1,721,183 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
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Lysosome Disrupting Transformable Peptide Amphiphiles & Orally Available CRISPR-Cas Ribonucleoprotein for Genome Editing
Get PDFNon-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial that is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, leading to the disruption of the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range, synergizing cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low-dose cisplatin chemotherapy. CPTNPs the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy. Crispr-Cas genome editing promises to revolutionize medicine as it is currently conceived; if it can overcome the challenge of target tissue delivery. Several CRISPR-Cas delivery systems have been developed which can systemically edit somatic tissue in vivo if IV delivered. However, no system currently exists which can edit somatic cells after the oral delivery of CRISPR-Cas. Hepatitis E virus like nanoparticles, were originally developed by the Cheng group and have previously been used to deliver plasmid-based vaccines orally, and are a promising platform for the oral delivery of nucleic acid and protein cargos. Herein we develop Cas9 ribonucleoprotein -loaded Hepatitis E virus-like nanoparticles capable of delivering CRISPR-Cas editing systems in vivo via the oral route. We demonstrate 39% editing efficiency in vitro and up to 10% editing efficiency in the crypts of small intestinal tissue. This is the first example of orally available Crispr-Cas gene editing.
Together these systems represent two novel nano-systems which make major advancements in self-assembling cancer therapeutics and orally available gene editing
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Radio-Enhancing Hafnium Cross-Linked Micelles for Drug-Delivery and Radiotherapy
No full textOver the past two decades, polymeric micelles have been investigated as carriers to provide increased solubility and improved in vivo circulation for anticancer drugs with poor distribution, such as paclitaxel (PTX) and doxorubicin. Furthermore, micelles approximately 10–100nm take advantage of the enhanced permeability and retention (EPR) effect for preferential localization to tumors. However, these micelles are thermo-dynamic systems constantly dissociating and associating into their monomers, thereby posing a challenge whereby these micelles fall below critical micelle concentration (CMC). To address this, hafnium (Hf), demonstrated as a radio-enhancer in metal- organic frameworks (MOFs), was utilized to cross-link linear-dendritic amphiphilic polymers (telodendrimers) to develop a self-assembling polymeric nanoparticle (NP) with enhanced stability. The dendrimer portion was synthesized via solution-phase condensation reactions beginning with MeO-PEG5000-NH2 utilizing stepwise peptide chemistry of branched lysine residues. The resulting amphiphilic dendrimer contained 8 terminal amines which were then coupled with 4 cholic acid (CA) moieties and 4 carboxylic acid (COOH) functional groups to yield a PEG5000-CA4/COOH4 telodendrimer. The resulting hybrid telodendrimers self-assembled into ~30 nm nanoparticles, as measured by dynamic light scattering (DLS), and upon addition of HfCl4, cross-linking chelation occurred to stabilize the nanoparticles up to 20 mg/mL of sodium dodecyl sulfate (SDS). Furthermore, this Hf-NP shows efficient drug loading and uptake by a number of cancer cell lines, as observed under confocal microscopy. Development of this novel hafnium cross-linked drug-delivery nanoparticle not only boasts increased in vivo stability during circulation, but also serves as a potent radio-enhancer for more efficacious radiotherapy
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Discovery and Characterization of New Membrane Active Peptides using One-Bead One-Compound Combinatorial Methods
No full textAll living cells are enclosed by biological membranes, comprising of lipid bilayers formed by self-assembly of phospholipids, membrane proteins, cholesterol etc. Membrane active peptides (MAPs) are peptides that interact with the lipid bilayer, perturbing the structure and function of the biological membranes, impacting the function of the living cells. Antimicrobial peptides (AMPs), are a subset of MAPs that interact with pathogenic microbial membranes, disrupting the integrity of the lipid bilayer, using mechanisms such as pore formation, resulting in membrane leakage and cell death. Since MAPs interact directly with cell membranes, they are becoming increasingly important as a possible solution to multi-drug resistant pathogens. Multi-drug resistant fungal infections due to opportunistic and pathogenic fungi are one of the most common infections in the world. Millions of people across the globe are affected by these infections and about 1.5 million people each year succumb to this disease. Amphotericin B and azole drugs such as fluconazole and ketoconazole are common anti-fungal agents that have been used for many years but have a variety of short-term and long-term side effects and have induced widespread resistance in fungi. Therefore, there is dire need for the discovery of novel membrane active peptides with antimicrobial activities, and understanding how they interact with cell membranes. By applying this knowledge, we hope to develop highly selective antifungal membrane active peptides.In this dissertation, we report on the successful use of one-bead one-compound (OBOC) combinatorial library method to discover new MAPs with antifungal properties. To better understand the mechanism of action of these MAPs, we have used various methods to biochemically and biologically characterize these peptides
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Studies of substrate specificity, regulation and inhibition of protein-tyrosine kinases
No full textProtein tyrosine kinases (PTKs) play a crucial role in the regulation of cell proliferation, differentiation and signal transduction. However, substrate specificity and recognition motifs are not clear for most PTKs. Traditional methodologies for identifying substrate recognition motifs are often difficult and inefficient. In this dissertation, a novel approach for rapid discovery of linear substrate motifs of protein kinases has been developed using cyclic AMP-dependent protein kinase (cAPK) as a model system. This method is based on the screening of random synthetic combinatorial peptide libraries on beads where each bead expresses only one peptide entity. The peptide motif identified was RRXS, which exactly matched the motif for cAPK reported in the literature. Using this approach, a fraction of the random peptide library was screened for substrates of c-Src PTK. A heptapeptide, YIYGSFK, was identified and has been proven to be an efficient and specific substrate for c-Src PTK. A relatively specific pseudosubstrate-based peptide inhibitor of c-Src PTK has been developed based on the structure of YIYGSFK. Furthermore, a fraction of the octapeptide library was screened for substrates of c-Abl PTK. Fourteen peptides have been identified. Four different consensus sequences have been obtained by comparing the amino acid sequences of these peptides, suggesting that c-Abl PTK may have a relatively broad substrate specificity. Using these identified peptides as substrates, intrinsic tyrosine kinase activities of c-Abl and Bcr-Abl PTKs were compared. The data have suggested that Bcr sequences may directly activate the kinase activity of Abl protein. In addition, roles of the SH2 and SH3 domains in the regulation of the intrinsic kinase activity of Bcr-Abl have been studied. The results have indicated that the SH2 domain rather than SH3 domain was required for the intrinsic kinase activity of Bcr-Abl oncoprotein. In summary, the use of the combinatorial peptide library method has revealed some new insights on the substrate specificity and recognition motifs of PTKs, and suggested that small linear peptide motifs are important in the substrate recognition and phosphorylation by PTKs although the other factors may also contribute to the substrate specificity of PTKs.This item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at [email protected] file replaced with corrected file October 2023
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A Two-Component Two-Step (TCTS) Transformable Nanoplatform Against Cancer Based on Bioorthogonal Click Chemistry
No full textTo enhance targeting precision and therapeutic efficacy in cancer treatment while minimizing off-target effects, a two-component two-step (TCTS) delivery platform integrating transformable–clickable nanoparticles (TCNPs) with bioorthogonal chemistry was developed, referred to as TCNP/TCTS cancer therapy. In the first step, TCNPs bearing tumor-targeting ligands, either dual ligands for epidermal growth factor receptor (EGFR) and α3β1 integrin (TCNP-I) or a ligand specific for α3β1 integrin (TCNP-II), and a trans-cyclooctene (TCO) moiety were administered intravenously to pretarget tumors. Upon receptor engagement, TCNPs transformed from micelles into nanofibrils within the tumor microenvironment, resulting in prolonged retention. After clearance from healthy tissues, a tetrazine (Tz)-modified prodrug administered on demand, would undergo rapid and selective Tz–TCO click ligation to covalently anchor the drug to tumor-localized nanofibrils. Amphiphilic transformable peptide monomers (TPMs), basic components of TCNP, were synthesized to construct TCNP-I or TCNP-II, optimized for nanofibrillar transformation and click conjugation. In vitro and in vivo studies demonstrated receptor-triggered transformation in solutions, on receptor-positive cancer cells, and in in vivo cancer models. Biodistribution analyses confirmed selective tumor accumulation and durable retention via in situ nanofibrillar transformation. The resulting nanofibrillar networks supported efficient bioorthogonal conjugation with methyltetrazine (mTz)-functionalized probes, achieving high tumor specificity and minimal off-target signals. Comparative evaluation identified mTz as the optimal tetrazine for in vivo use, owing to superior serum stability and sustained conjugation efficiency. For therapeutic evaluation, mTz derivatives of paclitaxel (PTX), cabazitaxel (CBZ), carboplatin (CRB), and oxaliplatin (OXA) were synthesized. Cytotoxicity screening identified mTz–CBZ, mTz-SS-CBZ, and mTz–OXA as the most potent candidates. In vitro, TCNP/TCTS strategy was found to enhance cytotoxicity through nanofibril-mediated capture and localized drug release. In vivo, TCNP/TCTS therapy using mTz–CBZ, mTz–SS–CBZ, and mTz–OXA, individually or in combination, was found to superior in both efficacy and toxicity profile, when compared to treatment with free drug(s). This TCNP/TCTS delivery platform is applicable not only to cancers but also to other diseases such as inflammatory conditions with leaky vasculatures. The mTz-payloads are not limited to chemotherapeutic agents and can also include immunomodulators, peptides, proteins, cytokines, oligonucleotides, and radionuclides
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
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