378 research outputs found
Legislating on Arbitration in Singapore: Linguistic Insights
No full textArbitration, a cost-effective and expeditious alternative to court litigation, takes place within complex and important national and international legal frameworks where legislation, rules, and conventions provide specialized regimes for the conduct of arbitrations. In recent years, Singapore has given evidence of a significant legislative activity in its fervor to make arbitration quicker and more efficient, and therefore has adopted domestic and international regimes that govern private commercial arbitration: the domestic Arbitration Act 2001 (AA) and the International Arbitration Act 2002 (IAA). While these laws differ from each other in matters of arbitral proceedings, they also reflect the best practice in dispute resolution used in the Asia Pacific Region, where Singapore is a regional and financial centre that serves as a gateway between East and West.
The purpose of this paper is to examine the arbitral regime and practice arising from the Singapore Arbitration Act 2001. The paper will look at the piece of legislative drafting from the perspective of language use in order to gain insights into the rhetorical and discursive features realized in the construction of the genre. First, the paper will outline the nature and topic of a two-ranked arbitral regime (AA – IAA) that is of relevance for the arbitration framework in Singapore. Secondly, the paper will analyze quantitatively and qualitatively the linguistic and textual choices realized in the professional/institutional practice and discourse of the genre, while also identifying those features which seem to constrain the accessibility and interpretation of legislative action performed in the genre. To the extent that Singapore inherited the Western-style legal culture of the English common law tradition, this part of the paper will also assess how the Singapore Arbitration Act borrowed semantic resources from the English Arbitration Act 1996 previously investigated by this author (Tessuto 2003), therefore giving rise to manifestations of “interdiscursivity” (Bhatia 2008, 2010a, 2011) from the discursive process and professional practice of English arbitration. Finally, the paper will draw some conclusions from the analysis of the most salient rhetorical and discursive data in the chosen genre, by adding as yet to our understanding of the intercultural and interdiscursive elements of drafting in the Eastern and Western socio-legal contexts
Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition
No full textHerein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris-based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization
Design, Synthesis, and Biomedical Applications of Glycotripods for Targeting Trimeric Lectins
No full textIn the last decades, various efforts have been made to synthesize optimal glycotripods for targeting trimeric glycoproteins like asialoglycoprotein receptor, hemagglutinin, and langerin. All these trimeric glycoproteins have sugar binding pockets which are highly selective for a particular carbohydrate ligand. Optimized glycotripods are high affinity binders and have been used for delivering drugs or even applied as drug candidates. The selection of the tripodal base scaffold together with the length and flexibility of the linker between the scaffold and sugar residue, as important design parameters are discussed in this review
Dual tumor- and subcellular-targeted photodynamic therapy using glucose-functionalized MoS2 nanoflakes for multidrug-resistant tumor ablation
No full textPhotodynamic therapy (PDT) is emerging as an efficient strategy to combat multidrug-resistant (MDR) cancer. However, the short half-life and limited diffusion of reactive oxygen species (ROS) undermine the therapeutic outcomes of this therapy. To address this issue, a tumor-targeting nanoplatform was developed to precisely deliver mitochondria- and endoplasmic reticulum (ER)-targeting PDT agents to desired sites for dual organelle-targeted PDT. The nanoplatform is constructed by functionalizing molybdenum disulfide (MoS2) nanoflakes with glucose-modified hyperbranched polyglycerol (hPG), and then loading the organelle-targeting PDT agents. The resultant nanoplatform Cy7.5-TG@GPM is demonstrated to mediate both greatly enhanced internalization within MDR cells and precise subcellular localization of PDT agents, facilitating in situ near-infrared (NIR)-triggered ROS generation for augmented PDT and reversal of MDR, causing impressive tumor shrinkage in a HeLa multidrug-resistant tumor mouse model. As revealed by mechanistic studies of the synergistic mitochondria- and ER-targeted PDT, ROS-induced ER stress not only activates the cytosine-cytosine-adenosine-adenosine thymidine/enhancer-binding protein homologous protein (CHOP) pro-apoptotic signaling pathway, but also cooperates with ROS-induced mitochondrial dysfunction to trigger cytochrome C release from the mitochondria and induce subsequent cell death. Furthermore, the mitochondrial dysfunction reduces ATP production and thereby contributes to the reversal of MDR. This nanoplatform, with its NIR-responsive properties and ability to target tumors and subcellular organelles, offers a promising strategy for effective MDR cancer therapy
Heteromultivalent topology-matched nanostructures as potent and broad-spectrum influenza A virus inhibitors
No full textHere, we report the topology-matched design of heteromultivalent nanostructures as potent and broad-spectrum virus entry inhibitors based on the host cell membrane. Initially, we investigate the virus binding dynamics to validate the better binding performance of the heteromultivalent moieties as compared to homomultivalent ones. The heteromultivalent binding moieties are transferred to nanostructures with a bowl-like shape matching the viral spherical surface. Unlike the conventional homomultivalent inhibitors, the heteromultivalent ones exhibit a half maximal inhibitory concentration of 32.4 ± 13.7 μg/ml due to the synergistic multivalent effects and the topology-matched shape. At a dose without causing cellular toxicity, >99.99% reduction of virus propagation has been achieved. Since multiple binding sites have also been identified on the S protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), we envision that the use of heteromultivalent nanostructures may also be applied to develop a potent inhibitor to prevent coronavirus infection
Force Spectroscopy Shows Dynamic Binding of Influenza Hemagglutinin and Neuraminidase to Sialic Acid
No full textThe influenza A virus infects target cells through multivalent interactions of its major spike proteins, hemagglutinin (HA) and neuraminidase (NA), with the cellular receptor sialic acid (SA). HA is known to mediate the attachment of the virion to the cell, whereas NA enables the release of newly formed virions by cleaving SA from the cell. Because both proteins target the same receptor but have antagonistic functions, virus infection depends on a properly tuned balance of the kinetics of HA and NA activities for viral entry to and release from the host cell. Here, dynamic single-molecule force spectroscopy, based on scanning force microscopy, was employed to determine these bond-specific kinetics, characterized by the off rate koff, rupture length xβ and on rate kon, as well as the related free-energy barrier ΔG and the dissociation constant KD. Measurements were conducted using surface-immobilized HA and NA of the influenza A virus strain A/California/04/2009 and a novel, to our knowledge, synthetic SA-displaying receptor for functionalization of the force probe. Single-molecule force spectroscopy at force loading rates between 100 and 50,000 pN/s revealed most probable rupture forces of the protein-SA bond in the range of 10–100 pN. Using an extension of the widely applied Bell-Evans formalism by Friddle, De Yoreo, and co-workers, it is shown that HA features a smaller xβ, a larger koff and a smaller ΔG than NA. Measurements of the binding probability at increasing contact time between the scanning force microscopy force probe and the surface allow an estimation of KD, which is found to be three times as large for HA than for NA. This suggests a stronger interaction for NA-SA than for HA-SA. The biological implications in regard to virus binding to the host cell and the release of new virions from the host cell are discussed
Heteromultivalent Nanogels as Highly Potent Inhibitors of <i>Pseudomonas Aeruginosa</i>
No full textThe increasing prevalence of microbial resistance requires new antibacterial concepts for selective targeting and killing of pathogenic bacteria. Here, we report the synthesis of a heteromultivalent nanogel system against Pseudomonas aeruginosa (P. aeruginosa). These nanogels are based on biocompatible polyglycerols and functionalized with sugar ligands fucose (Fuc) or galactose (Gal) for P. aeruginosa targeting. With a further modification of these nanogels with BMAP-18 short chain peptides (GRFKRFRKKFKKLFKKLS), we have achieved > 99.99% inactivation of planktonic and > 99.9% inactivation of biofilm-coated P. aeruginosa within 12 h of treatment. Additionally, the system demonstrates broad-spectrum antimicrobial potential, effectively inhibiting Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA). This modular design offers a promising strategy for the development of next-generation antimicrobial therapies targeting biofilm-associated infections and MDR bacteria
Topology‐Matching Design of an Influenza‐Neutralizing Spiky Nanoparticle‐Based Inhibitor with a Dual Mode of Action
No full textIn this study, we demonstrate the concept of “topology-matching design” for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle-based inhibitor (nano-inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano-inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano-inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano-inhibitor might be a potent antiviral for the treatment of influenza infection
- …
