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Spinal circuit mechanisms constrain therapeutic windows for ALS intervention:a computational modeling study
No full textAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1-motoneuron connections improved motor function and saved motoneurons in the SOD1G93A ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor-extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1G93A ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations. </p
Long-read spatial transcriptomics of patient-derived clear cell renal cell carcinoma organoids identifies heterogeneity and transcriptional remodelling following NUC-7738 treatment
No full textBackground: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is marked by pronounced intra-tumoural heterogeneity that complicates therapeutic response. Patient-derived organoids offer a physiologically relevant model to capture this diversity and evaluate treatment effects. When integrated with spatial transcriptomics, they might enable the mapping of spatially resolved transcriptional and isoform-level changes within the tumour microenvironment. Methods: We established a robust workflow for generating patient-derived ccRCC organoids, that are not passaged and retain original cellular components. These retain key features of the original tumours, including cancer cell, stromal, and immune components. Results: Spatial transcriptomic profiling revealed multiple transcriptionally distinct regions within and across organoids, reflecting the intrinsic heterogeneity of ccRCC. Isoform-level analysis identified spatially variable expression of glutaminase (GLS) isoforms, with heterogeneous distributions of both the GAC and KGA variants. Treatment with NUC-7738, a phosphoramidate derivative of 3′-deoxyadenosine, induced marked transcriptional remodelling of organoids, including alterations in ribosomal and mitochondrial gene expression. Conclusions: This study demonstrates that combining long-read spatial transcriptomics with patient-derived organoid models provides a powerful and scalable approach for dissecting gene and isoform-level heterogeneity in ccRCC and for elucidating spatially resolved transcriptional responses to novel therapeutics
Multivariate extreme values for dynamical systems
No full textWe establish a theory for multivariate extreme value analysis of dynamical systems. Namely, we provide conditions adapted to the dynamical setting which enable the study of dependence between extreme values of the components of ℝd-valued observables evaluated along the orbits of the systems. We study this cross-sectional dependence, which results from the combination of a spatial and a temporal dependence structures. We give several illustrative applications, where concrete systems and dependence sources are introduced and analysed
At-sea distribution of seals on the Northwest European Shelf:towards transboundary conservation and management
No full text1. Quantifying and mitigating transboundary effects of anthropogenic activity is a key challenge in environmental management, particularly for wide-ranging species such as large predators, fish and migratory birds, relying on habitats across multiple national jurisdictions. This challenge is especially complex in marine ecosystems, where the movement of species and impacts across borders is largely unobserved. Central-place foragers, such as pinnipeds and seabirds, exemplify this complexity: abundance is typically assessed on local (regional or national) scales on land, yet at-sea movements and drivers of abundance occur on broader transboundary scales. Resolving this mismatch is critical to effective conservation, especially in areas such as the Northwest European Shelf (NWES), which features globally important predator populations (including two pinniped species) alongside growing anthropogenic pressures and a mosaic of national maritime borders. 2. We model an unprecedented GPS dataset from 236 grey (Halichoerus grypus) and 606 harbour seals (Phoca vitulina) tracked in waters of seven countries across the NWES (United Kingdom, Ireland, France, Belgium, Netherlands, Germany and Denmark). Using regional habitat association models, we generate at-sea distribution estimates for both species at 5 km resolution, scaled to haulout counts, producing country-specific and NWES-wide density maps. 3. Analysis of the extent to which seals making foraging trips from one country occupy the Exclusive Economic Zones (EEZs) of other countries revealed substantial transboundary overlap, particularly for grey seals, and harbour seals in the southern North Sea. 4. A case study apportioning grey seal density within three adjacent offshore marine protected areas in different EEZs revealed that, where total density in a given area is required, overlooking transboundary distribution can underrepresent numbers by an order of magnitude. 5. Synthesis and applications. This study provides the first comprehensive, regionally scalable distribution estimates for pinnipeds across the NWES and its constituent countries. The modelling framework is adaptable to other central-place and migratory species, supporting transboundary biodiversity assessments and international conservation policy. We discuss common limitations and misconceptions of species distribution estimates, highlight priorities for future work and underscore the need for transboundary efforts to manage wide-ranging species, providing a foundation for future ecological modelling and decision-making across shared ecosystems
Formylation–decarbonylation relay strategy for the selective hydrogenation of CO<sub>2</sub> to CO
No full textWe report here an alternative approach to conducting the reverse water–gas shift (RWGS) reaction catalyzed by a ruthenium pincer complex and an amine. In this strategy, a secondary amine is first formylated by CO2 and H2 to make H2O and formamide. The formamide then undergoes decarbonylation to produce CO with the concomitant regeneration of the amine. Both steps, formylation and decarbonylation, were independently investigated through catalytic optimization studies and DFT computations at the PBE0-D3(BJ)PCM(THF)/def2-TZVP level. Using morpholine and Ru-MACHO pincer catalyst, a TON of 249 was achieved for the hydrogenation of CO2 to CO (at 70 bar, 170 °C for 90 h) with 100% selectivity
Holocene patterns of peat accumulation in Peruvian Amazonia
No full textPeatlands accumulate and store carbon over centuries to tens of millennia. Analysing the age structure of peatlands helps us to understand their genesis, development, and stability as carbon stores, and informs peatland management. Here we analyse new and previously published radiocarbon dates from peatlands in the Pastaza-Marañón Basin in Peru, the largest known peatland complex in Amazonia. We show that peatlands here are younger (< c. 8900 and frequently <2500 years old) than in many other parts of the tropics. Basal peat ages in extant peatlands vary depending on the geomorphological stability of the landscape, with younger basal dates typically occurring close to active river floodplains and older basal dates in more stable contexts. The data indicate that within individual peatlands, peat initiation may occur synchronously across a basin, or peat may spread laterally from one or more nucleation sites. Only two out of seven well-dated records show clear hiatuses in past peat accumulation, suggesting that carbon sequestration in some, but not all peatlands has been vulnerable to landscape hydrological change or climate change. Peatland ecosystems in the region are economically important sources of non-timber forest products, which it may be possible to harvest sustainably without biomass loss or drainage, but our analysis indicates that the peat itself accumulates too slowly to be considered as a renewable resource on economically meaningful timescales
Combined Ba-Cd isotope tracer in microbialites records biogeochemical metal cycling changes as a response to the Middle Miocene Badenian Salinity Crisis
No full textStromatolitic carbonates are vital archives for understanding the complex interactions among the microbial biosphere, hydrosphere, and atmosphere. At the Rabenkopf section in the Oberpullendorf Basin of the Parathetys, planar, undulated, and domal stromatolites of the Ritzing Formation record the Middle Miocene Badenian Salinity Crisis. We used the combined Ba-Cd isotope tracer along with trace element systematics to infer nutrient availability and primary productivity in a Neogene microbial environment under extreme environmental stress caused by basin restriction and related evaporation. We find that while productivity in microbial habitats during restricted conditions does not cease, the microbial communities adapt to changing nutrient conditions, developing isotopic signatures that are increasingly controlled by heterotrophic over phototrophic metabolism. Under restricted and freshwater input conditions, stromatolitic carbonates record lower Cd, Ba, and S isotopic conditions at variable, but negative, C isotopic conditions. Together with elevated Ba and Cd concentrations these hint at progressive organic matter remineralization via bacterial sulphate reduction or halophilic bacteria-mediated barite dissolution. In contrast, more open basin conditions correlate with heavier Ba, Cd and S isotopic conditions, arguing for the formation of micro-barites on extra polymeric substances from a marine sulphate pool and Rayleigh-type Cd isotope fractionation in ambient fluids to values similar to modern productive open surface ocean conditions. This work emphasises the importance of macro- and micronutrient availability and the adaptability of microbial environments during severe climatic and environmental changes in Earth’s history. Examining novel stable metal isotope systems, especially the combined Ba-Cd tracer, can serve as a blueprint for better understanding both ancient and modern microbial habitats affected by the ongoing climate crisis.<br/
Surgical fixation versus non-surgical care for children with a displaced medial epicondyle fracture of the elbow (the SCIENCE study):a multicentre, randomised controlled, superiority trial and economic evaluation
No full textBackground: Displaced medial epicondyle fractures are among the most controversial injuries in children, with increasing trends towards surgical fixation despite little supporting evidence. Approximately half of affected children undergo surgical fixation, while others receive non-surgical care. The SCIENCE trial aimed to determine whether surgical fixation to restore the position of the bone provides superior functional outcomes and is cost-effective compared with non-surgical care.Methods: We conducted a pragmatic multicentre, randomised, superiority trial across 59 hospitals in the UK, Australia, and New Zealand. Recruiting sites were secondary or tertiary care hospitals providing acute paediatric trauma care. Eligible participants were aged 7-15 years with a displaced medial epicondyle fracture and patients were excluded if the injury occurred more than 2 weeks prior, they had a medial epicondyle fragment that was incarcerated (trapped) within the joint, the injury was part of a complex elbow fracture (ie, extending into the joint), or there were additional fractured bones outside of the elbow. Participants were randomly assigned (1:1) to either surgical fixation or non-surgical care using a web-based randomisation software from Oxford Clinical Trials Research Unit, with minimisation (including a random element) stratified by centre and elbow dislocation status at presentation. Participants and their parents and carers could not be masked to treatment. Surgical fixation was performed under general anaesthesia and involved a surgical incision, restoration of the anatomical alignment, and fixing the fragment, typically with a screw or wires. Non-surgical care involved immobilisation of the elbow at approximately 90° of flexion using a cast, splint, or sling. Both groups were allowed mobilisation as pain allowed, although cast immobilisation beyond 4 weeks was discouraged. The primary outcome was upper limb function at 12 months, measured using the Patient Report Outcomes Measurement System (PROMIS) Upper Extremity Score for Children in the intention-to-treat population, which included all participants in the groups to which they were randomly assigned, irrespective of treatment received. Complications and serious adverse events were summarised in a safety (as-treated) population defined by treatment received. A within-trial economic evaluation was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time period. The trial was registered with ISRCTN, ISRCTN16619778; recruitment is complete and extended follow-up to age 16 years is ongoing.Findings: Between June 10, 2019, and Sept 22, 2023, 647 patients from 59 sites met the inclusion criteria. 146 patients were excluded (64 due to the injury being more than 2 weeks old and 24 because the epicondyle fragment was incarcerated within the joint), 161 families of children meeting the eligibility criteria declined to participate, and for five patients there was no clinician equipoise. 335 participants were randomly assigned to an intervention (166 to the non-surgical care group and 168 to the surgical fixation group) and one was immediately excluded due to a randomisation error. Primary outcome data were collected from 285 (85%) participants. 170 (51%) participants were female and 164 (49%) were male. Mean participant age at baseline was 11·7 years (SD 2·3). At 12 months post-randomisation, the PROMIS Upper Extremity score was 53·1 (SD 7·8) in the non-surgical care group and 54·3 (5·7) in the surgical fixation group (mean treatment difference, 1·57 [95% CI -0·01 to 3·14; p=0·052]). This estimate of treatment effect was below the clinically important difference specified (4 points), supporting the conclusion that a clinically important effect is unlikely. Additional episodes of surgery, either planned or related to complications, occurred in 24 participants in the surgical group and three in the non-surgical group. Among the 150 participants who underwent surgical fixation, there were 14 intraoperative complications from 13 (9%) participants, and seven participants had a postoperative complication (5% participants) each requiring surgery. Routine screw or wire removal was undertaken in a further 17 (11%) participants. From the 184 participants in the non-surgical group, there were five complications among four (2%) participants, three (2%) of which required additional surgery. The mean per patient cost from the NHS and Personal Social Services perspective was £2435 (95% CI 1812 to 3057) more for participants in the surgical fixation group with a mean per patient quality-adjusted life year difference of -0·008 (95% CI -0·039 to 0·024). The probability that surgical fixation is cost-effective at the £20 000 or £30 000 per quality-adjusted life year willingness-to-pay threshold was 0%.Interpretation: The SCIENCE trial demonstrates that surgical fixation offers no clinical benefit and is not cost-effective compared with non-surgical care, while exposing children to avoidable surgical risks. These findings suggest that non-surgical care should be adopted as the default management strategy for these injuries, regardless of initial elbow dislocation status.</p
A trade-off between efficiency and stability in a class of sky-blue organic light-emitting diodes
No full textThe stability of organic light-emitting diodes (OLEDs) is a key requirement for their use in commercial displays. One approach to increase the performance of the blue subpixel is to use thermally activated delayed fluorescence (TADF) emitters, which combine a small singlet-triplet gap, ΔEST, and non-trivial spin-orbit coupling to enable the harvesting of both singlet and triplet excitons to produce light; however, device stability is compromised due to long triplet lifetimes that increase the probability of the degradation of materials by biexcitonic and polaron events. In this work, we correlate the efficiency and stability of the device with the device structure, identifying possible origins for the trade-off between device efficiency and stability. By comparing a set of sky-blue emissive devices and fitting drift-diffusion simulations to intermittent optoelectronic measurements during stress-testing, the layers most affected by degradation can be determined. By coupling electrical simulations to an excitonic model, the contributions from biexcitonic and polaronic events to efficiency roll-off can be distinguished. We find that efficient but less stable devices suffer mainly from exciton-exciton annihilation, while stable but less efficient devices have excitons predominantly quenched by polarons. This implies that the device structure is responsible for determining non-radiative exciton pathways, and an efficient and stable OLED structure should aim to minimize exciton accumulation at high brightness
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