bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippo/Mst1 Stimulates Transcription of the Proapoptotic Mediator NOXA in a FoxO1-Dependent Manner
Authors: Valis Karel , Prochazka Lubomir , Boura Evzen , Chladova Jaromira , Obsil Tomas , Rohlena Jakub , Truksa Jaroslav , Dong Lan-Feng , Ralph Stephen J. , Neuzil Jiri 
Published: January 2011

Abstract
The proapoptotic protein Noxa, a member of the BH3-only Bcl-2 protein family, can effectively induce apoptosis in cancer cells, although the relevant regulatory pathways have been obscure. Previous studies of the cytotoxic effects of α-tocopheryl succinate (α-TOS) on cancer cells identified a mechanism whereby α-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site (DBE; DAF-16 binding element) in the NOXA promoter, and specific affinity of FoxO proteins to this DBE was confirmed by fluorescence anisotropy. FoxO1 and FoxO3a proteins accumulated in the nucleus of α-TOS–treated cells, and the drug-induced specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription in cancer cells was identified. Furthermore, the proapoptotic kinase Hippo/Mst1 was found to be strongly activated by α-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation, thereby reducing levels of NOXA transcription and apoptosis in cancer cells exposed to α-TOS. Thus, we have demonstrated that anticancer drugs, exemplified by α-TOS, induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway. We propose that activation of this pathway provides a new paradigm for developing targeted cancer treatments. Cancer Res; 71(3); 946–54. ©2011 AACR.
Imaging Colon Cancer Response Following Treatment with AZD1152: A Preclinical Analysis of [18F]Fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]Fluorothymidine Imaging
Authors: Moroz Maxim A. , Kochetkov Tatiana , Cai Shangde , Wu Jiyuan , Shamis Mikhail , Nair Jayasree , de Stanchina Elisa , Serganova Inna , Schwartz Gary K. , Banerjee Debabrata , Bertino Joseph R. , Blasberg Ronald G. 
Published: January 2011

Abstract
Purpose: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [18F]-labeled fluoro-2-deoxyglucose, [18F]FDG, and/or 3′-deoxy-3′-[18F]fluorothymidine, [18F]FLT, PET imaging.
Experimental design: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG, and [18F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions of thymidine synthesis in the two cell lines.
Results: Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 for AZD1152-HQPA was approximately 10 nmol/L in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared with HCT116 cells. The aforementioned results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts.
Conclusions: AZD1152 treatment showed antitumor efficacy in both colon cancer xenografts. Although [18F]FDG PET was inadequate in monitoring treatment response, [18F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well. Clin Cancer Res; 17(5); 1099–110. ©2011 AACR.
Noninvasive Estimation of the Rate of Relaxation by the Analysis of Intraventricular Pressure Gradients
Authors: Yotti Raquel , Bermejo Javier , Benito Yolanda , Antoranz J. Carlos , Desco M. Mar , Rodríguez-Pérez Daniel , Cortina Cristina , Mombiela Teresa , Barrio Alicia , Elízaga Jaime , Fernández-Avilés Francisco 
Published: January 2011

Background—
During late ejection, myocardial relaxation causes systolic flow to decelerate and stop, and this phenomenon is coupled with the generation of a pressure gradient inside the left ventricle (LV). We hypothesized that the peak reverse ejection intraventricular pressure difference (REIVPD) between the LV apex and the outflow tract could be a useful method to improve the assessment of LV relaxation using Doppler echocardiography.

Methods and Results—

Three sets of animal experiments and 1 clinical study were designed. In 6 pigs, a close relationship between REIVPD and the intensity of the relaxation wave (
R
rm
=0.89) was demonstrated using wave intensity analysis of high-fidelity pressure-volume-velocity data. In 19 animals, REIVPD sensitively detected modifications of the lusotropic state and closely correlated with the time constant of LV relaxation (τ) within animals (
R
rm
=−0.93). Load-dependence analysis in 5 pigs showed that REIVPD remained stable up to values of 35% to 40% acute preload reduction. Clinical validation was tested in 50 patients (23 with normal systolic function) undergoing simultaneous Doppler echocardiography and high-fidelity LV pressure measurements on the same beat. REIVPD and tissue Doppler mitral annulus velocity (e′) were independently related to τ, but the REIVPD · e′ product correlated better with τ than either variable separately (bootstrap-corrected correlation coefficients:
R
=−0.84 versus −0.71, and −0.70, respectively,
P
<0.05). Area under the receiver operating characteristic curve to predict impaired relaxation (τ>50 ms) for e′ · REIVPD was 0.96 (95% confidence interval, 0.85 to 0.99).

Conclusions—
The Doppler-derived REIVPD provides a sensitive, reliable, reproducible, and relatively load-independent index of the rate of LV relaxation. Combined with tissue Doppler measurements of longitudinal function, this method improves noninvasive assessment of LV relaxation in the clinical setting.
Long Hair as a Glory and as a Covering Removing an Ambiguity from 1 Cor 11:15
Authors: Massey Preston T. 
Published: January 2011

AbstractThis study addresses the issue of v. 15 in 1 Cor 11:2-16 from the perspective of a veiling custom. If veiling is in view (the position adopted here), then how does one confront the difficulty of reconciling the overall context with the exceptional statement in v. 15 that long hair for a woman is a glory. If, as the text argues, long hair is to be taken as a “glory,” by what logic could a woman understand that she should place a veil upon her head? This article provides a way out of the dilemma by showing how a veil can serve the double function of reflecting the hair’s beauty while at the same time preserving a symbol of female modesty.
Degrees of Anthropocentrism in Accounts of Wildlife-Vehicle Collisions
Authors: Kuha Mai 
Published: January 2011

AbstractAn investigation of language use in news stories about collisions involving vehicles and nonhuman animals in the wild reveals that reports of bird-airplane collisions tend to focus on the safety of the humans involved, even to the point of constructing the bird as a projectile, rather than a victim. Reports of land vehicles and boats colliding with larger nonhuman animals tend to demonstrate a greater concern for nonhuman participants, attributing greater responsibility to humans for the collisions, although they are more dangerous to humans. Although similar patterns are found in news reports in several languages and in several English-speaking countries, anthropocentrism alone does not fully explain the patterns in journalists’ choice of expressions and structures in these news stories.
The Shared Meal—a Therapeutical Device The Function and Meaning of Hos 6:6 in Matt 9:10-13
Authors: Ottenheijm Eric 
Published: January 2011

AbstractIn Matt 9:10-13, the disciples of Jesus are asked why their master eats with tax-collectors and sinners. Both the question and the threefold answer are analysed in this study. Wisdom traditions prescribe Torah teachers not to engage with blatant sinners. This approach becomes contested in the first century C.E., as is clear from Pharisaic disputes on sinners and tax-collectors. In his answer, Jesus characterises himself as the divine doctor, who stirs the capacity to repentance by his sheer presence. The quote of Hosea functions as a legal justification of this strategy. Hos 6:6 points to the concept of good works, benevolent actions that save even blatant sinners.
AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein
Authors: Steffen Björn , Knop Markus , Bergholz Ulla , Vakhrusheva Olesya , Rode Miriam , Köhler Gabriele , Henrichs Marcel-Philipp , Bulk Etmar , Hehn Sina , Stehling Martin , Dugas Martin , Bäumer Nicole , Tschanter Petra , Brandts Christian , Koschmieder Steffen , Berdel Wolfgang E. , Serve Hubert , Stocking Carol , Müller-Tidow Carsten 
Published: January 2011

Abstract
The most frequent translocation t(8;21) in acute myeloid leukemia (AML) generates the chimeric AML1/ETO protein, which blocks differentiation and induces self-renewal in hematopoietic progenitor cells. The underlying mechanisms mediating AML1/ETO-induced self-renewal are largely unknown. Using expression microarray analysis, we identified the Groucho-related amino-terminal enhancer of split (AES) as a consistently up-regulated AML1/ETO target. Elevated levels of AES mRNA and protein were confirmed in AML1/ETO-expressing leukemia cells, as well as in other AML specimens. High expression of AES mRNA or protein was associated with improved survival of AML patients, even in the absence of t(8;21). On a functional level, knockdown of AES by RNAi in AML1/ETO-expressing cell lines inhibited colony formation. Similarly, self-renewal induced by AML1/ETO in primary murine progenitors was inhibited when AES was decreased or absent. High levels of AES expression enhanced formation of immature colonies, serial replating capacity of primary cells, and colony formation in colony-forming unit-spleen assays. These findings establish AES as a novel AML1/ETO-induced target gene that plays an important role in the self-renewal phenotype of t(8;21)-positive AML.
Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling
Authors: Semple Kenrick , Nguyen Antony , Yu Yu , Wang Honglin , Anasetti Claudio , Yu Xue-Zhong 
Published: January 2011

Abstract
CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naive CD4 T cells (CD25−Foxp3−) by T-cell receptor stimulation with additional transforming growth factorβ (TGFβ) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2–inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling.
Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2
Authors: Wallace Daniel F. , McDonald Cameron J. , Ostini Lesa , Subramaniam V. Nathan 
Published: January 2011

AbstractThe induction of the iron-regulatory peptide hepcidin by proinflammatory cytokines is thought to result in the withholding of iron from invading pathogens. Hfe and transferrin receptor 2 (Tfr2) are involved in the homeostatic regulation of hepcidin and their disruption causes hereditary hemochromatosis (HH). To determine whether either Hfe or Tfr2 is involved in the inflammatory pathway regulating hepcidin, we analyzed the effect of inflammation in 3 mouse models of HH. The inflammatory response and indicators of iron homeostasis were measured in wild-type, Hfe−/−, Tfr2−/−, and Hfe−/−/Tfr2−/− mice injected with lipopolysaccharide (LPS). The administration of LPS significantly reduced serum iron in wild-type and Hfe−/− mice, with smaller reductions in Tfr2−/− and Hfe−/−/Tfr2−/− mice. Low basal levels of hepcidin in the Hfe−/−/Tfr2−/− mice were increased in response to LPS, but remained significantly lower than in the other strains of mice. These results suggest that despite the absence of Hfe and Tfr2, hepcidin is responsive to inflammation; however, the low basal expression and subsequent low levels of circulating hepcidin are insufficient to reduce serum iron effectively. This suggests that in HH, the iron-withholding response to invading pathogens may be inadequate, and this is especially the case in the absence of both Hfe and Tfr2.
Recovery of infectious virus from full-length cowpox virus (CPXV) DNA cloned as a bacterial artificial chromosome (BAC)
Authors: Roth Swaantje J , Höper Dirk , Beer Martin , Feineis Silke , Tischer B Karsten , Osterrieder Nikolaus 
Published: January 2011

Abstract
Transmission from pet rats and cats to humans as well as severe infection in felids and other animal species have recently drawn increasing attention to cowpox virus (CPXV). We report the cloning of the entire genome of cowpox virus strain Brighton Red (BR) as a bacterial artificial chromosome (BAC) in Escherichia coli and the recovery of infectious virus from cloned DNA. Generation of a full-length CPXV DNA clone was achieved by first introducing a mini-F vector, which allows maintenance of large circular DNA in E. coli, into the thymidine kinase locus of CPXV by homologous recombination. Circular replication intermediates were then electroporated into E. coli DH10B cells. Upon successful establishment of the infectious BR clone, we modified the full-length clone such that recombination-mediated excision of bacterial sequences can occur upon transfection in eukaryotic cells. This self-excision of the bacterial replicon is made possible by a sequence duplication within mini-F sequences and allows recovery of recombinant virus progeny without remaining marker or vector sequences. The in vitro growth properties of viruses derived from both BAC clones were determined and found to be virtually indistinguishable from those of parental, wild-type BR. Finally, the complete genomic sequence of the infectious clone was determined and the cloned viral genome was shown to be identical to that of the parental virus. In summary, the generated infectious clone will greatly facilitate studies on individual genes and pathogenesis of CPXV. Moreover, the vector potential of CPXV can now be more systematically explored using this newly generated tool.
Analysis on the reconstruction accuracy of the Fitch method for inferring ancestral states
Authors: Yang Jialiang , Li Jun , Dong Liuhuan , Grünewald Stefan 
Published: January 2011

Abstract

Background
As one of the most widely used parsimony methods for ancestral reconstruction, the Fitch method minimizes the total number of hypothetical substitutions along all branches of a tree to explain the evolution of a character. Due to the extensive usage of this method, it has become a scientific endeavor in recent years to study the reconstruction accuracies of the Fitch method. However, most studies are restricted to 2-state evolutionary models and a study for higher-state models is needed since DNA sequences take the format of 4-state series and protein sequences even have 20 states.

Results
In this paper, the ambiguous and unambiguous reconstruction accuracy of the Fitch method are studied for N-state evolutionary models. Given an arbitrary phylogenetic tree, a recurrence system is first presented to calculate iteratively the two accuracies. As complete binary tree and comb-shaped tree are the two extremal evolutionary tree topologies according to balance, we focus on the reconstruction accuracies on these two topologies and analyze their asymptotic properties. Then, 1000 Yule trees with 1024 leaves are generated and analyzed to simulate real evolutionary scenarios. It is known that more taxa not necessarily increase the reconstruction accuracies under 2-state models. The result under N-state models is also tested.

Conclusions
In a large tree with many leaves, the reconstruction accuracies of using all taxa are sometimes less than those of using a leaf subset under N-state models. For complete binary trees, there always exists an equilibrium interval [a, b] of conservation probability, in which the limiting ambiguous reconstruction accuracy equals to the probability of randomly picking a state. The value b decreases with the increase of the number of states, and it seems to converge. When the conservation probability is greater than b, the reconstruction accuracies of the Fitch method increase rapidly. The reconstruction accuracies on 1000 simulated Yule trees also exhibit similar behaviors. For comb-shaped trees, the limiting reconstruction accuracies of using all taxa are always less than or equal to those of using the nearest root-to-leaf path when the conservation probability is not less than

1
N

. As a result, more taxa are suggested for ancestral reconstruction when the tree topology is balanced and the sequences are highly similar, and a few taxa close to the root are recommended otherwise.
Context-dependent transcriptional regulations between signal transduction pathways
Authors: Hwang Sohyun , Kim Sangwoo , Shin Heesung , Lee Doheon 
Published: January 2011

Abstract

Background
Cells coordinate their metabolism, proliferation, and cellular communication according to environmental cues through signal transduction. Because signal transduction has a primary role in cellular processes, many experimental techniques and approaches have emerged to discover the molecular components and dynamics that are dependent on cellular contexts. However, omics approaches based on genome-wide expression analysis data comparing one differing condition (e.g. complex disease patients and normal subjects) did not investigate the dynamics and inter-pathway cross-communication that are dependent on cellular contexts. Therefore, we introduce a new computational omics approach for discovering signal transduction pathways regulated by transcription and transcriptional regulations between pathways in signaling networks that are dependent on cellular contexts, especially focusing on a transcription-mediated mechanism of inter-pathway cross-communication.

Results
Applied to dendritic cells treated with lipopolysaccharide, our analysis well depicted how dendritic cells respond to the treatment through transcriptional regulations between signal transduction pathways in dendritic cell maturation and T cell activation.

Conclusions
Our new approach helps to understand the underlying biological phenomenon of expression data (e.g. complex diseases such as cancer) by providing a graphical network which shows transcriptional regulations between signal transduction pathways. The software programs are available upon request.
NClassG+: A classifier for non-classically secreted Gram-positive bacterial proteins
Authors: Restrepo-Montoya Daniel , Pino Camilo , Nino Luis F , Patarroyo Manuel E , Patarroyo Manuel A 
Published: January 2011

AbstractBackgroundMost predictive methods currently available for the identification of protein secretion mechanisms have focused on classically secreted proteins. In fact, only two methods have been reported for predicting non-classically secreted proteins of Gram-positive bacteria. This study describes the implementation of a sequence-based classifier, denoted as NClassG+, for identifying non-classically secreted Gram-positive bacterial proteins.ResultsSeveral feature-based classifiers were trained using different sequence transformation vectors (frequencies, dipeptides, physicochemical factors and PSSM) and Support Vector Machines (SVMs) with Linear, Polynomial and Gaussian kernel functions. Nestedk-fold cross-validation (CV) was applied to select the best models, using the inner CV loop to tune the model parameters and the outer CV group to compute the error. The parameters and Kernel functions and the combinations between all possible feature vectors were optimized using grid search.ConclusionsThe final model was tested against an independent set not previously seen by the model, obtaining better predictive performance compared to SecretomeP V2.0 and SecretPV2.0 for the identification of non-classically secreted proteins. NClassG+ is freely available on the web athttp://www.biolisi.unal.edu.co/web-servers/nclassgpositive/
Systematic error detection in experimental high-throughput screening
Authors: Dragiev Plamen , Nadon Robert , Makarenkov Vladimir 
Published: January 2011

Abstract

Background
High-throughput screening (HTS) is a key part of the drug discovery process during which thousands of chemical compounds are screened and their activity levels measured in order to identify potential drug candidates (i.e., hits). Many technical, procedural or environmental factors can cause systematic measurement error or inequalities in the conditions in which the measurements are taken. Such systematic error has the potential to critically affect the hit selection process. Several error correction methods and software have been developed to address this issue in the context of experimental HTS [1–7]. Despite their power to reduce the impact of systematic error when applied to error perturbed datasets, those methods also have one disadvantage - they introduce a bias when applied to data not containing any systematic error [6]. Hence, we need first to assess the presence of systematic error in a given HTS assay and then carry out systematic error correction method if and only if the presence of systematic error has been confirmed by statistical tests.

Results
We tested three statistical procedures to assess the presence of systematic error in experimental HTS data, including the χ2 goodness-of-fit test, Student's t-test and Kolmogorov-Smirnov test [8] preceded by the Discrete Fourier Transform (DFT) method [9]. We applied these procedures to raw HTS measurements, first, and to estimated hit distribution surfaces, second. The three competing tests were applied to analyse simulated datasets containing different types of systematic error, and to a real HTS dataset. Their accuracy was compared under various error conditions.

Conclusions
A successful assessment of the presence of systematic error in experimental HTS assays is possible when the appropriate statistical methodology is used. Namely, the t-test should be carried out by researchers to determine whether systematic error is present in their HTS data prior to applying any error correction method. This important step can significantly improve the quality of selected hits.