Topological data analysis reveals a core gene expression backbone that defines form and function across flowering plants.

Since they emerged approximately 125 million years ago, flowering plants have evolved to dominate the terrestrial landscape and survive in the most inhospitable environments on earth. At their core, these adaptations have been shaped by changes in numerous, interconnected pathways and genes that collectively give rise to emergent biological phenomena. Linking gene expression to morphological outcomes remains a grand challenge in biology, and new approaches are needed to begin to address this gap. Here, we implemented topological data analysis (TDA) to summarize the high dimensionality and noisiness of gene expression data using lens functions that delineate plant tissue and stress responses. Using this framework, we created a topological representation of the shape of gene expression across plant evolution, development, and environment for the phylogenetically diverse flowering plants. The TDA-based Mapper graphs form a well-defined gradient of tissues from leaves to seeds, or from healthy to stressed samples, depending on the lens function. This suggests that there are distinct and conserved expression patterns across angiosperms that delineate different tissue types or responses to biotic and abiotic stresses. Genes that correlate with the tissue lens function are enriched in central processes such as photosynthetic, growth and development, housekeeping, or stress responses. Together, our results highlight the power of TDA for analyzing complex biological data and reveal a core expression backbone that defines plant form and function.

Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape.

Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.

G protein-coupled receptor (GPCR) gene variants and human genetic disease.

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other. GPCR variants disrupt ligand binding, G protein coupling, accessory protein function, receptor desensitization and receptor recycling. Next generation sequencing has made it possible to identify variants of uncertain significance (VUS). We discuss variants in receptors known to result in disease and in silico strategies for disambiguation of VUS such as sorting intolerant from tolerant and polymorphism phenotyping. Modeling of variants has contributed to drug development and precision medicine, including drugs that target the melanocortin receptor in obesity and interventions that reverse loss of gonadotropin-releasing hormone receptor from the cell surface in idiopathic hypogonadotropic hypogonadism. Activating and inactivating variants of the calcium sensing receptor (CaSR) gene that are pathogenic in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia have enabled the development of calcimimetics and calcilytics. Next generation sequencing has continued to identify variants in GPCR genes, including orphan receptors, that contribute to human phenotypes and may have therapeutic potential. Variants of the CaSR gene, some encoding an arginine-rich region that promotes receptor phosphorylation and intracellular retention, have been linked to an idiopathic epilepsy syndrome. Agnostic strategies have identified variants of the pyroglutamylated RF amide peptide receptor gene in intellectual disability and G protein-coupled receptor 39 identified in psoriatic arthropathy. Coding variants of the G protein-coupled receptor L1 (GPR37L1) orphan receptor gene have been identified in a rare familial progressive myoclonus epilepsy. The study of the role of GPCR variants in monogenic, Mendelian phenotypes has provided the basis of modeling the significance of more common variants of pharmacogenetic significance.

Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.

BACKGROUND: Occurrence of squamous cell carcinoma (SCC) even in early-stage, untreated chronic lymphocytic leukemia (CLL) patients can be a significant morbidity issue with occasional transformation into metastatic skin lesions. METHODS: CLL cells and extracellular vesicles (EVs) from CLL patients' blood/plasma were purified and used. Expression/activation of AXL and its functions in normal keratinocytes (HEKa) were assessed in vitro co-culture system and in SCC tissues. RESULTS: We detected aberrant activation of AXL, AKT and ERK-1/2 in SCC cell lines compared to HEKa. We also detected increased expression of AXL in primary SCC tissues obtained from CLL patients. Increased activation of AXL, AKT, ERK-1/2 and Src was discernible in HEKa upon co-culturing with CLL cells. Further analysis suggests that Gas6, a ligand of AXL, regulates AXL activation in co-cultured HEKa. Interestingly, exposure of HEKa cells to CLL plasma-derived EVs induced expression of AXL, P-AKT, and EMT-associated markers leading to migration of the cells. Finally, pharmacologic inhibition of AXL induced cell death in SCC lines in a dose dependent manner. CONCLUSIONS: Our findings that CLL cells likely are involved in driving SCC progression, at least in part, via activation of the AXL signaling axis, indicating that AXL inhibition may be beneficial for our CLL patients with SCC.

Experiences of hospital care for people with multiple long-term conditions: a scoping review of qualitative research.

BACKGROUND: Multiple long-term conditions-the co-existence of two or more chronic health conditions in an individual-present an increasing challenge to populations and healthcare systems worldwide. This challenge is keenly felt in hospital settings where care is oriented around specialist provision for single conditions. The aim of this scoping review was to identify and summarise published qualitative research on the experiences of hospital care for people living with multiple long-term conditions, their informal caregivers and healthcare professionals. METHODS: We undertook a scoping review, following established guidelines, of primary qualitative research on experiences of hospital care for people living with multiple long-term conditions published in peer-reviewed journals between Jan 2010 and June 2022. We conducted systematic electronic searches of MEDLINE, CINAHL, PsycInfo, Proquest Social Science Premium, Web of Science, Scopus and Embase, supplemented by citation tracking. Studies were selected for inclusion by two reviewers using an independent screening process. Data extraction included study populations, study design, findings and author conclusions. We took a narrative approach to reporting the findings. RESULTS: Of 8002 titles and abstracts screened, 54 papers reporting findings from 41 studies conducted in 14 countries were identified as eligible for inclusion. The perspectives of people living with multiple long-term conditions (21 studies), informal caregivers (n = 13) and healthcare professionals (n = 27) were represented, with 15 studies reporting experiences of more than one group. Findings included poor service integration and lack of person-centred care, limited confidence of healthcare professionals to treat conditions outside of their specialty, and time pressures leading to hurried care transitions. Few studies explored inequities in experiences of hospital care. CONCLUSIONS: Qualitative research evidence on the experiences of hospital care for multiple long-term conditions illuminates a tension between the desire to provide and receive person-centred care and time pressures inherent within a target-driven system focussed on increasing specialisation, reduced inpatient provision and accelerated journeys through the care system. A move towards more integrated models of care may enable the needs of people living with multiple long-term conditions to be better met. Future research should address how social circumstances shape experiences of care.

The use of natural language processing for the identification of ageing syndromes including sarcopenia, frailty and falls in electronic healthcare records: a systematic review.

BACKGROUND: Recording and coding of ageing syndromes in hospital records is known to be suboptimal. Natural Language Processing algorithms may be useful to identify diagnoses in electronic healthcare records to improve the recording and coding of these ageing syndromes, but the feasibility and diagnostic accuracy of such algorithms are unclear. METHODS: We conducted a systematic review according to a predefined protocol and in line with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Searches were run from the inception of each database to the end of September 2023 in PubMed, Medline, Embase, CINAHL, ACM digital library, IEEE Xplore and Scopus. Eligible studies were identified via independent review of search results by two coauthors and data extracted from each study to identify the computational method, source of text, testing strategy and performance metrics. Data were synthesised narratively by ageing syndrome and computational method in line with the Studies Without Meta-analysis guidelines. RESULTS: From 1030 titles screened, 22 studies were eligible for inclusion. One study focussed on identifying sarcopenia, one frailty, twelve falls, five delirium, five dementia and four incontinence. Sensitivity (57.1%-100%) of algorithms compared with a reference standard was reported in 20 studies, and specificity (84.0%-100%) was reported in only 12 studies. Study design quality was variable with results relevant to diagnostic accuracy not always reported, and few studies undertaking external validation of algorithms. CONCLUSIONS: Current evidence suggests that Natural Language Processing algorithms can identify ageing syndromes in electronic health records. However, algorithms require testing in rigorously designed diagnostic accuracy studies with appropriate metrics reported.

Double peroxidase and histone acetyltransferase AgTip60 maintain innate immune memory in primed mosquitoes.

Immune priming in Anopheles gambiae is mediated by the systemic release of a hemocyte differentiation factor (HDF), a complex of lipoxin A4 bound to Evokin, a lipid carrier. HDF increases the proportion of circulating granulocytes and enhances mosquito cellular immunity. Here, we show that Evokin is present in hemocytes and fat-body cells, and messenger RNA (mRNA) expression increases significantly after immune priming. The double peroxidase (DBLOX) enzyme, present in insects but not in vertebrates, is essential for HDF synthesis. DBLOX is highly expressed in oenocytes in the fat-body tissue, and these cells increase in number in primed mosquitoes. We provide direct evidence that the histone acetyltransferase AgTip60 (AGAP001539) is also essential for a sustained increase in oenocyte numbers, HDF synthesis, and immune priming. We propose that oenocytes may function as a population of cells that are reprogrammed, and orchestrate and maintain a broad, systemic, and long-lasting state of enhanced immune surveillance in primed mosquitoes.

A photoaffinity glycan-labeling approach to investigate immunoglobulin glycan-binding partners.

Glycans play a pivotal role in biology. However, because of the low-affinity of glycan-protein interactions, many interaction pairs remain unknown. Two important glycoproteins involved in B-cell biology are the B-cell receptor and its secreted counterpart, antibodies. It has been indicated that glycans expressed by these B-cell-specific molecules can modulate immune activation via glycan-binding proteins. In several autoimmune diseases, an increased prevalence of variable domain glycosylation of IgG autoantibodies has been observed. Especially, the hallmarking autoantibodies in rheumatoid arthritis, anti-citrullinated protein antibodies, carry a substantial amount of variable domain glycans. The variable domain glycans expressed by these autoantibodies are N-linked, complex-type, and α2-6 sialylated, and B-cell receptors carrying variable domain glycans have been hypothesized to promote selection of autoreactive B cells via interactions with glycan-binding proteins. Here, we use the anti-citrullinated protein antibody response as a prototype to study potential in solution and in situ B-cell receptor-variable domain glycan interactors. We employed SiaDAz, a UV-activatable sialic acid analog carrying a diazirine moiety that can form covalent bonds with proximal glycan-binding proteins. We show, using oligosaccharide engineering, that SiaDAz can be readily incorporated into variable domain glycans of both antibodies and B-cell receptors. Our data show that antibody variable domain glycans are able to interact with inhibitory receptor, CD22. Interestingly, although we did not detect this interaction on the cell surface, we captured CD79 ß glycan-B-cell receptor interactions. These results show the utility of combining photoaffinity labeling and oligosaccharide engineering for identifying antibody and B-cell receptor interactions and indicate that variable domain glycans appear not to be lectin cis ligands in our tested conditions.

Single-Cell and Subcellular Analysis Using Ultrahigh Resolution 21 T MALDI FTICR Mass Spectrometry.

The mammalian brain contains ∼20,000 distinct lipid species that contribute to its structural organization and function. The lipid profiles of cells change in response to a variety of cellular signals and environmental conditions that result in modulation of cell function through alteration of phenotype. The limited sample material combined with the vast chemical diversity of lipids makes comprehensive lipid profiling of individual cells challenging. Here, we leverage the resolving power of a 21 T Fourier-transform ion cyclotron resonance (FTICR) mass spectrometer for chemical characterization of individual hippocampal cells at ultrahigh mass resolution. The accuracy of the acquired data allowed differentiation of freshly isolated and cultured hippocampal cell populations, as well as finding differences in lipids between the soma and neuronal processes of the same cell. Differences in lipids include TG 42:2 observed solely in the cell bodies and SM 34:1;O2 found only in the cellular processes. The work represents the first mammalian single cells analyzed at ultrahigh resolution and is an advance in the performance of mass spectrometry (MS) for single-cell research.

Simple approaches to characterising multiple long-term conditions (multimorbidity) and rates of emergency hospital admission: Findings from 495,465 UK Biobank participants.

BACKGROUND: Numerous approaches are used to characterise multiple long-term conditions (MLTC), including counts and indices. Few studies have compared approaches within the same dataset. We aimed to characterise MLTC using simple approaches, and compare their prevalence estimates of MLTC and associations with emergency hospital admission in the UK Biobank. METHODS: We used baseline data from 495,465 participants (age 38-73 years) to characterise MLTC using four approaches: Charlson index (CI), Byles index (BI), count of 43 conditions (CC) and count of body systems affected (BC). We defined MLTC as more than two conditions using CI, BI and CC, and more than two body systems using BC. We categorised scores (incorporating weightings for the indices) from each approach as 0, 1, 2 and 3+. We used linked hospital episode statistics and performed survival analyses to test associations with an endpoint of emergency hospital admission or death over 5 years. RESULTS: The prevalence of MLTC was 44% (BC), 33% (CC), 6% (BI) and 2% (CI). Higher scores using all approaches were associated with greater outcome rates independent of sex and age group. For example, using CC, compared with score 0, score 2 had 1.95 (95% CI: 1.91, 1.99) and a score of 3+ had 3.12 (95% CI: 3.06, 3.18) times greater outcome rates. The discriminant value of all approaches was modest (C-statistics 0.60-0.63). CONCLUSIONS: The counts classified a greater proportion as having MLTC than the indices, highlighting that prevalence estimates of MLTC vary depending on the approach. All approaches had strong statistical associations with emergency hospital admission but a modest ability to identify individuals at risk.

Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Bayesian borrowing for basket trials with longitudinal outcomes.

Basket trials are a novel clinical trial design in which a single intervention is investigated in multiple patient subgroups, or "baskets." They offer the opportunity to share information between subgroups, potentially increasing power to detect treatment effects. Basket trials offer several advantages over running a series of separate trials, including reduced sample sizes, increased efficiency, and reduced costs. Primarily, basket trials have been undertaken in Phase II oncology settings, but could be a promising design in other areas where a shared underlying biological mechanism drives different diseases. One such area is chronic aging-related diseases. However, trials in this area frequently have longitudinal outcomes, and therefore suitable methods are needed to share information in this setting. In this paper, we extend three Bayesian borrowing methods for a basket design with continuous longitudinal endpoints. We demonstrate our methods on a real-world dataset and in a simulation study where the aim is to detect positive basketwise treatment effects. Methods are compared with standalone analysis of each basket without borrowing. Our results confirm that methods that share information can improve power to detect positive treatment effects and increase precision over independent analysis in many scenarios. In highly heterogeneous scenarios, there is a trade-off between increased power and increased risk of type I errors. Our proposed methods for basket trials with continuous longitudinal outcomes aim to facilitate their applicability in the area of aging related diseases. Choice of method should be made based on trial priorities and the expected basketwise distribution of treatment effects.

Transcriptome analysis of Pacific white shrimp (Liptopenaeus vannamei) after exposure to recombinant Vibrio parahaemolyticus PirA and PirB proteins.

Vibrio parahaemolyticus is a Gram-negative bacterium commonly found in marine and estuarine environments and is endemic among the global shrimp aquaculture industry. V. parahaemolyticus proteins PirA and PirB have been determined to be major virulence factors that contribute significantly to the development of acute hepatopancreatic necrosis disease. Our previous work had demonstrated the lethality of recombinant PirA and PirB proteins to Pacific white shrimp (Liptopenaeus vannamei). To understand the host response to these proteins, recombinant PirA and PirB proteins were administered using a reverse gavage method and individual shrimp were then sampled over time. Shrimp hepatopancreas libraries were generated and RNA sequencing was performed on the control and recombinant PirA/B-treated samples. Differentially expressed genes were identified among the assayed time points. Differentially expressed genes that were co-expressed at the later time points (2-, 4- and 6-h) were also identified and gene associations were established to predict functional physiological networks. Our analysis reveals that the recombinant PirA and PirB proteins have likely initiated an early host response involving several cell survival signaling and innate immune processes.

Remote collection of physical performance measures for older people: a systematic review.

Remotely collected physical performance measures could improve inclusion of under-served groups in clinical research as well as enabling continuation of research in pandemic conditions. It is unclear whether remote collection is feasible and acceptable to older patients, or whether results are comparable to face-to-face measures. We conducted a systematic review according to a prespecified protocol. We included studies with mean participant age ≥ 60 years, with no language restriction. Studies examining the gait speed, Short Physical Performance Battery, distance walk tests, grip strength, Tinetti score, Berg balance test, sit-to-stand test and timed up and go were included. Reports of feasibility, acceptability, correlation between remote and face-to-face assessments and absolute differences between remote and face-to-face assessments were sought. Data were synthesised using Synthesis Without Meta-analysis methodology; 30 analyses from 17 publications were included. Study size ranged from 10 to 300 participants, with a mean age ranging from 61 to >80 years. Studies included a broad range of participants and conditions. Most studies had a moderate or high risk of bias. Only two studies undertook assessment of acceptability or feasibility, reporting good results. Correlation between face-to-face and remote measures was variable across studies, with no measure showing consistently good correlation. Only nine studies examined the accuracy of remote measures; in six studies, accuracy was rated as good (<5% mean difference between face-to-face and remote measures). There is a lack of robust evidence that remote collection of physical performance measures is acceptable to patients, feasible or provides comparable results to face-to-face measures.

New Horizons in cellular senescence for clinicians.

Cellular senescence has emerged as a fundamental biological mechanism underpinning the ageing process and has been implicated in the pathogenesis of an increasing number of age-related conditions. Cellular senescence is a cell fate originally defined as an irreversible loss of replicative potential although it is now clear that it can be induced by a variety of mechanisms independent of replication and telomere attrition. The drivers include a persistent DNA damage response causing multiple alterations in cellular function. Senescent cells secrete a range of mediators that drive chronic inflammation and can convert other cells to the senescent state-the senescence-associated secretory phenotype. Much research to date has been conducted in animal models, but it is now clear that senescent cells accompany ageing in humans and their presence is an important driver of disease across systems. Proof-of-concept work suggests that preventing or reversing senescence may be a viable strategy to counteract human ageing and age-related disease. Possible interventions include exercise, nutrition and senolytics/senostatic drugs although there are a number of potential limitations to the use of senotherapeutics. These interventions are generally tested for single-organ conditions, but the real power of this approach is the potential to tackle multiple age-related conditions. The litmus test for this exciting new class of therapies, however, will be whether they can improve healthy life expectancy rather than merely extending lifespan. The outcomes measured in clinical studies need to reflect these aims if senotherapeutics are to gain the trust of clinicians, patients and the public.

Including older people in health and social care research: best practice recommendations based on the INCLUDE framework.

BACKGROUND: Older people are often explicitly or implicitly excluded from research, in particular clinical trials. This means that study findings may not be applicable to them, or that older people may not be offered treatments due to an absence of evidence. AIMS: The aim of this work was to develop recommendations to guide all research relevant to older people. METHODS: A diverse stakeholder group identified barriers and solutions to including older people in research. In parallel, a rapid literature review of published papers was undertaken to identify existing papers on the inclusion of older people in research. The findings were synthesised and mapped onto a socio-ecological model. From the synthesis we identified themes that were developed into initial recommendations that were iteratively refined with the stakeholder group. RESULTS: A range of individual, interpersonal, organisational, community and policy factors impact on the inclusion of older people in research. A total of 14 recommendations were developed such as removing upper age limits and comorbidity exclusions, involving older people, advocates and health and social care professionals with expertise in ageing in designing the research, and considering flexible or alternative approaches to data collection to maximise opportunities for participation. We also developed four questions that may guide those developing, reviewing and funding research that is inclusive of older people. CONCLUSION: Our recommendations provide up to date, practical advice on ways to improve the inclusion of older people in health and care research.

Development of a UK core dataset for geriatric medicine research: a position statement and results from a Delphi consensus process.

BACKGROUND: There is lack of standardisation in assessment tools used in geriatric medicine research, which makes pooling of data and cross-study comparisons difficult. METHODS: We conducted a modified Delphi process to establish measures to be included within core and extended datasets for geriatric medicine research in the United Kingdom (UK). This included three complete questionnaire rounds, and one consensus meeting. Participants were selected from attendance at the NIHR Newcastle Biomedical Research Centre meeting, May 2019, and academic geriatric medicine e-mailing lists. Literature review was used to develop the initial questionnaire, with all responses then included in the second questionnaire. The third questionnaire used refined options from the second questionnaire with response ranking. RESULTS: Ninety-eight responses were obtained across all questionnaire rounds (Initial: 19, Second: 21, Third: 58) from experienced and early career researchers in geriatric medicine. The initial questionnaire included 18 questions with short text responses, including one question for responders to suggest additional items. Twenty-six questions were included in the second questionnaire, with 108 within category options. The third questionnaire included three ranking, seven final agreement, and four binary option questions. Results were discussed at the consensus meeting. In our position statement, the final consensus dataset includes six core domains: demographics (age, gender, ethnicity, socioeconomic status), specified morbidities, functional ability (Barthel and/or Nottingham Extended Activities of Daily Living), Clinical Frailty Scale (CFS), cognition, and patient-reported outcome measures (dependent on research question). We also propose how additional variables should be measured within an extended dataset. CONCLUSIONS: Our core and extended datasets represent current consensus opinion of academic geriatric medicine clinicians across the UK. We consider the development and further use of these datasets will strengthen collaboration between researchers and academic institutions.

Attitudes and barriers to resistance exercise training for older adults living with multiple long-term conditions, frailty, and a recent deterioration in health: qualitative findings from the Lifestyle in Later Life - Older People's Medicine (LiLL-OPM) study.

BACKGROUND: Many older adults live with the combination of multiple long-term conditions (MLTC) and frailty and are at increased risk of a deterioration in health requiring interaction with healthcare services. Low skeletal muscle strength is observed in individuals living with MLTC and is central to physical frailty. Resistance exercise (RE) is the best available treatment for improving muscle strength, but little is known about the attitudes and barriers to RE in this group of older adults. This study therefore aimed to explore the knowledge of and attitudes towards RE, as well as the barriers and enabling factors, in older adults living with MLTC, frailty and a recent deterioration in health. METHODS: Fourteen participants aged 69-92 years (10 women) from the Lifestyle in Later Life - Older People's Medicine (LiLL-OPM) study were recruited from an Older People's Medicine Day Unit in Newcastle, UK. Participants were invited to take part in a semi-structured interview exploring their knowledge and attitudes as well as barriers and enabling factors to RE. Data were analysed using thematic analysis. RESULTS: The analysis generated three themes (1) a lack of awareness and understanding of RE, (2) a self-perceived inability to perform RE; physical and psychological barriers and (3) willingness to perform RE under expert guidance. There was a general lack of awareness and understanding of RE, with most participants having never heard of the term and being unaware of its potential benefits. When RE was described, participants stated that they would be willing to try RE, but it was apparent that an individualised approach underpinned by expert guidance would be required to support engagement. CONCLUSIONS: Older adults living with MLTC, frailty and a recent deterioration in health lack awareness and understanding of RE. Despite a range of barriers, this group appear willing to engage in RE if they are appropriately supported. There is a need to co-design and deliver effective strategies, including education, to raise awareness and understanding of RE, as well as promote engagement in RE, in this group of older adults.

Global variability in seawater Mg:Ca and Sr:Ca ratios in the modern ocean.

Seawater Mg:Ca and Sr:Ca ratios are biogeochemical parameters reflecting the Earth-ocean-atmosphere dynamic exchange of elements. The ratios' dependence on the environment and organisms' biology facilitates their application in marine sciences. Here, we present a measured single-laboratory dataset, combined with previous data, to test the assumption of limited seawater Mg:Ca and Sr:Ca variability across marine environments globally. High variability was found in open-ocean upwelling and polar regions, shelves/neritic and river-influenced areas, where seawater Mg:Ca and Sr:Ca ratios range from ∼4.40 to 6.40 mmol:mol and ∼6.95 to 9.80 mmol:mol, respectively. Open-ocean seawater Mg:Ca is semiconservative (∼4.90 to 5.30 mol:mol), while Sr:Ca is more variable and nonconservative (∼7.70 to 8.80 mmol:mol); both ratios are nonconservative in coastal seas. Further, the Ca, Mg, and Sr elemental fluxes are connected to large total alkalinity deviations from International Association for the Physical Sciences of the Oceans (IAPSO) standard values. Because there is significant modern seawater Mg:Ca and Sr:Ca ratios variability across marine environments we cannot absolutely assume that fossil archives using taxa-specific proxies reflect true global seawater chemistry but rather taxa- and process-specific ecosystem variations, reflecting regional conditions. This variability could reconcile secular seawater Mg:Ca and Sr:Ca ratio reconstructions using different taxa and techniques by assuming an error of 1 to 1.50 mol:mol, and 1 to 1.90 mmol:mol, respectively. The modern ratios' variability is similar to the reconstructed rise over 20 Ma (Neogene Period), nurturing the question of seminonconservative behavior of Ca, Mg, and Sr over modern Earth geological history with an overlooked environmental effect.

Staying in place and moving in space: Contrasting larval thermal sensitivity explains distributional changes of sympatric sea urchin species to habitat warming.

For marine ectotherms, larval success, planktonic larval duration and dispersal trajectories are strongly influenced by temperature, and therefore, ocean warming and heatwaves have profound impacts on these sensitive stages. Warming, through increased poleward flow in regions with western boundary currents, such as the East Australia Current (EAC), provides opportunities for range extension as propagules track preferred conditions. Two sea urchin species, Centrostephanus rodgersii and Heliocidaris tuberculata, sympatric in the EAC warming hotspot, exhibit contrasting responses to warming. Over half a century, C. rodgersii has undergone marked poleward range extension, but the range of H. tuberculata has not changed. We constructed thermal performance curves (TPC) to determine if contrasting developmental thermal tolerance can explain this difference. The temperatures tested encompassed present-day distribution and forecast ocean warming/heatwave conditions. The broad and narrow thermal optimum (Topt) ranges for C. rodgersii and H. tuberculata larvae (7.2 and 4.7°C range, respectively) matched their realized (adult distribution) thermal niches. The cool and warm temperatures for 50% development to the feeding larva approximated temperatures at adult poleward range limits. Larval cool tolerances with respect to mean local temperature differed, 6.0 and 3.8°C respectively. Larval warm tolerances were similar for both species as are the adult warm range edges. The larvae of both species would be sensitive to heatwaves. Centrostephanus rodgersii has stayed in place and shifted in space, likely due to its broad cold-warm larval thermal tolerance and large thermal safety margins. Phenotypic plasticity of the planktonic stage of C. rodgersii facilitated its range extension. In contrast, larval cold intolerance of H. tuberculata explains its restricted range and will delay poleward extension as the region warms. In a warming ocean, we show that intrinsic thermal biology traits of the pelagic stage provide an integrative tool to explain species-specific variation in range shift patterns.