1,720,955 research outputs found
T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis
Get PDFMultiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood-brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
CELLULAR AND MOLECULAR MECHANISMS OF CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA
No full textAcute Myeloid Leukemia (AML) remains an incurable disease, with a 5-year survival rate below 30%. While the introduction of new therapeutic approaches, such as targeted therapies and immunotherapy, has had a modest impact on AML prognosis, the standard treatment of AML is still based on chemotherapy regimens (like "7+3") that have been in use for over 50 years. Approximately 20% of patients do not respond to standard chemotherapy, and even among those who initially respond, around 50% eventually relapse due to the development of chemotherapy resistance. Chemoresistance is the cause of death for over 90% of AML patients.
The mechanisms underlying chemoresistance in AML are not yet fully understood, and targeted therapies aimed at preventing chemoresistance are not currently available. Chemoresistance in AML is primarily driven by non-genetic mechanisms. While leukemic stem cells (LSCs) have been implicated, recent studies suggest that AML blasts that survive chemotherapy, known as Chemotherapy Persistent Blasts, enter a senescence-like and diapause state. Though they can contribute to disease recurrence, these Persistent Blasts are not inherently therapy-resistant as they revert to a drug-sensitive state upon drug withdrawal. However, a lack of robust in vivo models of clinical chemoresistance in human AML hinders our understanding of these mechanisms. To address this, I aimed to generate in vivo models of truly chemoresistant AML to investigate non-genetic mechanisms of chemotherapy resistance.
I utilized mouse models of human AML, specifically Patient-Derived Xenografts (PDXs), to establish treatment protocols mimicking the standard "7+3" chemotherapy regimen used clinically. One model (AML9) mirrored the behavior of most patients treated with standard chemotherapy, exhibiting clinical remission followed by relapse. In contrast, the other model (AML20) showed a modest response to chemotherapy with rapid leukemia re-expansion. Notably, relapsed leukemias in both models were completely resistant to retreatment with the same chemotherapy regimen, and this resistant phenotype persisted even after re-transplantation. Extensive genomic profiling revealed that chemoresistance in relapsed leukemias was not associated with the emergence of de novo DNA mutations. AML9 and AML20 represent the first two available AML models of true clinical chemoresistance, mirroring primary and secondary resistance, respectively.
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To investigate mechanisms of chemoresistance in these models, I characterized the cellular and molecular properties of Chemotherapy Persistent Blasts isolated at the end of the chemotherapy regimen. To monitor and isolate quiescent blasts during leukemia growth and after chemotherapy treatment, I incorporated a label-retaining (LR) assay into the PDX models, enabling cell division tracking through inducible expression of H2B-GFP. I found that: i) in vitro, Persistent Blasts from both models exhibited significantly higher IC50 values compared to non-treated blasts, suggesting the induction or selection of a stable and cell- autonomous chemoresistant phenotype; ii) Quiescent blasts were slightly enriched among Persistent Blasts, but a portion of leukemia cells continued to proliferate during treatment, generating a population of Persistent Blasts of both proliferating and quiescent cells; iii) Persistent Blasts retained regenerative potential in vivo, primarily attributed to persistent quiescent blasts, suggesting that quiescence, while not a specific trait of chemoresistance, is integral to the relapsing properties of these cells; iv) the AML clonal structure remained unchanged after chemotherapy treatment, as determined by lineage tracing of Persistent Blasts and relapsed leukemias, suggesting that chemotherapy does not select specific cellular lineages; v) Persistent Blasts exhibited distinct transcriptional features compared to untreated leukemias, characterized by stem-cell signatures and activation of the Interferon (IFN) signaling pathway. Notably, IFN signaling activation was a distinguishing feature of both quiescent and proliferating blasts and was predictive of clinical response to standard chemotherapy in AML patients.
To investigate the contribution of the activated IFN signaling pathway to chemoresistance, I examined the effect of silencing IFI6, the top upregulated gene in the IFN signature. IFI6 silencing prolonged latency and reduced engraftment frequency in AMLs, due to its detrimental effect on leukemia-initiating cells (LICs). However, IFI6 silencing did not impact leukemia outgrowth kinetics. Strikingly, IFI6 silencing completely reversed the chemoresistant phenotype in both AML models in vivo and increased the chemosensitivity of established AML cell lines in vitro.
To further explore mechanism of IFI6-mediated chemo-sensitization, I investigated the interaction between IFI6 and STING. I found that IFI6 is upregulated upon chemotherapy treatment and relocates to the ERGIC compartment in proximity to STING, where STING activation by chemotherapy-induced DNA damage initiates a cascade leading to IFN signaling and cell death. Based on these findings, I initiated experiments to determine
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whether IFI6-mediated chemoresistance is due to its ability to downregulate STING activation, thereby preventing the execution of IFN-induced cell death
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