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Abstract In this review, we discuss current research on forest carbon risk from natural disturbance under climate change for the United States, with emphasis on advancements in analytical mapping and modeling tools that have potential to drive research for managing future long-term stability of forest carbon. As a natural mechanism for carbon storage, forests are a critical component of meeting climate mitigation strategies designed to combat anthropogenic emissions. Forests consist of long-lived organisms (trees) that can store carbon for centuries or more. However, trees have finite lifespans, and disturbances such as wildfire, insect and disease outbreaks, and drought can hasten tree mortality or reduce tree growth, thereby slowing carbon sequestration, driving carbon emissions, and reducing forest carbon storage in stable pools, particularly the live and standing dead portions that are counted in many carbon offset programs. Many forests have natural disturbance regimes, but climate change and human activities disrupt the frequency and severity of disturbances in ways that are likely to have consequences for the long-term stability of forest carbon. To minimize negative effects and maximize resilience of forest carbon, disturbance risks must be accounted for in carbon offset protocols, carbon management practices, and carbon mapping and modeling techniques. This requires detailed mapping and modeling of the quantities and distribution of forest carbon across the United States and hopefully one day globally; the frequency, severity, and timing of disturbances; the mechanisms by which disturbances affect carbon storage; and how climate change may alter each of these elements. Several tools (e.g. fire spread models, imputed forest inventory models, and forest growth simulators) exist to address one or more of the aforementioned items and can help inform management strategies that reduce forest carbon risk, maintain long-term stability of forest carbon, and further explore challenges, uncertainties, and opportunities for evaluating the continued potential of, and threats to, forests as viable mechanisms for forest carbon storage, including carbon offsets. A growing collective body of research and technological improvements have advanced the science, but we highlight and discuss key limitations, uncertainties, and gaps that remain.

Abstract Background Antenatal corticosteroids are recommended for women at risk of preterm birth from 24 to 34 weeks’ gestation as they reduce neonatal morbidity and mortality, but evidence regarding their long-term effects on offspring is limited. This study assessed general health and social outcomes 50 years after antenatal exposure to corticosteroids. Methods We assessed 424 adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. The first 717 mothers received two intramuscular injections of betamethasone (6 mg betamethasone sodium phosphate and 6 mg betamethasone acetate) or placebo given 24 h apart and the subsequent 398 received two injections of double dose betamethasone (12 mg betamethasone sodium phosphate and 12 mg betamethasone acetate) or equivalent volume of placebo. Follow-up included a health questionnaire and consent for access to administrative data sources. Outcome categories included mental health (depression, anxiety, bipolar affective disorder, schizophrenia and treatment or hospital admission for any mental health disorder), general health (chronic kidney disease, cancer diagnosis, bone fracture, oral health, allergies, functional difficulties and physical activity) and social outcomes (educational attainment, employment and criminal convictions). Investigators remained blinded to treatment allocation. Analyses were adjusted for gestational age at entry, sex and clustering. Results We assessed 424 adult offspring (46% of survivors; mean [SD] age 49.3 [1.0] years; 212 [50%] female). There was no difference in mental health, general health and social outcomes between those exposed to betamethasone and those exposed to placebo, with the exception that osteoporotic site fracture in adulthood was more likely to have occurred in the betamethasone group compared with placebo (adjusted relative risk 1.57, 95% CI 1.00, 2.48, p = 0.05). No dose–effect relationship was evident and there was no difference in the proportion with at least one fracture. Follow-up rate and lack of in-person assessments were the main limitations. Conclusions There is no evidence that antenatal corticosteroids have clinically important effects on general health and social outcomes up to 50 years of age.

Abstract Biohybrid solar fuel catalysts leverage natural light-driven enzymes to produce valuable fuel products. One useful biological platform for such a system is photosystem I, a pigment-protein complex that captures sunlight and converts it into chemical energy with near unity quantum efficiency, which generates low potential reducing equivalents for metabolism. Realizing and understanding the molecular basis for an approach that utilizes those electrons and stores solar energy as a fuel is therefore appealing. Here, we report the 2.27-Å global resolution cryo-EM structure of a photosystem I complex with bound platinum nanoparticles that catalyzes light-driven H2 production. The platinum nanoparticle binding sites and possible stabilizing interactions are described. Overall, the investigation reveals a direct structural look at a photon-to-fuels photosynthetic biohybrid system.

Abstract Motile cilia are critical structures that regulate early embryonic development and tissue homeostasis through synchronized ciliary motility. The formation of motile cilia is dependent on precisely controlled sequential processes including the generation, migration, and docking of centrioles/basal bodies as well as ciliary growth. Using the published proteomics data from various organisms, we identified proliferation-associated 2G4 as a novel regulator of ciliogenesis. Loss-of-function studies using Xenopus laevis as a model system reveal that Pa2G4 is essential for proper ciliogenesis and synchronized movement of cilia in multiciliated cells (MCCs) and the gastrocoel roof plate (GRP). Pa2G4 morphant MCCs exhibit defective basal body docking to the surface as a result of compromised Rac1 activity, apical actin network formation, and immature distal appendage generation. Interestingly, the regions that include the RNA-binding domain and the C-terminus of Pa2G4 are necessary for ciliogenesis in both MCCs and GRP cells. Our findings may provide insights into motile cilia-related genetic diseases such as Primary Ciliary Dyskinesia.

Abstract Many studies of azobenzene photoswitches are carried out in polar aprotic solvents as a first principles characterization of thermal isomerization. Among the most convenient polar aprotic solvents are chlorinated hydrocarbons, such as DCM. However, studies of azobenzene thermal isomerization in such solvents have led to spurious, inconclusive, and irreproducible results, even when scrupulously cleaned and dried, a phenomenon not well understood. We present the results of a comprehensive investigation into the root cause of this problem. We explain how irradiation of an azopyridine photoswitch with UV in DCM acts not just as a trigger for photoisomerization, but protonation of the pyridine moiety through photodecomposition of the solvent. Protonation markedly accelerates the thermal isomerization rate, and DFT calculations demonstrate that the singlet-triplet rotation mechanism assumed for many azo photoswitches is surprisingly abolished. This study implies exploitative advantages of photolytically-generated protons and finally explains the warning against using chlorinated solvent with UV irradiation in isomerization experiments.

Floodplains are unique environments that provide a dynamic link between terrestrial and aquatic systems. Intensification of human activity – particularly agriculture and urbanisation – has resulted in the degradation of floodplains worldwide. Restoration and sustainable management of floodplains requires holistic assessment and compromise between stakeholders to successfully balance environmental, economic, and social benefits. Yet, understanding these complex systems sufficiently to provide evidence-based recommendations is a challenge. We present the lessons learned from establishing an interdisciplinary research-based framework on the agricultural floodplain of Lake Saint Pierre, Québec, Canada, whose mandate was to a) understand and define key environmental, agricultural, and socioeconomic attributes of the landscape, b) quantify the trade-offs and synergies between these attributes across different agricultural practices, regions, and land uses, and c) explore novel agri-environmental management practices to assess their role in sustainable floodplain management. Within this manuscript, we explore the benefits that such an approach offers in evaluating sustainable floodplain land use. We found that an interdisciplinary research-based approach demonstrated important benefits such as knowledge transfer, more efficient use of resources (e.g., personnel, funding), and a flexible yet robust research framework. A framework of individual research projects connected to broader interdisciplinary themes allowed a more holistic synthesis of the floodplain systems and assessment of agri-environmental practices. By implicitly considering spatial and social scales, we conceptualised not just how redistribution of the land use types can meet sustainable management objectives, but also explored how compromises within existing uses can optimise socio-economic, agricultural and environmental dimensions and move towards a sustainable multifunctional landscape.

Abstract Hypoxia inducible transcription factors (HIFs) mediate the hypoxic response in metazoans. When sufficient O2 is present, Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases (human PHD1-3) promote HIFα degradation via prolyl-hydroxylation. We report crystallographic, spectroscopic, and biochemical characterization of stable and inactive PHD2.Fe(III).2OG complexes. Aerobic incubation of PHD2 with Fe(II) and 2OG enables formation of PHD2.Fe(III).2OG complexes which bind HIF1-2α to give inactive PHD2.Fe(III).2OG.HIF1-2α complexes. The Fe(III) oxidation state in the inactive complexes was shown by EPR spectroscopy. L-Ascorbate hinders formation of the PHD2.Fe(III).2OG.(+/-HIFα) complexes and slowly regenerates them to give the catalytically active PHD2.Fe(II).2OG complex. Crystallographic comparison of the PHD2.Fe(III).2OG.HIF2α complex with the analogous anaerobic Fe(II) complex reveals near identical structures. Exposure of the anaerobic PHD2.Fe(II).2OG.HIF2α crystals to O2 enables in crystallo hydroxylation. The resulting PHD2.product structure, manifests conformational changes compared to the substrate structures. The results have implications for the role of the PHDs in hypoxia sensing and open new opportunities for inhibition of the PHDs and other 2OG dependent oxygenases by promoting formation of stable Fe(III) complexes.

Abstract Cryo-EM particle identification from micrographs (“picking”) is challenging due to the low signal-to-noise ratio and lack of ground truth for particle locations. State-of-the-art computational algorithms (“pickers”) identify different particle sets, complicating the selection of the best-suited picker for a protein of interest. Here, we present REliable PIcking by Consensus (REPIC), a computational approach to identifying particles common to the output of multiple pickers. We frame consensus particle picking as a graph problem, which REPIC solves using integer linear programming. REPIC picks high-quality particles even when the best picker is not known a priori or a protein is difficult-to-pick (e.g., NOMPC ion channel). Reconstructions using consensus particles without particle filtering achieve resolutions comparable to those from particles picked by experts. Our results show that REPIC requires minimal (often no) manual intervention, and considerably reduces the burden on cryo-EM users for picker selection and particle picking. Availability: https://github.com/ccameron/REPIC .

Abstract Background Critical thinking about health choices is essential to avoid being misled by unreliable information and to use reliable information appropriately. The aim of this prospective meta-analysis was to synthesize the results of 1-year follow-up data from three cluster-randomized trials of an intervention designed to teach lower secondary school students to think critically about health choices. Only one other randomized trial has evaluated a school-based intervention to teach adolescents to think critically about health choices. That trial compared two teaching strategies to teach statistical reasoning. It did not assess long-term learning-retention. Methods We conducted the trials in Kenya, Rwanda, and Uganda. The intervention included providing a 2–3-day teacher training workshop and digital resources for ten lessons. The intervention focused on nine key concepts. We did not intervene in control schools. The primary outcome was a passing score on a test (≥ 9 of 18 multiple-choice questions answered correctly). We performed random effects meta-analyses to estimate the overall intervention effects. We calculated learning retention as the test results in the intervention schools after 1 year relative to just after the intervention, adjusted for chance. Results Altogether, 244 schools (11,344 students) took part in the three trials. Follow-up data was collected for 8298 students (73%). The overall odds ratio for the primary outcome after 1 year was 3.6 (95% CI: 1.9–7.1; p = 0.0001) in favor of the intervention, whereas it was 5.5 (95% CI: 3.0–10.2) just after the intervention. This corresponds to 25.6% (95% CI: 21.1–30.0%) more students in the intervention schools passing the test after 1 year versus 33.3% (95% CI: 28.7–37.8%) just after the intervention. Overall, 2273 (52.6%) of 4324 students in intervention schools had a passing score after 1 year compared to 3397 (58.1%) of 5846 students just after the intervention, indicating 88.3% learning retention. Conclusions One year after the intervention, we still found a positive effect on the ability of students to think critically about health choices, but 5.5% fewer students in the intervention schools had a passing score. The certainty of the evidence was also lower due to 27% of students being lost to follow-up. Trial registration The protocol for this prospective meta-analysis was registered with PROSPERO May 31, 2022, ID 336580. The three randomized trials were registered in the Pan African Clinical Trial Registry February 15, 2022, PACTR202203880375077; April 5, 2022, PACTR20220488391731; and April 14, 2022, PACTR202204861458660.

Abstract Preclinical methods are needed for screening potential Alzheimer’s disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. Long-term potentiation (LTP), which is a correlate of learning and memory, was induced in mature human iPSC-derived cortical neurons cultured on microelectrode arrays utilizing circuit patterns connecting two adjacent electrodes. We demonstrated an LTP system that modeled the MCI and pre-MCI stages of Alzheimer’s and validated this functional system utilizing four AD therapeutics, which was also verified utilizing patch-clamp electrophysiology. LTP was induced by tetanic electrical stimulation, and LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42-induced LTP impairment. The results illustrate the utility of the system as a validated platform to model MCI AD pathology, and potentially for the pre-MCI phase before significant neuronal death. This system also has the potential to become an ideal platform for high-content therapeutic screening for other neurodegenerative diseases.

Abstract Background Research is needed to better understand the specific challenges for autistic learners in informal STEM learning settings. This study aimed to increase inclusion in STEM museums, with a larger goal of increasing the impact (i.e., learning and application of knowledge during and after visits) of informal STEM learning settings for autistic youth. We conducted an online parent attitudes survey with 93 parents of autistic adolescents and 53 parents of adolescents in the general population to better understand the experiences of autistic adolescents when visiting STEM-related museums. Parent responses informed professional development training for museum staff at four partner museums, which taught strategies to better support autistic learners. Then, autistic adolescents (n = 20) and their parents were randomly assigned to visit one partner and one control museum. They were asked to report their experiences through an online survey and semi-structured interviews. Results Participants who completed the parent attitudes survey indicated significantly lower inclusion, engagement, and general impact of STEM museum visits among autistic adolescents compared to the general population comparison group. Parents of adolescents who visited partner and control museums reported higher STEM impact during visits to partner museums; however, parent-reported inclusion, engagement, and general impact did not differ significantly between partner and control museums. Qualitative analysis identified four themes (Spectrum of Museum Impact; Adolescent-Environment Fit; Barriers to Engagement, and Barrier Breakers), providing context for quantitative findings. Conclusions Findings underscore the need for increased inclusion for autistic individuals in informal STEM learning environments like museums. This project demonstrated feasibility of professional development training of forward-facing staff and identified several themes that should inform future efforts to improve inclusion in informal STEM learning settings.

Abstract Malaria is a potentially fatal infective illness caused due to parasites that belong to the Plasmodium genus, which are transferred to humans with the help of the stings of affected female Anopheles mosquitoes, and it persists as a serious public wellness problem worldwide. Cordia myxa is a medicinal plant that possesses various medicinal characteristics like antimicrobial, anti-inflammation, antioxidant, and antidiabetic activities, which makes it an important natural resource for the therapy of different maladies in traditional medicine. In this investigation, a certain network pharmacology method has been utilized to identify the potent active components, possible targets as well as signaling pathways present in C. myxa in relation to malaria therapy. The active compounds were submitted to molecular docking approaches to validate their successful activity against the potential targets. The study concluded that three constituents named cosmosiin, stigmastanol, robinetin, and quercetin were highly active and could regulate the expression of Interleukin 6 (IL6) and Cysteine-aspartic acid protease 3 (CASP3), which may act as a potential therapeutic target for malaria treatment. These analyses are validated by molecular dynamics simulation which reflects on the overall structural stability of the intermolecular conformation and interactions. These results can also be witnessed in simulation-based trajectories binding free energies, which concluded the significant role of electrostatic and van der Waals energies in total intermolecular interactions. Finally, we utilized machine learning to predict the anti-malarial activity of C. myxa compounds, comparing them with approved drugs. Using the Chemprop model and MAIP predictions, we assessed ten compounds, revealing their potential as lead anti-malarial agents. This study establishes a groundwork for comprehending the function of the anti-malaria action of C. myxa.

Regular population monitoring of imperilled charismatic species such as large carnivores is critical for conservation. However, the role of monitoring in conservation is frequently diminished due to: 1) surveys being implemented in isolation, 2) limited on-ground-capacity leading to infrequent monitoring, and 3) inappropriate methods being applied. Wildlife monitoring is often resource-intensive and the utility and cost of different field protocols is rarely reported. In this study we deployed two standard field protocols aimed at collecting data on African lions within a spatial capture-recapture framework. For our first protocol, we trained Uganda Wildlife Authority rangers in search-encounter techniques, the industry gold standard for monitoring lions. The second protocol involved deploying 32 paired stations of state-of-the-art infra-red camera traps. During the search-encounter protocol, two rangers covered 2939 km in 76 days, recording 102 detections (30 individuals) in a ~ 256 km2 area. The resulting density estimates (13.91 lions/100 km2, posterior SD = 2.34) yielded acceptable precision. Conversely, 64 camera traps over 1601 trap nights yielded two usable lion detections. We argue that where wildlife tourism rangers exist, they could be a powerful addition to future lion and wildlife census attempts across the continent. Our results confirm that the current technology of store-bought infra-red camera traps is not suitable for individual identification of lions, and therefore cannot be applied to analytical models that require unambiguous individual identities. However, we encourage the continued testing and advancement of infra-red camera trap technology since in many instances, this may be preferable to white-flash camera traps, which can yield individual identities for lions. Our study also shows the immense importance of the Nile Delta for African lions in Uganda’s Murchison Falls National Park, a protected area with both oil extraction and high rates of anthropogenic snaring pressure.

Abstract Background Management of rheumatoid arthritis (RA) relies on symptoms reported by patients during infrequent outpatient clinic visits. These reports are often incomplete and inaccurate due to poor recall, leading to suboptimal treatment decisions and outcomes. Asking people to track symptoms in-between visits and integrating the data into clinical pathways may improve this. However, knowledge on how to implement this into practice and its impact on services and outcomes remains scarce in RA. Therefore, we evaluate the comparative effectiveness and cost-effectiveness of integrated symptom tracking in people with RA over and above usual care, while generating insights on factors for successful implementation. Methods In this superiority stepped wedge cluster-randomized controlled trial with continuous recruitment short exposure design, 16 rheumatology outpatient departments (clusters) recruit a total of 732 people with active RA. They initially offer clinic visits according to standard of care before switching in pairs to visits with integrated symptom tracking. Clusters switch in randomized order every 3 weeks. Integrated symptom tracking consists of (1) a mobile app for patients to track their symptoms daily and other RA aspects weekly/monthly, and (2) an interactive dashboard visualizing the app data, which healthcare professionals access from their electronic health record system. Clinic visits happen according to usual practice, with tracked symptom data only reviewed during visits. Our primary outcome is a difference in marginal mean disease activity score at 12 ± 3 months between standard of care and integrated symptom tracking, after accounting for baseline values, cluster, and other covariates. Secondary outcomes include patient-reported disease activity, quality of life and quality-adjusted life-years, medication/resource use, consultation and decision-making experience, self-management, and illness perception. We also conduct interviews and observations as part of a parallel process evaluation to gather information on implementation. Discussion Our trial will generate high-quality evidence of comparative and cost-effectiveness of integrated symptom tracking compared to standard of care in people with RA, with our process evaluation delivering knowledge on successful implementation. This optimizes the chances of integrated symptom tracking being adopted more widely if we find it is (cost-) effective. Trial registration Registered 4-Jun-2024 on https://www.isrctn.com/ , ISRCTN51539448. Trial open science framework repository https://osf.io/sj9ha/ .

Abstract Background Ontologies are fundamental components of informatics infrastructure in domains such as biomedical, environmental, and food sciences, representing consensus knowledge in an accurate and computable form. However, their construction and maintenance demand substantial resources and necessitate substantial collaboration between domain experts, curators, and ontology experts. We present Dynamic Retrieval Augmented Generation of Ontologies using AI (DRAGON-AI), an ontology generation method employing Large Language Models (LLMs) and Retrieval Augmented Generation (RAG). DRAGON-AI can generate textual and logical ontology components, drawing from existing knowledge in multiple ontologies and unstructured text sources. Results We assessed performance of DRAGON-AI on de novo term construction across ten diverse ontologies, making use of extensive manual evaluation of results. Our method has high precision for relationship generation, but has slightly lower precision than from logic-based reasoning. Our method is also able to generate definitions deemed acceptable by expert evaluators, but these scored worse than human-authored definitions. Notably, evaluators with the highest level of confidence in a domain were better able to discern flaws in AI-generated definitions. We also demonstrated the ability of DRAGON-AI to incorporate natural language instructions in the form of GitHub issues. Conclusions These findings suggest DRAGON-AI's potential to substantially aid the manual ontology construction process. However, our results also underscore the importance of having expert curators and ontology editors drive the ontology generation process.

Abstract Objectives To analyse the presentation, management and long‐term outcomes of renal transplant patients who formed kidney stones in their allograft. The secondary aim was to identify risk factors for stone formation in this cohort. Materials and Methods Patient information from an institutional renal transplant database was used to identify individuals who both did and did not form kidney stones following renal transplantation. Computerized tomography (CT) imaging was used to make the diagnosis of kidney stones and measure stone size. Age‐ and gender‐matched controls never forming a stone in their allograft were used for comparative analysis to identify risk factors for stone formation in transplant patients. Results A total of 8835 transplant patients were included in the study, of which 128 (1.4%) formed a kidney stone in their allograft after surgery. The mean time to kidney stone identification was 6.2 years, and the mean number of stones formed was 1.7, with a mean maximum size dimension on a CT scan of 5.7 mm per stone. A total of 26 patients were subjected to stone‐removing procedures, the most common being ureteroscopy (42.3%). The primary intervention failed in eight patients requiring a secondary intervention, and percutaneous nephrolithotomy (PCNL) had the lowest success rate (60%). A total of 164 controls were identified. In comparison to controls, stone formers had lower serum calcium (p = 0.008), lower estimated glomerular filtration rates (p = 0.019), higher lymphocyte counts (p = 0.021) and greater rate of urinary tract infection (p = 0.003). Graft failure rates were the same (p = 0.524), but time to graft failure was significantly longer in stone patients compared with controls (p = 0.008). Conclusions The rate of stone formation is low in transplant patients. Success rates for stone treatment vary based on the surgery selected, with PCNL being the worst. Graft survival rates were equivocal, but survival time was better in stone patients. Our analysis calls for further investigation of this important topic.

Abstract Background Antibiotic resistant infections cause over 700,000 deaths worldwide annually. As antimicrobial stewardship (AMS) helps minimise the emergence of antibiotic resistance resulting from inappropriate use of antibiotics in healthcare, we developed ePAMS+ (ePrescribing-based Anti-Microbial Stewardship), an ePrescribing and Medicines Administration (EPMA) system decision-support tool complemented by educational, behavioural and organisational elements. Methods We conducted a non-randomised before-and-after feasibility trial, implementing ePAMS+ in two English hospitals using the Cerner Millennium EPMA system. Wards of several specialties were included. Patient participants were blinded to whether ePAMS+ was in use; prescribers were not. A mixed-methods evaluation aimed to establish: acceptability and usability of ePAMS+ and trial processes; feasibility of ePAMS+ implementation and quantitative outcome recording; and a Fidelity Index measuring the extent to which ePAMS+ was delivered as intended. Longitudinal semi-structured interviews of doctors, nurses and pharmacists, alongside non-participant observations, gathered qualitative data; we extracted quantitative prescribing data from the EPMA system. Normal linear modelling of the defined daily dose (DDD) of antibiotic per admission quantified its variability, to inform sample size calculations for a future trial of ePAMS+ effectiveness. Results The research took place during the SARS-CoV-2 pandemic, from April 2021 to November 2022. 60 qualitative interviews were conducted (33 before ePAMS+ implementation, 27 after). 1,958 admissions (1,358 before ePAMS+ implementation; 600 after) included 24,884 antibiotic orders. Qualitative interviews confirmed that some aspects of ePAMS+ , its implementation and training were acceptable, while other features (e.g. enabling combinations of antibiotics to be prescribed) required further development. ePAMS+ uptake was low (28 antibiotic review records from 600 admissions; 0.047 records per admission), preventing full development of a Fidelity Index. Normal linear modelling of antibiotic DDD per admission showed a residual variance of 1.086 (log-transformed scale). Unavailability of indication data prevented measurement of some outcomes (e.g. number of antibiotic courses per indication). Conclusions This feasibility trial encountered unforeseen circumstances due to contextual factors and a global pandemic, highlighting the need for careful adaptation of complex intervention implementations to the local setting. We identified key refinements to ePAMS+ to support its wider adoption in clinical practice, requiring further piloting before a confirmatory effectiveness trial. Trial registration ISRCTN Registry ISRCTN13429325, 24 March 2022.

Abstract Water is essential to the formation of intracontinental granites, but its origin remains elusive. Here we address this scientific problem by analyzing D/H isotopes of apatites, hydrous minerals in Jurassic and Early Cretaceous granites and basalts from eastern North China Craton, where water was previously interpreted as derived from subducting slab. Results reveal extremely low δD values in pristine Early Cretaceous granitic (−203‰ to −127‰) and basaltic (−197‰ to −107‰) apatites, contrasting with relatively high δD values (−137‰ to −47‰) in Jurassic granites. Given the depth-dependent D/H isotopic fractionation during slab dehydration and high-water contents in coeval primitive mafic magmas, the Early Cretaceous magma water is attributed to the stagnant slab within the mantle transition zone. Secular change in the depth of water aligns with steepening of subducting Paleo-Pacific plate from Jurassic to Early Cretaceous, demonstrating the potential of apatite H isotopes in tracing water origin in granites and basalts.

Background: Use of noise or music in experimental human studies requires balancing the need to avoid subjecting participants to potentially harmful noise levels while still reaching levels that will produce a measurable change in the primary outcome. Several methodological and ethical aspects must be considered. This study aims to summarize ethical and methodological aspects, and reported outcomes, of previously published experimental paradigms using loud noise/music. Methods and materials: Four databases (Medline, Central, Web of Science, and Scopus) and two trials registries (Clinicaltrials.gov and EU Clinical Trials) were searched. Extracted items had the details of author and year of publication, study design and purpose, population, setting timeline and material, selected battery test, and effect of noise/music on participants’ hearing. Results: Thirty-four studies were included. Exposure safety considerations were reported in five studies. Eleven studies assessing hearing loss used white or narrow-band noise [(NBN (0.5–4 kHz), up to 115 dBA, duration range: 3′–24 hours)], and 10 used pop music (up to 106 dBA, duration range: 10′–4 hours). Experimental setting varied significantly. Temporary thresholds shift (TTS) and reduction in distortion product otoacoustic emissions were found at 1–8 kHz, with maximum average TTS∼21.5 dB at 4 kHz after NBN and ∼11.5 dB at 6 kHz after music exposure. All participants recovered their hearing, except for one participant in one study. In the 13 non-hearing loss studies, no hearing testing was performed after exposure, but loud noise was associated with temporary stress, bradygastria, and cardiovascular changes. Noise-induced subjective stress may be higher for participants with tinnitus. Loud noise (100 dBA, 10′) increased diastolic and mean blood pressure only in participants with hypertension. Conclusion: Experimental exposure paradigms can produce temporary changes to hearing without measurable long-term health consequences. Methodological and ethical aspects identified in this review should be considered for the development of future paradigms.

Purpose: A systematic review to identify treatment approaches for the management of pain following peripheral nerve injury. Methods: A published literature search was performed for the concepts of peripheral nerve injury and pain management with related synonyms. The strategies were created using a combination of controlled vocabulary terms and keywords and were executed in Embase.com, Ovid-Medline All, and Scopus from database inception. Database searches were completed on August 22, 2023. Results: The initial search resulted in a total of 1,793 citations. In total, 724 duplicates were removed, leaving 1,069 unique citations remaining for analysis. This review excluded all papers that were not specific to pain following peripheral nerve injury. Case and cohort studies (n < 5) were also excluded. Thirty-two articles on pain management strategies after peripheral nerve injury remained, with years of publication ranging from 1981 to 2023. An additional four articles were identified by manual search. Of the 36 articles reviewed, 15 articles reported on the approach to the treatment of pain after a peripheral nerve injury, and the other 22 articles consisted of cohort and case series studies. Conclusions: There is a lack of literature describing efficacy of various treatment strategies for pain following peripheral nerve injuries. Few studies provide clear, stepwise clinical guidance for practicing physicians and other health care providers on the treatment of these complicated patients.

Peripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the repair setting. Sustained axon survival and regrowth and consequently functional outcomes of nerve repair in animal models are improved by the administration of neurotrophic factors, including glial cell-derived neurotrophic factor, nerve growth factor, sterile alpha and TIR motif containing 1, and erythropoietin. Targeted and sustained delivery of neurotrophic factors through gelatin-based nerve conduits, multiluminal conduits, and hydrogels have been shown to enhance the innate roles of these factors to promote expedient and accurate peripheral nerve regeneration in animal models. These delivery methods may help address the practical limitations to clinical use of neurotrophic factors, including systemic side effects and the need for carefully timed, precisely localized release schedules. In addition, tacrolimus has also improved peripheral nerve regrowth in animal models and has recently shown promise in addressing human disease. Ultimately, this realm of adjunct pharmacotherapies provides ample promise to improve patient outcomes and advance the field of peripheral nerve repair.

Purpose: Preoperative expectations play a major role in determining patient satisfaction after surgery. The aim of this study was to characterize patient’s preoperative expectations and postoperative perceptions of nerve gap repair surgery. Methods: We conducted a search of Embase, Scopus, and Web of Science databases for peer-reviewed articles that studied patient expectations, perceptions, and impressions of nerve gap repair in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies related to lumbar plexus radiculopathy, reimplantation, or patient satisfaction scores without patient testimony were excluded. Primary and secondary outcomes were patient’s preoperative expectations and postoperative perceptions of nerve gap repair surgery, respectively. Results: We included 11 studies evaluating a total of 462 patients. One study evaluated only patient expectations, six studies evaluated only patient perspectives, and four studies evaluated both. Patients were generally overly optimistic in their expectations of surgery. Postoperative satisfaction ranged from 82% to 86%, and 81% to 87% of patients would choose to undergo their surgery again knowing what they know now. Conclusions: Patient expectations in nerve gap repair are optimistic, and at times unrealistic. Patient satisfaction with nerve gap repair is high and subject to influence from preoperative education and postoperative outcomes of functional and sensory recovery. Clinical relevance: Surgeons should be aware that patient expectations of their postoperative outcomes can have substantial impacts on their perceived management and overall satisfaction. More emphasis should be placed on preoperative education and expectation management to optimize patient satisfaction.

Abstract Developing future climate projections begins with choosing future emissions scenarios. While scenarios are often based on storylines, here instead we produce a probabilistic multi-million-member ensemble of radiative forcing trajectories to assess the relevance of future forcing thresholds. We coupled a probabilistic database of future greenhouse gas emission scenarios with a probabilistically calibrated reduced complexity climate model. In 2100, we project median forcings of 5.1 watt per square meters (5th to 95th percentiles of 3.3 to 7.1), with roughly 0.5% probability of exceeding 8.5 watt per square meters, and a 1% probability of being lower than 2.6 watt per square meters. Although the probability of 8.5 watt per square meters scenarios is low, our results support their continued utility for calibrating damage functions, characterizing climate in the 22nd century (the probability of exceeding 8.5 watt per square meters increases to about 7% by 2150), and assessing low-probability/high-impact futures.

Abstract The essential l,d-transpeptidase of Mycobacterium tuberculosis (LdtMt2) catalyses the formation of 3 $$\to$$ → 3 cross-links in cell wall peptidoglycan and is a target for development of antituberculosis therapeutics. Efforts to inhibit LdtMt2 have been hampered by lack of knowledge of how it binds its substrate. To address this gap, we optimised the isolation of natural disaccharide tetrapeptide monomers from the Corynebacterium jeikeium bacterial cell wall through overproduction of the peptidoglycan sacculus. The tetrapeptides were used in binding / turnover assays and biophysical studies on LdtMt2. We determined a crystal structure of wild-type LdtMt2 reacted with its natural substrate, the tetrapeptide monomer of the peptidoglycan layer. This structure shows formation of a thioester linking the catalytic cysteine and the donor substrate, reflecting an intermediate in the transpeptidase reaction; it informs on the mode of entrance of the donor substrate into the LdtMt2 active site. The results will be useful in design of LdtMt2 inhibitors, including those based on substrate binding interactions, a strategy successfully employed for other nucleophilic cysteine enzymes.

Abstract The cumulative impacts of future climatic and socioeconomic change threaten the ability of freshwater catchments to provide essential ecosystem services. Stakeholders who manage freshwaters require decision-support tools that increase their understanding of catchment system resilience and support the appraisal of adaptive management options to inform decision-making. Our research aims to test the ability of a Bayesian Network model to identify adaptive management scenarios and test their effectiveness across future pathways to 2050. Using the predominantly arable river Eden catchment (320 km2) in eastern Scotland as a case study, we invited stakeholders from multiple sectors to participate in a series of workshops aimed at addressing water quality issues and achieving good ecological status in the catchment both now and in the future. Our participatory methods helped stakeholders overcome multiple layers of complexity and uncertainty associated with future-focused water management. Outputs of a Bayesian Network model simulated both current and future catchment resilience to inform the identification of six management scenarios. The effectiveness of each management scenario was tested using the Bayesian Network model. Two adaptive management scenarios increased catchment resilience and helped achieve good ecological status; a ‘Best Available Technology’ scenario, including aerobic granular sludge treatment, and a management scenario focused on ‘Resource Centre’, including phosphorus recovery from wastewater treatment works and constructed lagoons for crop irrigation. Stakeholders were interested in a 'Nature Based' management scenario including options such as wetland wastewater treatment methods and rural sustainable drainage systems, which improved water quality in the catchment, but had lower certainty in achieving desired outcome. Findings led to a recognition that innovative and collaborative action was required to improve current and future freshwater conditions.

Abstract Dune vegetation mediates dune-building through trapping wind-blown sand and reduces dune erosion by attenuating wave energy via above- and belowground biomass. Despite the role of vegetation in dune functions, the amount and distribution of biomass within a dune remains poorly quantified due to a lack of ample data. Our objectives were to determine the effects of management history and elevation on (1) dune belowground biotic structure and aboveground community composition and (2) to determine best predictors of belowground biomass. We sampled belowground biomass and sedimentology across the dune profile at sites in the Outer Banks, North Carolina, USA. Dunes were classified as either unmanaged (no anthropogenic interventions) or managed (sand fencing, vegetation planting, dune construction). Living belowground biomass was higher in unmanaged dunes and decreased with depth. Non-living belowground biomass was 50% higher than living biomass and with greater abundance in unmanaged dunes. Elevation was a significant covariate of living and non-living belowground biomass, vegetative cover and species richness. Plant community composition varied less in managed dunes and differed significantly from unmanaged dunes. Vegetative cover, species richness, elevation, sedimentology and management history were predictors of belowground biomass. These results underscore the influence of management and geomorphology on dune plant communities, which may influence erosion resistance.

Abstract Copper plays a key role in host-pathogen interaction. We find that during Leishmania major infection, the parasite-harboring macrophage regulates its copper homeostasis pathway in a way to facilitate copper-mediated neutralization of the pathogen. Copper-ATPase ATP7A transports copper to amastigote-harboring phagolysosomes to induce stress on parasites. Leishmania in order to evade the copper stress, utilizes a variety of manipulative measures to lower the host-induced copper stress. It induces deglycosylation and degradation of host-ATP7A and downregulation of copper importer, CTR1 by cysteine oxidation. Additionally, Leishmania induces CTR1 endocytosis that arrests copper uptake. In mouse model of infection, we report an increase in systemic bioavailable copper in infected animals. Heart acts as the major organ for diverting its copper reserves to systemic circulation to fight-off infection by downregulating its CTR1. Our study explores reciprocal mechanism of manipulation of host copper homeostasis pathway by macrophage and Leishmania to gain respective advantages in host-pathogen interaction.

Abstract The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS). AcpS is a highly conserved enzyme essential for bacterial survival that catalyzes the first step in lipid synthesis. To the best of our knowledge, there are no current antibiotics targeting AcpS making this drug development program of high interest. We synthesize a library of > 700 novel compounds targeting AcpS, from which 33 inhibit bacterial growth in vitro at ≤ 2 μg/mL. We demonstrate that compounds from this class have stand-alone activity against a broad spectrum of Gram-positive organisms and synergize with colistin to enable coverage of Gram-negative species. We demonstrate efficacy against clinically relevant multi-drug resistant strains in vitro and in animal models of infection in vivo including a difficult-to-treat ischemic infection exemplified by diabetic foot ulcer infections in humans. This antibiotic family could form the basis for several multi-drug-resistant antimicrobial programs.

Abstract We describe a process for rapid antibody affinity optimization by repertoire mining to identify clones across B cell clonal lineages based on convergent immune responses where antigen-specific clones with the same heavy (VH) and light chain germline segment pairs, or parallel lineages, bind a single epitope on the antigen. We use this convergence framework to mine unique and distinct VH lineages from rat anti-triggering receptor on myeloid cells 2 (TREM2) antibody repertoire datasets with high diversity in the third complementarity-determining loop region (CDR H3) to further affinity-optimize a high-affinity agonistic anti-TREM2 antibody while retaining critical functional properties. Structural analyses confirm a nearly identical binding mode of anti-TREM2 variants with subtle but significant structural differences in the binding interface. Parallel lineage repertoire mining is uniquely tailored to rationally explore the large CDR H3 sequence space in antibody repertoires and can be easily and generally applied to antibodies discovered in vivo.

In this study, we conducted morphological and molecular analyses of Perinereis wilsoni, a species being considered for aquaculture in China. We found this species difficult to identify because of its close morphological similarity to the sympatric P. mictodonta and thus sought genetic markers to more easily distinguish it and to investigate its phylogenetic relationship to P. mictodonta and other nereidids. For the first time, we sequenced, assembled, and annotated the complete mitochondrial genome, nuclear ribosomal sequences (18S-ITS1-5.8S-ITS2-28S), and four nuclear histone genes (H3-H2A-H2B-H4) of P. wilsoni. Comprehensive bioinformatics methods were employed to assemble the genome-skimming data of P. wilsoni to ensure assembly quality. Phylogenetic analyses based on five datasets of the available mitochondrial genomes (32 taxa in Nereididae, including 8 taxa in Perinereis), using maximum likelihood and Bayesian analyses, provide support for the monophyly of the genus Perinereis. In contrast, the P. nuntia species group, a subgroup within Perinereis, is nonmonophyletic. Perinereis wilsoni has a closer phylogenetic relationship with P. vancaurica and P. nuntia. Our study serves as a baseline for future work on the cultivation, reproductive biology, and phylogeny of P. wilsoni.

Abstract Alzheimer’s disease (AD) and more than twenty other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule-associated protein tau (MAPT). Although tau aggregation correlates with AD symptomology, the specific tau species, i.e., monomers, soluble oligomers, and insoluble aggregates that induce neurotoxicity are incompletely understood. We developed a light-responsive tau protein (optoTAU) and used viscosity-sensitive AggFluor probes to investigate the consequence(s) of tau aggregation in human neurons and identify modifiers of tau aggregation in AD and other tauopathies. We determined that optoTAU reproduces biological and structural properties of tau aggregation observed in human brains and the pathophysiological transition in tau solubility in live cells. We also provide proof-of-concept for the utilization of optoTAU as a pharmacological platform to identify modifiers of tau aggregation. These findings have broad implications for the characterization of aggregation-prone proteins and investigation of the complex relationship between protein solubility, cellular function, and disease progression.

Abstract Background The internet is a common source of health information for patients and caregivers. To date, content and information quality of YouTube videos on sarcoidosis has not been studied. The aim of our study was to investigate the content and quality of information on sarcoidosis provided by YouTube videos. Methods Of the first 200 results under the search term “sarcoidosis,” all English-language videos with content directed at patients were included. Two independent investigators assessed the content of the videos based on 25 predefined key features (content score with 0–25 points), as well as reliability and quality (HONCode score with 0–8 points, DISCERN score with 1–5 points). Misinformation contained in the videos was described qualitatively. Results The majority of the 85 included videos were from an academic or governmental source (n = 63, 74%), and median time since upload was 33 months (IQR 10–55). Median video duration was 8 min (IQR 3–13) and had a median of 2,044 views (IQR 504 − 13,203). Quality assessment suggested partially sufficient information: mean HONCode score was 4.4 (SD 0.9) with 91% of videos having a medium quality HONCode evaluation. Mean DISCERN score was 2.3 (SD 0.5). Video content was generally poor with a mean of 10.5 points (SD 0.6). Frequently absent key features included information on the course of disease (6%), presence of substantial geographical variation (7%), and importance of screening for extrapulmonary manifestations (11%). HONCode scores were higher in videos from academic or governmental sources (p = 0.003), particularly regarding “transparency of sponsorship” (p

Abstract Much of what we know about terrestrial life during the Carboniferous Period comes from Middle Pennsylvanian (~315–307 Mya) Coal Measures deposited in low-lying wetland environments1–5. We know relatively little about terrestrial ecosystems from the Early Pennsylvanian, which was a critical interval for the diversification of insects, arachnids, tetrapods, and seed plants6–10. Here we report a diverse Early Pennsylvanian trace and body fossil Lagerstätte (~320–318 Mya) from the Wamsutta Formation of eastern North America, distinct from coal-bearing deposits, preserved in clastic substrates within basin margin conglomerates. The exceptionally preserved trace fossils and body fossils document a range of vertebrates, invertebrates and plant taxa (n = 131), with 83 distinct foliage morphotypes. Plant-insect interactions include what may be the earliest evidence of insect oviposition. This site expands our knowledge of early terrestrial ecosystems and organismal interactions and provides ground truth for future phylogenetic reconstructions of key plant, arthropod, and vertebrate groups.

Abstract Graphene placed on hexagonal boron nitride (hBN) has received significant interest due to its excellent electrical performance and physics phenomena, such as superlattice Dirac points. Direct molecular beam epitaxy growth of graphene on hBN offers an alternative fabrication route for hBN/graphene devices. Here, we investigate the electronic transport of moiré field effect transistors (FETs) in which the conducting channel is monolayer graphene grown on hexagonal boron nitride by high temperature molecular beam epitaxy (HT-MBE). Alignment between hBN and HT-MBE graphene crystal lattices gives rise to a moiré-fringed hexagonal superlattice pattern. Its electronic band structure takes the form of a “Hofstadter butterfly”. When a strong magnetic field B is applied perpendicular to the graphene layer, the electrical conductance displays magneto-oscillations, periodic in B −1, over a wide range of gate voltages and temperatures up to 350 K. We attribute this behaviour to the quantisation of electronic charge and magnetic flux within each unit cell of the superlattice, which gives rise to so-called Brown-Zak oscillations, previously reported only in high-mobility exfoliated graphene. Thus, this HT-MBE graphene/hBN heterostructure provides a platform for observation of room temperature quantum effects and device applications.

Abstract Paleoclimate model simulations provide reference data to help interpret the geological record and offer a unique opportunity to evaluate the performance of current models under diverse boundary conditions. Here, we present a dataset of 35 climate model simulations of the warm early Eocene Climatic Optimum (EECO; ~ 50 million years ago) and corresponding preindustrial reference experiments. To streamline the use of the data, we apply standardised naming conventions and quality checks across eight modelling groups that have carried out coordinated simulations as part of the Deep-Time Model Intercomparison Project (DeepMIP). Gridded model fields can be downloaded from an online repository or accessed through a new web application that provides interactive data exploration. Local model data can be extracted in CSV format or visualised online for streamlined model-data comparisons. Additionally, processing and visualisation code templates may serve as a starting point for advanced analysis. The dataset and online platform aim to simplify accessing and handling complex data, prevent common processing issues, and facilitate the sharing of climate model data across disciplines.

Abstract Background The Ultra-Low Emission Zone (ULEZ), introduced in Central London in April 2019, aims to enhance air quality and improve public health. The Children's Health in London and Luton (CHILL) study evaluates the impact of the ULEZ on children's health. This analysis focuses on the one-year impacts on the shift towards active travel to school. Methods CHILL is a prospective parallel cohort study of ethnically diverse children, aged 6–9 years attending 84 primary schools within or with catchment areas encompassing London’s ULEZ (intervention) and Luton (non-intervention area). Baseline (2018/19) and one-year follow-up (2019/20) data were collected at school visits from 1992 (58%) children who reported their mode of travel to school ‘today’ (day of assessment). Multilevel logistic regressions were performed to analyse associations between the introduction of the ULEZ and the likelihood of switching from inactive to active travel modes, and vice-versa. Interactions between intervention group status and pre-specified effect modifiers were also explored. Results Among children who took inactive modes at baseline, 42% of children in London and 20% of children in Luton switched to active modes. For children taking active modes at baseline, 5% of children in London and 21% of children in Luton switched to inactive modes. Relative to the children in Luton, children in London were more likely to have switched from inactive to active modes (OR 3.64, 95% CI 1.21–10.92). Children in the intervention group were also less likely to switch from active to inactive modes (OR 0.11, 0.05–0.24). Moderator analyses showed that children living further from school were more likely to switch from inactive to active modes (OR 6.06,1.87–19.68) compared to those living closer (OR 1.43, 0.27–7.54). Conclusions Implementation of clean air zones can increase uptake of active travel to school and was particularly associated with more sustainable and active travel in children living further from school.

Accurate analysis of the rich information contained within X-ray spectra usually calls for detailed electronic structure theory simulations. However, density functional theory (DFT), time-dependent DFT and many-body perturbation theory calculations increasingly require the use of advanced codes running on high-performance computing (HPC) facilities. Consequently, many researchers who would like to augment their experimental work with such simulations are hampered by the compounding of nontrivial knowledge requirements, specialist training and significant time investment. To this end, we present Web-CONEXS, an intuitive graphical web application for democratizing electronic structure theory simulations. Web-CONEXS generates and submits simulation workflows for theoretical X-ray absorption and X-ray emission spectroscopy to a remote computing cluster. In the present form, Web-CONEXS interfaces with three software packages: ORCA, FDMNES and Quantum ESPRESSO, and an extensive materials database courtesy of the Materials Project API. These software packages have been selected to model diverse materials and properties. Web-CONEXS has been conceived with the novice user in mind; job submission is limited to a subset of simulation parameters. This ensures that much of the simulation complexity is lifted and preliminary theoretical results are generated faster. Web-CONEXS can be leveraged to support beam time proposals and serve as a platform for preliminary analysis of experimental data.

Abstract Background HyBryteTM is a photodynamic therapy of topical hypericin that has recently been shown to be safe and efficacious in early stage cutaneous T‐cell lymphoma (CTCL). However, its efficacy, absorption, and effect on heart function parameters in patients who require greater HyBryteTM exposure is unknown. Objectives The primary objectives in this study were to assess hypericin blood levels using a validated detection method with a cut‐off value of 0.05 ng/mL and to determine if topical HyBryteTM induces any electrocardiogram (EKG) changes during 8 weeks of treatment. A secondary endpoint of this study was to assess the effectiveness of HyBryteTM in this patient population as well as assessing a different additional light device than the one used in the Phase 3 HPN‐CTCL‐01/fluorescent light activated synthetic hypericin trial also entitled “A phase 3 multicenter randomised placebo‐controlled study to determine the efficacy of topical hypericin and light irradiation for the treatment of cutaneous T‐cell lymphoma”. Methods A confirmatory, prospective, open‐label, single‐centre, interventional study focused on stage IB and IIA mycosis fungoides with more than 10% of their body surface areas involved was performed. Results Hypericin concentration in K2EDTA whole blood samples collected before and after light activation at Weeks 4, 6 and 8 showed an average blood concentration of 0.13 ng/mL and achieved steady state by Week 4. EKGs were examined for clinical changes at each study visit, including changes in QT intervals and correction of heart rates. No significant clinical changes in EKGs were observed. Conclusions Hypericin does not appear to be significantly absorbed through the skin nor cause significant cardiac changes overall or prolong the QT interval when applied topically. A larger study is necessary to clearly define these results.

Abstract Post‐exercise hot (HWI) and cold (CWI) water immersion are popular strategies used by athletes in a range of sporting contexts, such as enhancing recovery or adaptation. However, prolonged heating bouts increase neuroendocrine responses that are associated with perceptions of fatigue. Fourteen endurance‐trained runners performed three trials consisting of two 45‐min runs at 95% lactate threshold on a treadmill separated by 6 h of recovery. Following the first run, participants completed one of HWI (30 min, 40°C), CWI (15 min, 14°C) or control (CON, 30 min rest in ambient conditions) in a randomised order. Perceived effort and recovery were measured using ratings of perceived exertion (RPE) and the Acute Recovery and Stress Scale (ARSS), whilst physiological responses including venous concentrations of a range of neuroendocrine markers, superficial femoral blood flow, heart rate and rectal temperature were measured. Exercise increased neuroendocrine responses of interleukin‐6, adrenaline and noradrenaline (all P 0.05), nor RPE (P = 0.68), despite differences in rectal temperature, superficial femoral blood flow following the first run, and participants’ expected recovery prior to the intervention (all P

Abstract Accurate measurements of glycaemic control and the underpinning regulatory mechanisms are vital in human physiology research. Glycaemic control is the maintenance of blood glucose concentrations within optimal levels and is governed by physiological variables including insulin sensitivity, glucose tolerance and β‐cell function. These can be measured with a plethora of methods, all with their own benefits and limitations. Deciding on the best method to use is challenging and depends on the specific research question(s). This review therefore discusses the theory and procedure, validity and reliability and any special considerations of a range common methods used to measure glycaemic control, insulin sensitivity, glucose tolerance and β‐cell function. Methods reviewed include glycosylated haemoglobin, continuous glucose monitors, the oral glucose tolerance test, mixed meal tolerance test, hyperinsulinaemic euglycaemic clamp, hyperglycaemic clamp, intravenous glucose tolerance test and indices derived from both fasting concentrations and the oral glucose tolerance test. This review aims to help direct understanding, assessment and decisions regarding which method to use based on specific physiology‐related research questions.

A greater degree of Late Quaternary hominin morphological variability is present in eastern Asia than previously assumed. Indeed, a number of distinct populations are present, some that now have new specific names: Homo floresiensis; H. luzonensis; H. longi; H. juluensis. With this piece, we describe the various groupings based on the current hominin fossil record of eastern Asia.

La-related proteins (LARPs) are a family of RNA-binding proteins that share a conserved La motif (LaM) domain. LARP1 plays a role in regulating ribosomal protein synthesis and stabilizing mRNAs and has a unique structure without an RNA binding RRM domain adjoining the LaM domain. In this study, we investigated the physical basis for LARP1 specificity for poly(A) sequences and observed an unexpected bias for sequences with single guanines. Multiple guanine substitutions did not increase the affinity, demonstrating preferential recognition of singly guanylated sequences. We also observed that the cyclic di-nucleotides in the cCAS/STING pathway, cyclic-di-GMP and 3‘,3’-cGAMP, bound with sub-micromolar affinity. Isothermal titration measurements were complemented by high-resolution crystal structures of the LARP1 LaM with six different RNA ligands, including two stereoisomers of a phosphorothioate linkage. The selectivity for singly substituted poly(A) sequences suggests LARP1 may play a role in the stabilizing effect of poly(A) tail guanylation. [Figure: see text]

ABSTRACTTranslation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation. Human genomes include both rare and more common mistranslating tRNA variants. We investigated three rare human tRNALeu variants that mis-incorporate Leu at phenylalanine or tryptophan codons. Expression of each tRNALeu anticodon variant in neuroblastoma cells caused defects in fluorescent protein production without significantly increased cytotoxicity under normal conditions or in the context of proteasome inhibition. Using tRNA sequencing and mass spectrometry we confirmed that each tRNALeu variant was expressed and generated mistranslation with Leu. To probe the flexibility of the entire genetic code towards Leu mis-incorporation, we created 64 yeast strains to express all possible tRNALeu anticodon variants in a doxycycline-inducible system. While some variants showed mild or no growth defects, many anticodon variants, enriched with G/C at positions 35 and 36, including those replacing Leu for proline, arginine, alanine, or glycine, caused dramatic reductions in growth. Differential phenotypic defects were observed for tRNALeu mutants with synonymous anticodons and for different tRNALeu isoacceptors with the same anticodon. A comparison to tRNAAla anticodon variants demonstrates that Ala mis-incorporation is more tolerable than Leu at nearly every codon. The data show that the nature of the amino acid substitution, the tRNA gene, and the anticodon are each important factors that influence the ability of cells to tolerate mistranslating tRNAs.

Abstract Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

Abstract Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors’ clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes.

Abstract Robust diagnostic tools and surveillance are crucial for malaria control and elimination efforts. Malaria caused by neglected Plasmodium parasites is often underestimated due to the lack of rapid diagnostic tools that can accurately detect these species. While nucleic-acid amplification technologies stand out as the most sensitive methods for detecting and confirming Plasmodium species, their implementation in resource-constrained settings poses significant challenges. Here, we present a Pan Plasmodium recombinase polymerase amplification lateral flow (RPA–LF) assay, capable of detecting all six human infecting Plasmodium species in low resource settings. The Pan Plasmodium RPA-LF assay successfully detected low density clinical infections with a preliminary limit of detection between 10–100 fg/µl for P. falciparum. When combined with crude nucleic acid extraction, the assay can serve as a point-of-need tool for molecular xenomonitoring. This utility was demonstrated by screening laboratory-reared Anopheles stephensi mosquitoes fed with Plasmodium-infected blood, as well as field samples of An. funestus s.l. and An. gambiae s.l. collected from central Africa. Overall, our proof-of-concept Pan Plasmodium diagnostic tool has the potential to be applied for clinical and xenomonitoring field surveillance, and after further evaluation, could become an essential tool to assist malaria control and elimination.

Abstract Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.

Abstract Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Abstract Nuclear power plants are aging around the world, and a precise assessment of irradiation damage in their components is needed. One key component, concrete, and specifically the silicates in its aggregates, can undergo significant expansion upon neutron radiation, which can lead to cracking and, ultimately, structural failure. However, assessing and predicting the extent of damage via neutron radiation is challenging due to reasons such as residual radioactivity and, most importantly, the high time involved. Here, we evaluate whether ion radiation can be a viable surrogate. Specifically, by employing Si2+ ion radiations and a comprehensive multi-modal imaging protocol, we report mineral-specific responses for key silicates such as quartz, albite, anorthite, and microcline. We find that 10 MeV Si2+ ions result in mineral expansions that are remarkably comparable to neutron radiation equivalent expansions (R2 = 0.86, RMSE = 1.29%), opening up pathways towards rapid assessment of silicates subject to irradiation.

Summary Background The composition of the root microbiome affects the host’s growth, with variation in the host genome associated with microbiome variation. However, it is not known whether this intra-specific variation of root microbiomes is a consequence of plants performing targeted manipulations of them to adapt to their local environment or varying passively with other traits. To explore the relationship between the genome, environment and microbiome, we sampled seeds from teosinte populations across its native range in Mexico. We then grew teosinte accessions alongside two modern maize lines in a common garden experiment. Metabarcoding was performed using universal bacterial and fungal primers to profile their root microbiomes. Results The root microbiome varied between the two modern maize lines and the teosinte accessions. We further found that variation of the teosinte genome, the ancestral environment (temperature/elevation) and root microbiome were all correlated. Multiple microbial groups significantly varied in relative abundance with temperature/elevation, with an increased abundance of bacteria associated with cold tolerance found in teosinte accessions taken from high elevations. Conclusions Our results suggest that variation in the root microbiome is pre-conditioned by the genome for the local environment (i.e. non-random). Ultimately, these claims would be strengthened by confirming that these differences in the root microbiome impact host phenotype, for example, by confirming that the root microbiomes of high-elevation teosinte populations enhance cold tolerance.