Polymers exhibiting lower critical solution temperatures as a route to thermoreversible gelators for healthcare

Funding Information: M.T.C. acknowledges support from the EPSRC (EP/T00813X/1). The University of Hertfordshire are thanked for funding the research project of P.H. Publisher Copyright: © 2020 The Authors. Advanced Functional Materials published by Wiley-VCH GmbHThe ability to trigger changes to material properties with external stimuli, so-called “smart” behavior, has enabled novel technologies for a wide range of healthcare applications. Response to small changes in temperature is particularly attractive, where material transformations may be triggered by contact with the human body. Thermoreversible gelators are materials where warming triggers reversible phase change from low viscosity polymer solution to a gel state. These systems can be generated by the exploitation of macromolecules with lower critical solution temperatures included in their architectures. The resultant materials are attractive for topical and mucosal drug delivery, as well as for injectables. In addition, the materials are attractive for tissue engineering and 3D printing. The fundamental science underpinning these systems is described, along with progress in each class of material and their applications. Significant opportunities exist in the fundamental understanding of how polymer chemistry and nanoscience describe the performance of these systems and guide the rational design of novel systems. Furthermore, barriers to translating technologies must be addressed, for example, rigorous toxicological evaluation is rarely conducted. As such, applications remain tied to narrow fields, and advancements will be made where the existing knowledge in these areas may be applied to novel problems of science.Peer reviewe

Poly(N-isopropyl acrylamide) – poly(ethylene glycol) – poly(N-isopropyl acrylamide) as a thermoreversible gelator for topical administration

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported licence: https://creativecommons.org/licenses/by-nc/3.0/.Poly(N-isopropyl acrylamide) – block– poly(ethylene glycol) – block– poly(N-isopropyl acrylamide) is known to exhibit a thermally-induced solution-to-gel transition in water, which may be exploited for biomedical applications. This “thermoreversible gelator” has great potential for application in topical drug delivery to the surfaces of the body such as the skin, eye, and vagina, but this has not yet been evaluated. This study evaluates PNIPAM98-PEG122-PNIPAM98 as a thermoreversible gelator for vaginal drug delivery, for the first time evaluating the effect of polymer concentration on gelation, studying rheological parameters relevant to topicals, measuring dissolution rates, stability and the phenomemon of mucoadhesion. Two drugs relevant to vaginal administration, progesterone and tenofovir disoproxil fumarate are investigated for use in the thermoreversible gelators, studying both hydrophobic and hydrophilic drug solubilisation and release. Throughout the study, comparison is made with poloxamer 407, the most commonly studied thermoreversible gelator. PNIPAM98-PEG122-PNIPAM98 exhibits several advantages for topical drug delivery, having low viscosity at room temperature to allow easy application, then exhibiting a gelation just below body temperature to form a viscous gel which is resistant to dissolution and relatively mucoadhesive. Drug release is highly dependent on temperature, with elevation to body temperature resulting in a dramatic retardation of progesterone release, which may be used in future medicines to provide sustained delivery of hydrophobic xenobiotics.Peer reviewedFinal Accepted Versio

Detection of HTLV-1 proviral DNA in cell-free DNA: potential for non-invasive monitoring of Adult T cell leukaemia/lymphoma using liquid biopsy?

Introduction: Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called ‘cell-free’ DNA (cfDNA) released from dying malignant cells encodes cancer-associated mutations. Thus, minimally invasive sampling of cfDNA in blood plasma can be used to diagnose, characterise and longitudinally monitor solid tumours at remote sites in the body. ~5% of carriers of Human T cell leukaemia virus type 1 (HTLV-1) develop Adult T cell leukaemia/lymphoma (ATL), and a similar percentage develop an inflammatory CNS disease, HTLV-1 associated myelopathy (HAM). In both ATL and HAM, high frequencies of HTLV-1 infected cells are present in the affected tissue: each carrying an integrated DNA copy of the provirus. We hypothesised that turnover of infected cells results in the release of HTLV-1 proviruses in cfDNA, and that analysis of cfDNA from infected cells in HTLV-1 carriers might contain clinically useful information pertaining to inaccessible sites in the body- e.g. for early detection of primary or relapsing localised lymphoma type ATL. To evaluate the feasibility of this approach, we tested for HTLV-1 proviruses in blood plasma cfDNA. Methods: CfDNA (from blood plasma) and genomic DNA (gDNA, from peripheral blood mononuclear cells, PBMC) was isolated from blood from 6 uninfected controls, 24 asymptomatic carriers (AC), 21 patients with HAM and 25 patients with ATL. Proviral (HTLV-1 Tax) and human genomic DNA (the beta globin gene, HBB) targets were quantified by qPCR using primer pairs optimised for fragmented DNA. Results: Pure, high quality cfDNA was successfully extracted from blood plasma of all study participants. When compared with uninfected controls, HTLV-1 carriers had higher concentrations of cfDNA circulating in their blood plasma. Patients with ATL who were not in remission had the highest levels of blood plasma cfDNA in any group studied. HTLV-1 proviral DNA was detected in 60/70 samples obtained from HTLV-1 carriers. The proviral load (percentage of cells carrying proviruses) was approximately tenfold lower in plasma cfDNA than in PBMC genomic DNA, and there was a strong correlation between the proviral load in cfDNA and PBMC genomic DNA in HTLV-1 carriers that did not have ATL. cfDNA samples in which proviruses were undetectable also had very low proviral load in PBMC genomic DNA. Finally, detection of proviruses in cfDNA of patients with ATL was predictive of clinical status: patients with evolving disease had higher than expected total amount of proviruses detectable in plasma cfDNA. Discussion: We demonstrated that (1) HTLV-1 infection is associated with increased levels of blood plasma cfDNA, (2) proviral DNA is released into blood plasma cfDNA in HTLV-1 carriers and (3) proviral burden in cfDNA correlates with clinical status, raising the possibility of developing assays of cfDNA for clinical use in HTLV-1 carriers

UKAIRO: internet-scale bandwidth detouring

The performance of content distribution on the Internet is crucial for many services. While popular content can be delivered efficiently to users by caching it using content delivery networks, the distribution of less popular content is often constrained by the bandwidth of the Internet path between the content server and the client. Neither can influence the selected path and therefore clients may have to download content along a path that is congested or has limited capacity. We describe UKAIRO, a system that reduces Internet download times by using detour paths with higher TCP throughput. UKAIRO first discovers detour paths among an overlay network of potential detour hosts and then transparently diverts HTTP connections via these hosts to improve the throughput of clients downloading from content servers. Our evaluation shows that by performing infrequent bandwidth measurements between 50 randomly selected PlanetLab hosts, UKAIRO can identify and exploit potential detour paths that increase the median bandwidth to public Internet web servers by up to 80%

Thermoresponsive poly(di(ethylene glycol) methyl ether methacrylate)-ran-(polyethylene glycol methacrylate) graft copolymers exhibiting temperature-dependent rheology and self-assembly

© 2021 The Authors. Published by Elsevier B.V. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Graft copolymers with brush-type architectures are explored containing poly (ethylene glycol) methacrylates copolymerized with “thermoresponsive” monomers which impart lower critical solution temperatures to the polymer. Initially, the chemical structure of the thermoresponsive polymer is explored, synthesizing materials containing N-isopropyl acrylamide, N,N-diethylacrylamide and diethylene glycol methyl ether methacrylate. Thermoresponsive graftcopolymers containing di(ethylene glycol) methyl ether methacrylate (DEGMA) exhibited phase transition temperature close to physiological conditions (ca 30 °C). The effect of polymer composition was explored, including molecular weight, PEG-methacrylate (PEGMA) terminal functionality and PEGMA/DEGMA ratios. Molecular weight exhibited complex relationships with phase behavior, where lower molecular weight systems appeared more stable above lower critical solution temperatures (LCST), but a lower limit was identified. PEGMA/DEGMA feed was able to control transition temperature, with higher PEGMA ratios elevating thermal transition. It was found that PEGMA terminated with methoxy functionality formed stablecolloidal structures above LCST, whereas those the hydroxy termini generally formed two phase sedimented systems when heated. Two thermoresponsive DEGMA-based graft polymers, poly(PEGMA7-ran-DEGMA170) and poly(PEGMA1-ran-DEGMA38), gave interesting temperature-dependent rheology, transitioning to a viscous state upon heating. These materials may find application in forming thermothickening systems which modify rheology upon exposure to the body’s heatPeer reviewe

A review of mission planning systems

A general definition of Mission Planning is given. The definition covers the full scope of an end-to-end mission planning system. Noting the mission-specific nature of most mission planning systems, a classification of autonomous spacecraft missions is made into Observatory, Survey, multi-instrument science, and Telecommunications missions. The mission planning approach for one mission in each category is examined critically. The following missions were chosen: ISO (Infrared Space Observatory); ERS-1 (European Remote Sensing Satellite); and Eureca (European Retrievable Carrier). The paper gives a summary of lessons learned from these missions suggesting improvements in areas such as requirements analysis, testing, user interfacing, rules, and constraints handling. The paper will also examine commonalities in functions, which could constitute a basis for identification of generic mission planning support tools

Hallucinations in Large Multilingual Translation Models

Large-scale multilingual machine translation systems have demonstrated remarkable ability to translate directly between numerous languages, making them increasingly appealing for real-world applications. However, when deployed in the wild, these models may generate hallucinated translations which have the potential to severely undermine user trust and raise safety concerns. Existing research on hallucinations has primarily focused on small bilingual models trained on high-resource languages, leaving a gap in our understanding of hallucinations in massively multilingual models across diverse translation scenarios. In this work, we fill this gap by conducting a comprehensive analysis on both the M2M family of conventional neural machine translation models and ChatGPT, a general-purpose large language model~(LLM) that can be prompted for translation. Our investigation covers a broad spectrum of conditions, spanning over 100 translation directions across various resource levels and going beyond English-centric language pairs. We provide key insights regarding the prevalence, properties, and mitigation of hallucinations, paving the way towards more responsible and reliable machine translation systems

Research Support in Australian Academic Libraries: Services, Resources, and Relationships

In the last decade Australian academic libraries have increasingly aligned their research support services with assessment criteria used in the national research evaluation exercise (Excellence for Research in Australia). The same period has seen growing interest in research impact outside of traditional measures, such as bibliometrics. Social media has provided opportunities for research dissemination and new tools, altmetrics, to measure these activities have emerged. This article reports on research into the extent and nature of research support services at Australian academic libraries, how the services are managed, and the factors that influence their development and delivery. Quantitative and qualitative research methods were used to compare the findings with an earlier study and to provide a deeper understanding of research support in Australia. Three key themes, services, staff and resourcing, and relationships, are discussed in relation to the management and challenges faced in providing research support

Thermoresponsive Triblock‐Copolymers of Polyethylene Oxide and Polymethacrylates: Linking Chemistry, Nanoscale Morphology, and Rheological Properties

© 2021 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/Abstract: Thermoreversible gels switch from a free‐flowing liquid state to an elastic gel mesophase upon warming, displaying the reverse transition upon cooling. While this phenomenon makes these advanced materials highly attractive in numerous fields, the generation of optimal materials of tailored rheology and transition temperatures is stifled by the lack of design principles. To address this need, a library of ABA copolymers has been prepared with “A” blocks exhibiting thermoresponsive behavior and “B” blocks of poly(ethylene glycol). This library evaluates the effect of “A” chemistry, probing three polymer classes, and A/B block molecular weight on thermally‐induced phase changes in solutions of the polymers. An exploration by rheometry coupled to Small‐Angle Neutron Scattering (SANS) elucidates temperature‐dependent hierarchical self‐assembly processes occurring on the nanoscale as well as bulk rheology. This process deciphered links between rheology and supracolloidal assemblies (sphere, ellipses, and cylinders) within the gel state with interactions probed further via structure factors. Several design principles are identified to inform the genesis of next‐generation thermoreversible gels, alongside novel materials exhibited thermoresponsive behavior in the solution state for use in applied healthcare technologies.Peer reviewedFinal Published versio