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Abstract N. gonorrhoeae, which causes the sexually transmissible infection gonorrhoea, remains a significant public health threat globally, with challenges posed by increasing transmission and antimicrobial resistance (AMR). The COVID-19 pandemic introduced exceptional circumstances into communicable disease control, impacting the transmission of gonorrhoea and other infectious diseases. Through phylogenomic and phylodynamic analysis of 5881 N. gonorrhoeae genomes from Australia, we investigated N. gonorrhoeae transmission over five years, including a time period during the COVID-19 pandemic. Using a novel cgMLST-based genetic threshold, we demonstrate persistence of large N. gonorrhoeae genomic clusters over several years, with some persistent clusters associated with heterosexual transmission. We observed a decline in both N. gonorrhoeae transmission and genomic diversity during the COVID-19 pandemic, suggestive of an evolutionary bottleneck. The longitudinal, occult transmission of N. gonorrhoeae over many years further highlights the urgent need for improved diagnostic, treatment, and prevention strategies for gonorrhoea.

Abstract How we move our bodies affects how we perceive sound. For instance, head movements help us to better localize the source of a sound and to compensate for asymmetric hearing loss. However, many auditory experiments are designed to restrict head and body movements. To study the role of movement in hearing, we developed a behavioral task called sound-seeking that rewarded freely moving mice for tracking down an ongoing sound source. Over the course of learning, mice more efficiently navigated to the sound. Next, we asked how sound-seeking was affected by hearing loss induced by surgical removal of the malleus from the middle ear. After bilateral hearing loss sound-seeking performance drastically declined and did not recover. In striking contrast, after unilateral hearing loss mice were only transiently impaired and then recovered their sound-seek ability over about a week. Throughout recovery, unilateral mice increasingly relied on a movement strategy of sequentially checking potential locations for the sound source. In contrast, the startle reflex (an innate auditory behavior) was preserved after unilateral hearing loss and abolished by bilateral hearing loss without recovery over time. In sum, mice compensate with body movement for permanent unilateral damage to the peripheral auditory system. Looking forward, this paradigm provides an opportunity to examine how movement enhances perception and enables resilient adaptation to sensory disorders.

Abstract Converging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX3CR1+ and CSF1R+ source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and formation of perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally.

Abstract The long and very long chain polyunsaturated fatty acids (LC-PUFAs) are preferentially transported by the mother to the fetus. Failure to supply LC-PUFAs is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting imperfectly understood interactions between dietary fatty acid intake and the molecular mechanisms of maternal supply. Here we employ a comprehensive approach combining untargeted and targeted lipidomics with transcriptional profiling of maternal and fetal tissues in mouse pregnancy. Comparison of wild-type mice with genetic models of impaired lipid metabolism allows us to describe maternal hepatic adaptations required to provide LC-PUFAs to the developing fetus. A late pregnancy-specific, selective activation of the Liver X Receptor signalling pathway dramatically increases maternal supply of LC-PUFAs within circulating phospholipids. Crucially, genetic ablation of this pathway in the mother reduces LC-PUFA accumulation by the fetus, specifically of docosahexaenoic acid (DHA), a critical nutrient for brain development.

Abstract We used a probabilistic reversal learning task to examine prediction error-driven belief updating in three clinical groups with psychosis or psychosis-like symptoms. Study 1 compared people with at-risk mental state and first episode psychosis (FEP) to matched controls. Study 2 compared people diagnosed with treatment-resistant schizophrenia (TRS) to matched controls. The design replicated our previous work showing ketamine-related perturbations in how meta-level confidence maintained behavioural policy. We applied the same computational modelling analysis here, in order to compare the pharmacological model to three groups at different stages of psychosis. Accuracy was reduced in FEP, reflecting increased tendencies to shift strategy following probabilistic errors. The TRS group also showed a greater tendency to shift choice strategies though accuracy levels were not significantly reduced. Applying the previously-used computational modelling approach, we observed that only the TRS group showed altered confidence-based modulation of responding, previously observed under ketamine administration. Overall, our behavioural findings demonstrated resemblance between clinical groups (FEP and TRS) and ketamine in terms of a reduction in stabilisation of responding in a noisy environment. The computational analysis suggested that TRS, but not FEP, replicates ketamine effects but we consider the computational findings preliminary given limitations in performance of the model.

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 Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants’ second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.

Abstract As spaceflight becomes more common with commercial crews, blood-based measures of crew health can guide both astronaut biomedicine and countermeasures. By profiling plasma proteins, metabolites, and extracellular vesicles/particles (EVPs) from the SpaceX Inspiration4 crew, we generated “spaceflight secretome profiles,” which showed significant differences in coagulation, oxidative stress, and brain-enriched proteins. While >93% of differentially abundant proteins (DAPs) in vesicles and metabolites recovered within six months, the majority (73%) of plasma DAPs were still perturbed post-flight. Moreover, these proteomic alterations correlated better with peripheral blood mononuclear cells than whole blood, suggesting that immune cells contribute more DAPs than erythrocytes. Finally, to discern possible mechanisms leading to brain-enriched protein detection and blood-brain barrier (BBB) disruption, we examined protein changes in dissected brains of spaceflight mice, which showed increases in PECAM-1, a marker of BBB integrity. These data highlight how even short-duration spaceflight can disrupt human and murine physiology and identify spaceflight biomarkers that can guide countermeasure development.

Abstract Adaptive laboratory evolution experiments provide a controlled context in which the dynamics of selection and adaptation can be followed in real-time at the single-nucleotide level. And yet this precision introduces hundreds of degrees-of-freedom as genetic changes accrue in parallel lineages over generations. On short timescales, physiological constraints have been leveraged to provide a coarse-grained view of bacterial gene expression characterized by a small set of phenomenological parameters. Here, we ask whether this same framework, operating at a level between genotype and fitness, informs physiological changes that occur on evolutionary timescales. Using a strain adapted to growth in glucose minimal medium, we find that the proteome is substantially remodeled over 40 000 generations. The most striking change is an apparent increase in enzyme efficiency, particularly in the enzymes of lower-glycolysis. We propose that deletion of metabolic flux-sensing regulation early in the adaptation results in increased enzyme saturation and can account for the observed proteome remodeling.

Abstract The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.

Abstract In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe–critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p

Abstract Airborne transmission of SARS-CoV-2 aerosol remains contentious. Importantly, whether cough or breath-generated bioaerosols can harbor viable and replicating virus remains largely unclarified. We performed size-fractionated aerosol sampling (Andersen cascade impactor) and evaluated viral culturability in human cell lines (infectiousness), viral genetics, and host immunity in ambulatory participants with COVID-19. Sixty-one percent (27/44) and 50% (22/44) of participants emitted variant-specific culture-positive aerosols 95%). There is considerable heterogeneity in potential infectiousness i.e., only 29% of participants were probably highly infectious (produced culture-positive aerosols

Abstract In the UK nearly 54,000 infections were caused by serious resistant bacteria in 2022 but there is a lack of evidence regarding the long-term impact on patients’ lives nor what support they need. This research aimed to answer the question: “What are the key elements of experience and support needs of people living with AMR in the UK?”. In-depth semi-structured interviews were undertaken with nine people who had been living with resistant infections or colonisation for 12-months or longer. Interpretive Phenomenological Analysis was used to study the accounts and illustrate individuals’ experiences and support-needs. Participants experienced marginalisation and isolation but also empowerment; described across three major themes: (1) I live in fear and stigma: The long-term impact of AMR; (2) I am battling on my own: A journey toward self-advocacy; and (3) I like to share my story: The role of AMR communities. All participants perceived a lack of knowledge, information, and support from clinicians; difficulties accessing reliable and understandable information; and lack of understanding from family and friends. Charities and online groups provided support with coping with their situation and improving mental health and wellbeing. Understandable and relatable information regarding the science of AMR, transmission, prevention, and living with AMR needs to be provided by clinicians and healthcare services around the time of diagnosis to readily available after diagnosis.

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 CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Background The concept of core outcome sets (COS) has been introduced in China for about 10 years. In recent years, some Chinese researchers also committed to developing COS, though the majority of COS are ongoing. However, there were more than 500 published COS for research in the COMET database by 2020. The extent of availability of COS for the top 25 diseases with the highest burden in China is unknown. In addition, the uptake of COS in clinical trials for these diseases is unknown, along with the knowledge, perceptions, and views of the clinical trialist community in China on the use of COS in relation to choosing outcomes for their research. Methods The main burden of disease in China will be identified. Then we will search the COMET database to identify if there are ongoing or completed relevant COS research A COS published since 2012 would be preferred to one published before 2012 for the analysis of COS uptake if one meets the eligibility criteria. We will extract scopes of published eligible COS, including condition, population, interventions, and core outcomes. Then we will search the Chinese Clinical Trial Registry using disease names for each disease that has a published COS. We will assess the overlap in scope between clinical trials and COS. Then we will conduct an online survey and semi-structured interviews to identify the knowledge and perceptions of COS among primary investigators of included clinical trials. Discussion This research will fill in gaps between COS and the burden of disease in China. Understanding clinical trialists’knowledge and perceptions of COS may help dissemination and application of COS in the future. Trial registration This research is registered in Core Outcome Measures in Effectiveness: https://www.comet-initiative.org/Studies/Details/2563.

Porphyry-type Cu ± Au ± Mo deposits form in the upper (ca. 2–5 km deep) parts of large, long-lived magmatic-hydrothermal systems in which mineralising fluids are thought to be derived from mid-to shallow-crustal magma chambers. Increasingly, however, magmatic systems are viewed as consisting of mush with minor and transient lenses of magma, with mush being a variably packed framework of crystals with interstitial melt and magmatic volatile phase (MVP). In this context, questions remain as to the source (mainly depth) and mechanisms of transport and focussing of the vast volumes of fluids required for shallow level porphyry-type mineralisation. Even more problematic is a paucity of first-order textural evidence for the presence of mush in magmatic-hydrothermal systems, including those which host porphyry-type deposits. To address this, we have studied the aplitic porphyry cupola of the Saginaw Hill magmatic system, Tuscon, Arizona, United States, where magmatic-hydrothermal features are exceptionally well exposed, including a massive silica cap, quartz unidirectional solidification textures (USTs), stockworks of multiple generations of variably mineralised quartz veins and mineralised miarolitic cavities. From field-to micro-scale textural and geochemical studies, particularly observations of vermiform quartz between earlier generations of magmatic quartz and feldspar, we evidence the development of fluid pathways through mush at the magmatic-hydrothermal transition. These are shown to connect and provide fluids and ore constituents to the mineralised miarolitic cavities and early quartz vein stockworks. We suggest that this process should be considered in all new genetic, exploration and numerical models for porphyry and similar types of magmatic-hydrothermal ore-deposits.

Wearable robotic exoskeletons designed to assist human movement should integrate with the neuromusculoskeletal system. This means assisting movement while not perturbing motor control. We sought to test if passive ankle exoskeletons, which have been shown to successfully assist human gait, affect neuromuscular control of an exaggerated anterior–posterior standing sway task. Participants actively swayed while wearing an ankle exoskeleton that provided 0, 42 or 85 Nm rad−1 of additional stiffness to the ankle joint in resistance to dorsiflexion. Sway amplitude was controlled via biofeedback to elicit similar ankle angle displacements across conditions. With greater exoskeleton stiffness, participants swayed at lower sway-cycle frequencies and slower centre of pressure speeds. Furthermore, increasing exoskeleton stiffness resulted in longer operating lengths of the medial gastrocnemius and overall reduced plantar flexor muscle activation. For the soleus, there was also a temporal shift in the cross-correlation of its electromyogram with the centre of pressure displacement, meaning that muscle activation peaked later than anterior sway displacement. Together, these data suggest that assistive ankle exoskeletons influence neuromuscular control of ankle-based sway tasks. Changes in fascicle lengths could influence afferent feedback signals and the short-range stiffness of ankle muscles, while shifts in muscle activation timing suggest changes in neural control. The observed neuromuscular adaptations to exoskeleton assistance demonstrate the potential implications for standing balance and overall movement control, prompting future investigations.

Abstract Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Abstract The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Abstract The conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS1) using 19F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS1. Numerical analysis of the kinetic data of neurotensin binding to NTS1 shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs.

Abstract Studying animal models furthers our understanding of Parkinson’s disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson’s disease in mice.

Abstract In childhood, language outcomes following brain injury are inversely related to age. Neuroimaging findings suggest that extensive representation and/or topological redundancy may confer the pediatric advantage. Here, we assess whole brain and language network resilience using in silico attacks, for 85 children participating in a magnetoencephalography (MEG) study. Nodes are targeted based on eigenvector centrality, betweenness centrality, or at random. The size of each connected component is assessed after iterated node removal; the percolation point, or moment of dis-integration, is defined as the first instance where the second largest component peaks in size. To overcome known effects of fixed thresholding on subsequent graph and resilience analyses, we study percolation across all possible network densities, within a Functional Data Analysis (FDA) framework. We observe age-related increases in vulnerability for random and betweenness centrality-based attacks for whole-brain and stories networks (adjusted-p

Coastal and ocean management in the United States is a complex issue requiring an equally complex management policy. Federal policy has historically been carried out in a siloed (sector-by-sector) fashion causing inefficient and bureaucratic management by federal agencies. The Obama administration took a novel approach to coastal and ocean management by signing an executive order that brought together federal agencies and empowered regional stakeholders, creating a first of its kind comprehensive National Ocean Policy. In 2018, former President Donald Trump rescinded the Obama-era policy and enacted his own version of National Ocean Policy that shifted authority to the states and focused on the economic potential of American waters. This research addresses a significant challenge in federal management of a complex natural resource. Here we identify common management strategies between different administrations to provide insights for future attempts at National Ocean Policy. We collect policy documents, press releases, and congressional testimony from high-level stakeholders and identified the most common themes over a 12-year period from 2009-2021. We find three common themes between the administrations even though their policies varied in strategy and scope: 1) the importance of a strong and enduring marine economy, 2) creating a strategic and efficient ocean policy, and 3) devolving authority from the federal government to state and regional decision-makers. We argue that coastal and ocean management via executive order is too easily rescinded to have a lasting impact. These novel findings highlight potential strategies for bipartisan cooperation in future attempts at National Ocean Policy.

Background Digital health literacy (DHL) is the ability to find, understand, and appraise online health-related information, as well as apply it to health behavior. It has become a core competence for navigating online information and health service environments. DHL involves solving ill-structured problems, where the problem and its solution are not clearcut and may have no single answer, such as in the process of sensemaking. We employ and expand on information foraging theory to address how experts and novices in information retrieval perform a search task. Our overarching aim is to pinpoint best practices and pitfalls in understanding and appraising health-related information online to develop a digital intervention to increase DHL and critical thinking. Methods In this feasibility study, we recruited a total of twenty participants for our expert and novice subsamples. We collected sociodemographic data with a self-developed survey, video data through an observation protocol of a 10-minute search task, as well as audio-video data via a retrospective think-aloud. The three, multimodal data streams were transcribed and aligned. Codes were developed inductively in several iterations, then applied deductively to the entire dataset. Tabularized, coded and segmented qualitative data were used to create various quantitative models, which demonstrate viability for the qualitative and statistical comparison of our two subsamples. Results Data were visualized with Epistemic Network Analysis to analyze code co-occurrences in the three aligned data streams, and with Qualitative/Unified Exploration of State Transitions to examine the order in which participants in our two subsamples encountered online content. Conclusions This paper describes our methods and planned analyses elaborated with mock figures. Quantifying qualitative data, aligning data streams, and representing all information in a tabularized dataset allows us to group data according to various participant attributes and employ data visualization techniques to pinpoint patterns therein.

Background The concept of core outcome sets (COS) has been introduced in China for about 10 years. In recent years, some Chinese researchers also committed to developing COS, though the majority of COS are ongoing. However, there were more than 500 published COS for research in the COMET database by 2020. The extent of availability of COS for the top 25 diseases with the highest burden in China is unknown. In addition, the uptake of COS in clinical trials for these diseases is unknown, along with the knowledge, perceptions, and views of the clinical trialist community in China on the use of COS in relation to choosing outcomes for their research. Methods The main burden of disease in China will be identified. Then we will search the COMET database to identify if there are ongoing or completed relevant COS research A COS published since 2012 would be preferred to one published before 2012 for the analysis of COS uptake if one meets the eligibility criteria. We will extract scopes of published eligible COS, including condition, population, interventions, and core outcomes. Then we will search the Chinese Clinical Trial Registry using disease names for each disease that has a published COS. We will assess the overlap in scope between clinical trials and COS. Then we will conduct an online survey and semi-structured interviews to identify the knowledge and perceptions of COS among primary investigators of included clinical trials. Discussion This research will fill in gaps between COS and the burden of disease in China. Understanding clinical trialists’knowledge and perceptions of COS may help dissemination and application of COS in the future. Trial registration This research is registered in Core Outcome Measures in Effectiveness: https://www.comet-initiative.org/Studies/Details/2563.

Abstract Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

Abstract Current guidelines recommend office blood pressures (BP) be taken in a seated position when screening for hypertension (HTN). Seated BP is known to have limited accuracy in detecting high BP, while the utility of standing BP in diagnosing HTN is unknown. We conducted a cross-sectional study to determine the incremental value of standing BP in diagnosing HTN. Seated, standing, and 24-h ambulatory BPs (ABPM) were obtained in adults without known cardiovascular disease, HTN, or BP medication use. Presence of HTN was defined by the 2017 ACC/AHA and the 2023 ESH HTN guidelines based on ABPM. Area under the receiver-operating-characteristic curve (AUROC) was used to evaluate the diagnostic accuracy of seated and standing BP. Sensitivity and specificity of standing BP was determined using cut-offs derived from Youden’s Index, while sensitivity and specificity of seated BP was determined using the cut-off of 130/80 mmHg and by 140/90 mmHg. Among 125 participants (mean age 49 ± 17 years; 62% female; 24% Black), 33.6% of them had HTN. Sensitivity and specificity of seated systolic BP (SBP) was 43% and 92%, respectively. Cut-offs selected by Youden’s index for standing SBP/diastolic BP (DBP) were 124/81 mmHg according to the 2017 ACC/AHA HTN guidelines, and 123.5/83.5 mmHg according to the 2023 ESH HTN guidelines. Sensitivity and specificity of standing SBP was 71% and 67%, respectively. The AUROC of standing SBP (0.81 [0.71–0.92]) was significantly higher than seated SBP (0.70 [0.49–0.91]), when HTN was defined as average 24-h SBP ≥ 125 mmHg. Moreover, the addition of standing to seated SBP (0.80 [0.68–0.92]) improved HTN detection when compared to seated SBP. These patterns were consistent for both the 2017 ACC/AHA and the 2023 ESH definitions for HTN. In summary, standing BP, alone or in combination with seated BP, outperformed seated BP alone in diagnosing HTN in adults.

Abstract The present study successfully combined a stoichiometric bioenergetic approach with an endpoint stochastic model to simultaneously determine specific dynamic action, metabolic substrate use and whole-body protein synthesis in juvenile slipper lobster Thenus australiensis. Juvenile lobsters were fasted for 48 h to investigate routine metabolism before receiving a single meal of formulated feed containing 1% 15N-labeled Spirulina. Postprandial oxygen consumption rate, dissolved inorganic carbon, and total nitrogen excretion returned to the pre-feeding level within 24 h. The rate of whole-body protein synthesis was 0.76 ± 0.15 mg CP g−1 day−1, with a significant reduction from 24 to 48 h post-feeding. The postprandial increase in whole-body protein synthesis accounted for 13–19% of total oxygen uptake. Protein was the primary energy substrate for 48 h fasted (45% oxygen consumption) and post-feeding lobster (44%), suggesting that dietary protein was not efficiently used for growth. The secondary energy substrate differed between carbohydrates in 48 h fasted and lipids in post-feeding lobsters. The present study recommends integrating protein synthesis into protein requirement experiments of marine ectotherms to acquire a more comprehensive picture of protein and energy metabolism and nutritional physiology crucial for formulating cost-effective aquafeeds.

Abstract Assembly of ribosomes in bacteria is highly efficient, taking ~2-3 min, but this makes the abundance of assembly intermediates very low, which is a challenge for mechanistic understanding. Genetic perturbations of the assembly process create bottlenecks where intermediates accumulate, facilitating structural characterization. We use cryo-electron microscopy, with iterative subclassification to identify intermediates in the assembly of the 50S ribosomal subunit from E. coli. The analysis of the ensemble of intermediates that spans the entire biogenesis pathway for the 50 S subunit was facilitated by a dimensionality reduction and cluster picking approach using PCA-UMAP-HDBSCAN. The identity of the cooperative folding units in the RNA with associated proteins is revealed, and the hierarchy of these units reveals a complete assembly map for all RNA and protein components. The assembly generally proceeds co-transcriptionally, with some flexibility in the landscape to ensure efficiency for this central cellular process under a variety of growth conditions.

Abstract A great diversity of crustacean zooplankton found in inland and coastal waters produce embryos that settle into bottom sediments to form an egg bank. Embryos from these banks can remain dormant for centuries, creating a reservoir of genetic diversity. A large body of literature describes the ecological and evolutionary importance of zooplankton egg banks. However, literature on the physiological traits behind dormancy in crustacean zooplankton are limited. Most data on the physiology of dormancy comes from research on one species of anostracan, the brine shrimp, Artemia franciscana. Anoxia-induced dormancy in this species is facilitated by a profound and reversible acidification of the intracellular space. This acidification is accompanied by a reversible depletion of adenosine triphosphate (ATP). The present study demonstrates that acidification of the intracellular space also occurs in concert with a depletion of nucleoside triphosphates (NTPs) in the Antarctic copepod, Boeckella poppei. Like A. franciscana, the depletion of NTPs and acidification are rapidly reversed during aerobic recovery in B. poppei. These data provide the first comparative evidence that extreme dormancy under anoxia in crustacean zooplankton is associated with intracellular acidification and an ability to recover from the depletion of ATP.

Abstract Simultaneous imaging of nine fluorescent proteins is demonstrated in a single acquisition using fluorescence lifetime imaging microscopy combined with pulsed interleaved excitation of three laser lines. Multicolor imaging employing genetically encodable fluorescent proteins permits spatio-temporal live cell imaging of multiple cues. Here, we show that multicolor lifetime imaging allows visualization of quadruple labelled human immunodeficiency viruses on host cells that in turn are also labelled with genetically encodable fluorescent proteins. This strategy permits to simultaneously visualize different sub-cellular organelles (mitochondria, cytoskeleton, and nucleus) during the process of virus entry with the potential of imaging up to nine different spectral channels in living cells.

More than 20 previously reported lines of independent evidence from clinical observations, studies in laboratory animal models, pharmacokinetic considerations, and numerous temporal and spatial associations indicate that numerous genetic and environmental factors leading to inflammation and oxidative stress confer vulnerability to the aberrant metabolism of acetaminophen during early development, leading to autism spectrum disorder (ASD). Contrary to this conclusion, multivariate analyses of cohort data adjusting for inflammation-associated factors have tended to show little to no risk of acetaminophen use for neurodevelopment. To resolve this discrepancy, here we use in silico methods to create an ideal (virtual) population of 120,000 individuals in which 50% of all cases of virtual ASD are induced by oxidative stress-associated cofactors and acetaminophen use. We demonstrate that Cox regression analysis of this ideal dataset shows little to no risk of acetaminophen use if the cofactors that create aberrant metabolism of acetaminophen are adjusted for in the analysis. Further, under-reporting of acetaminophen use is shown to be a considerable problem for this analysis, leading to large and erroneously low calculated risks of acetaminophen use. In addition, we argue that factors that impart susceptibility to acetaminophen-induced injury, and propensity for acetaminophen use itself, can be shared between the prepartum, peripartum, and postpartum periods, creating additional difficulty in the analysis of existing datasets to determine risks of acetaminophen exposure for neurodevelopment during a specific time frame. It is concluded that risks of acetaminophen use for neurodevelopment obtained from multivariate analysis of cohort data depend on underlying assumptions in the analyses, and that other evidence, both abundant and robust, demonstrate the critical role of acetaminophen in the etiology of ASD.

Darwin’s theory of evolution by natural selection was revolutionary because it provided a mechanism by which variation could be selected. This mechanism can only operate on living systems and thus cannot be applied to the origin of life. Here, we propose a viable alternative mechanism for prebiotic systems: autocatalytic selection, in which molecules catalyze reactions and processes that lead to increases in their concentration. Crucially, this provides a driver for increases in concentrations of molecules to a level that permits prebiotic metabolism. We show how this can produce high levels of amino acids, sugar phosphates, nucleotides and lipids and then lead on to polymers. Our outline is supported by a set of guidelines to support the identification of the most likely prebiotic routes. Most of the steps in this pathway are already supported by experimental results. These proposals generate a coherent and viable set of pathways that run from established Hadean geochemistry to the beginning of life.

Abstract Background Macroalgae blooms (Sargassum sp.) occur annually in The Bahamas due to the integration of various events related to human intercession with the roles of algae in biogeochemical cycles. These blooms are of great concern, as they are associated with many negative effects; thus, the primary aims of this study were to assess the quality of soils collected from South, Central, and North Long Island, and to determine whether Sargassum sp. can be used as a biofertilizer for soils on Long Island. A 60-day pot trial method was established to determine the efficacy of different concentrations (1%, 5%, and 10%) of Sargassum sp. as a biofertilizer on cherry tomato cultivation. Additionally, the soil quality before and after fertilizer amendment was evaluated. Results The results show that Sargassum sp. increased nutrient content of the soil, specifically nitrate nitrogen and phosphorus; however, plant growth performance parameters (plant height, leaf number, bud number, flower number, and root and shoot weights) were negatively affected. Conclusions Due to the obtained results, it is recommended that serious consideration be taken when utilizing Sargassum sp. as a biofertilizer because the pH and type of soil in Long Island, Bahamas, affects the bioavailability of the nutrients released from the algae. Graphical abstract

Abstract Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Abstract This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency

Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory 80% concentration < 1 μg/mL). For continuous outcomes, the CP approach performs nearly as well as the PC approach when the individual-bnAb prediction algorithms have strong performance, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.

Sexually transmitted infections (STIs) have a profound impact on sexual and reproductive health worldwide. Syphilis, gonorrhea, chlamydia, and trichomoniasis are four currently curable STIs. However, most STI cases are asymptomatic and not detected without laboratory diagnostics. Hepatitis B virus, herpes simplex virus, human immunodeficiency virus (HIV), and human papillomavirus (HPV) are four viral and incurable infections, but they can be mitigated by treatment. We investigated the prevalence of selected sexually transmitted pathogens and their relationship with HPV and HIV infection in women from Maputo, the capital of Mozambique. A cross-sectional study was conducted on 233 non-pregnant women seeking health care relating to gynecological symptoms in Mavalane Health facilities in Maputo, between the 1st of February 2018 and the 30th of July 2019. Cervical brush samples were collected and DNA was extracted. Selected STIs including HPV were detected using multiplex STD and HPV Direct Flow Chip Kits through a manual Hybrispot platform (Vitro, Master Diagnostica, Sevilla, Spain). HIV testing was performed using rapid tests: Determine HIV 1/2 test (Alere Abbott Laboratories, Tokyo, Japan) for screening, and UniGold HIV (Trinity Biotech, Ireland) for confirmation. All women (n = 233) were negative for Haemophilus ducreyi and Herpes Simplex Virus-1 (HSV-1). Among the 233 women, a high prevalence of STIs was found (89%), 63% of the women were positive for HPV and 24% were HIV positive. Treponema pallidum (TP), Trichomonas vaginalis (TV), Herpes Simplex Virus-2 (HSV-2), and Chlamydia trachomatis (CT) were detected in 17%, 14%, 8%, and 8% of the women, respectively. As a common phenomenon, vaginal discharge (90%) was the lower genital tract symptom reported by the majority of the women. Co-infection with any STI and HPV was detected in 56% (130/233) while 45% (59/130) of the co-infections were with high-risk HPV (hrHPV) genotypes. Among the HPV-positive participants, infection by TP was the most prevalent (27%). In total, 28% (66/233) of the participants were positive for any hrHPV genotypes. Co-infection with any STI and HIV was found in 15% (34/233) of the study participants. There was a significant association between HPV infection and TP (p = 0.039) and HSV-2 (p = 0.005). TV, TP, and CT-S1-CT-S2 positivity were significantly more prevalent in HIV-positive participants. Pathobionts Ureaplasma urealyticum/parvum and Mycoplasma hominis were detected in 84.0% (195/233) and 45% (105/233), respectively. This present study describes a high prevalence of STIs. Co-infection between HPV and STIs was found in the majority of the study subjects. The high prevalence of HPV emphasizes the need for HPV vaccination to prevent cervical cancer in this population. Management of STIs is also important in women presenting with gynecological symptoms.

The effects of turbidity and sedimentation stress on early life stages of corals are poorly understood, particularly in Atlantic species. Dredging operations, beach nourishment, and other coastal construction activities can increase sedimentation and turbidity in nearby coral reef habitats and have the potential to negatively affect coral larval development and metamorphosis, reducing sexual reproduction success. In this study, we investigated the performance of larvae of the threatened Caribbean coral species Orbicella faveolata exposed to suspended sediments collected from a reef site in southeast Florida recently impacted by dredging (Port of Miami), and compared it to the performance of larvae exposed to sediments collected from the offshore, natal reef of the parent colonies. In a laboratory experiment, we tested whether low and high doses of each of these sediment types affected the survival, settlement, and respiration of coral larvae compared to a no-sediment control treatment. In addition, we analyzed the sediments used in the experiments with 16S rRNA gene amplicon sequencing to assess differences in the microbial communities present in the Port versus Reef sediments, and their potential impact on coral performance. Overall, only O. faveolata larvae exposed to the high-dose Port sediment treatment had significantly lower survival rates compared to the control treatment, suggesting an initial tolerance to elevated suspended sediments. However, significantly lower settlement rates were observed in both Port treatments (low- and high-dose) compared to the control treatment one week after exposure, suggesting strong latent effects. Sediments collected near the Port also contained different microbial communities than Reef sediments, and higher relative abundances of the bacteria Desulfobacterales, which has been associated with coral disease. We hypothesize that differences in microbial communities between the two sediments may be a contributing factor in explaining the observed differences in larval performance. Together, these results suggest that the settlement success and survival of O. faveolata larvae are more readily compromised by encountering port inlet sediments compared to reef sediments, with potentially important consequences for the recruitment success of this species in affected areas.

Campylobacter hepaticus, the causative agent of Spotty Liver Disease (SLD) is an important disease in cage-free egg producing chickens causing mortality and production drops. C. hepaticus is a slow growing Campylobacter easily overgrown by fecal bacteria. It is currently only reliably isolatable from bile samples. A selective media for isolation from feces or environment would assist diagnosis and impact assessment. Growth of five Australian C. hepaticus isolates was studied using Horse blood agar (HBA), sheep blood agar (SBA), Bolton, Preston and Brain Heart Infusion (BHI) base media. Blood and/or bile were added to Bolton, Preston and BHI medias. C. jejuni was used as a positive control. Plates were incubated in duplicate under microaerophilic conditions at 42°C for 10 days and examined at days 3-5 and 7-10 of incubation. Each isolate was examined for sensitivity to 14 antimicrobials using HBA sensitivity plates. Growth was inhibited by BHI and by added bile, while blood improved growth. Further replicates using SBA, HBA, Bolton and Preston media showed best growth on Bolton agar with blood. All five C. hepaticus isolates were resistant to trimethoprim and vancomycin, while four were also resistant to rifampicin and bacitracin. Media based upon Bolton plus blood supplemented with vancomycin and trimethoprim might be used as the most appropriate media for selective growth of C. hepaticus. The addition of bile to media for C. hepaticus isolation and growth will inhibit growth and is not advised.

ObjectivesThe Social media, Smartphone use and Self-Harm (3S-YP) study is a prospective observational cohort study to investigate the mechanisms underpinning associations between social media and smartphone use and self-harm in a clinical youth sample. We present here a comprehensive description of the cohort from baseline data and an overview of data available from baseline and follow-up assessments.MethodsYoung people aged 13-25 years were recruited from a mental health trust in England and followed up for 6 months. Self-report data was collected at baseline and monthly during follow-up and linked with electronic health records (EHR) and user-generated data.FindingsA total of 362 young people enrolled and provided baseline questionnaire data. Most participants had a history of self-harm according to clinical (n = 295, 81.5%) and broader definitions (n = 296, 81.8%). At baseline, there were high levels of current moderate/severe anxiety (n = 244; 67.4%), depression (n = 255; 70.4%) and sleep disturbance (n = 171; 47.2%). Over half used social media and smartphones after midnight on weekdays (n = 197, 54.4%; n = 215, 59.4%) and weekends (n = 241, 66.6%; n = 263, 72.7%), and half met the cut-off for problematic smartphone use (n = 177; 48.9%). Of the cohort, we have questionnaire data at month 6 from 230 (63.5%), EHR data from 345 (95.3%), social media data from 110 (30.4%) and smartphone data from 48 (13.3%).ConclusionThe 3S-YP study is the first prospective study with a clinical youth sample, for whom to investigate the impact of digital technology on youth mental health using novel data linkages. Baseline findings indicate self-harm, anxiety, depression, sleep disturbance and digital technology overuse are prevalent among clinical youth. Future analyses will explore associations between outcomes and exposures over time and compare self-report with user-generated data in this cohort.

BackgroundSelf-harm and suicide behaviours are a major public health concern. Several factors are associated with these behaviours among military communities. Identifying these factors may have important implications for policy and clinical services. The aim of this review was to identify the risk and protective factors associated with self-harm and suicide behaviours among serving and ex-serving personnel of the United Kingdom Armed Forces, Canadian Armed Forces, Australian Defence Force and New Zealand Defence Force.MethodsA systematic search of seven online databases (PubMed, Web of Science, Embase, Global Health, PsycINFO, PTSDpubs and CINAHL) was conducted alongside cross-referencing, in October 2022. Following an a priori PROSPERO approved protocol (CRD42022348867), papers were independently screened and assessed for quality. Data were synthesised using a narrative approach.ResultsOverall, 28 papers were included: 13 from Canada, 10 from the United Kingdom, five from Australia and none from New Zealand. Identified risk factors included being single/ex-relationship, early service leavers, shorter length of service (but not necessarily early service leavers), junior ranks, exposure to deployment-related traumatic events, physical and mental health diagnoses, and experience of childhood adversity. Protective factors included being married/in a relationship, higher educational attainment, employment, senior ranks, and higher levels of perceived social support.ConclusionAdequate care and support are a necessity for the military community. Prevention and intervention strategies for self-harm and suicide behaviours may be introduced early and may promote social networks as a key source of support. This review found a paucity of peer-reviewed research within some populations. More peer-reviewed research is needed, particularly among these populations where current work is limited, and regarding modifiable risk and protective factors.

Urban trees are at risk of stress due to heat island effects and the increased proportion of impervious areas surrounding them. Among pests of trees, insect borers such as bark beetles (Coleoptera: Curculionidae) and flatheaded borers (Coleoptera: Buprestidae) are some of the most devastating, frequently colonizing stressed trees. The objective of this study was to explore the effects of biotic and abiotic risk factors on borer attacks on trees in urban areas. In the summer of 2021 and 2022, this study was conducted in 50 urban sites in Atlanta and Augusta, Georgia (USA). Specific factors explored include overall tree health, differentially warmer maximum and minimum temperatures of sites compared to surrounding areas, tree species, and the percentage of impervious surface surrounding trees. Generalized linear models and zero-inflated models explored how these factors were related to damage from these borers. The number of borer attacks on trees increased with higher percentage impervious area. As the two most commonly encountered trees, Acer rubrum was found to be significantly more susceptible to attack from borers than Ulmus parvifolia. Unhealthy trees were more likely to experience more frequent and more severe borer attack. Trees with increased impervious cover around them as well as those with differentially warmer daily maximum and minimum temperatures relative to surrounding were more likely to be attacked.

Planning for the impacts of climate change requires accurate projections by Earth system models (ESMs). ESMs, as developed by many research centres, estimate changes to weather and climate as atmospheric greenhouse gases (GHGs) rise, and they inform the influential Intergovernmental Panel on Climate Change (IPCC) reports. ESMs are advancing the understanding of key climate system attributes. However, there remain substantial inter-ESM differences in their estimates of future meteorological change, even for a common GHG trajectory, and such differences make adaptation planning difficult. Until recently, the primary approach to reducing projection uncertainty has been to place an emphasis on simulations that best describe the contemporary climate. Yet a model that performs well for present-day atmospheric GHG levels may not necessarily be accurate for higher GHG levels and vice versa. A relatively new approach of emergent constraints (ECs) is gaining much attention as a technique to remove uncertainty between climate models. This method involves searching for an inter-ESM link between a quantity that we can also measure now and a second quantity of major importance for describing future climate. Combining the contemporary measurement with this relationship refines the future projection. Identified ECs exist for thermal, hydrological and geochemical cycles of the climate system. As ECs grow in influence on climate policy, the method is under intense scrutiny, creating a requirement to understand them better. We hypothesise that as many Earth system components vary in both space and time, their behaviours often satisfy large-scale differential equations (DEs). Such DEs are valid at coarser scales than the equations coded in ESMs which capture finer high-resolution grid-box-scale effects. We suggest that many ECs link to such effective hidden DEs implicit in ESMs and that aggregate small-scale features. An EC may exist because its two quantities depend similarly on an ESM-specific internal bulk parameter in such a DE, with measurements constraining and revealing its (implicit) value. Alternatively, well-established process understanding coded at the ESM grid box scale, when aggregated, may generate a bulk parameter with a common “emergent” value across all ESMs. This single emerging parameter may link uncertainties in a contemporary climate driver to those of a climate-related property of interest. In these circumstances, the EC combined with a measurement of the driver that is uncertain constrains the estimate of the climate-related quantity. We offer simple illustrative examples of these concepts with generic DEs but with their solutions placed in a conceptual EC framework.