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Abstract Correct mitotic spindle size is required for accurate chromosome segregation during cell division. It is controlled by mechanical forces generated by molecular motors and non-motor proteins acting on spindle microtubules. However, how forces generated by individual proteins enable bipolar spindle organization is not well understood. Here, we develop tools to measure contributions of individual molecules to this force balance. We show that microtubule plus-end binding proteins act at microtubule tips synergistically with minus-end directed motors to produce a system that can generate both pushing and pulling forces. To generate pushing force, the system harnesses forces generated by the growing tips of microtubules providing unique contribution to the force balance distinct from all other motors that act in the mitotic spindle. Our results reveal that microtubules are essential force generators for establishing spindle size and pave the way for understanding how mechanical forces can be fine-tuned to control the fidelity of chromosome segregation.

DNA collections are a valuable type of Natural Science collection, enabling the validation of past research, serving as a source for new genomic studies and supporting ex situ conservation. The DiSSCo Flanders DNA collection working group, aiming to advance and "unlock" their DNA collections, identified the need for: 1) actively sharing best practices regarding the management of DNA collections; and 2) providing guidance on how to bring theory into practice. By combining best practice examples from within the working group with available literature and brainstorming ideas, the working group co-created two outputs, referred to as: the "Challenges" and the "Key". The Challenges are a list of obstacles to DNA collection management, which shape the structure of the linked Key and can also be used to spark discussion amongst stakeholders. The Key is a tool that guides users through the maturation process of their DNA collection in a standardised way. It stimulates holistic growth, breaks down the needed work into manageable steps and helps to decide priorities during the process. Furthermore, the Key facilitates communication with both internal stakeholders and external DNA collection managers. The Key distinguishes itself from other self-assessment tools in several ways: it includes (re)investigation of the collection’s purpose and context; it is specialised for DNA collections; it delivers concrete goals linked to relevant information and shared experience; and it is inclusive, targeting all Natural Science DNA collections, regardless of their context or size.

Abstract Most published prediction models for Coronavirus Disease 2019 (COVID-19) were poorly reported, at high risk of bias, and heterogeneous in model performance. To tackle methodological challenges faced in previous prediction studies, we investigated whether model updating and extending improves mortality prediction, using the Intensive Care Unit (ICU) as a proxy. All COVID-19 patients admitted to seven ICUs in the Euregio-Meuse Rhine during the first pandemic wave were included. The 4C Mortality and SEIMC scores were selected as promising prognostic models from an external validation study. Five predictors could be estimated based on cohort size. TRIPOD guidelines were followed and logistic regression analyses with the linear predictor, APACHE II score, and country were performed. Bootstrapping with backward selection was applied to select variables for the final model. Additionally, shrinkage was performed. Model discrimination was displayed as optimism-corrected areas under the ROC curve and calibration by calibration slopes and plots. The mortality rate of the 551 included patients was 36%. Discrimination of the 4C Mortality and SEIMC scores increased from 0.70 to 0.74 and 0.70 to 0.73 and calibration plots improved compared to the original models after updating and extending. Mortality prediction can be improved after updating and extending of promising models.

Abstract Provision of non-invasive vascular imaging results to individuals has been shown to improve cardiovascular disease risk factor control: its impact on diet remains uncertain. In this two-arm, single-blind, parallel, 12-week randomized controlled trial, 240 participants, 57.5% females aged 60–80 y had abdominal aortic calcification and clinical assessments performed at a hospital clinic. Participants were randomized 1:1 to receive (intervention n = 121) or not (control n = 119) their calcification results. Both groups received educational resources on cardiovascular disease risk control and were unblinded to the intervention. Outcome measures were performed at baseline and 12 weeks. The primary outcomes of the study were changes in fruit and vegetable intake measures over 12 weeks assessed using plasma carotenoid concentrations (biomarkers of FV intake) and a food frequency questionnaire. Secondary outcomes included 12-week changes in other aspects of the diet, physical activity, body weight, blood pressure, heart rate, lipid profile, glucose concentrations, estimated cardiovascular disease risk score, and medication use. Between-group differences were tested using linear mixed-effects regression. There were no between-group differences in the primary outcomes at 12 weeks: plasma carotenoids (mean difference +0.03 µg/mL [95%CI −0.06, 0.13]) and fruit and vegetable intakes (+18 g/d [−37, 72]). However, the provision of calcification results led to between-group differences in serum total (−0.22 mmol/L [−0.41, −0.04]) and non-HDL (−0.19 mmol/L [−0.35, −0.03]) cholesterol, and estimated cardiovascular disease risk score (−0.24% [−0.47, −0.02]). No between-group differences were seen for other secondary outcomes. In this work, providing vascular imaging results did not improve diet but did improve some cardiovascular disease risk factors (Australian and New Zealand Clinical Trials Registry ACTRN12618001087246).

We review how the international modelling community, encompassing integrated assessment models, global and regional Earth system and climate models, and impact models, has worked together over the past few decades to advance understanding of Earth system change and its impacts on society and the environment and thereby support international climate policy. We go on to recommend a number of priority research areas for the coming decade, a timescale that encompasses a number of newly starting international modelling activities, as well as the IPCC Seventh Assessment Report (AR7) and the second UNFCCC Global Stocktake. Progress in these priority areas will significantly advance our understanding of Earth system change and its impacts, increasing the quality and utility of science support to climate policy. We emphasize the need for continued improvement in our understanding of, and ability to simulate, the coupled Earth system and the impacts of Earth system change. There is an urgent need to investigate plausible pathways and emission scenarios that realize the Paris climate targets – for example, pathways that overshoot 1.5 or 2 °C global warming, before returning to these levels at some later date. Earth system models need to be capable of thoroughly assessing such warming overshoots – in particular, the efficacy of mitigation measures, such as negative CO2 emissions, in reducing atmospheric CO2 and driving global cooling. An improved assessment of the long-term consequences of stabilizing climate at 1.5 or 2 °C above pre-industrial temperatures is also required. We recommend Earth system models run overshoot scenarios in CO2-emission mode to more fully represent coupled climate–carbon-cycle feedbacks and, wherever possible, interactively simulate other key Earth system phenomena at risk of rapid change during overshoot. Regional downscaling and impact models should use forcing data from these simulations, so impact and regional climate projections cover a more complete range of potential responses to a warming overshoot. An accurate simulation of the observed, historical record remains a fundamental requirement of models, as does accurate simulation of key metrics, such as the effective climate sensitivity and the transient climate response to cumulative carbon emissions. For adaptation, a key demand is improved guidance on potential changes in climate extremes and the modes of variability these extremes develop within. Such improvements will most likely be realized through a combination of increased model resolution, improvement of key model parameterizations, and enhanced representation of important Earth system processes, combined with targeted use of new artificial intelligence (AI) and machine learning (ML) techniques. We propose a deeper collaboration across such efforts over the coming decade. With respect to sampling future uncertainty, increased collaboration between approaches that emphasize large model ensembles and those focussed on statistical emulation is required. We recommend an increased focus on high-impact–low-likelihood (HILL) outcomes – in particular, the risk and consequences of exceeding critical tipping points during a warming overshoot and the potential impacts arising from this. For a comprehensive assessment of the impacts of Earth system change, including impacts arising directly as a result of climate mitigation actions, it is important that spatially detailed, disaggregated information used to generate future scenarios in integrated assessment models be available for use in impact models. Conversely, there is a need to develop methods that enable potential societal responses to projected Earth system change to be incorporated into scenario development. The new models, simulations, data, and scientific advances proposed in this article will not be possible without long-term development and maintenance of a robust, globally connected infrastructure ecosystem. This system must be easily accessible and useable by modelling communities across the world, allowing the global research community to be fully engaged in developing and delivering new scientific knowledge to support international climate policy.

Abstract PhD students are particularly vulnerable to experiencing poor mental health. Mental health concerns that arise during their studies can not only affect their study progress but also have long-lasting impacts on their mental health after their studies. Extensive research has been conducted on the mental health of university students, but few studies have focused on PhD students and even fewer on PhD students in Australia. The present study investigated demographic, occupational, psychological, social, and relational determinants of mental health symptoms (depression, anxiety, and suicidality) in PhD students in Australia. PhD students enrolled in Australian universities were invited to complete an online survey. Results from regression analyses identified key determinants of mental health symptoms in our sample of PhD students (N = 302). In particular, higher levels of imposter thoughts, perfectionism discrepancy, and loneliness were strong predictors of depression, anxiety, and suicidality. These findings contribute to our understanding of the mental health of PhD students in Australia. Importantly, these findings inform areas of focus where potential strategies can be implemented to better protect the mental health of this population. For example, strategies that mitigate loneliness or foster effective, collaborative student-supervisor relationships.

Abstract The malaria parasites Plasmodium falciparum and Plasmodium vivax differ in key biological processes and associated clinical effects, but consequences on population-level transmission dynamics are difficult to predict. This co-endemic malaria study from Guyana details important epidemiological contrasts between the species by coupling population genomics (1396 spatiotemporally matched parasite genomes, primarily from 2020–21) with sociodemographic analysis (nationwide patient census from 2019). We describe how P. falciparum forms large, interrelated subpopulations that sporadically expand but generally exhibit restrained dispersal, whereby spatial distance and patient travel statistics predict parasite identity-by-descent (IBD). Case bias towards working-age adults is also strongly pronounced. P. vivax exhibits 46% higher average nucleotide diversity (π) and 6.5x lower average IBD. It occupies a wider geographic range, without evidence for outbreak-like expansions, only microgeographic patterns of isolation-by-distance, and weaker case bias towards adults. Possible latency-relapse effects also manifest in various analyses. For example, 11.0% of patients diagnosed with P. vivax in Greater Georgetown report no recent travel to endemic zones, and P. vivax clones recur in 11 of 46 patients incidentally sampled twice during the study. Polyclonality rate is also 2.1x higher than in P. falciparum, does not trend positively with estimated incidence, and correlates uniquely to selected demographics. We discuss possible underlying mechanisms and implications for malaria control.

Abstract Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.

Abstract The geosphere and the microbial biosphere have co-evolved for ~3.8 Ga, with many lines of evidence suggesting a hydrothermal habitat for life’s origin. However, the extent that contemporary thermophiles and their hydrothermal habitats reflect those that likely existed on early Earth remains unknown. To address this knowledge gap, 64 geochemical analytes were measured and 1022 metagenome-assembled-genomes (MAGs) were generated from 34 chemosynthetic high-temperature springs in Yellowstone National Park and analysed alongside 444 MAGs from 35 published metagenomes. We used these data to evaluate co-variation in MAG taxonomy, metabolism, and phylogeny as a function of hot spring geochemistry. We found that cohorts of MAGs and their functions are discretely distributed across pH gradients that reflect different geochemical provinces. Acidic or circumneutral/alkaline springs harbor MAGs that branched later and are enriched in sulfur- and arsenic-based O2-dependent metabolic pathways that are inconsistent with early Earth conditions. In contrast, moderately acidic springs sourced by volcanic gas harbor earlier-branching MAGs that are enriched in anaerobic, gas-dependent metabolisms (e.g. H2, CO2, CH4 metabolism) that have been hypothesized to support early microbial life. Our results provide insight into the influence of redox state in the eco-evolutionary feedbacks between thermophiles and their habitats and suggest moderately acidic springs as early Earth analogs.

Abstract T-cells play a critical role in multiple aspects of human health and disease. However, to date the genetic determinants of human T-cell abundance have not been studied at scale because assays quantifying T-cell abundance are not widely used in clinical or research settings. The complete blood count clinical assay quantifies lymphocyte abundance which includes T-cells, B-cells, and NK-cells. To address this gap, we directly estimate T-cell fractions from whole genome sequencing data in over 200,000 individuals from the multi-ethnic TOPMed and All of Us studies. We identified 27 loci associated with T-cell fraction. Interrogating electronic health records identified clinical phenotypes associated with T-cell fraction, including notable changes in T-cell proportions that were highly dynamic over the course of pregnancy. In summary, by estimating T-cell fraction, we obtained new insights into the genetic regulation of T-cells and identified disease consequences of T-cell fractions across the human phenome.

Abstract The greater amberjack Seriola dumerili is a promising candidate for aquaculture production. This study compares the ovary transcriptome of greater amberjack sampled in the wild (WILD) with hatchery-produced breeders reared in aquaculture sea cages in the Mediterranean Sea. Among the seven sampled cultured fish, three were classified as reproductively dysfunctional (DysF group), while four showed no signs of reproductive alteration (NormalF group). The DysF fish showed 1,166 differentially expressed genes (DEGs) compared to WILD females, and 755 DEGs compared to the NormalF. According to gene ontology (GO) analysis, DysF females exhibited enrichment of genes belonging to the biological categories classified as Secreted, ECM-receptor interaction, and Focal adhesion. Protein–protein interaction analysis revealed proteins involved in the biological categories of ECM-receptor interaction, Enzyme-linked receptor protein signaling, Wnt signal transduction pathways, and Ovulation cycle. KEGG pathway analysis showed DEGs involved in 111 pathways, including Neuroactive ligand-receptor interaction, Steroid hormone biosynthesis, Cell cycle, Oocyte meiosis, Necroptosis, Ferroptosis, Apoptosis, Autophagy, Progesterone-mediated oocyte maturation, Endocytosis and Phagosome, as well as Hedgehog, Apelin, PPAR, Notch, and GnRH signalling pathways. Additionally, DysF females exhibited factors encoded by upregulated genes associated with hypogonadism and polycystic ovary syndrome in mammals. This study -which is part of a broader research effort examining the transcriptome of the entire reproductive axis in greater amberjack of both sexes-, enhances our comprehension of the mechanisms underlying the appearance of reproductive dysfunctions when fish are reared under aquaculture conditions.

Abstract The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Abstract Since their first observation in 2017, atomically thin van der Waals (vdW) magnets have attracted significant fundamental, and application-driven attention. However, their low ordering temperatures, T c , sensitivity to atmospheric conditions and difficulties in preparing clean large-area samples still present major limitations to further progress, especially amongst van der Waals magnetic semiconductors. The remarkably stable, high-T c vdW magnet CrSBr has the potential to overcome these key shortcomings, but its nanoscale properties and rich magnetic phase diagram remain poorly understood. Here we use single spin magnetometry to quantitatively characterise saturation magnetization, magnetic anisotropy constants, and magnetic phase transitions in few-layer CrSBr by direct magnetic imaging. We show pristine magnetic phases, devoid of defects on micron length-scales, and demonstrate remarkable air-stability down the monolayer limit. We furthermore address the spin-flip transition in bilayer CrSBr by imaging the phase-coexistence of regions of antiferromagnetically (AFM) ordered and fully aligned spins. Our work will enable the engineering of exotic electronic and magnetic phases in CrSBr and the realization of novel nanomagnetic devices based on this highly promising vdW magnet.

It has been shown that a theoretically derived relation between annual global mean temperature variability and climate sensitivity held in the CMIP5 climate model ensemble (Cox et al., 2018a, hereafter CHW18). This so-called emergent relationship was then used with observations to constrain the value of equilibrium climate sensitivity (ECS) to about 3 °C. Since this study was published, CMIP6, a newer ensemble of climate models has become available. Schlund et al. (2020) showed that many of the emergent constraints found in CMIP5 were much weaker in the newer ensemble, including that of CHW18. As the constraint in CHW18 was based on a relationship derived from reasonable physical principles, it is of interest to find out why it is weaker in CMIP6. Here, we look in detail at the assumptions made in deriving the emergent relationship in CHW18 and test them for CMIP5 and CMIP6 models. We show one assumption, that of low correlation and variation between ECS and the internal variability parameter, a parameter that captures chaotic internal variability and sub-annual (fast) feedbacks, that while true for CMIP5 is not true for CMIP6. When accounted for, an emergent relationship appears once again in both CMIP ensembles, implying the theoretical basis is still applicable while the original assumption in CHW18 is not. Unfortunately, however, we are unable to provide an emergent constraint in CMIP6 as observational estimates of the internal variability parameter are too uncertain.

Abstract To explore complex biological questions, it is often necessary to access various data types from public data repositories. As the volume and complexity of biological sequence data grow, public repositories face significant challenges in ensuring that the data is easily discoverable and usable by the biological research community. To address these challenges, the National Center for Biotechnology Information (NCBI) has created NCBI Datasets. This resource provides straightforward, comprehensive, and scalable access to biological sequences, annotations, and metadata for a wide range of taxa. Following the FAIR (Findable, Accessible, Interoperable, and Reusable) data management principles, NCBI Datasets offers user-friendly web interfaces, command-line tools, and documented APIs, empowering researchers to access NCBI data seamlessly. The data is delivered as packages of sequences and metadata, thus facilitating improved data retrieval, sharing, and usability in research. Moreover, this data delivery method fosters effective data attribution and promotes its further reuse. This paper outlines the current scope of data accessible through NCBI Datasets and explains various options for exploring and downloading the data.

Abstract The microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1’s activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints.

Abstract Frailty is a complex trait. Twin studies and high-powered Genome Wide Association Studies conducted in the UK Biobank have demonstrated a strong genetic basis of frailty. The present study utilized summary statistics from a Genome Wide Association Study on the Frailty Index to create and test the predictive power of frailty polygenic risk scores (PRS) in two independent samples – the Lothian Birth Cohort 1936 (LBC1936) and the English Longitudinal Study of Ageing (ELSA) aged 67–84 years. Multiple regression models were built to test the predictive power of frailty PRS at five time points. Frailty PRS significantly predicted frailty, measured via the FI, at all-time points in LBC1936 and ELSA, explaining 2.1% (β = 0.15, 95%CI, 0.085–0.21) and 1.8% (β = 0.14, 95%CI, 0.10–0.17) of the variance, respectively, at age ~ 68/ ~ 70 years (p

Abstract Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10−9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10−16 and CPA3; p = 2.39 × 10−14) and wound healing (FN1; p = 7.63 × 10−9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.

Abstract Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age‐related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age‐associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5–22.1 years (human equivalent ≈30–88 years). Weighted‐gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism‐oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty‐acid β‐oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose‐dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix‐induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy‐related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age‐related cardiac diseases, offering novel insights into early age‐related mechanisms.

Recent decadal trends of deoxygenation in the global ocean interior have resulted in the expansion and shoaling of oxygen minimum zones (OMZs). When the OMZs upper bound nears the euphotic zone a unique community of phytoplankton, residing in extremely low light (

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations.

Density-dependent competition for food influences the foraging behaviour and demography of colonial animals, but how this influence varies across a species’ latitudinal range is poorly understood. Here we used satellite tracking from 21 Northern Gannet Morus bassanus colonies (39% of colonies worldwide, supporting 73% of the global population) during chick-rearing to test how foraging trip characteristics (distance and duration) covary with colony size (138–60 953 breeding pairs) and latitude across 89% of their latitudinal range (46.81–71.23° N). Tracking data for 1118 individuals showed that foraging trip duration and maximum distance both increased with square-root colony size. Foraging effort also varied between years for the same colony, consistent with a link to environmental variability. Trip duration and maximum distance also decreased with latitude, after controlling for colony size. Our results are consistent with density-dependent reduction in prey availability influencing colony size and reveal reduced competition at the poleward range margin. This provides a mechanism for rapid population growth at northern colonies and, therefore, a poleward shift in response to environmental change. Further work is required to understand when and how colonial animals deplete nearby prey, along with the positive and negative effects of social foraging behaviour.

Summary: Abdominal and thoracic aortic aneurysms (AAAs, TAAs) remain a major cause of deaths worldwide, in part due to the lack of reliable prognostic markers or early warning signs. Sox6 has been found to regulate renin controlling blood pressure. We hypothesized that Sox6 may serve as an important regulator of the mechanisms contributing to hypertension-induced aortic aneurysms. Phenotype and laboratory-wide association scans in a clinical cohort found that SOX6 gene expression is associated with aortic aneurysm in subjects of European ancestry. Sox6 and tumor necrosis factor alpha (TNF-α) expression were upregulated in aortic tissues from patients affected by either AAA or TAA. In Sox6 knockout mice with angiotensin-II-induced AAA, we found that Sox6 plays critical role in the development and progression of AAA. Our data support a regulatory role of SOX6 in the development of hypertension-induced AAA, suggesting that Sox6 may be a therapeutic target for the treatment of aortic aneurysms.

Abstract The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus (NiV). RV3, previously known as parainfluenza type 3, for which no vaccines or antivirals have been approved, causes respiratory tract infections in vulnerable populations. The RV3 fusion (F) protein is inherently metastable and will likely require prefusion (preF) stabilization for vaccine effectiveness. Here we used structure-based design to stabilize regions involved in structural transformation to generate a preF protein vaccine antigen with high expression and stability, and which, by stabilizing the coiled-coil stem region, does not require a heterologous trimerization domain. The preF candidate induces strong neutralizing antibody responses in both female naïve and pre-exposed mice and provides protection in a cotton rat challenge model (female). Despite the evolutionary distance of paramyxovirus F proteins, their structural transformation and local regions of instability are conserved, which allows successful transfer of stabilizing substitutions to the distant preF proteins of RV1 and NiV. This work presents a successful vaccine antigen design for RV3 and provides a toolbox for future paramyxovirus vaccine design and pandemic preparedness.

Abstract The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1–42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0–23) hospitalisations with epilepsy and 4 (95%CI 0–6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

Abstract Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Abstract The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-β (Aβ) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aβ plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aβ1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aβ clearance and accumulation of amyloid plaques.

Abstract Highlanders and lowlanders of Papua New Guinea have faced distinct environmental stress, such as hypoxia and environment-specific pathogen exposure, respectively. In this study, we explored the top genomics regions and the candidate driver SNPs for selection in these two populations using newly sequenced whole-genomes of 54 highlanders and 74 lowlanders. We identified two candidate SNPs under selection - one in highlanders, associated with red blood cell traits and another in lowlanders, which is associated with white blood cell count – both potentially influencing the heart rate of Papua New Guineans in opposite directions. We also observed four candidate driver SNPs that exhibit linkage disequilibrium with an introgressed haplotype, highlighting the need to explore the possibility of adaptive introgression within these populations. This study reveals that the signatures of positive selection in highlanders and lowlanders of Papua New Guinea align closely with the challenges they face, which are specific to their environments.

Abstract Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Abstract Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

Abstract DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Abstract Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1β) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production—all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation.

Background Identifying stars belonging to different classes is vital in order to build up statistical samples of different phases and pathways of stellar evolution. In the era of surveys covering billions of stars, an automated method of identifying these classes becomes necessary. Methods Many classes of stars are identified based on their emitted spectra. In this paper, we use a combination of the multi-class multi-label Machine Learning (ML) method XGBoost and the PySSED spectral-energy-distribution fitting algorithm to classify stars into nine different classes, based on their photometric data. The classifier is trained on subsets of the SIMBAD database. Particular challenges are the very high sparsity (large fraction of missing values) of the underlying data as well as the high class imbalance. We discuss the different variables available, such as photometric measurements on the one hand, and indirect predictors such as Galactic position on the other hand. Results We show the difference in performance when excluding certain variables, and discuss in which contexts which of the variables should be used. Finally, we show that increasing the number of samples of a particular type of star significantly increases the performance of the model for that particular type, while having little to no impact on other types. The accuracy of the main classifier is ∼0.7 with a macro F1 score of 0.61. Conclusions While the current accuracy of the classifier is not high enough to be reliably used in stellar classification, this work is an initial proof of feasibility for using ML to classify stars based on photometry.

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread in the population. We recently reported the production of bovine colostrum-derived antibodies that can neutralize the virus. These have been formulated into a nasal spray. The immunoglobulin preparation is capable of blocking interaction of the trimeric spike protein (Tri S) of SARS-CoV-2 with the cellular receptor angiotensin-converting enzyme 2 (ACE2), entry of a pseudovirus carrying the Tri S into ACE2 over-expressing human embryonic kidney (HEK) cells, and entry of the virus into live Vero E6 cells. Using an ELISA assay, we demonstrate here that this holds true for different SARS-CoV-2 variants of concern. Using the ferret transmission model, we show that the nasal spray formulation of anti-SARS-CoV-2 immunoglobulins efficiently blocks transmission of SARS-CoV-2 from infected to uninfected ferrets. The results indicate that the use of the nasal spray in humans can add an effective additional layer of protection against the virus, and might be applicable for other viruses of the upper respiratory tract.

This study aims to develop an automated framework for the characterization of materials which are both hyper-elastic and viscoelastic. This has been evaluated using human articular cartilage (AC). AC (26 tissue samples from 5 femoral heads) underwent dynamic mechanical analysis with a frequency sweep from 1 to 90 Hz. The conversion from a frequency- to time-domain hyper-viscoelastic material model was approximated using a modular framework design where finite element analysis was automated, and a genetic algorithm and interior point technique were employed to solve and optimize the material approximations. Three orders of approximation for the Prony series were evaluated at N = 1, 3 and 5 for 20 and 50 iterations of a genetic cycle. This was repeated for 30 simulations of six combinations of the above all with randomly generated initialization points. There was a difference between N = 1 and N = 3/5 of approximately ~5% in terms of the error estimated. During unloading the opposite was seen with a 10% error difference between N = 5 and 1. A reduction of ~1% parameter error was found when the number of generations increased from 20 to 50. In conclusion, the framework has proved effective in characterizing human AC.

Abstract In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.

Antarctic krill (Euphausia superba) aggregations are important in the Southern Ocean ecosystem; however, the amount of energy that krill swarms contain is unknown. We assessed the population structure of E. superba swarms in East Antarctica for two different sectors corresponding to the study areas of the ENRICH (2019) and TEMPO (2021) voyages. We also estimated swarm energy content based on calorific values for whole animals and key tissues (gonads, digestive gland, and muscle). A relationship between the energy content of muscle and gonads in gravid and adult females was detected: The higher the energy content in muscle tissue, the lower the energy content in the gonad tissue. This relationship was consistent for different female maturity stages, suggesting a trade-off in energy allocation between somatic growth and reproduction. Females will redirect energy to gonad development at the expense of somatic growth. Total swarm energy was calculated using the volumetric density of each swarm estimated from an acoustic survey. Four swarm types (A-D) were determined based on the body length and maturity stage of the individuals. The highest energy contents were found in Type B swarms, composed predominantly of adult males and females, and Type D swarms, comprising mostly gravid females. Trends in swarm demographic composition and energy content were consistent between surveys. We recommend swarm energy be incorporated into ecosystem models to represent energy transfer to top predators.

Summary: Key to a biologists’ capacity to understand data is the ability to make meaningful conclusions about differences in experimental observations. Typically, data are noisy, and conventional methods rely on replicates to average out noise and enable univariate statistical tests to assign p-values. Yet thresholding p-values to determine significance is controversial and often misleading, especially for omics datasets with few replicates. This study introduces PERCEPT, an alternative that transforms data using an ad-hoc scaling factor derived from p-values. By applying this method, low confidence effects are suppressed compared to high confidence ones, enabling clearer patterns to emerge from noisy datasets. The effectiveness of PERCEPT scaling is demonstrated using simulated datasets and published omics studies. The approach reduces the exclusion of datapoints, enhances accuracy, and enables nuanced interpretation of data. PERCEPT is easy to apply for the non-expert in statistics and provides researchers a straightforward way to improve data-driven analyses.

Abstract Earth System Models (ESMs) continue to diagnose a wide range of carbon budgets for each level of global warming. Here, we present emergent constraints on the carbon budget as a function of global warming, which combine the available ESM historical simulations and future projections for a range of scenarios, with observational estimates of global warming and anthropogenic CO2 emissions to the present day. We estimate mean and likely ranges for cumulative carbon budgets for the Paris targets of 1.5 °C and 2 °C of global warming of 812 [691, 933] PgC and 1048 [881, 1216] PgC, which are more than 10% larger than the ensemble mean values from the CMIP6 models. The linearity between cumulative emissions and global warming is found to be maintained at least until 4 °C, and is consistent with an effective Transient Climate Response to Emissions (eTCRE) of 2.1 [1.8, 2.6] °C/1000PgC, from a global warming of 1.2 °C onwards.

Abstract Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.

Abstract Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals with mosaic continental ancestry backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across segments with shared ancestry in admixed genomes. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses for traits with associated variants exhibiting ancestral-differential effects. Leveraging data from the Women’s Health Initiative study, we show that GAUDI improves PRS prediction of white blood cell count and C-reactive protein in African Americans by > 64% compared to alternative methods, and even outperforms PRS-CSx with large European GWAS for some scenarios. We believe GAUDI will be a valuable tool to mitigate disparities in PRS performance in admixed individuals.

Abstract Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.

The International Guidelines on Human Rights and Drug Policy recommend that states commit to adopting a balanced, integrated, and human rights-based approach to drug policy through a set of foundational human rights principles, obligations arising from human rights standards, and obligations arising from the human rights of particular groups. In respect of the Guidelines and standing obligations under UN Treaties, Canada must adopt stronger and more specific commitments for a human rights-based, people-centered, and public health approach. This approach must commit to the decriminalization of people who use drugs and include the decriminalization of possession, purchase, and cultivation for personal consumption. In this report, we will first turn to the legal background of Canada's drug laws. Next, we will provide an overview of ongoing law reform proposals from civil society groups, various levels of government, the House of Commons, and the Senate. We end with a three-staged approach to reform and a series of targeted recommendationscr.

Abstract A working group from the Global Library of Underwater Biological Sounds effort collaborated with the World Register of Marine Species (WoRMS) to create an inventory of species confirmed or expected to produce sound underwater. We used several existing inventories and additional literature searches to compile a dataset categorizing scientific knowledge of sonifery for 33,462 species and subspecies across marine mammals, other tetrapods, fishes, and invertebrates. We found 729 species documented as producing active and/or passive sounds under natural conditions, with another 21,911 species deemed likely to produce sounds based on evaluated taxonomic relationships. The dataset is available on both figshare and WoRMS where it can be regularly updated as new information becomes available. The data can also be integrated with other databases (e.g., SeaLifeBase, Global Biodiversity Information Facility) to advance future research on the distribution, evolution, ecology, management, and conservation of underwater soniferous species worldwide.

Abstract Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This “cell biopsy” method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.

Abstract Nicotine vaping products (NVPs) and heated tobacco products (HTPs) are designed to replicate the sensory and behavioural aspects of smoking cigarettes while avoiding combustion. The success of these products as harm reduction tools will partially depend on their ability to satisfy smokers and alleviate nicotine-related withdrawal symptoms. This study aims to compare short-term effects of NVPs (Juul and Aspire PockeX) versus HTPs (IQOS) on smoking-related withdrawal relief, product satisfaction, intention to switch to NVP/HTP, perceptions and attitudes in UK adult cigarette smokers naïve to these products. In a randomized cross-over study, 45 participants visited the lab twice, at each visit trying one of the two products (NVP/HTP) and completing a questionnaire. Responses were normalized on a 0–100% scale and mean differences (MD) between NVP and HTP scores computed, with positive and negative MD values indicating greater endorsement for NVP and HTP, respectively. Cigarette cravings were reduced similarly (~ 20.0%) by both products (MD = 4.5%, 95%Confidence Interval (CI) − 4.8, 13.8). Direct positive effects (MD = − 3.5%, 95%CI − 7.2, 0.2) and adverse side effects (MD = 1.8%, 95%CI − 0.3, 3.8) were comparable after each product use, though marginally favouring HTPs. HTPs were perceived as more satisfying overall (MD = − 13.2%, 95%CI − 20.3 − 6.1) than NVPs but both were perceived as similarly addictive (MD = 3.6%, 95%CI − 4.6, 11.8), relative to cigarettes. Intention to switch to either product was comparable (MD = 4.0%, 95%CI − 5.7, 13.8). Comparison of acute use of NVP versus HTP in a sample of UK smokers naïve to these products suggests that HTPs are perceived as more satisfying than NVPs, though still less satisfying than cigarettes. Registration: The analysis plan was pre-registered, and it is available at https://osf.io/6ymdu

Abstract Information exchange between two distant parties, where information is shared without physically transporting it, is a crucial resource in future quantum networks. Doing so with high-dimensional states offers the promise of higher information capacity and improved resilience to noise, but progress to date has been limited. Here we demonstrate how a nonlinear parametric process allows for arbitrary high-dimensional state projections in the spatial degree of freedom, where a strong coherent field enhances the probability of the process. This allows us to experimentally realise quantum transport of high-dimensional spatial information facilitated by a quantum channel with a single entangled pair and a nonlinear spatial mode detector. Using sum frequency generation we upconvert one of the photons from an entangled pair resulting in high-dimensional spatial information transported to the other. We realise a d = 15 quantum channel for arbitrary photonic spatial modes which we demonstrate by faithfully transferring information encoded into orbital angular momentum, Hermite-Gaussian and arbitrary spatial mode superpositions, without requiring knowledge of the state to be sent. Our demonstration merges the nascent fields of nonlinear control of structured light with quantum processes, offering a new approach to harnessing high-dimensional quantum states, and may be extended to other degrees of freedom too.