Miracle-dz/UniFAR-FTUs huggingface dataset:
B16 as a Mouse Model for Human Melanoma

This unit details protocols for in vivo models of subcutaneous growth and pulmonary metastases of B16 melanoma. Therapeutic approaches include the use of B16.GM‐CSF and rVVmTRP‐1 to induce autoimmune vitiligo and tumor protection. The induction and use of gp100‐specific therapeutic cytotoxic T lymphocytes (CTL) are discussed. Methods are also included for CTL induction, isolation and testing, CTL maintenance, and adoptive transfer. Support protocols detail the testing of mouse sera for presence of MDA‐specific antibodies by immunoblotting and ELISA, respectively. Additional sections, including growing B16 melanoma, enumerating pulmonary metastases, and use of recombinant viruses for vaccination, are discussed together with safety concerns.
In-situ Reactive Interfacial Compatibilization and Properties of Polylactide/Sisal Fiber Biocomposites via Melt-blending with Epoxy-functionalized Oligomer

To improve the interfacial bonding of sisal fiber reinforced polylactide biocomposites, polylactide (PLA) and sisal fibers (SF) were melt-blended to fabricate bio-based composites via in situ reactive interfacial compatibilization with the addition of an epoxy-functionalized oligomer (ADR). The FTIR analysis and SEM characterization demonstrated that PLA molecular chain was bonded to the fiber surface and epoxy-functionalized oligomer played a hinge-like role between sisal fibers and PLA matrix, which resulted in improved interfacial adhesion between fibers and PLA matrix. The interfacial reaction and microstructures of composites were further investigated by thermal and rheological analyses, which indicated that the mobility of the PLA molecular chain in composites was restricted because of the introduction of ADR oligomer, which in turn reflected the improved interfacial interaction between SF and PLA matrix. These conclusions were further investigated by the calculated activation energies of glass transition relaxation (△Ea) of composites via dynamic mechanical analysis. The mechanical properties of PLA/SF composites were simultaneously reinforced and toughened via addition of ADR oligomer. The interfacial interaction and structure-properties relationship of composites are key points of this study.
TARV: Tree‐based Analysis of Rare Variants Identifying Risk Modifying Variants in CTNNA2 and CNTNAP2 for Alcohol Addiction

Since the development of next generation sequencing (NGS) technology, researchers have been extending their efforts on genome‐wide association studies (GWAS) from common variants to rare variants to find the missing inheritance. Although various statistical methods have been proposed to analyze rare variants data, they generally face difficulties for complex disease models involving multiple genes. In this paper, we propose a tree‐based analysis of rare variants (TARV) that adopts a nonparametric disease model and is capable of exploring gene–gene interactions. We found that TARV outperforms the sequence kernel association test (SKAT) in most of our simulation scenarios, and by notable margins in some cases. By applying TARV to the study of addiction: genetics and environment (SAGE) data, we successfully detected gene CTNNA2 and its 43 specific variants that increase the risk of alcoholism in women, with an odds ratio (OR) of 1.94. This gene has not been detected in the SAGE data. Post hoc literature search also supports the role of CTNNA2 as a likely risk gene for alcohol addiction. In addition, we also detected a plausible protective gene CNTNAP2, whose 97 rare variants can reduce the risk of alcoholism in women, with an OR of 0.55. These findings suggest that TARV can be effective in dissecting genetic variants for complex diseases using rare variants data.
Midlife Cardiovascular Risk Factors and Late‐Life Unrecognized and Recognized Myocardial Infarction Detect by Cardiac Magnetic Resonance: ICELAND‐MI, the AGES‐Reykjavik Study

Background Associations of atherosclerosis risk factors with unrecognized myocardial infarction (UMI) are unclear. We investigated associations of midlife risk factors with UMI and recognized MI (RMI) detected 31 years later by cardiac magnetic resonance. Methods and Results The Reykjavik Study (1967–1991) collected serial risk factors in subjects, mean (SD) age 48 (7) years. In ICELAND‐MI (2004–2007), 936 survivors (76 (5) years) were evaluated by cardiac magnetic resonance. Analysis included logistic regression and random effects modeling. Comparisons are relative to subjects without MI. At baseline midlife evaluation, a modified Framingham risk score was significantly higher in RMI and in UMI versus no MI (7.4 (6.3)%; 7.1 (6.2)% versus 5.4 (5.8)%, P<0.001). RMI and UMI were more frequent in men (65%, 64% versus 43%; P<0.0001). Baseline systolic and diastolic blood pressure were significantly higher in UMI (138 (17) mm Hg versus 133 (17) mm Hg; P<0.006; 87 (10) mm Hg versus 84 (10) mm Hg; P<0.02). Diastolic BP was significantly higher in RMI (88 (10) mm Hg versus 84 (10) mm Hg; P<0.02). Cholesterol and triglycerides were significantly higher in RMI (6.7 (1.1) mmol/L versus 6.2 (1.1) mmol/L; P=0.0005; and 1.4 (0.7) mmol/L versus 1.1 (0.7) mmol/L; P<0.003). Cholesterol trended higher in UMI (P=0.08). Serial midlife systolic BP was significantly higher in UMI versus no MI (β [SE] = 2.69 [1.28] mm Hg, P=0.04). Serial systolic and diastolic BP were significantly higher in RMI versus no MI (4.12 [1.60] mm Hg, P=0.01 and 2.05 [0.91] mm Hg, P=0.03) as were cholesterol (0.43 [0.11] mmol/L, P=0.0001) and triglycerides (0.3 [0.06] mmol/L, P<0.0001). Conclusions Midlife vascular risk factors are associated with UMI and RMI detected by cardiac magnetic resonance 31 years later. Systolic blood pressure was the most significant modifiable risk factor associated with later UMI.
Action Research and Social Change in Sport: An Introduction to the Special Issue

Although sport has evidenced phenomenal growth throughout this century, the directions of sport's growth have been widely criticized. The growth and resulting criticisms challenge sport managers and sport management researchers to reexamine their methods and their assumptions. Articles in this special issue explore the redesign of sport systems and the tasks of redressing inequities in sport service delivery. They raise significant issues about the role of knowledge in the empowerment of managers and clients. The articles suggest the value of incorporating both qualitative and quantitative methods in action research, and challenge traditional distinctions between “applied” and “basic” research. They demonstrate the merit of case-based research, and illustrate the utility of collaborations between researchers and the persons they study. The study of social change in sport promises to provide a useful context for the elaboration of theories and models about the management of sport.
Energy efficient in-memory AES encryption based on nonvolatile domain-wall nanowire

The widely applied Advanced Encryption Standard (AES) encryption algorithm is critical in secure big-data storage. Data oriented applications have imposed high throughput and low power, i.e., energy efficiency (J/bit), requirements when applying AES encryption. This paper explores an in-memory AES encryption using the newly introduced domain-wall nanowire. We show that all AES operations can be fully mapped to a logic-in-memory architecture by non-volatile domain-wall nanowire, called DW-AES. The experimental results show that DW-AES can achieve the best energy efficiency of 24 pJ/bit, which is 9X and 6.5X times better than CMOS ASIC and memristive CMOL implementations, respectively. Under the same area budget, the proposed DW-AES exhibits 6.4X higher throughput and 29% power saving compared to a CMOS ASIC implementation; 1.7X higher throughput and 74% power reduction compared to a memristive CMOL implementation.
Induction of Novel Agonist Selectivity for the ADP-Activated P2Y1 Receptor Versus the ADP-Activated P2Y12 and P2Y13 Receptors by Conformational Constraint of an ADP Analog

ADP is the cognate agonist of the P2Y1, P2Y12, and P2Y13 receptors. With the goal of identifying a high potency agonist that selectively activates the P2Y1 receptor, we examined the pharmacological selectivity of the conformationally constrained non-nucleotide analog (N)-methanocarba-2MeSADP [(1′S,2′R, 3′S,4′R,5′S)-4-[(6-amino-2-methylthio-9H-purin-9-yl)-1-diphosphoryloxymethyl]bicyclo[3.1. 0]hexane-2,3-diol] among the three ADP-activated receptors. Each P2Y receptor was expressed transiently in COS-7 cells, and inositol lipid hydrolysis was quantified as a measure of receptor activity. In the case of the Gi-linked P2Y12 and P2Y13 receptors, a chimeric G protein, Gαq/i, was coexpressed to confer a capacity of these Gi-linked receptors to activate phospholipase C. 2MeSADP (2-methylthio-ADP) was a potent agonist at all three receptors exhibiting EC50 values in the sub to low nanomolar range. In contrast, whereas (N)-methanocarba-2MeSADP was an extremely potent (EC50 = 1.2 ± 0.2 nM) agonist at the P2Y1 receptor, this non-nucleotide analog exhibited no agonist activity at the P2Y12 receptor and very low activity at the P2Y13 receptor. (N)-Methanocarba-2MeSADP also failed to block the action of 2MeSADP at the P2Y12 and P2Y13 receptors, indicating that the (N)-methanocarba analog is not an antagonist at these receptors. The P2Y1 receptor selectivity of (N)-methanocarba-2MeSADP was confirmed in human platelets where it induced the shape change promoted by P2Y1 receptor activation without inducing the sustained platelet aggregation that requires simultaneous activation of the P2Y12 receptor. These results provide the first demonstration of a high-affinity agonist that discriminates among the three ADP-activated P2Y receptors, and therefore, introduce a potentially important new pharmacological tool for delineation of the relative biological action of these three signaling proteins.
Revealing and modifying non-local variations in a single image

We present an algorithm for automatically detecting and visualizing small non-local variations between repeating structures in a single image. Our method allows to automatically correct these variations, thus producing an 'idealized' version of the image in which the resemblance between recurring structures is stronger. Alternatively, it can be used to magnify these variations, thus producing an exaggerated image which highlights the various variations that are difficult to spot in the input image. We formulate the estimation of deviations from perfect recurrence as a general optimization problem, and demonstrate it in the particular cases of geometric deformations and color variations.
Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody

Building Better Vaccines Vaccines are one of the most effective tools to protect against infectious diseases. Unfortunately, vaccines for diseases with the highest global health burdens, such as HIV, malaria, and tuberculosis, are not yet available. Koff et al. (p. 1064) review the latest advances in vaccine development and why these particular diseases remain such a challenge. Respiratory syncytial virus (RSV) is a serious cause of morbidity and mortality in infants and young children worldwide. Although a prophylactic antibody is available for children at high risk, a vaccine is much needed. As a potential step toward this goal, McLellan et al. (p. 1113, published online 25 April) solved the cocrystal structure of a neutralizing antibody (D25) bound to the prefusion F protein of RSV. Knowledge of the structure of the prefusion protein should help to guide vaccine design and the development of additional therapeutics. The prefusion conformation of respiratory syncytial virus protein F has been trapped by a neutralizing antibody. The prefusion state of respiratory syncytial virus (RSV) fusion (F) glycoprotein is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab. The cocrystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed D25 to lock F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to the newly identified site of vulnerability, which we named antigenic site Ø. These studies should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease.
The Ripple Effects of Deceptive Reporting

Deceptive information transmission is a pervasive phenomenon in organizations and markets. Although institutions and firms devote a great deal of resources to promoting norms of honesty, little is known about how defectors can affect these environments. We find that when strong norms for truthful behavior exist, dishonest acts have ripple effects on unrelated, anonymous parties. These results suggest that ethical codes can have unintended consequences in the cases in which individuals choose to be dishonest. In addition, agents who care strongly about truthfulness resist the urge to pay deception forward. We present evidence that implies that agents who pay forward deceptive communication are acting on their emotions.
γδ T Cells Protect the Liver and Lungs of Mice from Autoimmunity Induced by Scurfy Lymphocytes

γδ T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG−/−) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCRα−/− recipients, which lack αβ T cells but have γδ T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes. Cotransfer of γδ T cells, but not B cells, prevented hepatitis and pneumonitis in RAG−/− recipients of scurfy lymphocytes. γδ T cells in the TCRα−/− recipients of scurfy cells markedly expanded and expressed a highly activated (CD62LloCD44hi) phenotype. The activated γδ T cells expressed high levels of CD39 and NKG2D on their cell surface. A high frequency of scurfy T cells in TCRα−/− recipients produced IL-10, suggesting that γδ T cells may enhance suppressor cytokine production from scurfy T cells in TCRα−/− recipients. This study indicates that γδ T cells may contribute to the maintenance of immunological homeostasis by suppressing autoreactive T cells in liver and lung.
A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency

Polymorphisms in folate‐related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781‐6823ATT(7–9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT7, whereas Alleles 2 and 3 consist of ATT8 and ATT9, respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case–control logistic regression (P=0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts. Hum Mutat 30:1–7, 2009. © 2009 Wiley‐Liss, Inc.
CD72 Negatively Regulates KIT-Mediated Responses in Human Mast Cells

KIT activation, through binding of its ligand, stem cell factor, is crucial for normal mast cell growth, differentiation, and survival. Furthermore, KIT may also contribute to mast cell homing and cytokine generation. Activating mutations in KIT lead to the dysregulated mast cell growth associated with the myeloproliferative disorder, mastocytosis. We investigated the potential of downregulating such responses through mast cell inhibitory receptor activation. In this study, we report that the B cell-associated ITIM-containing inhibitory receptor, CD72, is expressed in human mast cells. Ligation of CD72 with the agonistic Ab, BU40, or with recombinant human CD100 (rCD100), its natural ligand, induced the phosphorylation of CD72 with a resulting increase in its association with the tyrosine phosphatase SH2 domain-containing phosphatase-1. This, in turn, resulted in an inhibition of KIT-induced phosphorylation of Src family kinases and extracellular-regulated kinases (ERK1/2). As a consequence of these effects, KIT-mediated mast cell proliferation, chemotaxis, and chemokine production were significantly reduced by BU40 and rCD100. Furthermore, BU40 and rCD100 also downregulated the growth of the HMC1.2 human mast cell line. Thus, targeting CD72 may provide a novel approach to the suppression of mast cell disease such as mastocytosis.
A Grounded Theory Perspective on Leadership in Multicultural Schools

The methodology of grounded theory has great potential to contribute to our understanding of leadership within particular substantive contexts. Leadership is a global phenomenon, but appears to have a variety of attributes and seems to elude clear definition. In this research we argue that such variation is contextually derived. Leadership is not only a socially influenced process but also a relation-influenced process that occurs within a social system. The focus in this paper is on the challenges facing leaders engaged in multicultural education. In general, grounded theorists seek to develop theory inductively from systematically gathered and analysed data. An integrative picture or story is developed from this process. In the present instance we explore how conducting grounded theory research according to a qualitative approach accentuates the need to understand and explain contextualised leadership. We conclude by suggesting how leaders might overcome challenges in multicultural education.
Rembrandt: Helping Personalized Medicine Become a Reality through Integrative Translational Research

Finding better therapies for the treatment of brain tumors is hampered by the lack of consistently obtained molecular data in a large sample set and the ability to integrate biomedical data from disparate sources enabling translation of therapies from bench to bedside. Hence, a critical factor in the advancement of biomedical research and clinical translation is the ease with which data can be integrated, redistributed, and analyzed both within and across functional domains. Novel biomedical informatics infrastructure and tools are essential for developing individualized patient treatment based on the specific genomic signatures in each patient's tumor. Here, we present Repository of Molecular Brain Neoplasia Data (Rembrandt), a cancer clinical genomics database and a Web-based data mining and analysis platform aimed at facilitating discovery by connecting the dots between clinical information and genomic characterization data. To date, Rembrandt contains data generated through the Glioma Molecular Diagnostic Initiative from 874 glioma specimens comprising ∼566 gene expression arrays, 834 copy number arrays, and 13,472 clinical phenotype data points. Data can be queried and visualized for a selected gene across all data platforms or for multiple genes in a selected platform. Additionally, gene sets can be limited to clinically important annotations including secreted, kinase, membrane, and known gene-anomaly pairs to facilitate the discovery of novel biomarkers and therapeutic targets. We believe that Rembrandt represents a prototype of how high-throughput genomic and clinical data can be integrated in a way that will allow expeditious and efficient translation of laboratory discoveries to the clinic. (Mol Cancer Res 2009;7(2):157–67)
All-cause and cardiovascular mortality associated with sulphonylurea and metformin therapy in type 2 diabetes

ABSTRACT Purpose: To test the hypothesis that cumulative exposure to sulphonylurea (SU) or metformin (MET) have different effects on mortality when taken as a replacement or add-on of one for the other. Methods: All consecutive diabetes patients aged over 20 years were screened at their first diabetes outpatient visit between 2001 and 2008 (n = 79869). Only patients on MET (n = 11374) or SU (n = 18502) monotherapy were retained. All patients were followed up for death until December 31, 2011, but censored at first exposure to anything else besides MET/SU. Adjusted time-dependent Cox regression and competing risk regression analysis, with daily updates of treatment modalities were performed. Results: Mean age was 62.1 ± 11.2 years and follow-up was 4.6 ± 3.2 years (138496 person-years). Adjusted all-cause and cardiovascular mortality rates were significantly higher in MET as compared with SU group. All-cause mortality hazard ratios (HR) for cumulative time exposure were as follows: HR 0.956 (95%CI 0.951–0.962, p < 0.001) for SU added to MET, HR 1.092 (95%CI 1.087–1.096, p < 0.001) for SU replacing MET, HR 0.979 (95%CI 0.975–0.983, p < 0.001) for MET added to SU, and HR 1.127 (95%CI 1.118–1.136, p < 0.001) for MET replacing SU. Conclusion(s): The effect on all-cause mortality was beneficial for MET+SU combined therapy, but deleterious for either SU replacing MET, or MET replacing SU. There were no major outcome differences when analyzing individual SU, or specific mortality.
Incorporating Gene-Environment Interaction in Testing for Association with Rare Genetic Variants

Objectives: The incorporation of gene-environment interactions could improve the ability to detect genetic associations with complex traits. For common genetic variants, single-marker interaction tests and joint tests of genetic main effects and gene-environment interaction have been well-established and used to identify novel association loci for complex diseases and continuous traits. For rare genetic variants, however, single-marker tests are severely underpowered due to the low minor allele frequency, and only a few gene-environment interaction tests have been developed. We aimed at developing powerful and computationally efficient tests for gene-environment interaction with rare variants. Methods: In this paper, we propose interaction and joint tests for testing gene-environment interaction of rare genetic variants. Our approach is a generalization of existing gene-environment interaction tests for multiple genetic variants under certain conditions. Results: We show in our simulation studies that our interaction and joint tests have correct type I errors, and that the joint test is a powerful approach for testing genetic association, allowing for gene-environment interaction. We also illustrate our approach in a real data example from the Framingham Heart Study. Conclusion: Our approach can be applied to both binary and continuous traits, it is powerful and computationally efficient.