1,720,994 research outputs found
Serum Microrna 362-3P as a Potential Biomarker to Predict the Extent of Drug-Induced Qt Interval Lengthening Among Heart Failure Patients
No full textBackground:The sensitivity to drug-induced QT prolongation is highly variable in heart failure (HF) patients. QT interval prolongation can lead to a life-threatening ventricular arrhythmia known as torsade de Pointes (TdP), which can result in sudden cardiac death. Although QT prolongation is a surrogate marker for sudden cardiac death, the extent of drug-induced QT prolongation, and thus TdP, is largely unpredictable. Therefore, developing a biomarker to predict patients’ sensitivity to drug-induced QTc prolongation could have a profound clinical impact. MicroRNA (miR) are recognized as important regulators of cardiovascular function as they shape the transcriptome by targeting mRNAs for repression of translation. Our multidisciplinary research group has demonstrated that miR-362-3p regulates a potassium channel (i.e., hERG) that is the most widely implicated in drug-induced QTc prolongation. The primary objects of this analysis focus on characterizing serum miR-362-3p expression in the circulation as a potential biomarker to predict subject’s susceptibility to ibutilide exposure induced QT-interval prolongationMethods:The dataset utilized to develop the PK-PD models were collected from a previous clinical study carried out by Tisdale et al. (Tisdale, et al. 2020). A total of 22 adult subjects who met the inclusion and exclusion criteria were enrolled and divided into three groups: a group of patients with heart failure with preserved ejection fraction (HFpEF, n=10), a group of patients with heart failure with reduced ejection fraction (HFrEF, n=2), and ten healthy subjects in the control group who were matched to subjects in the HFpEF group for age and sex. Following a baseline day of triplicate 12-lead ECGs, all subjects received ibutilide 0.003 mg/kg intravenously infused over 10 minutes. Serial collection of blood samples to determine serum Ibutilide concentrations (HPLC/MS), serum miR-362-3 expression (qPCR), with triplicate ECG readings were obtained pre-and-post ibutilide administration. To describe ibutilide serum concentration exposure and the relationship with Fridericia-corrected QT (QTF) intervals, a non-linear mixed effect modeling approach was used along with clinical and demographic data, and serum miR-362-3p expression was evaluated as potential covariates on the PK/PD model.Results:A three-compartment model best described the time course of ibutilide concentrations profile with a proportional residual error. The individual ibutilide concentrations time profile was then used in an indirect response model where ibutilide concentrations are indirectly driving the QT interval prolongation through inhibition of the output (Kout) parameters linked to an indirect response model with zero‐order input parameter best described the ibutilide concentrations QT interval lengthening relationship. The Individual PK/PD parameters using the base model for the Imax and IC50 were 11.4% (9.9% RES) and 0.36 (8.4% RES) ng/mL, respectively. Following stepwise forwarding inclusion steps, the final covariate analyses identified circulating miR-362- 3p expression associated with a history of myocardial infarction covariate influencing both the Imax and IC50 ( p\u3c0.05).Conclusions:An indirect response model has been developed to describe the effects of ibutilide concentrations on QT-intervals. Although the semi-mechanistic model could not be developed; serum miR-362-3p expression was identified as a significant predictor for ibutilide-induced QTinterval prolongation. Moreover, the upregulation of serum miR-362-3p expression enhanced IC50 seen after ibutilide administration. The potential use of miR-362-3p as a biomarker warrants further investigation to identify patients at the greatest risk of TdP
Calcium/Calmodulin-Dependent Protein Kinase II Regulation of the Slow Delayed Rectifier Potassium Current, IKs, During Sustained Beta-Adrenergic Receptor Stimulation
No full textBackground: Sustained elevations in catecholaminergic signaling, mediated primarily through β-adrenergic receptor (β-AR) stimulation, are a hallmark neurohormonal alteration in heart failure (HF) that contribute to pathophysiologic cardiac remodeling. An important pathophysiological change during sustained β-AR stimulation is functional inhibition of the slow delayed rectifier potassium current, IKs, which has been demonstrated to prolong action potential duration (APD) and increase ventricular arrhythmogenesis in HF. Though functional inhibition of IKs has been consistently reproduced in cellular, animal, and limited human studies of HF, the mechanisms that mediate IKs inhibition during HF remain poorly understood.In addition, HF results in aberrant calcium handling that is known to contribute to the disease. HF has been demonstrated to increase the expression and function of calcium/calmodulin-dependent protein kinase II (CaMKII), a key regulator of calcium homeostasis and excitation-contraction coupling in cardiomyocytes. Enhanced CaMKII signaling has been consistently demonstrated to contribute to increased arrhythmogenesis in a number of cardiac diseases, including HF. CaMKII is a known pathological regulator of many cardiac ion channels resulting in APD prolongation and the development of arrhythmias.Objective: This investigation aims to assesses the potential for CaMKII regulation of KCNQ1 (pore-forming subunit of IKs) during sustained β-AR stimulation and to characterize the potential functional implications on IKs. Furthermore, this investigation seeks to elucidate the mechanism underlying CaMKII-mediated IKs inhibition during sustained β-AR stimulation.Methods: Phosphorylation of KCNQ1 was assessed using a tandem liquid chromatography- mass spectrometry/ mass spectrometry (LCMS/MS) approach during sustained β-AR stimulation via treatment with 100 nM isoproterenol (ISO) for 4-24 hours and during co-expression with KCNE1. Whole-cell, voltage-clamp patch clamp electrophysiology experiments were performed in HEK 293 cells transiently co-expressing wild-type (WT) or mutant KCNQ1 (mutations conferring mimics of dephosphorylation and phosphorylation were introduced at phosphorylation sites identified by LCMS/MS) and KCNE1 (auxiliary subunit) during ISO treatment, treatment with CaMKII or protein kinase A (PKA) inhibitors, or during lentiviral δCaMKII overexpression. A robotic peptide synthesizer was used to create fifteen residue peptide fragments on a nitrocellulose membrane corresponding to KCNQ1 intracellular domains and the KCNQ1 residues identified via LCMS/MS; membranes were incubated with activated CaMKII or PKA in the presence of radiolabeled ATP to identify potential sites of phosphorylation. Bimolecular fluorescence complementation (BiFC) experiments were performed in HEK 293 cells to assess the impact of CaMKII-mediated KCNQ1 phosphorylation on the interaction of KCNQ1 and KCNE1 subunits. Protein immunoblot experiments were performed to (1) assess CaMKII activation during ISO treatment and (2) to assess plasma membrane expression of KCNQ1 and KCNE1 subunits with mimics of differential KCNQ1 phosphorylation following a membrane protein biotinylation procedure.Results: In Aim 1, we investigated the regulation of the KCNQ1 carboxyl terminus during sustained β-AR stimulation and assessed the associated functional implications on IKs. An LCMS/MS approach identified five novel KCNQ1 carboxyl terminal sites that demonstrated basal phosphorylation, with T482 and S484 having enhanced phosphorylation during treatment with 100 nM ISO for 24 hours (pThe focus of Aim 2 was to assess the potential for CaMKII signaling to regulate increased KCNQ1 phosphorylation and reduced IKs function during sustained β-AR stimulation. Peptide fragments corresponding to the KCNQ1 carboxyl terminal sites demonstrating basal phosphorylation via LCMS/MS analysis were synthesized on a nitrocellulose membrane and exposed to activated δCaMKII. Only peptide fragments corresponding to S484 demonstrated CaMKII phosphorylation. Patch clamp experiments demonstrated that CaMKII inhibition via the chemical inhibitor KN-93 (p=0.02) and the peptide inhibitor CN21 (pAim 3 investigated the mechanism through which CaMKII-mediated phosphorylation at KCNQ1 S484 inhibits IKs function. To assess whether interaction with KCNE1 affects KCNQ1 phosphorylation, we performed LCMS/MS experiments during expression of KCNQ1 alone and during co-expression with KCNE1. Phosphorylation at S484 was reduced during co-expression with KCNE1 relative to expression of KCNQ1 alone (pConclusion: CaMKII phosphorylates KCNQ1 S484 during sustained β-AR stimulation to inhibit IKs function. S484 phosphorylation inhibits IKs function by disrupting the interaction between KCNQ1 and KCNE1 subunits and by reducing the plasma membrane expression of KCNQ1 and KCNE1. Pathological regulation of KCNQ1 by CaMKII (and subsequent inhibition of IKs) during sustained β-AR stimulation may contribute to increased arrhythmogenesis during physiologic states of chronically increased catecholaminergic tone, such as during HF.</div
A Translational Approach to Identify Microrna that Regulate the Voltage-Gated Potassium Channel, Kcnh2
No full textThe human ether-a-go-go-related gene (hERG, KCNH2) potassium channel has been implicated in diverse physiological and pathological processes. The KCNH2 gene encodes a rectifier voltage-gated potassium channel (Kv 11.1) that governs the chief repolarizing current, IKr, which is essential for normal electrical activity in excitable cells such as cardiomyocytes. It is also involved in cell growth and apoptosis regulation in non-excitable cells, such as tumor cells. Dysfunction of hERG is associated with potentially lethal complications, including diseases and sudden death under certain circumstances. While the mechanisms regulating KCNH2 expression remain unclear, recent data suggested that microRNAs (miRNAs) are involved, particularly in the context of several pathologic effects.miRNA is a class of RNA defined by its conserved, short, non-coding nature. miRNAs are important regulators of gene expression at the post-transcriptional level that bind through complimentary annealing to the 3’ untranslated regions (3’ UTRs) of target mRNAs, resulting in mRNA destabilization and translational repression. The primary objectives of this research were to 1) identify miRNAs regulating KCNH2 expression in cancer, 2) investigate the potential association between miR-362-3p expression and risk of drug-induced QT interval lengthening, and 3) identify miRNAs potentially regulating KCNH2 expression and function in cardiac cells.Through bioinformatics approaches, five miRNAs were identified to potentially regulate KCNH2 expression and function in breast cancer cells. The five identified miRNAs were validated through a Dual-Luciferase Assay using the KCNH2 3′ UTR. Only miR-362-3p was validated to bind to the KCNH2 3’ UTR, decreasing luciferase activity by 10% ± 2.3 (P \u3c 0.001, n = 3) when compared to cells transfected with luciferase plasmid alone. miR-362-3p was also the only miRNA that its expression positively correlated with overall survival of patients with breast cancer from The Cancer Genome Atlas-Cancer Genome (TCGA) database by log-rank test (HR: 0.39, 95% CI: 0.18 to 0.82, P = 0.012). Cell proliferation was assessed by MTS assay (3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) 48 hours following transfection in breast cancer cell lines, including SK-BR-3 and MCF-7. miR-362-3p significantly decreased proliferation of SK-BR-3 and MCF-7 cells by 23% ± 8.7 (P = 0.014, n = 3) and 11.7% ± 1.0 (P \u3c 0.001, n = 3), respectively. Cell cycle phases in SK-BR-3 and MCF-7 cells were differentiated by flow cytometry 48 hours following transfection. miR-362-3p and hERG siRNA (positive control) significantly increased the accumulation of cells in G0/G1 phase in MCF-7 by 11.7% (from 51.1% ± 0.64 to 57.1 ± 0.96, P = 0.002, n = 3) and 10% (from 51.1% ± 0.64 to 56.8 ± 0.96, P \u3c 0.001, n = 3), respectively.The demonstrated ability of miR-362-3p to regulate hERG in breast cancer cells coupled with previously published data that indicated an alteration of miR-362-3p expression during HF and a potential association between its expression and QT interval prolongation suggesting an important role for this miRNA in regulation of hERG function during HF. Therefore, the contribution of miR-362-3p to hERG function was investigated in patients administered the QT prolonging drug ibutilide, known to inhibit hERG. A total of 22 patients completed a prospective, parallel-group comparative study during which they received subtherapeutic doses (0.003 mg/kg) of ibutilide. The study was originally designed to investigate the influence of heart failure with preserved ejection fraction (HFpEF) on response to drug-induced QT prolongation
The development of a pharmacokinetic model describing the disposition of efavirenz and its two major metabolites; 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz
No full textEfavirenz (EFV) is currently recommended by the international AIDS society as part of a combination regimen for the initial treatment of human immunodeficiency virus (HIV) infected patients. Efavirenz therapeutic response and toxicity are associated with high inter-individual variability. This variability could be attributed to variation of EFV pharmacokinetics (PK). Efavirenz is metabolized by the cytochrome P450 (CYP) metabolizing enzymes, primarily by the CYP2B6 isoenzyme. Inter-individual variability of CYP2B6 may partially explain the variability associated with EFV. The goal of this research direction was to develop a PK model to describe the disposition of EFV and its major metabolites that could be used to evaluate the impact of CYP2B6 genotype on the estimated PK parameters. Pharmacokinetic models were fit to plasma concentration-time data of EFV and its major metabolites using a standard two-stage approach and a one-stage analysis (non-linear mixed effect modeling). The initial parameters for the modeling procedure were estimated using compartmental and non-compartmental mathematical procedures. Model discrimination was based on diagnostic plots that included individual plasma concentrations versus time plots, predicted versus observed concentrations plots, and statistical analyses. One way analysis of variance (ANOVA) was used to compare the final model-estimated PK parameters between subjects with the wild type (*1/*1), *1/*6, and *6/*6 CYP2B6 genotype. Efavirenz disposition was characterized by a two-compartment model following first order absorption. Approximately 45% of EFV total clearance was through the metabolic formation of 8-hydroxyefavirenz (8-OH EFV). The disposition of 8-OH EFV was characterized by a two-compartment model. Further hydroxylation into 8,14-dihydroxyefavirenz (8,14-diOH EFV) accounted for approximately 95% of the 8-OH EFV total clearance. The disposition of 8,14-diOH EFV was characterized by one-compartment model. There was no statistically significant difference in the primary PK parameters of EFV or its major metabolites between the 3 CYP2B6 genotypes (*1/*1, *1/*6, and *6/*6) in this single dose study. This is the first pharmacokinetic model developed describing EFV and its major metabolites. This model may be utilized to assess the effect of CYP2B6 genotype and other sources of variability during steady state conditions. Ultimately, this may help guide the optimal dosing of EFV to achieve desired clinical outcomes
DESIGNING COMBINATION DRUG REGIMENS TO IMPROVE GLIOBLASTOMA CHEMOTHERAPY: A PHARMACOKINETIC PHARMACODYNAMIC MODELING APPROACH
No full textDespite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma (GBM) remains fatal; the median survival time is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Poor prognosis for GBM can be attributed to several factors, including failure of drugs to cross the blood-brain-barrier (BBB), tumor heterogeneity, invasiveness, and angiogenesis. Development of tumor resistance, particularly to temozolomide (TMZ) and IR, creates a substantial clinical challenge. The primary focus of the work described herein was to develop a modeling and simulation approach that could be applied to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, TMZ was combined with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. To accomplish this objective, an integrated PKPD modeling approach was used. A PK model for each drug was first defined. PK models were subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models was tumor static concentration (TSC) curves of TMZ in combination with small molecule inhibitors that identify combination drug exposures predicted to arrest tumor growth. This approach was applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib (ACB) efficacy in combination with TMZ in a U87 GBM xenograft model. TSC was also constructed for TMZ in combination with RG7388 (MDM2 inhibitor) based on the data from an in-vivo study that evaluated effects on tumor growth suppression of these small molecule inhibitors in combination with TMZ in GBM 10 patient derived xenografts.In GBM 43 mouse xenografts, emergence of resistance to TMZ treatment was identified. Thus, a resistance integrated PKPD model was developed to predict tumor growth kinetics after treatment with TMZ in GBM 43 tumors. Population PK models in immune deficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice for TMZ and small molecule inhibitors (GDC0068/RG7112) were developed based on a combination of data obtained from an in-vivo study and published sources. Subsequently, PK models were linked to tumor volume data obtained from GBM 43 subcutaneous xenografts. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 40%) compared to a base tumor growth inhibition model in GBM 43 that did not incorporate resistance development. Graphical diagnostics of the resistance incorporated PKPD tumor growth inhibition model demonstrated a superior fit compared to the base model, and accurately captured the emergence of resistance to the TMZ monotherapy treatment observed in the GBM 43 patient derived xenograft model.</p
Influence of Cyp2b6 Genotype on Variability in Efavirenz Pharmacokinetic and the Associated QT Interval Prolongation
No full textEfavirenz (EFV)-based regimens have strong virological efficacy toward human immunodeficiency virus (HIV) type 1 infections. However, the high rates of EFV-associated toxicity limits its use in some patients. Efavirenz variability in efficacy and toxicity is largely attributed to its unique pharmacokinetic profile. Efavirenz is extensively metabolized by cytochrome P450 (CYP) mediated hydroxylation in addition to minor glucuronidation pathways. Several in vitro and in vivo studies report the contribution of the highly polymorphic CYP2A6, 2B6, and 3A4/5 to EFV metabolism and hence the considerable variability in its pharmacokinetics and therapeutic outcomes. The first objective of this research was to develop a pharmacogenetic-based pharmacokinetic model that adequately described the disposition of EFV and its major metabolites. Plasma concentrations of EFV and its major metabolites were determined (0-120h) following a single oral dose of 200 mg. Population pharmacokinetic analysis using non-linear mixed effects modeling was performed to assess the influence of various patients covariated on EFV disposition. CYP2B6 genotype was the primary pharmacogenetic covariate that influenced EFV exposure. The model-based predictions of EFV steady-state concentrations following 200, 400, and 600 mg daily doses were performed using the developed model. Daily doses of 600 mg achieved significantly higher steady-state concentration among CYP2B6*6/*6 compared to the other CYP2B6 genotype patient groups. This suggests that CYP2B6*6/*6 may be at increased risk of adverse events which includes the well-established central nervous system toxicity and the potential cardiotoxicity. Efavirenz has been associated with potential cardiotoxicity in the form of QT-interval prolongation and torsade de pointes, which is a life-threatening polymorphic ventricular tachycardia. Drugs that prolong QT-interval, inhibit the rapid component of the delayed rectifier potassium current (IKr) which is coded by the human Ether-a-go-go-Related Gene (hERG). Inhibition of the hERG-related potassium channel and hence inhibition of IKr in cardiac tissue results in prolonged ventricular repolarization, and consequently lengthening of the QT interval on electrocardiograms. Consequently, the effect of EFV was assessed on human embryonic kideney (HEK293) cells stably expressing hERG as an underlying mechanism for the potential EFV associated QT-interval lengthening. Potassium tail currents through hERG channels were recorded in this cellular model using the whole cell patch clamp technique after exposure to ascending EFV concentrations (0-2.5 µg/mL). The effect of EFV on hERG currents was studied inthe presence and absence of functional expression of CYP2B6 enzyme. Efavirenz inhibited hERG currents (both inward and outward) in a concentration dependent manner at physiologically relevant concentrations. Maximum inhibitory effect was estimated to be 92% ± 255% and 55% ± 4% for both inward and outward currents respectively (P\u3c0.05). The inhibitory concentration at half the maximal effect (IC50) was estimated to be 0.2 ± 0.2 µg/mL (inward) and 1.9 ± 3.2 µg/mL (outward). Functional expression of CYP2B6 attenuated EFV-inhibitory effect on hERG currents (P\u3c0.05).
In a placebo-controlled clinical trial, EFV-associated QT-interval prolongation did not exceed the United States Food and Drug Administration (FDA)-adopted threshold of QT-prolonging medications. However, the underlying pharmacogenetics of the metabolizing enzymes, specifically CYP2B6 was not reported. Therefore the ability of EFV to lengthen the QT-interval was assessed in healthy volunteers with respect to CYP2B6 genotype. QT intervals were measured from electrocardiograms of healthy subjects (n=57), who received EFV 600 mg/day for 17 days. The time-matched difference in Fridericia- corrected Δ(QTc)F intervals were calculated. Calculated Δ(QTc)F was compared to the FDA-adopted threshold which is defined by a mean change of +5 msec with an upper bound of the two-sided 90% confidence interval (CI) of 10 msec. The FDA-adopted threshold was not met among CYP2B6*1/*1 subjects (normal metabolizers). Among, intermediate metabolizers (CYP2B6*1/*6), the FDA-threshold was exceeded at 6 hours following EFV administration with a mean Δ(QTc)F of +6 msec and 90% CI [1; 11]. A larger change was observed among slow metabolizers (CYP2B6*6/*6) at 6 and 12 hours following EFV administration of +11 msec; 90% CI [8; 14] and +15 msec; 90% CI [1; 28] respectively. This suggests that CYP2B6*6 allele carriers may be at an increased risk for EFV-induced (QT c)F interval lengthening at steady-state
MicroRNA Regulation of hERG-Related Current: Potential Role in Heart Failure-Associated Arrhythmias
No full textSudden cardiac death, mainly attributable to arrhythmic causes, underlies a large proportion of deaths among patients with heart failure (HF). HF is associated with electrical remodeling caused by a wide array of changes in cardiac ion channels, including a down-regulation of the hERG-related repolarizing potassium current IKr. The precise molecular mechanisms underlying the down-regulation of IKr in heart failure remain poorly understood. In this research, we examine a novel mechanism for the regulation of I Kr in heart failure by microRNA. MicroRNAs (miRs) are a group of small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Through genome-wide profiling of microRNA expression, our lab has identified microRNA 362-3p (miR-362-3p) to be associated with a SNP previously linked to QT interval duration and a down-regulation of hERG mRNA. In addition, miR-362-3p has been shown to bind to the 3’ untranslated region of hERG and to downregulate hERG at the mRNA and protein levels. The effects of miR-362-3p on IKr function and its expression in the failing human heart are unknown. The primary objectives of this research were 1) to assess the functional effect of miR-362-3p on hERG-related current, and 2) to assess the expression of miR-362-3p in the failing human myocardium. The effects of miR-362-3p on hERG currents were assessed using cellular electrophysiology techniques in SK-Br-3 and HL-1 cells following transfection with either miR-362-3p mimic or negative control. In SK-Br-3 cells, peak inward IKr tail currents recorded at -120 mV 48 hours post-transfection were significantly lower in cells transfected with miR-362-3p compared to control (p=0.038). In HL-1 cells, there was no statistically significant difference in mean peak tail current amplitude between groups over the voltage range -40 to +50 mV at 24 hours following transfection (p=0.52). At 48 hours post-transfection, the mean peak tail current amplitude recorded over the voltage range from -40 to +50 mV was significantly lower in miR-362-3p-transfected cells compared to control cells (p\u3c0.001). The mean ± SE peak tail current recorded at +20 mV in the miR-362-3p group was 2.2 ± 0.4 pA/pF compared to 4.1 ± 0.7 pA/pF in the control group (p=0.03). Quantitative RT-PCR was performed to investigate differences in miR-362-3p and hERG expression in ventricular tissue samples from failing and non-failing human hearts (control). The normalized expression of miR-362-3p was significantly higher in the heart failure with reduced ejection fraction (HFrEF) group compared to control with a mean fold change of 1.56 ± 0.28 (p=0.05). The normalized expression of hERG was significantly lower in the HFrEF group compared to control with a mean fold change in expression of 0.66 ± 0.28 (p=0.01). In this research, miR-362-3p has been identified as a candidate regulator of hERG function. Evidence is also presented that miR-362-3p is upregulated in the ventricular tissue of patients with heart failure. Further studies are needed to show the functional link between miR-362-3p and IKr in heart failure. Presence of a functional link would warrant evaluation of miR-362-3p as a novel therapeutic target for the prevention and/or treatment of arrhythmias in heart failure
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
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