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Osteoblasts sense extracellular levels of phosphate to control the local expression of phosphatases for matrix mineralisation
No full textThe provision of inorganic phosphate (P i) for biomineralisation is under systemic and local control. Locally, osteoblast production of phosphatases such as tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 is required for normal skeletal mineralisation and osteoblasts may sense extracellular P i concentrations to control local phosphatase activity and thereby “fine-tune” P i production and delivery for biomineralisation. This has been poorly explored and this study examined the ability of osteoblasts to sense and respond to extracellular P i to control the local expression of TNAP and PHOSPHO1. Extracellular P i downregulated the expression of PHOSPHO1 and TNAP by human primary osteoblasts at both mRNA and protein levels. Increasing P i concentrations also reduced the mRNA expression of the type III Na- P i co-transporters, PiT-1 and PiT-2 and selectively enhanced ERK1/2 phosphorylation. Inhibition of PiT-1 and PiT-2 by Foscarnet or MEK1/2 by UO126 abolished the downregulation of PHOSPHO1 and ALPL expression by extracellular Pi. Moreover, extracellular P i phosphorylated fibroblast growth factor receptor (FGFR) substrate 2α (FRS2α) and this activation was abolished by Foscarnet. Also, blocking FGFR signalling inhibited the phosphorylation of ERK1/2 and prevented the decrease in ALPL and PHOSPHO1 expression by extracellular P i. Similar results were observed in cultured murine calvaria. Osteoblast matrix mineralisation by extracellular P i was dependent upon type III Na- P i co-transporters and FGFR signalling. In conclusion, these results suggest an interplay between FGFR and P i transporters is required for osteoblasts to sense and respond to extracellular P i. This understanding advances our knowledge of the molecular control of physiological bone mineralisation by osteoblasts.</p
Localized Rift Valley fever virus persistence explains epidemic and interepidemic dynamics and guides control strategies
No full textRift Valley fever (RVF) is an emerging disease with devastating impacts on livestock health and livelihoods. The risk of RVF virus (RVFV) emergence in new regions and the effectiveness of a strategy for preventing establishment are impacted by how infection persists at local scales. Multiple mechanisms have been proposed for its persistence in regions prone to epidemics, including maintenance via transovarial transmission (TOT) but whether and how TOT can support local persistence is not well understood. Through the development of host- and multi-vector climate-driven simulation models to recreate observed patterns of prevalence and outbreak frequency, we show that TOT has the potential to play an important role in local persistence through seasonal cold or dry periods. Local persistence required annual low-level transmission of RVFV concurrently with substantial TOT, whereas the infrequent large outbreaks hampered long-term persistence in our simulations. We show that under this mode of local persistence, large outbreaks can be prevented with low-level vaccination, but that the long-term local persistence can only be interrupted with many years of sustained vaccination. Determining the role of TOT in persistence is critical for designing countermeasures to prevent establishment after emergence.</p
Bacterial contamination on mobile phones in the theatre area of a large veterinary hospital: Bacterial contamination of mobile phones
No full textBACKGROUND: Mobile phones are commonly used in clinical areas, including theatre, anaesthesia and patient preparation. Contamination rates of 72.6%-100% for mobile phones are reported in human healthcare, including multidrug-resistant bacteria in more than 30%. Veterinary studies are limited to Staphylococcus only, but similarly high levels of contamination are reported. METHODS: The personal and work mobile phones of veterinarians and nurses were swabbed for bacterial culture. Gram morphology and colony-forming units per millilitre (CFU/mL) were recorded for each bacteria grown. Participants completed an anonymous survey detailing habits of phone usage and hygiene.RESULTS: Swabs from 39 mobile phones were collected, with 16 of 39 (41%) positive for bacterial contamination. Gram-positive cocci were most common (38.4%), with 5.13% Gram-positive coccobacilli, 5.13% Gram-positive rods and 2.56% Gram-negative rods. Veterinarians' mobile phones had a significantly higher incidence of contamination than nurses' (62.5% vs. 6.7%; p = 0.007). More personal phones were contaminated than work phones (52.6% vs. 30%). Two mobile phones had growth of colonies more than 4000 CFU/mL. Mobile phone usage in clinical areas was reported by 76.2% of 21 participants, 57.1% cleaned their mobile phone less than weekly, 23.8% used non-antibacterial items to clean with and 23.8% had recently used their mobile phone in the bathroom. CONCLUSIONS: Bacterial contamination of mobile phones was common, with veterinarians having a significantly higher incidence compared to nurses. Gram-positive cocci were most common, but Gram-positive coccobacilli, Gram-positive rods and Gram-negative rods were also present. Mobile phone hygiene could be usefully included in infection control guidelines as they are potential fomites for healthcare-associated infections.</p
Small theropod dominated dinosaur footprint assemblages in the Middle Jurassic Valtos Sandstone and Kilmaluag Formations on the Isle of Skye, Scotland.
No full textMiddle Jurassic deposits on the Isle of Skye, Scotland, are improving our understanding of the distribution, palaeoenvironmental preferences and behaviour of theropod dinosaurs from a time when the global fossil record is sparse. Here, we describe and classify 185 Bathonian-aged ex situ dinosaur tracks from Skye’s Trotternish Peninsula—many described for the first time and imaged using photogrammetric techniques—into four morphotypes within a new Hebridean series. In the freshwater, closed-lagoonal Kilmaluag Formation at Lùb Score, smaller morphotypes are more abundant than larger equivalents in the freshwater–brackish fluviodeltaic Valtos Sandstone Formation at Valtos. Although assessable outcrops of track-bearing horizons are limited, we infer that the proximity to, or suitability of, specific palaeoenvironments for different-sized trackmakers may influence assemblage composition. Scarce surfaces with multiple tracks indicate potential trackmaker behaviours in respective palaeoenvironments, including foraging at Valtos and post-hatchling care at Lùb Score. The tracks most likely represent traces of a large megalosaurid and multiple smaller-bodied basal coelurosaurian or non-coelurosaurian (e.g. Ceratosauria, Megalosauroidea, Allosauroidea) theropods. The documentation of these trackmakers and their behaviours further enriches our understanding of dinosaur faunas during this poorly known time
A digital intervention to improve mental health and interpersonal resilience for young people who have experienced online sexual abuse:The i-Minds non-randomised feasibility clinical trial and nested qualitative study
No full textBackgroundNo evidence-based support for young people who have experienced technology-assisted sexual abuse exists. The project’s aims were to develop a digital intervention that improves mentalisation (the ability to understand the minds of oneself and others that underlies behaviour) to reduce the risk for revictimisation and future harm and improve young people’s resilience.ObjectivesTo co-design a mentalisation-based digital intervention; determine its feasibility, acceptability, safety and usability; and determine how to best integrate this into practice.MethodsA mixed-methods, non-randomised study in young people aged 12–18 years exposed to technology-assisted sexual abuse across two United Kingdom sites. We adapted an existing mentalisation-based therapy manual and co-designed a digital health intervention (app) using participatory methods. Recommendations from our pre-trial qualitative work with healthcare professionals supporting young people with technology-assisted sexual abuse and lived experience consultation informed app development and trial procedures. The primary outcome was the feasibility and acceptability of delivering the digital intervention measured against relevant fields of the Consolidated Standards of Reporting Trials statement for feasibility studies. Intervention safety was reported against an adverse events procedure. Usability was guided by the framework for analysing and measuring usage and engagement data in digital interventions. Acceptability was examined using qualitative methods. The planned sample size of the feasibility clinical trial was 60 young people.ResultsBetween May 2022 and March 2023, 147 young people were screened for eligibility for the feasibility clinical trial; 72 referrals were made and 43 young people were allocated to receive the intervention. We found that it was possible to recruit and retain participants to this trial. Quantitative and qualitative data showed that the i-Minds app was safe, acceptable and associated with promising signals of efficacy on valuable outcomes post treatment, including technology-assisted-sexual-abuse-related post-traumatic symptoms, resilience, internalising symptoms and reflective functioning. Most participants accessed or completed app modules. User feedback indicated that participants had a positive experience using the app, positively increasing their knowledge/understanding of their own mental health and their motivation to address their mental health difficulties. Practitioners identified the barriers to implementing i-Minds into routine practice as not being involved in its design at the outset, possible impact on workload and whether digital health interventions might replace routine care. Facilitators included the distinct nature and specificity of the i-Minds app for the target group and its ability to support young people on service waiting lists
The devil in the details:Dynamic prediction of loan portfolio profitability with macroeconomic drivers through multi-state modelling
No full textIn typical loan portfolios such as mortgages and credit cards, many accounts often experience different stages of delinquency before eventually recovering, fully repaying their balance, or defaulting. From the lender perspective, these events, coupled with the state of the economy, can affect cash-flow and profitability significantly. This paper presents a novel framework for dynamic monitoring future expected profit margins and cash flows of loan accounts, taking into account (i) individual risk profiles, (ii) macroeconomic trends, and (iii) transitions between different stages of delinquency. We make three contributions. First, we show a method to predict future cash flows and profit margins over the life of a loan where the predicted probabilities of an account jumping between delinquency states are obligor specific, time varying, adjusted to be competing risks and dependent on predictions from a macroeconomic model. This model is much more comprehensive model than those in the literature. Second, we investigate different methods to compute optimised cut-offs to be used with the transition probabilities to predict jumps an account is expected to make between different states of delinquency. Third, we illustrate the method using a large sample of 30-year term mortgages and show the expected profit margins for segments of the portfolio. The method will be particularly useful to lenders, who must comply with IFRS9 or CECL.</p
Assembling global security law and the politics of scale-making:The Global Counterterrorism Forum (GCTF)
Get PDFThis article rethinks ‘the global’ by analysing the emergence and growth of the Global Counterterrorism Forum (GCTF), an informal platform of multilateral counterterrorism co-operation which has been instrumental in the making of post-9/11 global security law and governance. It problematises and empirically analyses how global scale is enacted through the socio-material practices of translation and assemblage that have been deployed in the construction, maintenance and extension of the GCTF governance network. Drawing from interviews with policy experts and GCTF members, and from participant-observation in GCTF and UN events, the article contributes to the theme of the Special Issue and wider legal debates about the spatiotemporal dynamics of global law and governance by critically analysing how global scale is fabricated in practice and unpacking the politics of GCTF’s global scale-making processes. Focusing on specific techniques and norm-creation processes of the GCTF, like watch-listing toolkits and ‘good-practice’ documents on foreign terrorist fighters (FTFs) and countering violent extremism (CVE), the article analyses how translation, problematisation and enrolment practices have assembled the GCTF as an ‘apolitical’ global security governance body. Our approach opens novel possibilities for socio-legal research on the politics of scale-making and critiquing global security power in action through empirical attention to its assemblage practices
Tissue-specific consequences of tag fusions on protein expression in transgenic mice
Get PDFGenetic fusion of protein tags is widely used to study protein functions in vivo. It is well known that tag fusion can cause unwanted changes in protein stability, but whether this is an inherent property of the tagged protein, or can be influenced by the cell and tissue environment, is unclear. Using a series of genome edited mouse models, we show that tag-dependent changes in protein expression can vary across different primary cell and tissue contexts. In one case (Ncaph2), a C-terminal auxin inducible degron fusion strongly increased protein stability in some tissues but decreased it in others. Destabilisation resulted from tissue-specific ‘leakage’ of the auxin-inducible degron, which depended on TIR1 expression, and occurred selectively in the small intestine where basal concentrations of auxin / indole-3-acetic acid can reach levels that are sufficient to trigger protein degradation in cultured cells. Stabilisation occurred in post-mitotic cells via an endogenous degradation signal situated at the Ncaph2 C-terminus, which normally undergoes activation upon cell cycle exit, but is inactivated by C-terminal tag fusion. Our results highlight the underappreciated importance of cell and tissue environment in determining the consequences of tag fusions on protein expression, which may be particularly important in animal models that contain diverse cell types
Guidance for research ethics committees and researchers on designing research in the age of AI
Get PDFThis paper is concerned with the implications of artificial intelligence (AI), and particularly the impact of generative AI content, on the work and processes of university/institution Research Boards (IRBS) or Research Ethics Committees (RECs). RECs are groups of individuals appointed to formally review research proposals and can be established by universities, research organisations or health care providers to determine whether proposed research meets agreed upon ethical standards. In the United States, IRBs perform a similar function. The intention is that this paper provides some background and context on emerging issues arising from unwanted use of AI, and it is intended to inform those reviewing research ethics proposals so that they are better able to consider the potential risks and impact of AI. By highlighting key questions, principles, best practices, and some practical recommendations, we hope this paper will support ethics board members to more confidently provide appropriate oversight and advice for researchers, helping them ensure their ethical approach and research design is fit for purpose in the current context where AI infiltration is becoming more commonplace.This paper first provides an overview of a changing research landscape that requires an awareness of the capabilities and potential disruption posed by AI tools. In section 2 it introduces the potential challenges to researchers arising from widespread access to AI, especially generative AI. Section 3 gives an overview of the various ethics guidelines and resources in circulation and comments on their applicability for individual researchers, committees, institutions and industry. The specific dimensions of applying some of these guidelines to research are delineated in section 4. Section 5 focuses on RECs’ roles in upholding ethical standards and the complexities that AI brings. Section 6 provides comprehensive guidance for RECS in the areas of 1) Guidelines provided to researchers, 2) Risk/impact assessments, 3) Challenges to be aware of and 4) Addressing unethical research. The paper offers conclusions in section 7, and in section 8 offers a comprehensive set of recommendations aimed at both committee and institutional level, which can be used as a guide or checklist
Legal challenges in tackling AI-generated child sexual abuse material within the UK - REPORT
Get PDFThis report critically reviews the regulatory context of the UK on the topic of accountability around child sexual abuse material (CSAM) created via generative Artificial Intelligence (gen-AI) on a reserved and devolved level. The legislation that is relevant for cases of AI-generated CSAM focuses on two types of indecent images. One type is indecent pseudo-photographs, meaning photographs as well as videos and films made by computer graphics that have a photo-realistic appearance, i.e., they look real. The other type covers prohibited pseudo-images that do not look realistic, such as drawings and cartoons or hentai and manga. We found that there is good coverage around a series of offences with regards to pseudo-photographs, i.e., the acts of making, taking, possessing, and disseminating pseudo-photographs are all covered, irrespective of the technology used, thus covering cases of generative AI or deepfakes. This is evidenced by the first emerging case in England, where an offender who created CSAM using generative AI was arrested, charged, and sentenced to 18 years in prison. That said, the law is silent on whether the criminalisation of indecent pseudo-photographs of children extends in cases of fictitious children. This protection tends to be less efficient with regards to non-realistic images, including cartoons, manga and drawings. While possession and dissemination are criminalised for real and fictitious children, the act of making such imagery is not criminalised in England and Wales. The largest gap in protection with regards to the above imagery exists in Scotland, as the making and possession of indecent non-realistic images in Scotland is not criminalised. The nation that seems to have the most robust legislative framework against all acts related to indecent non-realistic images is Northern Ireland. This report also discusses the topic of paedophile manuals, Online Safety Act, case law, compensation and AI tools utilised to create pseudo-CSAM
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