hsu Fang-Rong 
Published: December 2011

Abstract

Background
Cardiovascular disease is the chief cause of death in Taiwan and many countries, of which myocardial infarction (MI) is the most serious condition. Hyperlipidemia appears to be a significant cause of myocardial infarction, because it causes atherosclerosis directly. In recent years, copy number variation (CNV) has been analyzed in genomewide association studies of complex diseases. In this study, CNV was analyzed in blood samples and SNP arrays from 31 myocardial infarction patients with hyperlipidemia.

Results
We identified seven CNV regions that were associated significantly with hyperlipidemia and myocardial infarction in our patients through multistage analysis (P<0.001), at 1p21.3, 1q31.2 (CDC73), 1q42.2 (DISC1), 3p21.31 (CDCP1), 10q11.21 (RET) 12p12.3 (PIK3C2G) and 16q23.3 (CDH13), respectively. In particular, the CNV region at 10q11.21 was examined by quantitative real-time PCR, the results of which were consistent with microarray findings.

Conclusions
Our preliminary results constitute an alternative method of evaluating the relationship between CNV regions and cardiovascular disease. These susceptibility CNV regions may be used as biomarkers for early-stage diagnosis of hyperlipidemia and myocardial infarction, rendering them valuable for further research and discussion.
13-hydroxy linoleic acid increases expression of the cholesterol transporters ABCA1, ABCG1 and SR-BI and stimulates apoA-I-dependent cholesterol efflux in RAW264.7 macrophages
Authors: Kämmerer Ines , Ringseis Robert , Biemann Ronald , Wen Gaiping , Eder Klaus 
Published: December 2011

Abstract

Background
Synthetic activators of peroxisome proliferator-activated receptors (PPARs) stimulate cholesterol removal from macrophages through PPAR-dependent up-regulation of liver × receptor α (LXRα) and subsequent induction of cholesterol exporters such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type 1 (SR-BI). The present study aimed to test the hypothesis that the hydroxylated derivative of linoleic acid (LA), 13-HODE, which is a natural PPAR agonist, has similar effects in RAW264.7 macrophages.

Methods
RAW264.7 macrophages were treated without (control) or with LA or 13-HODE in the presence and absence of PPARα or PPARγ antagonists and determined protein levels of LXRα, ABCA1, ABCG1, SR-BI, PPARα and PPARγ and apolipoprotein A-I mediated lipid efflux.

Results
Treatment of RAW264.7 cells with 13-HODE increased PPAR-transactivation activity and protein concentrations of LXRα, ABCA1, ABCG1 and SR-BI when compared to control treatment (P < 0.05). In addition, 13-HODE enhanced cholesterol concentration in the medium but decreased cellular cholesterol concentration during incubation of cells with the extracellular lipid acceptor apolipoprotein A-I (P < 0.05). Pre-treatment of cells with a selective PPARα or PPARγ antagonist completely abolished the effects of 13-HODE on cholesterol efflux and protein levels of genes investigated. In contrast to 13-HODE, LA had no effect on either of these parameters compared to control cells.

Conclusion
13-HODE induces cholesterol efflux from macrophages via the PPAR-LXRα-ABCA1/SR-BI-pathway.
The fine specificity of IgM anti-citrullinated protein antibodies (ACPA) is different from that of IgG ACPA
Authors: Suwannalai Parawee , Willemze Annemiek , van Toorn Linda , Stoeken-Rijsbergen Gerrie , Levarht Nivine , Drijfhout Jan Wouter , J Huizinga Tom W , M Toes Rene E , Trouw Leendert A 
Published: December 2011

Abstract
Introduction
The antigen recognition pattern of immunoglobulin M (IgM) could, when directed against protein antigens, provide an indication of the antigenic moieties triggering new B cells. The half-life of IgM is short and memory B cells against T-cell-dependent protein antigens typically produce IgG and not IgM antibodies. In this study, we analyzed whether a difference exists between the fine specificity of IgM versus IgG anti-citrullinated protein antibodies (ACPAs).

Methods
We determined the fine specificity of IgM and IgG ACPAs in 113 ACPA-positive rheumatoid arthritis patients with IgM cyclic citrullinated peptide 2 (CCP2) levels above 100 AU/ml. Fine specificity was assessed by performing ELISA using citrullinated peptides derived from vimentin, fibrinogen-β, fibrinogen-α and α-enolase, as well as citrullinated proteins fibrinogen and myelin basic protein. The arginine counterparts were used as controls.

Results
Recognition of defined citrullinated antigens by IgM ACPA was confined to samples that also displayed recognition by IgG ACPA. However, the IgM ACPA response displayed a more restricted antigen recognition profile than IgG ACPA (OR = 0.26, P < 0.0001).

Conclusion
Our data show that several defined citrullinated antigens are recognized only by IgG ACPA, whereas others are also recognized by IgM ACPA. These observations suggest that not all citrullinated antigens are able to activate new B cells despite concurrent recognition by IgG ACPA.
Dipyridamole augments the antiinflammatory response during human endotoxemia
Authors: Ramakers Bart P , Riksen Niels P , Stal Thijmen H , Heemskerk Suzanne , van den Broek Petra , Peters Wilbert HM , van der Hoeven Johannes G , Smits Paul , Pickkers Peter 
Published: December 2011

Abstract
Introduction
In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia.

Methods
In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo.

Results
Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-α (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia.

Conclusions
Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines.

Trial registration
ClinicalTrials (NCT): NCT01091571.