1,721,159 research outputs found
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
Dispelling 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
Immunologische aandoeningen met cutane manifestaties: exploratie van de genetische en immunologische basis
No full textThe skin functions as a barrier against invasion of pathogens from the environment. This function is fulfilled by first, rich variety of microflora being housed on the skin to outcompete potential harmful microbes in the environment for survival; second, the complex structural architecture of the skin, e.g. the stratified nature of outer epidermis and inner dermis, presence of tight junctions, etc; and third, the constant presence of competent immune cells to effectively clear infections. However, in situations such as observed in genetically pre-disposed individuals, the skin barrier can be breached leading to recurrent or chronic susceptibility to infections like S. aureus and candida. Other cutaneous disorders like pruritus, vitiligo, psoriasis, and keratosis, etc have been observed. Usually, no treatment regimens exist for patients except for targeted treatment of recurring infections or bone marrow/stem cell transplantation. Such treatments have drawbacks such as development of resistant strains or graft versus host disease (GVHD) respectively. Understanding the molecular mechanism underlying the pathophysiology of such disorders is key to designing therapeutic interventions. This study focused on understanding the genetic and immunological defects underlying two different immune disorders with cutaneous manifestations. First, we sought to understand the transcriptional mechanism Aire (autoimmune regulator) uses to regulate the gene expression of pancreatic-specific antigens in the thymic medulla in promoting tolerance towards the antigens. The Â#Hierarchical modelÂ# of gene regulation was tested in a thymus, in a situation whereby Aire adopts peripheral Pdx1 gene regulation mechanism. This mechanism allows thymic expression of pancreatic TRAs such as insulin (Ins2) and Sst in order to promote tolerance to these antigens. Gene expression analysis revealed that although thymic gene expression of Pdx1, Ins2 and Sst are Aire-dependent, Ins2 and Sst thymic gene expression could proceed in the absence of Pdx1. When tolerance towards insulin was monitored using insHEL transgenic system, our data showed no difference in the amount of tolerogenic insHEL-specific 3A9 TCR cells in Pdx1-deficient and Pdx1-sufficient thymic environment. These results suggest that although Aire drives the thymic expression of the transcription factor Pdx1 and its downstream autoantigens such as insulin, the thymic Pdx1 expression is not necessary for tolerogenic insulin expression in the thymus, thus, Aire does not use the Pdx1-dependent peripheral regulation pathways in the thymus. Our data supports a model for direct transcriptional activity on Aire-regulated genes in the thymus. Secondly, we focused on exploring the genetic and immunological bases of a case study patient clinically diagnosed with OS. Exome sequencing data revealed novel Gly573Ala mutation with potential damaging effect to the TRPV3 protein. This identification verifies and re-enforces the establishment of mutation in TRPV3 as the underlying genetic defect in OS. Additionally, a look at the immune profile resulted in the identification of immune dysregulation in the OS patient, particularly, hyper IgE, eosinophilia and high levels of Tfh cells. The immune dysregulation could be the primary defect with cutaneous manifestation of hyperkeratosis lesions. It could also be a secondary consequence of a primary cutaneous defect. Our data uncover the need for further investigation to 1) determine the penetrance of the immune dysregulation in other OS cases, 2) ascertain the pathophysiological mechanism of the immune dysregulation. In conclusion, the present study provides insights into the molecular mechanism of two immune disorders that present with cutaneous defects. In the case of APS1, our data supported the idea that the transcriptional regulatory mechanism of Aire is via direct targeting of Aire-dependent TRAs, although Â#hierarchicalÂ# transcription seemed plausible. This suggests that future studies should be geared toward a direct transcriptional mechanism by Aire. On the other hand, alternative approach to testing #hierarchical# model should consider TFs other than the known peripheral TFs that regulate the TRAs. In the OS study, the identification of novel Gly573Ala mutation contributes to the knowledge of clinical variants of TRPV3 which could be placed in database curated for clinical variants. More so, data on the detailed immune profile and immune dysregulation in a case of OS is the first to be reported. Our data, thus, sets the grounds for further studies regarding immunological component of OS pathophysiology.status: Publishe
Targeted editing of the PSIP1 gene encoding LEDGF/p75 as a functional cure for HIV
No full textGene therapy has long held promise to correct a variety of human diseases. Discovery of the Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR), the mechanism of the CRISPR-based prokaryotic adaptive immune system (CRISPR-associated system, Cas) and its repurposing into a potent gene editing tool has revolutionized the field of molecular biology and generated excitement for new and improved gene therapies. Additionally, the simplicity and flexibility of the CRISPR/Cas9 site-specific nuclease system has led to its widespread use in many biological research areas including development of model cell lines, discovering mechanisms of disease, identifying disease targets, development of transgenic animals and plants, and transcriptional modulation.
One potential application for CRISPR/Cas9 currently being explored is cell re-engineering to combat HIV/AIDS.
To fulfill a productive infection cycle the human immunodeficiency virus (HIV) relies on host-cell factors. Interference with these co-factors has demonstrated to be effective in protecting cells against HIV infection, as exemplified by the natural occurring CCR5 del mutations and the ablation of HIV co-receptor CCR5 using zinc finger nucleases.
An alternative target being explored in this thesis is LEDGF/p75. LEDGF/p75, encoded by the PSIP1 gene, is used by the lentiviral integrase (IN) protein in the pre-integration complex of HIV to bind host-cell chromatin and thus, facilitating proviral integration. LEDGF/p75 depletion results in defective HIV replication. However, as its cellular function, LEDGF/p75 tethers cellular proteins and their respective complexes to the host-cell genome. We assessed CRISPR KO and, in addition, used site-specific editing of the PSIP1 locus using CRISPR/Cas to target the aspartic acid residue in position 366 and mutated it to asparagine (D366N) to disrupt the interaction with HIV IN but retain LEDGF/p75 cellular function. The resulting cell lines demonstrated successful disruption of the LEDGF/p75 HIV-IN interaction without affecting binding with cellular binding partners. In line with LEDGF/p75 depleted cells, D366N cells did not support HIV replication, in part due to the limited integration efficiency. In addition, we have confirmed that the provirus that had managed to integrate showed only negligible transcriptional activity thus, in effect, remained transcriptionally silent.
Taken together, these results support the potential of site-directed CRISPR/Cas9 mediated knock-in to render cells more resistant to HIV infection and provides an additional strategy to protect patient-derived T-cells against HIV-1 infection as part of cell-based therapy.status: Publishe
Genetic and cellular characterisation of Foxp3+ regulatory T cells during health and disease
No full textRegulatory T cells (Treg) are indispensible for the prevention of devastating immune dysregulation. The work described in this thesis provides a unique new insight into regulatory T cell biology demonstrating that after partial Treg depletion, levels of IL-2 rise significantly, allowing the unaffected Treg not only to survive but also to rapidly repopulate the niche in a co-stimulation dependent manner, with a temporary overshoot in numbers. From the detailed study of the Bcl-2 family of apoptosis/survival regulators we found that Mcl-1 and Bim are essential for regulating Treg survival and apoptosis, respectively, while Bcl-XL and Bcl-2 are not. From the finding that Mcl-1 expression is influenced by IL-2 availability, we have uncovered a potential mechanism by which IL-2 is capable of regulating apoptosis levels during perturbations in the size of the Treg niche. In addition, we found that thymus-derived Treg are able to participate in a germinal centre (GC) response by adopting a phenotype reminiscent of the cells they were found to regulate: the follicular T helper subset (Tfh). We show that follicular Treg (Tfr) limit the size of the Tfh pool, thereby limiting the help to GC B cells and ensuring the generation of high affinity antibodies and protective B cell memory.status: Publishe
Genetic and immunological characterization of a hyper-IgE Syndrome pedigree
Get PDFDissertação de Mestrado em Biotecnologia para as Ciências da SaúdeCompreender o sistema imunológico e como é influenciado pelo genoma são processos fundamentais para desvendar a base genética da regulação e desregulação imunológica. Os avanços das ferramentas genéticas e estratégias de sequenciação potenciam a identificação de mutações causadoras de doenças mal compreendidas como a síndrome de hiper-IgE (HIES). HIES é uma imunodeficiência primária cujas características incluem eczema, infecções pulmonares recorrentes e níveis séricos de IgE extremamente elevados. HIES tem sido associada à herança mendeliana de mutações em STAT3, DOCK8 e TYK2, no entanto, a maior parte dos casos não tem causa genética conhecida. Neste estudo, trabalhamos uma família com dois casos de HIES. Os pacientes deste estudo, filhos de pais consanguíneos, foram diagnosticados com HIES, no entanto nenhuma mutação foi encontrada em STAT3, DOCK8 ou TYK2. Recorrendo a “whole-exome sequencing” encontrou-se um SNP codificante raro em CARD11. Este SNP foi considerado o melhor candidato para explicar o fenótipo do paciente, devido às semelhanças com o fenótipo murino de deficiência em Card11 (dermatite atópica, aumento dos níveis séricos de IgE e resposta imune mediada por células Th2). Com base nisto, a hipótese de que este SNP era a causa de HIES nos doentes foi formulada. Contudo, os nossos resultados excluem CARD11 de ser o gene causador do fenótipo clínico. A elaboração do perfil imunológico de um dos paciente revelou uma diminuição de células Th2, Tregs e células T CD4+ naïve, e um aumento nas células CD4+ em CD8+ de memória. Em suma, estes resultados sugerem que a HIES apresentada pelos pacientes pertence a uma nova categoria, quer de foro genético, quer de foro imunológico. Pesquisa adicional é necessária para identificar a causa da doença nesta família e pode contribuir para uma melhor compreensão da produção de IgE e de doenças mediadas por IgE.Understanding the immune system and how it is influenced by the genome are key steps for unraveling the genetic basis of immunological regulation and dysregulation. Advances in genetic tools and sequencing strategies potentially allow us to identify novel disease-causing mutations in poorly understood diseases such as hyper-IgE syndrome (HIES). HIES is a primary immune deficiency characterized by eczema, recurrent skin and lung infection, and greatly increased serum levels of IgE. HIES has been linked to a Mendelian inheritance of mutations in STAT3, DOCK8 and TYK2, however, most cases do not have a known genetic cause. In this study we worked on a family which manifested two cases of HIES in children of consanguineous parents. The patients of this study were diagnosed with HIES, yet no mutation in STAT3, DOCK8 orTYK2 were found. Resorting to whole-exome sequencing we found a rare coding SNP in CARD11, which was considered the best candidate to explain the patient’s phenotype due to the similarities to the Card11-deficient mouse phenotype (atopic dermatitis, increased serum levels of IgE and Th2-driven immune response). Based on this we hypothesized that this SNP was causing HIES in the patients, however our results rule out CARD11 as the causable gene for the clinical phenotype. The immune phenotyping of one of the patient revealed a decrease in Th2 cells, Tregs and naïve CD4+ T cells, and an increase in memory CD4+ and CD8+ T cells. Together, these results suggest a novel category of HIES, in genetic and immunologic basis. Additional research to identify the disease causation in this family may contribute for the better understanding of IgE production and IgE-mediated diseases
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