Miracle-dz/UniFAR-FTUs huggingface dataset:
The Selective Anaplastic Lymphoma Receptor Tyrosine Kinase Inhibitor ASP3026 Induces Tumor Regression and Prolongs Survival in Non–Small Cell Lung Cancer Model Mice

Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non–small cell lung cancer (NSCLC). Echinoderm microtubule–associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality. Mol Cancer Ther; 13(2); 329–40. ©2014 AACR.
Structural Basis for Pattern Recognition by the Receptor for Advanced Glycation End Products (RAGE)*

The receptor for advanced glycated end products (RAGE) is a multiligand receptor that is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. The ability of RAGE to recognize advanced glycated end products (AGEs) formed by nonenzymatic glycoxidation of cellular proteins places RAGE in the category of pattern recognition receptors. The structural mechanism of AGE recognition was an enigma due to the diversity of chemical structures found in AGE-modified proteins. Here, using NMR spectroscopy we showed that the immunoglobulin V-type domain of RAGE is responsible for recognizing various classes of AGEs. Three distinct surfaces of the V domain were identified to mediate AGE-V domain interactions. They are located in the positively charged areas of the V domain. The first interaction surface consists of strand C and loop CC ′, the second interaction surface consists of strand C ′, strand F, and loop FG, and the third interaction surface consists of strand A ′ and loop EF. The secondary structure elements of the interaction surfaces exhibit significant flexibility on the ms-μs time scale. Despite highly specific AGE-V domain interactions, the binding affinity of AGEs for an isolated V domain is low, ∼10 μm. Using in-cell fluorescence resonance energy transfer we show that RAGE is a constitutive oligomer on the plasma membrane. We propose that constitutive oligomerization of RAGE is responsible for recognizing patterns of AGE-modified proteins with affinities less than 100 nm.
Edinburgh Research Explorer Differential expression of selected histone modifier genes in human solid cancers

Background: Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Here we report characteristic patterns of expression of 12 members of 3 classes of chromatin modifier genes in 6 different cancer types: histone acetyltransferases (HATs)- EP300, CREBBP , and PCAF ; histone deacetylases (HDACs)- HDAC1, HDAC2, HDAC4, HDAC5, HDAC7A , and SIRT1 ; and histone methyltransferases (HMTs)- SUV39H1 and SUV39H2 . Expression of each gene in 225 samples (135 primary tumours, 47 cancer cell lines, and 43 normal tissues) was analysedby QRT-PCR, normalized with 8 housekeeping genes, and given as a ratio by comparison with a universal reference RNA. Results: This involved a total of 13,000 PCR assays allowing for rigorous analysis by fitting a linear regression model to the data. Mutation analysis of HDAC1, HDAC2, SUV39H1 , and SUV39H2 revealed only two out of 181 cancer samples (both cell lines) with significant coding-sequence alterations. Supervised analysis and Independent Component Analysis showed that expression of many of these genes was able to discriminate tumour samples from their normal counterparts. Clustering based on the normalized expression ratios of the 12 genes also showed that most samples were grouped according to tissue type. Using a linear discriminant classifier and internal cross-validation revealed that with as few as 5 of the 12 genes, SIRT1, CREBBP, HDAC7A, HDAC5 and PCAF , most samples were correctly assigned. Conclusion: The expression patterns of HATs, HDACs, and HMTs suggest these genes are important in neoplastic transformation and have characteristic patterns of expression depending on tissue of origin, with implications for potential clinical application.
Role of the Trypanosoma brucei natural cysteine peptidase inhibitor ICP in differentiation and virulence

ICP is a chagasin‐family natural tight binding inhibitor of Clan CA, family C1 cysteine peptidases (CPs). We investigated the role of ICP in Trypanosoma brucei by generating bloodstream form ICP‐deficient mutants (Δicp). A threefold increase in CP activity was detected in lysates of Δicp, which was restored to the levels in wild type parasites by re‐expression of the gene in the null mutant. Δicp displayed slower growth in culture and increased resistance to a trypanocidal synthetic CP inhibitor. More efficient exchange of the variant surface glycoprotein (VSG) to procyclin during differentiation from bloodstream to procyclic form was observed in Δicp, a phenotype that was reversed in the presence of synthetic CP inhibitors. Furthermore, we showed that degradation of anti‐VSG IgG is abolished when parasites are pretreated with synthetic CP inhibitors, and that parasites lacking ICP degrade IgG more efficiently than wild type. In addition, Δicp reached higher parasitemia than wild type parasites in infected mice, suggesting that ICP modulates parasite infectivity. Taken together, these data suggest that CPs of T. brucei bloodstream form play a role in surface coat exchange during differentiation, in the degradation of internalized IgG and in parasite infectivity, and that their function is regulated by ICP.
1 Updating the Role of Reduced Graphene Oxide Ink 2 on Field Emission Devices in Synergy with Charge 3 Transfer Materials 4

Hydroiodic acid (HI) treated reduced graphene oxide (rGO) ink/conductive polymeric 20 composites are considered as promising cold cathodes in terms of high geometrical aspect ratio and 21 low field emission (FE) threshold devices. In this study, four simple, cost-effective, solution22 processed approaches for rGO-based field effect emitters were developed, optimized and 23 compared; rGO layers were coated on a) n+ doped Si substrate, b) n+-Si/P3HT:rGO, c) n+24 Si/PCDTBT:rGO and d) n+-Si/PCDTBT:PC71BM:rGO composites, respectively. The fabricated 25 emitters were optimized by tailoring the concentration ratios of their preparation and field emission 26 characteristics. In a critical composite ratio, FE performance was remarkably improved compared 27 to the pristine Si, as well as n+-Si/rGO field emitter. In this context, the impact of various materials, 28 such as polymers, fullerene derivatives, as well as different solvents on rGO function reinforcement 29 and consequently on FE performance upon rGO-based composites preparation was investigated. 30 The field emitter consisted of n+-Si/PCDTBT:PC71BM(80%):rGO(20%)/rGO displayed a field 31 enhancement factor of ∼2850, with remarkable stability over 20h and low turn-on field in 0.6V/μm. 32 High-efficiency graphene-based FE devices realization paves the way towards low-cost, large-scale 33 electron sources development. Finally, the contribution of this hierarchical, composite film 34 morphology was evaluated and discussed. 35
Neural Cell Adhesion Molecule Induces Intracellular Signaling via Multiple Mechanisms of Ca 2 Homeostasis

The neural cell adhesion molecule (NCAM) plays a pivotal role in the development of the nervous system, promoting neuronal differentiation via homophilic (NCAM–NCAM) as well as heterophilic (NCAM-fibroblast growth factor receptor [FGFR]) interactions. NCAM-induced intracellular signaling has been shown to affect and be dependent on the cytoplasmic Ca2 concentration ([Ca2 ]i). However, the molecular basis of this remains unclear. In this study, we determined [Ca2 ]i regulating mechanisms involved in intracellular signaling induced by NCAM. To mimic the effect of homophilic NCAM interaction on [Ca2 ]i in vitro, we used a peptide derived from a homophilic binding site of NCAM, termed P2, which triggers signaling cascades similar to those activated by NCAM–NCAM interaction. We found that P2 increased [Ca2 ]i in primary hippocampal neurons. This effect depended on two signaling pathways. The first pathway was associated with activation of FGFR, phospholipase C , and production of diacylglycerol, and the second pathway involved Src-family kinases. Moreover, NCAMmediated Ca2 entry required activation of nonselective cation and T-type voltage-gated Ca2 channels. These channels, together with the Src-family kinases, were also involved in neuritogenesis induced by physiological, homophilic NCAM interactions. Thus, unanticipated mechanisms of Ca2 homeostasis are shown to be activated by NCAM and to contribute to neuronal differentiation.
Towards an Integrated Value Adding Management Model for FM and CREM

Purpose: To present an integrated process model of adding value by Facilities Management (FM) and Corporate Real Estate Management (CREM) that is a generalisation of existing conceptual frameworks and aims to be a basis for management of added value in practice. Background: The growing research on the added value of FM and CREM over the last decade has resulted in the development of several conceptual frameworks and the collection of much empirical data in practice. However, the practical application of current knowledge has shown to be limited and difficult. The reasons seem to be that the different frameworks are too complex and lack of common terminology and clear operationalisations of intervention-impact relationships. Approach (Theory/Methodology): A generalised Value Adding Management process model is developed based on a common cause-effect model identified in existing conceptual frameworks combined with the basic process model of input → throughput → output. The proposed model consists of interventions as input, management of implementation as throughput and added value as output/outcome. Results and practical implications: The Value Adding Management model provides a simple framework which aims at supporting the practical management and measurement of added value. A typology with six types of FM/CREM interventions is developed from earlier research. The concept of Value Adding Management is investigated and the 12 most important added value parameters are identified. Research limitations: The process model still has to be tested on its empirical validity and practical applicability. This is being done and will be presented in a forthcoming book on how to manage and measure value adding by FM and CREM. Originality/value: The Value Adding Management process model condensates research in an original and simple model with the potential to make value adding management more applicable in practice.
The Influence of Hmong Americans' Acculturation and Cultural Identity on Attitudes toward Seeking Professional Mental Health Care and Services in Comparison to Traditional Health Beliefs and Practices

The Hmong people have endured a long history of war-related trauma, and they have settled in different parts of the world. As a consequence, many Hmong people may have experienced various levels of psychological symptoms and have limited knowledge and resources for treatment and interventions. Issues of acculturation, cultural identity, traditional beliefs & practices, seeking traditional medical interventions, and religious beliefs may influence helpseeking behaviors from professional psychological services. Data, including demographic information, were gathered from two Hmong American churches located in southeast Michigan. The results showed that seeking professional services was correlated with both acculturation and traditional beliefs & practices. Acculturation and traditional beliefs & practices each contributed unique variance to help-seeking behaviors. This suggests that both low levels of acculturation and high levels of traditional beliefs & practices could result in people being less likely to seek mental health services. In this sample, Hmong Americans preferred God over traditional beliefs, such as Shamanism. The implications of these findings will be discussed.
Sex determination of prehistoric human paleofeces.

Analysis of 12 prehistoric human paleofecal specimens from the Mammoth Cave System, Kentucky has produced the first estimate of biological sex using fecal material from ancient humans. Accelerator mass spectrometry (AMS) radiocarbon dating indicates that the specimens range in age from ca. 2700 B.P. to 2300 B.P. Dietary contents and steroids were extracted and analyzed. Chromatography and radioimmunoassay were used to measure levels of testosterone and estradiol in both modern fecal reference samples and in ancient feces. Results indicate that all 12 paleofeces were probably deposited by males whose diet included a variety of native crops and wild plants. These preliminary analyses have the potential to revolutionize the investigation of gender difference in diet, health, and nutrition.
Manifestations of copper excess 1,2

Although copper is an essential micronutrient normally subject to effective homeostatic control, excess dietary intakes can in some circumstances be toxic. Susceptibility to copper toxicosis depends, however, on many factors, including species, genetics, age, and diet. This appears to reflect not only variations in the efficiency of the absorption and excretion of copper but also differences in the intake of other hepatotoxic or protective factors, differences in the cellular distribution of copper, and differences in the expression of specific copper transport and storage proteins. Many of the toxic effects of copper, such as increased lipid peroxidation in cell membranes and DNA damage, are related to its role in the generation of oxygen free radicals. Am J Clin Nutr 1998(suppl);67:1069S–73S.
The CA domain of the respiratory complex I is required for normal embryogenesis in Arabidopsis thaliana.

The NADH-ubiquinone oxidoreductase [complex I (CI), EC 1.6. 5.3] of the mitochondrial respiratory chain is the principal entry point of electrons, and vital in maintaining metabolism and the redox balance. In a variety of eukaryotic organisms, except animal and fungi (Opisthokonta), it contains an extra domain composed of putative gamma carbonic anhydrases subunits, named the CA domain, which was proposed to be essential for complex I assembly. There are two kinds of carbonic anhydrase subunits: CAs (of which there are three) and carbonic anhydrase-like proteins (CALs) (of which there are two). In plants, the CA domain has been linked to photorespiration. In this work, we report that Arabidopsis mutant plants affected in two specific CA subunits show a lethal phenotype. Double homozygous knockouts ca1ca2 embryos show a significant developmental delay compared to the non-homozygous embryos, which show a wild-type (WT) phenotype in the same silique. Mutant embryos show impaired mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) accumulation. The characteristic embryo greening does not take place and fewer but larger oil bodies are present. Although seeds look dark brown and wrinkled, they are able to germinate 12 d later than WT seeds. However, they die immediately, most likely due to oxidative stress.Since the CA domain is required for complex I biogenesis, it is predicted that in ca1ca2 mutants no complex I could be formed, triggering the lethal phenotype. The in vivo composition of a functional CA domain is proposed.
Isoform-specific subcellular targeting of glucose transporters in mouse fibroblasts

GLUT1, the erythrocyte glucose transporter, and GLUT4, the adipose/muscle transporter, were each expressed in NIH-3T3 cells by retrovirus-mediated gene transfer. In fibroblasts overexpressing GLUT1, basal as well as insulin-stimulated deoxyglucose uptake was increased. Expression of GLUT4 was without affect on either basal or hormone stimulated hexose uptake. Localization of each of the transporters by indirect immunofluorescence revealed that, whereas GLUT1 was found primarily on the cell surface, GLUT4 was directed to vesicles in a perinuclear distribution and throughout the cytoplasm. The GLUT4- containing compartment represented neither Golgi complex nor lysosomes, as evidenced by the failure of lgp110 or Golgi mannosidase to co- localize. However, there was substantial overlap between the distribution of GLUT4 and the transferrin receptor, and some colocalization of the transporter isoform with the manose-6-phosphate receptor. In addition, when FITC-wheat germ agglutinin bound to the cell surface was allowed to internalize at 37 degrees C, it concentrated in vesicular structures coincident with GLUT4 immunoreactivity. These data establish that GLUT1 and GLUT4 contain within their amino acid sequences information which dictates targeting to distinct cellular compartments. Moreover, GLUT4 can be recognized by those cellular factors which direct membrane proteins to the endosomal pathway.
Analysis of Consumer Perceptions on Payday Loan Services, Asset Ownership, and Financial Management Education

Payday loan services, asset ownership, and financial management have been issues of interest to many consumers and scholars. Using a cross-sectional survey, we analyzed perceptions on payday loan services, asset ownership, and financial management education. The results showed that, only a small number of respondents used payday loan services. A majority had savings and checking accounts, and owned a vehicle; however, a majority did not own an IDA or a home. Furthermore, many were willing to participate in a financial management workshop. We also found that selected socioeconomic factors had statistically significant effects on selected indicators. For instance, gender had a statistically significant effect on using payday loan services. Age and household income had statistically significant effects on owning a home. The number of children under 18 years, gender, age, and household income had statistically significant effects on the willingness to participate in a financial management workshop. The findings show that socioeconomic factors may be important, and should be considered in policies regarding payday loan services, asset ownership, and financial management. Keywords: Payday Loan Services, Asset Ownership, Financial Education, Financial Management, Socioeconomic Factors
Probabilistic models for analyzing the availability and profit of a deteriorating 2-out-of-4 system

This paper deals with modelling and evaluating the availability and profit of a linear consecutive 2-out-of-4 system exposed to three consecutive stages of deterioration before failure. The system will pass through three consecutive stages of deterioration: slow, medium and fast before failure. The failure and repair times are assumed to be exponentially distributed. Explicit expressions for the system availability, the probability of a repairman being busy due to the failure of a unit, or due to the replacement of failed units, and the profit function have been derived using a probabilistic approach. The impacts of the failure and repair rate on system availability and profit have been investigated. The results of this paper will enhance system performance and ensure the timely execution of appropriate maintenance and improvement, and thus is a major tool for decision making, planning and optimisation.
The Effective Provision of Pre-School Education Project: Findings from the pre-school period

The Effective Provision of Pre-School Education (EPPE) project is the first major European longitudinal study of a national sample of young children’s development (intellectual and social/behavioural) between the ages of 3 and 7 years. To investigate the effects of pre-school education for 3 and 4 year olds, the EPPE team collected a wide range of information on over 3,000 children, their parents, their home environments and the pre-school settings they attended. Settings (141) were drawn from a range of providers (local authority day nursery, integrated centres, playgroups, private day nurseries, maintained nursery schools and maintained nursery classes). A sample of ‘home’ children (who had no or minimal pre-school experience) was recruited to the study at entry to school for comparison with the pre-school group. In addition to investigating the effects of pre-school provision on young children’s development, EPPE explores the characteristics of effective practice (and the pedagogy which underpin them) through twelve intensive case studies of settings with positive child outcomes. EPPE has demonstrated the positive effects of high quality provision on children’s intellectual and social/behavioural developmental. This brief on the main findings of the research related to the pre-school period (for children aged 3 or 4 years of age to entry into primary school).
JEL Classifications : G 30 , G 34 , K 22 The Disappearing Delaware Effect

Refining and extending the methodology introduced by Daines (2001), I present evidence that firms incorporated in Delaware were worth 2-3% more than non-Delaware firms during the period 1991-1996, but not significantly more after 1996. I present two potential explanations for this "disappearing" Delaware effect. First, doctrinal movements in the mid1990s might have solidified the Just Say No defense in Delaware, making Delaware’s corporate law undifferentiated from the corporate law of other states. Second, “adaptive devices” (Kahan & Rock 2002), notably the increase in stock compensation during the 1990s, might have made takeover law no longer a binding constraint in many M&A transactions. I find some support in the empirical evidence for both of these explanations. * I thank George Baker, Lucian Bebchuk, Robert Daines, Marcel Kahan, Reinier Kraakman, Mark Ramseyer, Mark Roe, Leo Strine, and workshop participants at Georgetown Law School and Harvard Business School for helpful comments and discussions. The Disappearing Delaware Effect Guhan Subramanian Harvard Law School