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A palindromic triplex architecture for DNA-templated synthesis designed for the core of a synthetic ribosome
Get PDFWe demonstrate a triplex-based architecture for DNA-templated synthesis. This study is motivated by progress towards the development of a synthetic ribosome – autonomous, genetically programmable, molecular machinery for synthesis. Such schemes for the creation and evolution of chemically diverse DNA-tagged chemical libraries rely on hybridization reactions of oligonucleotide adapters to control sequential, DNA-templated reactions of covalently attached building blocks. To enable parallel one-pot library synthesis it is desirable that any building block can be incorporated at any position in a product oligomer: this is incompatible with geometries commonly used for DNA-templated synthesis which require alternate reactants to be attached to 3′ and 5′ termini of their adapters. Our triplex-based architecture overcomes this problem by templating reactions between building blocks attached to adapters with identical structures. It is intended to form the core of programmable molecular machinery for multistep synthesis. Here, we use single-step coupling reactions to characterize the triplex reaction template
Soil property-dependent toxicity and oxidative stress induced by perfluorooctanoic acid in <i>Caenorhabditis elegans</i>
Get PDFPerfluorooctanoic acid (PFOA), a persistent organic pollutant frequently detected in soils, has received increasing attention due to growing demands for soil environmental guideline values that ensure acceptable ecological risk. However, systematic evaluations of PFOA ecotoxicity under realistic soil conditions remain limited. In this study, Caenorhabditis elegans (C. elegans) was used as a model soil organism, following ISO 10872, to assess PFOA-induced effects on growth, fertility, and reproduction after seven days of exposure in six representative Chinese soils. Oxidative stress responses were also measured, including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). PFOA exposure significantly inhibited all biological endpoints, with EC50 values of 28 ∼ 59 mg·kg−1 for growth, 19 ∼ 53 mg·kg−1 for fertility (expressed as the percentage of gravid adults), and 19 ∼ 39 mg·kg−1 for reproduction. Soil physicochemical properties strongly influenced toxicity. Stepwise regression analysis identified cation exchange capacity (CEC), organic matter (OM), and free Fe oxides (FeFO) as major predictors of growth toxicity, explaining 89.7 % of the variance (P < 0.05). For fertility and reproduction, total Fe (Fetotal) was the primary determinant, while the addition of pH, amorphous Fe/Al oxides (FeAO, AlAO), and total Al (Altotal) further improved model performance. PFOA also induced pronounced oxidative stress, evidenced by increased ROS and MDA levels and biphasic SOD and CAT responses, indicating disruption of antioxidant defenses at higher exposures. Overall, these findings clarify how soil geochemistry modulates the bioavailability and ecological toxicity of PFOA, providing essential evidence for developing soil quality standards, environmental guideline values, and improved ecological risk assessments
Local reach, global significance? The politics of scale and the competing imaginaries of the UK research impact agenda
Get PDFOne of the often-criticised aspects of the impact agenda in the UK is its narrow understanding of research impact, particularly in terms of the geographical reach. Local impact is indeed one of the most under-reported categories of the REF impact. This omission is significant as it has important consequences for the practices of knowledge production and use, including political (e.g. knowledge supply to local governments), strategic (e.g. the role of universities in local communities) and equity (e.g. elite-facing knowledge work) considerations. This paper aims to critically unpack the causes and consequences of the geographical bias of the REF impact agenda by mobilising conceptual tools from the field of human geography, in particular, the notion of the ‘scale’ as a socially constructed phenomenon. Drawing on interviews with academics, experts and policymakers involved in impact activities, this paper unpacks the meanings and practices behind ‘local’, ‘national’ and ‘international’ impact. The paper explores how actors collapse, stretch, or reframe ‘scale’ of their impact to meet competing demands—invoking local importance and the civic university ideal on one hand, and positioning themselves as globally excellent on the other. The paper argues that the Research Excellence Framework, as a performative policy instrument, reproduces scalar hierarchies by implicitly rewarding impact with broader geographic reach. Therefore, the analysis of the politics of scale of research impact sheds light on the broader phenomenon of unintended consequences of research assessment by unveiling the mechanisms behind the discrepancies between research assessment guidelines and their enactments in measurement practice
Digital transformation through innovation:The human-AI decision spectrum
Get PDFThe rapidly changing and increasingly complex processes enabled by artificial intelligence (AI) applications challenge the conventional concepts of innovation. In contrast to a general perception that AI adoption can augment innovation output, managers still lack empirical guidance on how to structure innovation processes with human-AI interaction across time and space. Drawing on observations from case studies in the aerospace, heavy engineering, information technology, and pharmaceutical sectors, this paper presents the development of a conceptual model for digital innovation to represent (i) Learning Processes (LPs) focusing on knowledge creation and knowledge reuse and (ii) Product Development Processes (PDPs) leading to radical and incremental changes. The conceptual model is inductively developed based on a theory building approach using multiple case studies. A set of transformative characteristics centralized on Originality, Reliability, Transferability, and Adaptability (ORTA) are identified to guide decision-making along multi-stage and cross-layer innovation processes involving cyclical handoffs between humans and machine agents. These ORTA characteristics form a base for strategic decision-making along the Human and AI decision spectrum suited to prepare companies for survival and prosperity in their journeys of digital transformation
Making Sense of Researching Crises:Reflections on Work in Gaza
Get PDFA research perspective on crises, based on experience of community researcher training and a trauma recovery project in Gaza where qualitative methods are put to use by mental health professionals. Inspired by these agents of change in the built environment and literature on disaster research, the authors offer reflections on the impacts and challenges involved. The paper ends with a call for a new understanding of ‘crisis research’, as a mode of inquiry grounded in shared humanity, relational ethics, and community-based sense-making in recovery from disasters
The development of a risk threshold to aid risk stratified approach to monitoring for haematological, hepatic and/or renal adverse drug reactions during established cs DMARD treatment for systemic autoimmune rheumatic diseases:a RAND/UCLA Appropriateness Method consensus study
Get PDFObjectiveTo explore how appropriate different intervals between monitoring blood tests are considered in relation to the risk of clinically significant adverse drug reactions in adults prescribed conventional synthetic DMARDs (csDMARDs) for ≥1 year for systemic autoimmune rheumatic diseases (SARD).MethodsA RAND/UCLA Appropriateness Method consensus study was undertaken. Members of the BSR csDMARD guideline working group who manage adults with SARD participated. Experts rated the extent to which intervals between blood tests were appropriate using Likert-type scales with responses from 1 (totally inappropriate) to 9 (totally appropriate) for nine scenarios with 5-year predicted risk of discontinuing treatment due to abnormal monitoring blood tests from 5% to 25%. Median score and the number that voted 1–3 (inappropriate), 4–6 (unsure) and 7–9 (appropriate) were calculated for every interval in each scenario. Scenarios for which agreement could not be reached in the first round were recirculated, enclosing individual round 1 response and the panel median score. Consensus that an interval was appropriate for a scenario was reached where the median panel score was ≥7 and up to six experts rated <7. The results were discussed with patient and public involvement members and experts.ResultsTwenty-one of the 27 invitees participated. They comprised 11 consultants/GPs, five specialist nurses, three pharmacists and two rheumatology specialty trainees. Consensus was reached for all scenarios. Six- and three-monthly blood tests were agreed as appropriate when the predicted risk was ≤10% and >10% over 5 years, respectively.ConclusionA threshold to aid risk-stratified monitoring during established csDMARD treatment was agreed for adults with SARD.</div
The Real‐Time Advanced Ionospheric Data Assimilation (AIDA) Model
Get PDFThe Advanced Ionospheric Data Assimilation (AIDA) is a real-time data assimilation model of global 3D ionosphere and plasmasphere electron density. Changes in the local space environment can occur on very short timescales, particularly during disturbed geomagnetic conditions. This space weather has an impact on many modern systems including Global Navigation Satellite System (GNSS) signals and High Frequency radio communications. To provide an ionospheric specification in real-time, AIDA ingests data streams from over 2000 GNSS receivers, along with ionosonde-derived characteristics. These measurements are assimilated using a particle filter into the empirical NeQuick ionosphere model and Neustrelitz Plasmasphere Model. The GNSS receiver Differential Code Biases are solved self-consistently using Rao-Blackwellized particle filtering. AIDA consists of a real-time Ultrarapid model and a near-real-time Rapid model at a 90-min latency. These models are also forecast six hours into the future, meaning AIDA produces two separate nowcasts of the current ionospheric state (Ultrarapid and the 90-min forecast of the Rapid product). AIDA is assessed using an operational validation program which shows that the Rapid 90-min forecast model provides the best nowcast performance during quiet conditions, with improvements of ∼ 12% in foF2 and hmF2 root mean square error (RMSE) when compared to the background. The Ultrarapid model provides the best nowcast during disturbed conditions, with improvements of 27%−38% in foF2 RMSE. Both the Rapid and Ultrarapid models are also validated using in situ electron density measurements from Swarm, showing overall global improvement in electron density specification
Microscale-patterned SERS substrates with exceptional uniformity:Addressing reproducibility challenges
Get PDFAchieving reproducible, quantitative signals remains a critical barrier for the broad adoption of Surface-Enhanced Raman Scattering (SERS) in analytical applications. Here, we introduce an innovative, mask-free laser-lithography fabrication approach to produce uniform arrays of gold-coated nanowells that significantly improve uniformity and reproducibility across large substrate areas compared to conventional methods. The substrates feature precisely controlled periodic arrays of sub-micron wells (500–2000 nm diameter) uniformly coated with a thin gold layer, generating localised and multiplexed plasmonic hot spots. By coupling the substrates to an advanced analytical workflow, we achieve spatial variations below 5% in SERS intensity across large mapping areas on most surfaces, addressing the uniformity challenges inherent in conventional SERS substrates. Using benzenethiol (BT) and Rhodamine 6G (R6G) as model analytes, we demonstrate quantitative detection with analytical enhancement factors of (1.00 ± 0.01 ) × 105 (BT) and (3.98 ± 0.10 ) × 105 (R6G) respectively. Importantly, the reported analytical enhancement factors account for spatial variations and multiple Raman peaks, ensuring reproducible and reliable values unlike conventional EFs based on isolated hot spots and single Raman modes. The developed approach addresses critical challenges in reproducibility and quantitative calibration, establishing a robust and well-characterized SERS substrate platform upon which future application-specific sensing protocols can be developed
A systematic review with meta-analysis of the mastoid emissary foramen:implications for posterior cranial fossa surgery
Get PDFIntroduction: The mastoid emissary foramen (MEF), transmitting the mastoid emissary vein, is a key anatomical structure encountered during posterior cranial fossa and cerebellopontine angle approaches. Injury to this variable venous pathway may result in significant hemorrhage. However, published data regarding the prevalence and morphology of the MEF remain inconsistent.Methods: A systematic review with meta-analysis was conducted according to PRISMA 2020 and Evidence-based Anatomy guidelines. Four databases were searched for osteological and imaging studies reporting MEF prevalence or morphometry were included. Pooled prevalence and morphometric estimates were calculated using random-effects models.Results: Twenty-one studies comprising 8,689 skull sides were included. The pooled prevalence of the MEF was 74% (95% CI: 65.16-82.03), with absence in 26%. A single MEF was most common (53%), while multiple MEFs were present in 16% of cases. Two, three, and four MEFs were observed in 12%, 4%, and 0.6% of cases, respectively. Nationality influenced the prevalence of multiple MEFs, whereas laterality and study type did not. The pooled mean diameter of the MEF was 2 mm (95% CI: 1.55-3.14).Conclusions: The MEF is a common but highly variable anatomical structure. Awareness of its prevalence and morphology is essential for neurosurgical planning, emphasizing the importance of high-resolution preoperative imaging to minimize vascular complications during posterior cranial fossa approaches.</p
Age-related sarcopenia and the gut microbiome:mechanistic insights into the gut-muscle axis and potential microbiome based therapeutic interventions
Get PDFAgeing is associated with a loss of skeletal muscle mass, strength and function, termed sarcopenia. The presence of sarcopenia is known to be problematic leading to an increased risk of falls, fractures and mortality. Age-related changes in the gut microbiome, characterized by reduced diversity and altered metabolite production, may compromise intestinal barrier function, leading to increased permeability. These age-associated changes in the gut microbiome led to changes in circulating microbial metabolites and toxins, such as a decrease in short-chain fatty acids, an increase in lipopolysaccharides and an imbalance in bile acid production. Together these alterations may contribute to the development of sarcopenia through impairments in muscle protein turnover. Currently, lifestyle-based approaches e.g., exercise and diet, alongside the use of pre-, pro- and post-biotics have been proposed as strategies to target the gut-muscle axis and combat the risk of sarcopenia in the expanding ageing population. However, little evidence is available to support their use within clinical settings. Several new strategies including the nutraceutical Urolithin A and faecal microbiome transplants (FMT) have been suggested to treat age-related sarcopenia. This review provides insight into the potential interactions of the gut microbiome and skeletal muscle with ageing and sarcopenia development, alongside potential new and existing countermeasures
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