1,720,972 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
The Role of Bacterial Amyloids In Regulating Gastrointestinal Homeostasis
No full textMany bacterial species exist in nature as part of highly structured multicellular communities known as biofilms. Amyloids, proteins with a conserved β-sheet quarternary structure, show high resistance to many chemical and enzymatic processes including proteinase K and SDS treatments and are produced as essential adhesins during biofilm formation. Curli fibers expressed by Enterobacteriaceae family members including E. coli and S. Typhimurium are the most studied amyloids to date. Curli-like fibers are also produced by members of the predominant phyla found in the host gastrointestinal microbiota in environmental biofilms. Curli fibers are the predominant microbial-associated molecular pattern (MAMP) on enteric bacteria recognized by the Toll-like receptor (TLR) 2/1-heterodimer complex. Interestingly, the TLR2/1 complex has been implicated as a key player in modulating gastrointestinal homeostasis. The focus of the current studies centered on the innate immune recognition of curli fibers by cells of the gastrointestinal tract and how that contributes to gastrointestinal homeostasis. In the first phase of our studies, utilizing intestinal epithelial cells polarized on semi-permeable tissue culture inserts (Transwells®), we observed that the recognition of curli fibers on Salmonella enterica serovar Typhimurium by intestinal epithelial cells led to the augmentation of the intestinal epithelial barrier in a PI3K-dependent manner. We also observed that bacterial translocation of S. Typhimurium from the apical side to the basolateral side of the Transwell system was limited when curli fibers were present. Furthermore, infection of mice with S. Typhimurium showed that translocation of bacteria from the intestinal lumen into the cecal tissue and mesenteric lymph nodes was limited in C57BL/6 mice as compared to TLR2 knockout mice. In the second phase of our studies, we sought to further investigate the effect that curli fibers exert on gastrointestinal homeostasis through the induction of immunomodulatory cytokines such as Interleukin 10 (IL10) from subepithelial lamina propria cells. IL10 has been shown to contribute to the maintenance of the intestinal epithelial barrier and IL10-deficient mice develop lethal colitis within the first 2-3 months of life. 6-8 week-old female C57BL/6 and TLR2-/- mice were given 5mg/kg of curli fibers via intraperitoneal injection. Subsequent RT-PCR analysis of the small intestine showed a significant expression of Il10 in C57BL/6 that was absent in TLR2-/- mice. Interestingly, no changes in Ifnγ or Tgfβ mRNA were observed in these mice. This response was gut-specific, as Il10 was not detected at all in the spleen. Furthermore, in a chemically-induced colitis model, we observed that the administration of curli fibers to 8-week old Balb/c mice ameliorated disease severity as compared to colitic mice that received mock treatments. Interestingly, Il10 was also induced in the colons of colitic mice that received curli and which were euthanized 6 days after colitis was induced. Our results suggest that curli fibers induce IL10 production via a TLR2-dependent manner to dampen inflammation in the gastrointestinal tract. Overall, our results partially describe a novel role for curli amyloid fibers produced by commensal bacteria in modulating gastrointestinal health and homeostasis. We propose that the induction of immunomodulatory cytokine such as IL10 by amyloid fibers is an important mechanism utilized by commensal bacterial to confer beneficial effects that benefit both the host and microbe. We also propose curli fibers as a potential alternative in the treatment of inflammatory bowel disease.Microbiology and Immunolog
Variations on the Author
No full text“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
No full textWe 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
Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses
No full textEthanol (EtOH) abuse is the third leading cause of preventable death in the United States. Mounting evidence indicates that EtOH-induced neuropathology may result from multicellular responses in which microglia cells play a prominent role. Purinergic receptor signaling plays a key role in regulating microglial function and, more importantly, mediates EtOH-induced effects. In our current study we sought to determine the effects of EtOH on microglial cell function, specifically the role of purinergic receptor X4 (P2X4) in EtOH-mediated microglial responses. Our results show a significant up-regulation of P2X4 gene expression as analyzed by real-time qPCR and protein expression as analyzed by flow cytometry in embryonic stem cell-derived microglial cells (ESdM) after 48 hours of EtOH treatment, as compared to untreated controls. Calcium mobilization in EtOH treated ESdM cells was found to be P2X4R- dependent using 5-BDBD, a selective P2X4R antagonist. Blocking P2X4R signaling with 5-BDBD decreased the level of calcium mobilization compared to EtOH treatment alone. EtOH decreased migration of microglia towards fractalkine (CX3CL1) by 75% following 48 hours of treatment compared to control. CX3CL1-dependent migration was confirmed to be P2X4 receptor-dependent using the antagonist 5-BDBD, which reversed the effects as compared to EtOH alone. Similarly, 48 hours of EtOH treatment significantly decreased phagocytosis of microglia by 15% compared to control. 5-BDBD pre-treatment prior to EtOH treatment significantly increased microglial phagocytosis. These findings demonstrate that P2X4 receptor may play a role in modulating important regulatory functions in microglia in the context of EtOH abuse. P2X4R plays an important regulatory function in microglia. P2X4 is involved in a myriad of molecular signaling such as proliferation, activation of transcription factors, specifically through the MAPK pathway, and ATP signaling. Here, we also investigated the intracellular signal transduction pathway that influences P2X4R expression in microglia in response to EtOH. We found EtOH (100 mM) decreased phosphorylated AKT and extracellular signal-regulated kinase (ERK) cascades in ESdM cells. EtOH effect on ERK phosphorylation was completely inhibited by U0126, an inhibitor of MEK 1 and 2. However, PD98095, a potent inhibitor of MEK1 but a weak inhibitor of MEK2 had modest effect on phosphorylated ERK1/2 suggesting a possible role of MEK2-dependent ERK signaling in modulating EtOH induced effects on microglia. Utilization of 5-BDBD, a selective P2X4R antagonist reversed the EtOH-induced effect on phosphorylated AKT and ERK. Next we wanted to examine the effects of EtOH on transcription factor activity to determine the signaling mediators, which may play a role in EtOH-induced increase in P2X4R in microglia. EtOH increased transcriptional activity of NFκB, NFAT, and CREB,, however 5-BDBD blocked the effect on CREB transcriptional activity alone, suggesting a specific role of CREB in EtOH-induced expression of P2X4R in microglia. In summary, EtOH affects the expression of P2X4R in microglial cells and contributes to aberrant microglial effector function including phagocytosis and migration as well as alterations in calcium mobilization. Furthermore, pharmacological blockade with a selective P2X4R antagonist reversed the action, suggesting that P2X4R may play a role in mediating EtOH-induced effects on microglia. EtOH decreased expression of ERK and AKT, which was blocked with the P2X4R antagonist, suggesting EtOH effect may contribute to irregular microglial signaling. Investigations regarding transcription factor NFκB, NFAT and CREB activity in response to EtOH, all showed an increase after EtOH treatment, however P2X4R antagonist only had an effect on CREB, blocking the effect of EtOH on its activity. Determining the mechanism underlying EtOH-induced increase in P2X4R expression still remains unclear. This research was conducted to investigate the importance of P2X4R signaling in EtOH-mediate microglial function. Although many more questions remain unanswered, these experiments have provided evidence to target purinergic receptor X4 as a potential mediator of EtOH-induced effects in microglia.Patholog
The CCAAT-box binding transcription factor, nuclear factor-Y (NF-Y) regulates transcription of human aldo-keto reductase 1C1 (AKR1C1) gene
No full textDihydrodiol dehydrogenases are a family of aldo-keto reductases (AKR1Cs) involved in the metabolism of steroid hormones and xenobiotics. Whilst, several phase II drugs as well as endogenous & exogenous steroids/steroid metabolites have been identified as inducers of gene transcription, the cellular transcription factors controlling the expression of AKR1C1 are incompletely elucidated. Herein, we have cloned and characterized the proximal promoter region of the human AKR1C1 gene that controls its transcription. The 5’ flanking proximal promoter region of the AKR1C1 gene consists of a TATA box and an inverted CCAAT binding site. Deletion analysis of the 5’-flanking, ~3.0 kb region of the human AKR1C1 gene identified the region between -128 to -88 as the minimal proximal promoter essential for basal transcription of AKR1C1 in human ovarian (2008 & 2008/C13*), lung (H23 & A549) and liver carcinoma (HepG2) cells. Antioxidant response elements (ARE) have been shown to modulate the transcription ofv genes coding for phase II drug metabolizing enzymes. Cloning of the ARE upstream of the AKR1C1 proximal promoter resulted in increased transcription in human lung adenocarcinoma and liver hepatoblastoma cells but not in human ovarian carcinoma cells. Further, ARE increased the induction of the AKR1C1 gene in response to treatment with phase II drug inducers. However, ARE did not induce the transcription of AKR1C1 gene promoter in the presence of cisplatin in any of the cell lines. A computational analysis utilizing the Alibaba 2.0 on the proximal AKR1C1 gene promoter region was performed to identify potential transcription factor binding sites. Based on this analysis, a set of potential, putative transcription factor binding sites for Oct1, Sp1, Cp-1/NF-Y, CEBP, p40X, USF, NF1 and AP-2 were identified in the region -180 to -88 of the AKR1C1 gene promoter. Site-directed mutagenesis studies indicated that the transcription factor binding sites for NF-Y/CEBP were involved in controlling the basal transcription of AKR1C1 in all the cancer cells studied. Electrophoretic mobility shift (EMSAs) and gel supershift assays demonstrated that the transcription factor NF-Y preferentially binds to the inverted CCAAT box at -109ATTGG-105 of the AKR1C1 gene. Chromatin immunoprecipitation (ChIP) analysis confirmed the in vivo association between NF-Y and human AKR1C1 gene promoter in human ovarian, lung and liver carcinoma cells. Further, ectopic expression of NF-Y’s increased the AKR1C1 gene transcription, whereas expression of a dominant-negative NF-YA or knockdown of NF-YA by siRNA transfection, decreased the AKR1C1 gene transcription. A 2-fold increase in AKR1C1 transcription was observed specifically in cisplatin-treated 2008 cells that was CCAAT box-dependent. These results indicate that NF-Y regulates basal transcription of AKR1C1 in human ovarian, lung and liver carcinoma cells and cisplatin-induced transcription in human ovarian carcinoma cells.Patholog
THE ROLE OF P2X7R IN METHAMPHETAMINE-INDUCED BEHAVIORAL CHANGES AND MICROGLIAL EFFECTOR FUNCTIONS
No full textMethamphetamine (METH) is a powerful psychostimulant with a high abuse liability. Due to its potent and long lasting effects in the central nervous system (CNS), METH addiction is a major and growing public health concern. Dextro-METH or the racemic mixture of the two isomers can be consumed through oral, nasal, and anal administrations, or injected intravenously or subcutaneously, and there is no FDA approved therapeutic for the treatment of METH addiction. METH abuse causes many deleterious physiological effects, such as anxiety, mood disturbances, and visual and auditory hallucinations. In addition, neuroimaging studies have demonstrated altered structural and functional changes in the brain associated with emotion and memory, as well as reduced motor speed and impaired verbal learning. Current literature implicates microglia, the resident macrophages of the CNS, as major mediators of the neurological side effects. Upon activation, microglia undergo a morphological change to an amoeboid shape with increased capacity for migration, phagocytosis and cytokine production. Although the initial microglial activation is poorly understood, METH-induced microgliosis precedes dopaminergic neurotoxicity, and drugs that prevent glial activation are candidate therapies for METH addiction. Microglia express purinergic receptors, ligand-gated ion channels, which have been implicated in a variety of chronic inflammatory and neurodegenerative processes. In particular, P2X7R is activated by pathological concentrations of ATP. I show the concurrent increases in P2X7R expression with Iba-1, a marker of microglial activation after chronic METH treatment in vivo. I confirmed the METH-induced increases in P2X7R protein and mRNA expression in the Embryonic Stem cell derived microglia (ESdM) cell line. siRNA knockdown of P2X7R in ESdM significantly reduced the METH-induced TNF-α secretion, compared to scrambled siRNA. Furthermore, I demonstrated METH-induced microglial migration and phagocytosis is blocked by pretreatment with a P2X7R antagonist, A-438079. When administered in vivo, the P2X7R antagonist A-438079 did not affect the locomotor activity of mice, as determined by ambulation, stereotypy and total activity at lower doses (5, 10 mg/kg) but it did decrease METH-induced stereotypy and ambulation at the higher dose tested (50mg/kg). The 10mg/kg dose of A-438079 was effective at blocking METH-induced expression of conditioned place preference, a behavioral assay that measures the appetitive value of a compound. This data suggests that P2X7R antagonism may be useful as a therapy for METH addiction. P2X7R activation is known to activate the inflammasome complex and lead to the generation and shedding of extracellular vesicles (EVs). EVs are classified as exosomes or microvesicles, and contain protein, mRNA and miRNA that alter the biological activity of target cells. I used electron microscopy, nanosight quantification, and confocal imaging techniques to confirm that METH causes the increase in primary human microglia-derived exosomes, which are around 100nm in size. Compared to control exosomes, METH causes significant decreases in packaged miR-124, mir-186 and miR-9, as analyzed by qPCR. These miRNAs are associated with many neuroimmune and neurodegenerative disorders, and indicate a possible mechanism for METH-dependent increased P2X7R expression seen in previous analyses. Taken together, these studies highlight the importance of P2X7R in METH-induced microgliosis. Our findings indicate that purinergic mechanisms contribute to altered microglia effector functions during stimulant abuse, and that modulating the glial response during addiction may have potential therapeutic implications.Biomedical Science
Dispelling the Myths Behind First-author Citation Counts
No full textWe 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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