1,721,118 research outputs found
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Empirical Reverse Engineering of Vaccine Neoantigens
No full textSince the advent of immunization, vaccines have been composed of natural antigens pulled from the proteome of the infectious agent. To pick potentially protective antigens, pathogens must be deeply studied to elucidate their life cycles, patterns of protein expression, and interactions with their hosts. This reliance on understanding pathogen biology requires the etiology of disease to be known, hampers the speed of vaccine development, and generates vaccines with curtailed efficacy. Infectious pandemics and the cancer epidemic provide unambiguous motivation for the creation of an agnostic platform to develop potent vaccines.Here, we outline our vaccine development approach to (1) characterize T-cell receptors (TCRs) responding to an insult, (2) perform antigen discovery for discovered TCRs, and (3) vaccinate with found, novel neoantigens. We hypothesize that novel, synthetic peptide ligands can effectively prime the same repertoire of na�ve T cells that clonally respond to infection. To find the optimal synthetic antigens, we designed a NFκB-driven, cell-based antigen discovery platform to interrogate TCRs with a diverse and streamlined pool of peptide antigens. Using our functional, unbiased method to screen for peptide ligands, we performed antigen discovery for known TCRs and novel TCRs from an in vivo cancer model. Our platform was specific, sensitive, and tunable in finding TCR-activating antigens. The system was able to successfully find cognate antigens for known TCRs. When performing antigen discovery for T cells resulting from an in vivo tumor model, our platform found antigens corresponding to known, expressed tumor antigens. Furthermore, we found that a streamlined peptide library can reduce peptide library complexity while still providing useful information on TCR-binding motifs. Our future directions include in vitro and in vivo testing with discovered neoantigens for known and novel TCRs.Overall, identifying TCRs and screening TCR-binding ligands can aid in the development of vaccines in the fields of infection, cancer, allergy, autoimmunity, and transplantation. Our long-term goal is to bring about a new method for developing effective antigens for vaccines by identifying peptides that stimulate discovered, insult-specific protective T cells. If successful, our approach will have a major impact on vaccinology: we enable the possibility of developing effective vaccines without having to identify the insult as an initial step, a major boon for emerging infections or epidemics of known or unknown etiology
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Enhancing Tumor-Infiltrating T cells with an Exclusive Fuel Source
Get PDFSolid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is a building block of cellulose, contains a β-1,4-glycosidic bond that cannot be hydrolyzed by animals (or their tumors), but fungal and bacterial organisms have evolved enzymes to catabolize cellobiose and use the resulting glucose. By equipping T cells with two proteins that enable import and hydrolysis of cellobiose, we demonstrate that supplementation of cellobiose during glucose withdrawal restores T cell cytokine production and cellular proliferation. Murine tumor growth is suppressed, and survival is prolonged. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. Beyond cancer, this approach could be used to answer questions about the regulation of glucose metabolism across many cell types, biological processes, and diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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Macromolecular structures of receptor-ligand complexes from developmental neurobiology and cancer biology
Get PDFDispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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