The performance of rockfall barriers have been traditionally assessed using standardized impact tests such as SEL and MEL (EOTA 2018); that quantify the barrier service and maximum energy levels, respectively. Unfortunately, these types of tests only provide information for very specific loading conditions, i.e. centered impacts, that fail to consider the way different loading conditions affect the barrier response. It has been shown that, given a certain block kinetic force, changes in the block size (Buzzi and Krummenacher 2014) and impact position (Zhao et al. 2020), can make the difference between withstand and failure. In recent years, numerical approaches such as Finite (FEM, Gentilini et al. 2013) and Discrete (DEM, Bertrand et al. 2012) Element Method have been used to overcome these limitations and investigate more complex loading conditions (Song et al. 2018). However, this type of analysis is still mostly limited to research institutions and universities as it requires a certain degree of computational power and technical expertise, which might not be available to the end user (i.e. engineering firms). Metamodels, also known as surrogate models, are a type of high-level models that aim to approximate the behavior of lower-level, higher fidelity models, reducing the computational burden. They have shown promising results in the scope of rockfall protection, where they have been used to predict failure modes under different loading conditions (Mentani et al. 2016; Toe et al. 2018). In this paper, we combine the efficiency of a meta-model built using a DEM barrier model with the predictive abilities of the block propagation code Hy-Stone (Lanfranconi et al. 2020) to provide site-specific results with increased computational efficiency and ease of use compared to the standard numerical approaches.
A fully non-linear PFEM platform developed for coupled flow and deformation processes in saturated structured soils is employed in this work to explore the possibility of modeling the occurrence of strain localization and the evolution of the displacement field in the post-localization regime without the pathological mesh-dependence typically observed in conventional non-linear FEM simulation. The proposed formulation adopts an isotropic hardening elastoplastic model for bonded geomaterials, developed in the framework of multiplicative plasticity, equipped with non-local hardening laws of the integral type for both density- and bonding-related internal variables. These hardening laws provide the material with an internal length scale based on the size of the neighborhood where the non-local averaging is performed. A number of PFEM simulations of plane strain compression tests on ideal calcarenite specimens have been performed to explore the convergence of the numerical solution in the post-localization regime as the element size is reduced. The convergence study is focused on simulations with non-uniform, adaptive discretizations, exploring the convergence of the solution as the adopted minimum element size of the mesh is reduced. The results of the convergence study demonstrate the effectiveness of the adopted non-local approach in eliminating the pathological mesh-dependence in presence of strain localization, in the context of h-adaptive PFEM simulations.
Background Undergraduate emergency medicine (EM) training is important because all medical graduates are expected to have basic emergency knowledge and skills regardless of their future speciality. EM clerkship should provide opportunities to improve not only knowledge and skills but also the self-efficacy of learners. This study aims to evaluate the expectations, opinions, and self-efficacy beliefs of medical students during a 4-week mandatory EM clerkship. Methods This study used a prospective longitudinal design with quantitative and qualitative survey methods. It includes final year medical students of the 2015–2016 academic year. Voluntary de-identified pre- and post-clerkship surveys included 25 statements. The post-clerkship survey included two open-ended questions asking participants to identify the best and worst three aspects of EM clerkship. Responses were analysed to determine themes or commonalities in participant comments indicative of the EM clerkship learning experiences and environment. Results Sixty-seven out of seventy-nine (85%) students responded to both pre- and post-clerkship surveys. Medical students’ expectations of EM clerkships’ effect on knowledge and skill acquisition were high, and a 4-week mandatory EM clerkship was able to meet their expectations. Medical students had very high expectations of EM clerkships’ educational environment. In most aspects, their experiences significantly exceeded their expectations ( p value < 0.001). The only exception was the duration of clerkship, which was deemed insufficient both at the beginning and at the end ( p value: 0.92). The students perceived that their self-efficacy improved significantly in the majority of basic EM skills and procedures ( p value < 0.001). Emergent qualitative themes in the study also supported these results. Conclusion This study showed that a 4-week mandatory EM clerkship increased medical students' perceived self-efficacy in basic emergency management skills. The EM clerkship met students' expectations on knowledge and skill acquisition, and exceeded students’ expectations on educational environment.
Journal peer review regulates the flow of ideas through an academic discipline and thus has the power to shape what a research community knows, actively investigates, and recommends to policymakers and the wider public. We might assume that editors can identify the ‘best’ experts and rely on them for peer review. But decades of research on both expert decision-making and peer review suggests they cannot. In the absence of a clear criterion for demarcating reliable, insightful, and accurate expert assessors of research quality, the best safeguard against unwanted biases and uneven power distributions is to introduce greater transparency and structure into the process. This paper argues that peer review would therefore benefit from applying a series of evidence-based recommendations from the empirical literature on structured expert elicitation. We highlight individual and group characteristics that contribute to higher quality judgements, and elements of elicitation protocols that reduce bias, promote constructive discussion, and enable opinions to be objectively and transparently aggregated.
Inhaled corticosteroid (ICS) therapy is widely prescribed without a history of exacerbations and consensus guidelines suggest withdrawal of ICS in these patients would reduce the risk of side effects and promote cost-effective prescribing. The study describes the prescribing behaviour in the United Kingdom (UK) in relation to ICS withdrawal and identifies clinical outcomes following withdrawal using primary and secondary care electronic health records between January 2012 and December 2017. Patients with a history ≥12 months’ exposure who withdrew ICS for ≥6 months were identified into two cohorts; those prescribed a long-acting bronchodilator maintenance therapy and those that were not prescribed any maintenance therapy. The duration of withdrawal, predictors of restarting ICS, and clinical outcomes were compared between both patient cohorts. Among 76,808 patients that had ≥1 prescription of ICS in the study period, 11,093 patients (14%) withdrew ICS therapy at least once during the study period. The median time without ICS was 9 months (IQR 7–14), with the majority (71%) receiving subsequent ICS prescriptions after withdrawal. Patients receiving maintenance therapy with a COPD review at withdrawal were 28% less likely to restart ICS (HR: 0.72, 95% CI 0.61, 0.85). Overall, 69% and 89% of patients that withdrew ICS had no recorded exacerbation event or COPD hospitalisation, respectively, during the withdrawal. This study provides evidence that most patients withdrawing from ICS do not experience COPD exacerbations and withdrawal success can be achieved by carefully planning routine COPD reviews whilst optimising the use of available maintenance therapies.
Phonetic elements of brand names can convey a range of specific meanings. However, an integrated understanding of the sound symbolism of brand names remains elusive. Here, we classify sound symbolism in brand names based on three key dimensions of the semantic differential (evaluation, potency, and activity). In particular, we demonstrated that the sound symbolism of brand names can be explained in terms of the two dimensions of evaluation and potency (but not activity). The presence of higher-frequency sounds (front vowels, fricative, and voiceless consonants) in brand names tends to be associated with concepts linked to higher evaluation and lower potency, whereas lower-frequency sounds (back vowels, stop, and voiced consonants) tend to be more strongly associated with concepts linked to lower evaluation and higher potency. This study provides an integrative understanding of sound symbolism in brand names in terms of semantic differential meanings.
Ubiquitylation enzymes are involved in all aspects of eukaryotic biology and are frequently disrupted in disease. One example is the E3 ubiquitin ligase RNF12/RLIM, which is mutated in the developmental disorder Tønne-Kalscheuer syndrome (TOKAS). RNF12 TOKAS variants largely disrupt catalytic E3 ubiquitin ligase activity, which presents a pressing need to develop approaches to assess the impact of variants on RNF12 activity in patients. Here, we use photocrosslinking activity-based probes (photoABPs) to monitor RNF12 RING E3 ubiquitin ligase activity in normal and pathogenic contexts. We demonstrate that photoABPs undergo UV-induced labelling of RNF12 that is consistent with its RING E3 ligase activity. Furthermore, photoABPs robustly report the impact of RNF12 TOKAS variants on E3 activity, including variants within the RING domain and distal non-RING regulatory elements. Finally, we show that this technology can be rapidly deployed in human pluripotent stem cells. In summary, photoABPs are versatile tools that can directly identify disruptions to RING E3 ubiquitin ligase activity in human disease, thereby providing new insight into pathogenic mechanisms.
Kinetochore protein phosphorylation promotes the correction of erroneous microtubule attachments to ensure faithful chromosome segregation during cell division. Determining how phosphorylation executes error correction requires an understanding of whether kinetochore substrates are completely (i.e., all-or-none) or only fractionally phosphorylated. Using quantitative mass spectrometry (MS), we measured phospho-occupancy on the conserved kinetochore protein Hec1 (NDC80) that directly binds microtubules. None of the positions measured exceeded ∼50% phospho-occupancy, and the cumulative phospho-occupancy changed by only ∼20% in response to changes in microtubule attachment status. The narrow dynamic range of phospho-occupancy is maintained, in part, by the ongoing phosphatase activity. Further, both Cdk1-Cyclin B1 and Aurora kinases phosphorylate Hec1 to enhance error correction in response to different types of microtubule attachment errors. The low inherent phospho-occupancy promotes microtubule attachment to kinetochores while the high sensitivity of kinetochore-microtubule attachments to small changes in phospho-occupancy drives error correction and ensures high mitotic fidelity.
The United Nations declaration of a climate urgency in 2020 has intensified the need for change in energy systems across the world. This has resulted in political attention increasingly shifting to the development of low-carbon energy infrastructure. In the case of Colombia, the energy transition has brought a focus on the La Guajira region for its potential wind energy resources and the associated need for new transmission infrastructure. La Guajira is characterised by an extractive-based economy, poor socioeconomic performance and a large indigenous population. This research uses the energy justice framework to examine the justice dynamics that affect the acceptance of a proposed transmission line project. With a special focus on procedural, distributive and recognition justice, the findings that are also based on semi-structured interviews reveal interrelated equity concerns. They further highlight that recognition justice can be an underpinning force of a just transition to a low-carbon economy. The research results follow previous research but also significantly demonstrates that the roles of community advisors and experts are influential. They can foster or block energy justice. Further, this study provides evidence that the ongoing energy transition has a major hurdle of procedural justice through social acceptance. This has occurred mainly due to the legacy effects of the operations of conventional energy sources in the region. This advances the case that to achieve a just transition to a low-carbon economy, unjust legacy policies and actions of the fossil fuel industry have to be addressed.
Aims/hypothesis Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. Methods We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. Results The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m²) and DKD (microalbuminuria or worse) phenotype (p=9.8×10⁻⁹; although not withstanding correction for multiple testing, p>9.3×10⁻⁹). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN–RESP18, GPR158, INIP–SNX30, LSM14A and MFF; p<2.7×10⁻⁶). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10⁻⁶). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10⁻¹¹). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10⁻⁸] and negatively with tubulointerstitial fibrosis [p=2.0×10⁻⁹], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10⁻¹⁶], and SNX30 expression correlated positively with eGFR [p=5.8×10⁻¹⁴] and negatively with fibrosis [p<2.0×10⁻¹⁶]). Conclusions/interpretation Altogether, the results point to novel genes contributing to the pathogenesis of DKD. Data availability The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages (https://t1d.hugeamp.org/downloads.html; https://t2d.hugeamp.org/downloads.html; https://hugeamp.org/downloads.html). Graphical abstract
Background Public health teams (PHTs) in England and Scotland engage to varying degrees in local alcohol licensing systems to try to reduce alcohol-related harms. No previous quantitative evidence is available on the effectiveness of this engagement. We aimed to quantify the effects of PHT engagement in alcohol licensing on selected health and crime outcomes. Methods 39 PHTs in England (n = 27) and Scotland (n = 12) were recruited (of 40 contacted) for diversity in licensing engagement level and region, with higher activity areas matched to lower activity areas. Each PHT's engagement in licensing for each 6 month period from April 2012 to March 2019 was quantified using a new measure (PHIAL) developed using structured interviews, documentary analyses, and expert consultation. Outcomes examined were ambulance callouts, alcohol-related hospital admissions, alcohol-related and alcohol-specific mortality and violent, sexual and public order offences. Timeseries were analysed using multivariable negative binomial mixed-effects models. Correlations were assessed between each outcome and 18-month average PHIAL score (primary metric), cumulative PHIAL scores and change in PHIAL scores. Additionally, 6-month lagged correlations were also assessed. Findings There was no clear evidence of any associations between the primary exposure metric and the public health or crime outcomes examined, nor between cumulative PHIAL scores or change in PHIAL score and any outcomes. There were no significant associations in England or Scotland when analysed separately or between outcomes and lagged exposure metrics. Interpretation There is no clear evidence that allocating PHT resources to engaging in alcohol licensing is associated with downstream reductions in alcohol-related health harms or crimes, in the short term or over a seven year follow-up period. Such engagement likely has benefits in shaping the licensing system to take account of health issues longer term, but as current systems cannot reduce alcohol availability or contain online sales, their potential benefits are somewhat constrained. Funding The ExILEnS project is funded by the NIHR Public Health Research Programme (project number 15/129/11). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN. Patients and methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical detection thresholds), Grooved pegboard test, and patient-reported outcomes measures (PROMS) were conducted for comparison. Results: In controls (25 females, 20 males; 24-81 years), females exhibited greater mean MC density compared with males (49.9 ± 7.1 vs 30.9 ± 4.2 MC/3 × 3 mm; P = .03). Differences existed across age by decade (P < .0001). Meissner's corpuscle density was correlated with mechanical detection (ρ = -0.51), warm detection (ρ = -0.47), cold pain (ρ = 0.49) thresholds (P < .01); and completion time on the Grooved pegboard test in both hands (P ≤ .02). At baseline, patients had reduced MC density vs age and gender-matched controls (P = .03). Longitudinal assessment of MC density revealed significant relationships with QST and PROMS. Inter-rater reliability of MC count showed an intraclass correlation of 0.96 (P < .0001). Conclusions: The findings support the clinical utility of RCM in CIPN as it provides meaningful markers of sensory nerve dysfunction. Novel, prospective assessment demonstrated the ability to detect subclinical deficits in patients at risk of CIPN and potential to monitor neuropathy progression.
Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.
This study is the first to examine the impact of FinTech firms on bank financial stability. Using a sample of 26 banks from an emerging market (Malaysia), over the period 2003–2018, we find that the development of FinTech firms over time increases bank financial stability. We uncover further evidence that FinTech firms’ impact on bank financial stability holds when we conduct sub-sample analyses by bank size, bank type (Islamic vis-à-vis conventional), and level of corporate governance. The results are robust to alternative model specifications, measures of financial stability, and FinTech.
The p97 / Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 are essential to unfold ubiquitylated proteins in many areas of eukaryotic cell biology. In yeast, Cdc48-Ufd1-Npl4 is controlled by a quality control mechanism, whereby substrates must be conjugated to at least five ubiquitins. Here we show that mammalian p97-UFD1-NPL4 is governed by a complex interplay between additional p97 cofactors and the number of conjugated ubiquitins. Using reconstituted assays for the disassembly of ubiquitylated CMG (Cdc45-MCM-GINS) helicase by human p97-UFD1-NPL4, we show that the unfoldase has a high ubiquitin threshold for substrate unfolding, which can be reduced by the UBX proteins UBXN7, FAF1 or FAF2. Our data indicate that the UBX proteins function by binding to p97-UFD1-NPL4 and stabilising productive interactions between UFD1-NPL4 and K48-linked chains of at least five ubiquitins. Stimulation by UBXN7 is dependent upon known ubiquitin binding motifs, whereas FAF1 and FAF2 use a previously uncharacterised coiled-coil domain to reduce the ubiquitin threshold of p97-UFD1-NPL4. We show that deleting the Ubnx7 and Faf1 genes impairs CMG disassembly during S-phase and mitosis and sensitises cells to reduced ubiquitin ligase activity. These findings indicate that multiple UBX proteins are important for the efficient unfolding of ubiquitylated proteins by p97-UFD1-NPL4 in mammalian cells.
According to conventional storage theory, the difference between spot and futures prices (known as the ‘basis’) can be explained by the total cost of storing a commodity for a specific period of time. The theory predicts a positive relationship between inventory levels and the basis, and a negative correlation between inventories and marginal convenience yield. We investigate whether there is a defined and quantifiable relationship between inventory levels and market structure – defined as the basis or the corresponding degree of contango/backwardation – and what the exact nature of that relationship might be. The major drivers of inventories – the cost of carry, convenience yield and spread options value – are estimated for eight major international storage hubs using daily data from December 21, 2015, to January 25, 2019. The analysis indicates that basic predictions of inventory theory are valid for daily and weekly frequencies but become less reliable for lower frequency data. We propose an alternative: a spread option-based formulation that adds a locational dimension to the theory and is based on the prices of crude oil at different locations, factoring in costs of storage and transportation, and the time required to transport oil between them. This methodology offers a viable alternative to the traditional cost of carry approach; it can estimate implied convenience yields and the shadow price of inventories. The data and methodology proposed in this study can give policy makers a better understanding of implied convenience yields, shadow storage prices, and market direction. It can also facilitate the construction of timely and efficient policies in the domains of energy security, market stability, and the management of public crude oil inventories. A better understanding of the relationship between inventories and the term structure of oil prices can assist market participants in trading, hedging and inventory management.
This paper examines the role of convergent media and the film, Windrush Betrayal (2020), in representing and challenging borders, mobilities and UK government immigration policies. Print and digital news provide important contexts for exploring media geographies of current events. Documentary film is also a provocative medium for investigative analyses that go beyond more general headline reporting. This study seeks to expand on earlier studies by examining how complementary mediums such as digital news media and film can respond to each other and become part of dynamic transnational conversations around place and identity. Media formats have been pushed to incorporate new settings and styles as Covid-19 restrictions have been implemented and alternative approaches utilised in media production. Adopting innovative techniques for filming in response to pandemic restrictions, Windrush Betrayal illustrates the ongoing impacts of immigration policies on Caribbean Diaspora populations in the UK. This paper provides a timely opportunity to tease out the ways in which changes in government immigration policies, media work practices and the production of migration narratives can highlight hidden geographical stories and marginalised voices.
Institution pages aggregate content on ResearchGate related to an institution. The members listed on this page have self-identified as being affiliated with this institution. Publications listed on this page were identified by our algorithms as relating to this institution. This page was not created or approved by the institution. If you represent an institution and have questions about these pages or wish to report inaccurate content, you can contact us here.