The global mining industry is growing in footprint and continues to occupy new locations globally in support of the energy transition. Associated mining activities like land clearing, blasting and truck haulage are known to generate dust, creating a range of environmental and health hazards. However, research tracking the global spatial and temporal patterns of mine-related dust has been lacking. This study assesses global spatio-temporal patterns of mine dust and factors that influence those distributions both globally and in localized Australian contexts through generalized additive models (GAMs). Spatial patterns of mine dust are evaluated using Local Indicators of Spatial Association (LISA), and the results indicate significant geographic heterogeneity - elevated levels of Aerosol Optical Depth (AOD) were identified in tropical mining areas in South Asia, West Africa, and Southeast Asia, whereas lower levels of AOD were observed in the United States and Australia. Our statistical analysis indicates that GAMs effectively captured the variability in AOD (global R2 = 0.71; local R2 = 0.62). However, ground-based PM₁₀ measurements were a more reliable indicator of site-specific mining activity, showing a stronger relationship with mine production (r = 0.6). This study highlights key data uncertainties and complexities influencing our understanding of the impacts of mine dust beyond the local scale. Notably, it highlights an inconsistent disconnect between mines influencing regional dust levels, versus regional dust levels impacting mine operations themselves. It also underscores the importance of developing a standardized method for on-site dust monitoring at all mines worldwide and an improved network of in-situ measurement stations in support of better outcomes for the environment and human health.
Recent events, including increases in cost-of-living, may have influenced gambling behaviour and harm in Great Britain. This study aimed to describe trends in gambling frequency, harm from gambling, self-identified gambling problems, and treatment among British adults from 2021 to 2024. It also examined trends in weekly gambling and harm from gambling within priority sociodemographic groups. Data (pooled N = 50,872) came from the annual repeat cross-sectional online panel ASH Smokefree Great Britain Survey, weighted to reflect the British population. Time trends were assessed using multinomial and log-binomial regression, with survey year as predictor. Additional models assessed trends in subgroups (non-homeowner, socioeconomically disadvantaged, mental health treatment, smoking, vaping, cannabis use, exceeding drinking guidelines, age, gender, nation). Approximately half of adults gambled in the past year. Daily gambling increased from 1.1% (95% CI: 1.0-1.3) in 2021 to 1.7% (1.5-1.9) in 2024; treated gambling disorder also increased, from 0.9% (0.6-1.2) in 2021 to 1.6% (1.3-2.0) in 2024. The highest prevalence of weekly gambling was among those exceeding drinking guidelines (in 2024: 28.7%; 16.7-30.9) and those using cannabis (in 2024: 28.4%; 25.7-31.2). Younger people gambled less frequently but experienced higher rates of harm from others' gambling than older people. There was an increase in gambling activity and related harm. In absolute terms and assuming figures are representative, approximately 366,000 more adults in Great Britain had a gambling disorder in 2024 than in 2021, though data for 2021 may be disproportionately impacted by the Covid-19 pandemic. Monitoring these trends and investing in harm prevention and support strategies is crucial.
Monolayer and multilayer MoS2are extremely fascinating materials for optoelectronics, particularly in scenarios involving high excitation carrier densities. Consequently, it is essential to understand the various processes and their associated time scales in monolayer and multilayer two-dimensional materials under such high excitation densities. Here, We demonstrate that carrier dynamics in monolayer and multilayer MoS2exhibit distinctly different behaviors above the Mott density, with monolayers showing faster carrier relaxation and enhanced many-body interactions compared to multilayers. Despite the similarity in band structure near theK-point and the formation of A-excitons, pronounced differences in the transient response are observed, highlighting the influence of the overall band structure. Exciton dissociation, bandgap renormalization, and intervalley relaxation play a consequential role in dictating the ultrafast transient properties of these samples. The study in this paper provides a detailed understanding of the fundamental optoelectronic properties of the two-dimensional MoS2at high excitation densities, paving the way for its potential applications in various photonic and optoelectronic domains.
Anatomical changes during proton therapy (PT) often necessitate plan adaptation. In online adaptation, re-optimizing using the original planning constraints has been proposed to speed-up the optimization time. However, the re-optimized plan may not reach the original plan quality. For this, an interactive dose modification (IDM) tool offers a promising approach, whereby fluences of proton pencil beams can be locally varied via interactive dose manipulations. We assessed the feasibility of using the IDM tool to improve the daily optimized plan, in cases where some clinical objectives are unmet.
Approach: The IDM tool enables users to click on the dose distribution to locally increase/decrease dose, and underlying pencil beam weights, with immediate visual feedback. Four cases, treated with PT and exhibiting anatomical changes, were retrospectively studied in a simulated adaptive workflow (16 daily images were used). For each case, we compared three plans: a) re-calculated (but not re-optimized) on daily anatomy without adaptation, b) a plan re-optimized using the original planning constraints, c) a plan re-optimized as in b) but followed by modification using the IDM tool. We evaluated clinical endpoint fulfillment, dose deviations to clinical goals, and required modification time.
Main results: Overall, plan a) resulted in 40 clinical endpoints being unmet that were fulfilled in the original plan, with deviations up to 9.4 Gy(RBE); plan b) resulted in 34 such endpoints, with deviations ≤2.5 Gy(RBE); and plan c) reduced these to 3 and deviations to ≤0.5 Gy(RBE). Target coverage (D98%,D95%) remained within 4 Gy(RBE) of the original plan for plan a) and 2.5 Gy(RBE) for b) and c). Average time for IDM was 2 minutes (30s-6 minutes).
Significance: The IDM tool enables efficient improvement of plan quality in adaptive PT. Its speed, intuitiveness and effectiveness in restoring clinical goals supports its potential integration into routine online adaptive workflows.
The dynamic shear modulus and anelastic properties of MgAl2O4 spinel have been measured using a forced torsion pendulum between 600 K and 1400 K at frequencies of 0.01-10 Hz. A Debye-like peak in the internal frictionQ-1is observed at ~1057 K at 1 Hz, accompanied by a corresponding modulus defect in the shear modulusGof order 4 GPa (~20% of the unrelaxed modulus). Both the loss peak and the modulus dispersion are well described by a single thermally activated relaxation time, and the loss peak shifts systematically to higher temperature with increasing frequency, with no hysteresis between heating and cooling. Arrhenius analysis of the peak positions yields an activation energy of 331 kJ mol-1. The peak is approximately 1.8 times broader than an ideal single-relaxation-time Debye peak, and this excess width is independent of frequency, reflecting the distribution of local Mg-Al exchange environments. We attribute the relaxation to stress-induced, vacancy-mediated Mg-Al exchange between tetrahedral and octahedral sites, the direct anelastic analogue of Zener relaxation in substitutional alloys. The result provides a mechanical-spectroscopic demonstration of cation-exchange anelasticity in MgAl2O4, and shows that non-convergent order-disorder generates a distinct dynamical signature within the seismic frequency band.
We present a genome assembly from an individual female Archiearis parthenias (Orange Underwing; Arthropoda; Insecta; Lepidoptera; Geometridae). The assembly contains two haplotypes with total lengths of 528.46 megabases and 426.17 megabases. Most of haplotype 1 (99.61%) is scaffolded into 26 chromosomal pseudomolecules, including the W and Z sex chromosomes. Haplotype 2 was assembled to scaffold level. The mitochondrial genome has also been assembled, with a length of 17.24 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.
Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies that target phospholipids and phospholipid-binding proteins, and are identified clinically by anticardiolipin, anti-β2-glycoprotein I, or lupus anticoagulant assays. While aPL is a well-established mediator of thrombosis through both proinflammatory and prothrombotic pathways, the role of aPL in arrhythmogenesis including atrial fibrillation (AF) and its association with AF-related thromboembolic outcomes remains poorly defined. In small observational studies, testing positive for aPL has been reported in up to 20% of patients with AF and has been associated with a higher risk of ischemic stroke and other thromboembolic events. In this mini review, in addition to sharing a succinct summary on prevalence and pathogenicity of aPL in various vascular and thrombotic conditions, we specifically summarize the existing body of literature investigating the association between aPL and AF prevalence and clinical outcomes. Furthermore, we describe the rationale and study design of the TaPL-AF (Thrombophilia with aPL in Atrial Fibrillation) study, an ongoing investigation leveraging Mass General Brigham (MGB) Biobank data to provide evidence on the incidence and prognostic relevance of aPL positivity in AF and explore the impact of aPL on the effectiveness of direct oral anticoagulants in preventing thromboembolic events. These efforts aim to define the clinical relevance of aPL in AF, including their potential role in refining thromboembolic risk stratification and guiding anticoagulation strategies.
Accurate cancer detection in large non-pedunculated colorectal polyps (LNPCPs) remains challenging for general endoscopists. We evaluated whether teaching six gross morphological "blink" features could improve accuracy of cancer detection. This prospective interventional study assessed general endoscopists evaluating 20 LNPCP images (7 with histologically confirmed submucosal invasive cancer including four deep invasions ≥ 1000 µm, 13 benign). Participants assessed images before and after a 2-minute educational video introducing six blink features: spontaneous bleeding, depression, fold deformation, extra redness, ulceration, and chicken-skin mucosa. Primary outcome was change in miss-rate for cancer detection. Generalized linear mixed models accounted for clustering within raters and polyps. The 165 participants included gastroenterology consultants (63.6%), trainees (21.2%), students (1.8%) and colorectal surgeons (13.3%) with median colonoscopy experience of 6.5 years. Post-intervention, the cancer miss rate decreased four-fold from 26.6% (95% confidence interval [CI] 13.4-46.0) to 5.7% (95% CI 2.4-12.8). The improvement was consistent across experience levels. The false alarm rate increased less than two-fold from 25.0% (95% CI 15.1-38.5) to 42.2% (95% CI 27.7-58.2). Multivariable analysis identified spontaneous bleeding (odds ratio [OR] 3.92; 95% CI 3.11-4.96), extra redness (OR 3.66; 95% CI 3.09-4.33), and depression (OR 3.06; 95% CI 2.58-3.64) as independent predictors of cancer among general endoscopists. Mean blink features per polyp were 1.08 (95% CI 0.82-1.40) for benign lesions vs 2.46 (95% CI 1.85-3.12) for cancers. Teaching six blink features to general endoscopists led to a four-times reduction in cancer miss rates in an image-based evaluation. Although specificity decreased, this trade-off favors patient safety because false positives trigger established clinical safeguards whereas missed cancers risk inappropriate endoscopic resection with potentially irreversible consequences.
We present a genome assembly from an individual male Aethes tesserana (Downland Conch; Arthropoda; Insecta; Lepidoptera; Tortricidae). The assembly contains two haplotypes with total lengths of 486.12 megabases and 482.92 megabases. Most of haplotype 1 (99.81%) is scaffolded into 30 chromosomal pseudomolecules, including the Z sex chromosome. Haplotype 2 was assembled to scaffold level. The mitochondrial genome has also been assembled, with a length of 15.54 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces genomes for eukaryotic species found in Britain and Ireland.
We present a genome assembly from an individual male Limonius poneli (click beetle; Arthropoda; Insecta; Coleoptera; Elateridae). The assembly contains two haplotypes with total lengths of 1 351.61 megabases and 1 247.44 megabases. Most of haplotype 1 (99.07%) is scaffolded into 10 chromosomal pseudomolecules, including the X sex chromosome, while 98.81% of the haplotype 2 assembly is scaffolded into 9 chromosomal pseudomolecules. The mitochondrial genome has also been assembled, with a length of 16.69 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.
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We present a genome assembly from an individual female Phaleria cadaverina (darkling beetle; Arthropoda; Insecta; Coleoptera; Tenebrionidae). The genome sequence has a total length of 367.34 megabases. Most of the assembly (75.2%) is scaffolded into 11 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled, with a length of 15.61 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces genomes for eukaryotic species found in Britain and Ireland.
This essay offers a re-examination of Tom Nairn's lifelong prediction of an impending Break-Up of Britain, against the backdrop of the Union's apparent resilience since the publication of his magnum opus in 1977. Specifically, it considers Nairn's conceptualization of the end of empire as the necessary precursor event that doomed the UK to inevitable destruction. What Perry Anderson terms the 'protracted delay' between Nairn's predictions and their fulfilment provides a useful vantage point to reconsider Nairn's thesis with the benefit of more than 50 years' hindsight. It is argued that Nairn's Gramscian model and his inherently structural view of empire tended to screen out the complex social interface between Britain and the wider imperial world. For all the crucial explanatory power he attributed to the empire's demise, he almost never exemplified his argument with reference to any specific part of it or referred to the corrosive effects of any given decolonizing moment. To gauge the empire's full significance, then, requires a larger frame of reference, comprising not only the unitary UK state but also the empire-wide affinities that were so crucial to popular investments in being British. To the extent that Nairn was right about the intricate nexus tying the Union to Britain's global coordinates, it was not always for the right reasons.
In the early 1990s, it seemed that new technologies were opening up new possibilities for the organization of work and community life. This article focuses on the development of telecottages and the televillage through the decade to explore one vision of a new kind of rural community life based around these technologies, which gained support from a range of rural development interests, and how they worked in practice. The telecottage was designed to be a hub for teleworking, also offering training and computer hire for locals. However, telecottages soon became a bubble, as upwards of a hundred opened around the UK through the decade, yet struggled to find their niche in an increasingly competitive marketplace of internet cafes and affordable home computers. Though propped up by funding from local authorities, most failed to become self-sufficient. Alongside this, the development of the first televillage, in Wales, intended to house teleworkers, also demonstrates how hopes of innovative forms of in-person community would fail to materialize. This story of techno-optimism shines a light on how technology was seen as a pathway to rural regeneration in the 1990s.
In August 2023, the United Kingdom introduced alcohol taxation reforms designed to encourage alcohol producers to lower the alcoholic strength of their products. This study aims to quantify the extent of reformulation of alcoholic drinks sold in the off-trade in Great Britain between 2018 and 2025 and explore the role the tax reforms may have played. We used continuous longitudinal data on alcohol purchases from Worldpanel by Numerator's Take Home data to examine changes between 2018 and 2025 in the mean alcohol-by-volume (ABV) of all alcohol sold, identify specific product reformulations and examine how their timing related to the 2023 tax reforms. We also explored growth in the < 3.5% ABV beer market, for which tax rates were cut in the reforms. The average ABV of all alcohol rose from 17.2% in late 2018 to 17.7% in June 2022, before falling to 16.7% in December 2025. We identified 557 reformulations, of which 50% were for wine and 17% were for beer. Reformulations increased substantially following the reforms, with the proportion of the beer market, measured in pure alcohol, sold below 3.5% ABV increasing from 1.1% in 2022 to 18.1% in 2025. Our findings suggest that the 2023 UK alcohol tax reforms appear to have contributed to an increase in reformulations that reduced the strength of alcoholic drinks. In turn, these may have played a role in reductions in the overall ABV of alcoholic drinks purchases. Following the reforms, there was a large and immediate increase in the market share of lower-strength beers.
We present a genome assembly of Quercus cerris (Turkey oak; Streptophyta; Magnoliopsida; Fagales; Fagaceae). The genome sequence has a total length of 777.39 megabases. Most of the assembly (99.89%) is scaffolded into 12 chromosomal pseudomolecules. The mitochondrial sequences have lengths of 380.47 and 15.0 kilobases and the plastid genome assembly has a length of 161.2 kilobases. Gene annotation of this assembly on Ensembl identified 25 805 protein-coding genes. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.
Umbrella protocols have recently come to be widely used in clinical trial designs. However, the value of this approach in public health is less well recognized. The coronavirus disease 2019 (COVID-19) pandemic highlighted the need for rapid, reliable and scalable evaluation of diagnostic technologies. In the United Kingdom of Great Britain and Northern Ireland, this need prompted the development of an umbrella research protocol enabling multiple clinical evaluation studies of similar designs to be undertaken under a single overarching preapproved ethics and governance framework. We describe the development, implementation and evolution of this protocol, which was designed to support timely assessment of the performance of in vitro diagnostic devices and associated testing approaches in various settings. The umbrella protocol allowed studies to be started quickly during the pandemic, reduced administrative burdens, supported regulatory submissions and enabled prospective collection of samples for surveillance. While the system described reflects British governance structures, the principles underpinning this approach, including proportionality (ensuring oversight requirements are appropriate to the risk level), standardization and preapproved flexibility, are applicable to many settings. The protocol now forms part of the United Kingdom's wider pandemic preparedness structure and illustrates how preapproved, adaptable research frameworks can accelerate evidence generation during outbreaks. The world is now assessing lessons from the COVID-19 pandemic and it is timely to consider how research systems can support innovative designs such as umbrella protocols. We therefore summarize lessons learnt and practical considerations to support other countries seeking to adopt similar approaches within their own ethical and regulatory systems. De nous jours, les protocoles-cadres sont largement employés dans le design des essais cliniques. Cependant, l’intérêt de cette approche en matière de santé publique est moins bien reconnu. En effet, la pandémie de COVID-19 a mis en évidence la nécessité d’une évaluation rapide, fiable et évolutive des technologies de diagnostic. Au Royaume-Uni, ce besoin a conduit à l’élaboration d’un protocole de recherche global permettant de mener plusieurs études d’évaluation clinique de design similaire dans le cadre d’un cadre global préapprouvé en matière d’éthique et de gouvernance. Nous décrivons l’élaboration, la mise en œuvre et l’évolution de ce protocole, qui a été conçu pour faciliter l’évaluation en temps opportun des performances des dispositifs de diagnostic in vitro et des approches de test associées dans divers contextes. Ce protocole-cadre a permis de lancer rapidement des études pendant la pandémie, d’alléger les charges administratives, de faciliter les demandes d’autorisation réglementaire et de permettre le prélèvement prospectif d’échantillons à des fins de surveillance. Si le système décrit reflète les structures de gouvernance britanniques, les principes qui sous-tendent cette approche, notamment la proportionnalité (garantissant que les exigences en matière de surveillance sont adaptées au niveau de risque), la normalisation et la flexibilité préapprouvée, s’appliquent à de nombreux contextes. Ce protocole fait désormais partie intégrante de la structure plus large du Royaume-Uni dans la préparation aux pandémies et illustre la façon dont des cadres de recherche préapprouvés et adaptables permettent d’accélérer la production de données scientifiques lors d’épidémies. Le monde tire actuellement les leçons de la pandémie de COVID-19 et le moment est venu d’examiner la manière dont les systèmes de recherche sont capables de soutenir des designs innovants tels que les protocoles-cadres. Nous résumons donc les enseignements tirés et les considérations pratiques afin d’aider d’autres pays qui souhaitent adopter des approches similaires au sein de leurs propres systèmes éthiques et réglementaires. Los protocolos marco han pasado a utilizarse ampliamente en el diseño de ensayos clínicos en los últimos años. Sin embargo, el valor de este enfoque en salud pública es menos reconocido. La pandemia de la enfermedad por coronavirus de 2019 (COVID-19) destacó la necesidad de una evaluación rápida, fiable y escalable de las tecnologías de diagnóstico. En el Reino Unido de Gran Bretaña e Irlanda del Norte, esta necesidad dio lugar al desarrollo de un protocolo de investigación marco que permite llevar a cabo múltiples estudios de evaluación clínica con diseños similares bajo un único marco general de ética y gobernanza previamente aprobado. Se describe el desarrollo, la implementación y la evolución de este protocolo, diseñado para apoyar la evaluación oportuna del rendimiento de dispositivos de diagnóstico in vitro y de los enfoques de prueba asociados en diversos contextos. El protocolo marco permitió iniciar estudios rápidamente durante la pandemia, redujo la carga administrativa, facilitó la presentación ante las autoridades regulatorias y permitió la recogida prospectiva de muestras para la vigilancia. Aunque el sistema descrito refleja las estructuras de gobernanza británicas, los principios que sustentan este enfoque, como la proporcionalidad (asegurar que los requisitos de supervisión sean adecuados al nivel de riesgo), la estandarización y la flexibilidad previamente aprobada, son aplicables en numerosos contextos. El protocolo forma ahora parte de la estructura más amplia de preparación frente a pandemias del Reino Unido y demuestra cómo los marcos de investigación adaptables y previamente aprobados pueden acelerar la generación de evidencia durante brotes. En la actualidad, la comunidad internacional está evaluando las lecciones de la pandemia de la COVID-19, y resulta oportuno considerar cómo los sistemas de investigación pueden apoyar diseños innovadores como los protocolos marco. Por ello, se resumen las lecciones aprendidas y las consideraciones prácticas para apoyar a otros países que deseen adoptar enfoques similares dentro de sus propios sistemas éticos y regulatorios. أصبح استخدام البروتوكولات الشاملة شائعًا في الآونة الأخيرة في تصميم التجارب الإكلينيكية. مع ذلك، فإن قيمة هذا الأسلوب في الصحة العامة لا تتمتع بالتقدير بالشكل الكافي. إن جائحة مرض فيروس كورونا لعام 2019 (كوفيد 19) قد أوضحت الحاجة إلى تقييم سريع وموثوق وقابل للتطوير لتقنيات التشخيص. في المملكة المتحدة لبريطانيا العظمى وأيرلندا الشمالية، دفعت هذه الحاجة إلى تطوير بروتوكول بحثي شامل يُتيح إجراء دراسات تقييم إكلينيكي متعددة، وذات تصميمات متشابهة، ليتم الاضطلاع بها ضمن إطار عمل أخلاقي وتابع للحوكمة بشكل شامل مُعتمد مسبقًا. في هذا البحث، نحن نقوم بوصف هذا البروتوكول وكيفية تنفيذه وتطويره، والذي تم تصميمه لدعم التقييم في الوقت المناسب لأداء أجهزة التشخيص المختبري، وأساليب الاختبار المرتبطة بها في مختلف الأوضاع. وقد أتاح البروتوكول الشامل بدء الدراسات بسرعة أثناء الجائحة، وحد من الأعباء الإدارية، ودعم تقديم الطلبات التنظيمية، وسمح بجمع العينات بشكل استباقي لأغراض المراقبة. بينما يعكس النظام الموصوف البنى التحتية للحوكمة البريطانية، فإن المبادئ التي يقوم عليها هذا الأسلوب، بما في ذلك التناسب (ضمان ملاءمة متطلبات الرقابة لمستوى المخاطر)، والتوحيد القياسي، والمرونة المعتمدة مسبقًا، تُعد قابلة للتطبيق في العديد من الأوضاع. يشكل البروتوكول الآن جزءًا من البنية التحتية للاستعداد على نطاق أوسع للأوبئة في المملكة المتحدة، ويوضح كيف يمكن لأطر عمل البحث المعتمدة مسبقًا، والقابلة للتكيف، أن تُسرّع من استنتاج الأدلة أثناء تفشي الأوبئة. يشهد العالم الآن تقييمًا للدروس المستفادة من جائحة كوفيد 19، وقد حان الوقت للنظر في كيف يمكن لأنظمة البحث دعم التصاميم المبتكرة مثل البروتوكولات الشاملة. لذلك، نحن نلخص الدروس المستفادة والاعتبارات العملية لدعم الدول الأخرى التي تسعى إلى تبني أساليب مماثلة ضمن أنظمتها الأخلاقية والتنظيمية. 近年来，总括协议已广泛应用于临床试验设计。但是，该方法在公共卫生领域的价值尚未得到广泛认可。2019 冠状病毒病 (COVID-19) 大流行疫情凸显了对诊断技术进行快速、可靠和可扩展评估的需求。这一需求促使大不列颠及北爱尔兰联合王国制定了总括研究协议，从而允许在预先批准的单一总体伦理和治理框架下开展多项设计相似的临床评估研究。我们对旨在支持在不同环境下对体外诊断器械以及相关检测方法的性能进行及时评估的该协议的制定、实施和演变情况进行了详细描述。总括协议允许在大流行疫情期间快速启动研究，减轻了行政负担，支持向监管机构提交申请，并实现了监测用前瞻性样品采集。尽管所描述系统反映了英国的治理结构，但是支持该方法的各项原则【包括相称性（确保监督要求与风险水平相符）、标准化以及预先批准的灵活性】适用于多种环境。该协议现已成为联合王国更广泛的大流行疫情应对准备架构的组成部分，并阐明了预先批准的可调整研究框架在疫情爆发期间是如何加速证据生成的。全世界目前都在评估从 COVID-19 大流行疫情中汲取的经验教训，且此时正是探讨研究系统是如何支持诸如总括协议之类的创新设计的大好时机。因此，我们总结了汲取的经验教训以及切合实际的考量因素，以支持其他力求在其自有的伦理和监管系统内采纳类似方法的国家。. Зонтичные протоколы в последнее время нашли более широкое применение в дизайне клинических исследований. Однако ценность таких протоколов для общественного здравоохранения признана пока еще не столь широко. Пандемия коронавирусной инфекции 2019 года (COVID-19) подчеркнула потребность в быстрой, надежной и масштабируемой оценке диагностических технологий. В Соединенном Королевстве Великобритании и Северной Ирландии данная потребность привела к разработке зонтичного исследовательского протокола, позволяющего проводить серию исследований по клинической оценке со схожим дизайном в рамках единой, заранее одобренной системы этического и регуляторного контроля. Авторы описывают разработку, внедрение и эволюцию данного протокола, предназначенного для своевременной оценки характеристик устройств для диагностики in vitro и соответствующих подходов к проведению исследований в различных условиях. Применение зонтичного протокола позволило быстро инициировать исследования во время пандемии, снизить административную нагрузку, оптимизировать процесс подачи документов в регулирующие органы и обеспечить проспективный сбор образцов для эпидемиологического надзора. Хотя описанная система отражает специфику британской системы управления, фундаментальные принципы данного подхода, включая пропорциональность (обеспечение соответствия требований контроля уровню риска), стандартизацию и заранее одобренную гибкость, применимы во многих странах. В настоящее время данный протокол является частью более широкой системы обеспечения готовности Соединенного Королевства Великобритании и Северной Ирландии к пандемиям и демонстрирует, каким образом заранее утвержденные адаптивные исследовательские рамки могут ускорить получение доказательных данных в условиях вспышек заболеваний. На фоне переосмысления уроков пандемии COVID-19 для мирового сообщества настало время подумать о том, каким образом исследовательские системы могут поддерживать инновационные способы организации исследований, такие как зонтичные протоколы. В связи с этим в статье обобщены полученные выводы и практические соображения с целью оказания поддержки другим странам, стремящимся внедрить аналогичные подходы в рамках своих национальных этических и регуляторных систем.
Mycolic acids are key components of the mycobacterial cell envelope, contributing to its structural integrity and intrinsic resistance to environmental stress. The polyketide synthase Pks13 catalyzes the final Claisen condensation step in mycolic acid biosynthesis and is conserved across Corynebacteriales. While the catalytic cysteine within the ketosynthase (KS) domain is established as essential for activity, the role of surrounding residues in supporting catalysis remains less well understood. Herein, we utilized a Mycobacterium smegmatis conditional pks13 mutant, and subsequent complemented strains harbouring a plasmid-borne copy of pks13 to probe the functional importance of selected residues within the KS domain from previous structural studies. These site-directed mutagenesis studies identified Asp264 as critical for Pks13 function. The D264A strain showed severely impaired growth along with a pronounced loss of mycolate synthesis and mycolate-containing lipids: trehalose dimycolate (TDM) and trehalose monomycolate (TMM). In contrast, other mutations had either little or no significant effect on cell viability or mycolate synthesis or mycolate-containing lipids. Structural modelling of the KS domain suggests that loss of Asp264 disrupts the local active-site environment, resulting in compaction of the binding pocket and altered conformation of a loop proximal to the catalytic residue Cys267. Together, these findings demonstrate that Asp264 is essential for Pks13 function and likely contributes to maintaining the structural environment of the KS domain.
We present a genome assembly of Polygonum maritimum (Sea Knotgrass; Streptophyta; Magnoliopsida; Caryophyllales; Polygonaceae). The genome sequence has a total length of 428.64 megabases. Most of the assembly (99.95%) is scaffolded into 10 chromosomal pseudomolecules. The mitochondrial sequence has a length of 352.4 kilobases and the plastid genome assembly has a length of 163.31 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.