Diclofenac sodium ion exchange resin complex loaded melt cast films for sustained release ocular delivery

The goal of the present study is to develop polymeric matrix films loaded with a combination of free diclofenac sodium (DFSfree) and DFS:Ion exchange resin complexes (DFS:IR) for immediate and sustained release profiles, respectively. Effect of ratio of DFS and IR on the DFS:IR complexation efficiency was studied using batch processing. DFS:IR complex, DFSfree, or a combination of DFSfree+DFS:IR loaded matrix films were prepared by melt-cast technology. DFS content was 20% w/w in these matrix films. In vitro transcorneal permeability from the film formulations were compared against DFS solution, using a side-by-side diffusion apparatus, over a 6 h period. Ocular disposition of DFS from the solution, films and corresponding suspensions were evaluated in conscious New Zealand albino rabbits, 4 h and 8 h post-topical administration. All in vivo studies were carried out as per the University of Mississippi IACUC approved protocol. Complexation efficiency of DFS:IR was found to be 99% with a 1:1 ratio of DFS:IR. DFS release from DFS:IR suspension and the film were best-fit to a Higuchi model. In vitro transcorneal flux with the DFSfree+DFS:IR(1:1)(1 + 1) was twice that of only DFS:IR(1:1) film. In vivo, DFS solution and DFS:IR(1:1) suspension formulations were not able to maintain therapeutic DFS levels in the aqueous humor (AH). Both DFSfree and DFSfree+DFS:IR(1:1)(3 + 1) loaded matrix films were able to achieve and maintain high DFS concentrations in the AH, but elimination of DFS from the ocular tissues was much faster with the DFSfree formulation. DFSfree+DFS:IR combination loaded matrix films were able to deliver and maintain therapeutic DFS concentrations in the anterior ocular chamber for up to 8 h. Thus, free drug/IR complex loaded matrix films could be a potential topical ocular delivery platform for achieving immediate and sustained release characteristics

Agency and servitude in platform labour:a feminist analysis of blended cultures

Digital labour platforms have become important sites of negotiation between expressions of micro-entrepreneurship, worker freedom and dignity of work. In the Global South, these negotiations are overlaid on an already fraught relationship mediated by the dynamics of caste and culture, to the usual politics of difference. Urban Company (UC), an app-based, on-demand platform in India that connects service providers offering home-based services to potential customers, lists professionalised services that have hitherto been considered part of a ‘culture of servitude’, performed by historically marginalised groups afforded little dignity of labour. Such platforms offer the possibility of disrupting the entrenched ‘master-servant’ relationship that exists in many traditional cultures in the Global South by their ostensibly professional approach. While service providers now have the opportunity for self-employment and gain ‘respectability’ by being associated with the platform, UC claims to have leveraged AI to automate discipline in everything the providers do. Using interviews with UC women service providers involved in beauty work and software development engineers, this paper explores the agency afforded to service partners in both professional and personal spheres. Further, we propose the term blended cultures to think about the ways in which algorithms and human cultures mutually (re)make each other.</p

Vistaar: Diverse Benchmarks and Training Sets for Indian Language ASR

Improving ASR systems is necessary to make new LLM-based use-cases accessible to people across the globe. In this paper, we focus on Indian languages, and make the case that diverse benchmarks are required to evaluate and improve ASR systems for Indian languages. To address this, we collate Vistaar as a set of 59 benchmarks across various language and domain combinations, on which we evaluate 3 publicly available ASR systems and 2 commercial systems. We also train IndicWhisper models by fine-tuning the Whisper models on publicly available training datasets across 12 Indian languages totalling to 10.7K hours. We show that IndicWhisper significantly improves on considered ASR systems on the Vistaar benchmark. Indeed, IndicWhisper has the lowest WER in 39 out of the 59 benchmarks, with an average reduction of 4.1 WER. We open-source all datasets, code and models.Comment: Accepted in INTERSPEECH 202

LIM and SH3 Protein -1 Modulates CXCR2-Mediated Cell Migration

BACKGROUND: The chemokine receptor CXCR2 plays a pivotal role in migration of neutrophils, macrophages and endothelial cells, modulating several biological responses such as angiogenesis, wound healing and acute inflammation. CXCR2 is also involved in pathogenesis of chronic inflammation, sepsis and atherosclerosis. The ability of CXCR2 to associate with a variety of proteins dynamically is responsible for its effects on directed cell migration or chemotaxis. The dynamic network of such CXCR2 binding proteins is termed as "CXCR2 chemosynapse". Proteomic analysis of proteins that co-immunoprecipitated with CXCR2 in neutrophil-like dHL-60 cells revealed a novel protein, LIM and SH3 protein 1 (LASP-1), binds CXCR2 under both basal and ligand activated conditions. LASP-1 is an actin binding cytoskeletal protein, involved in the cell migration. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that CXCR2 and LASP-1 co-immunoprecipitate and co-localize at the leading edge of migrating cells. The LIM domain of LASP-1 directly binds to the carboxy-terminal domain (CTD) of CXCR2. Moreover, LASP-1 also directly binds the CTD of CXCR1, CXCR3 and CXCR4. Using a site-directed and deletion mutagenesis approach, Iso323-Leu324 of the conserved LKIL motif on CXCR2-CTD was identified as the binding site for LASP-1. Interruption of the interaction between CXCR2-CTD and LIM domain of LASP-1 by dominant negative and knock down approaches inhibited CXCR2-mediated chemotaxis. Analysis for the mechanism for inhibition of CXCR2-mediated chemotaxis indicated that LASP-1/CXCR2 interaction is essential for cell motility and focal adhesion turnover involving activation of Src, paxillin, PAK1, p130CAS and ERK1/2. CONCLUSIONS/SIGNIFICANCE: We demonstrate here for the first time that LASP-1 is a key component of the "CXCR2 chemosynapse" and LASP-1 interaction with CXCR2 is critical for CXCR2-mediated chemotaxis. Furthermore, LASP-1 also directly binds the CTD of CXCR1, CXCR3 and CXCR4, suggesting that LASP-1 is a general mediator of CXC chemokine mediated chemotaxis. Thus, LASP-1 may serve as a new link coordinating the flow of information between chemokine receptors and nascent focal adhesions, especially at the leading edge. Thus the association between the chemokine receptors and LASP-1 suggests to the presence of a CXC chemokine receptor-LASP-1 pro-migratory module in cells governing the cell migration

Responding to global challenges in food, energy, environment and water: Risks and options assessment for decision-Making

We analyse the threats of global environmental change, as they relate to food security. First, we review three discourses: (i) ‘sustainable intensification’, or the increase of food supplies without compromising food producing inputs, such as soils and water; (ii) the ‘nexus’ that seeks to understand links across food, energy, environment and water systems; and (iii) ‘resilience thinking’ that focuses on how to ensure the critical capacities of food, energy and water systems are maintained in the presence of uncertainties and threats. Second, we build on these discourses to present the causal, risks and options assessment for decision-making process to improve decision-making in the presence of risks. The process provides a structured, but flexible, approach that moves from problem diagnosis to better risk-based decision-making and outcomes by responding to causal risks within and across food, energy, environment and water systems

High-dimensional one-way quantum processing implemented on d-level cluster states

Taking advantage of quantum mechanics for executing computational tasks faster than classical computers 1 or performing measurements with precision exceeding the classical limit 2,3 requires the generation of specific large and complex quantum states. In this context, cluster states 4 are particularly interesting because they can enable the realization of universal quantum computers by means of a ‘one-way’ scheme 5, where processing is performed through measurements 6. The generation of cluster states based on sub-systems that have more than two dimensions, d-level cluster states, provides increased quantum resources while keeping the number of parties constant 7, and also enables novel algorithms 8. Here, we experimentally realize, characterize and test the noise sensitivity of three-level, four-partite cluster states formed by two photons in the time 9 and frequency 10 domain, confirming genuine multi-partite entanglement with higher noise robustness compared to conventional two-level cluster states 6,11–13. We perform proof-of-concept high-dimensional one-way quantum operations, where the cluster states are transformed into orthogonal, maximally entangled d-level two-partite states by means of projection measurements. Our scalable approach is based on integrated photonic chips 9,10 and optical fibre communication components, thus achieving new and deterministic functionalities

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference