High exposure of global tree diversity to human pressure.

Safeguarding Earth's tree diversity is a conservation priority due to the importance of trees for biodiversity and ecosystem functions and services such as carbon sequestration. Here, we improve the foundation for effective conservation of global tree diversity by analyzing a recently developed database of tree species covering 46,752 species. We quantify range protection and anthropogenic pressures for each species and develop conservation priorities across taxonomic, phylogenetic, and functional diversity dimensions. We also assess the effectiveness of several influential proposed conservation prioritization frameworks to protect the top 17% and top 50% of tree priority areas. We find that an average of 50.2% of a tree species' range occurs in 110-km grid cells without any protected areas (PAs), with 6,377 small-range tree species fully unprotected, and that 83% of tree species experience nonnegligible human pressure across their range on average. Protecting high-priority areas for the top 17% and 50% priority thresholds would increase the average protected proportion of each tree species' range to 65.5% and 82.6%, respectively, leaving many fewer species (2,151 and 2,010) completely unprotected. The priority areas identified for trees match well to the Global 200 Ecoregions framework, revealing that priority areas for trees would in large part also optimize protection for terrestrial biodiversity overall. Based on range estimates for >46,000 tree species, our findings show that a large proportion of tree species receive limited protection by current PAs and are under substantial human pressure. Improved protection of biodiversity overall would also strongly benefit global tree diversity.

Combinatorial patterns of graded RhoA activation and uniform F-actin depletion promote tissue curvature.

During development, gene expression regulates cell mechanics and shape to sculpt tissues. Epithelial folding proceeds through distinct cell shape changes that occur simultaneously in different regions of a tissue. Here, using quantitative imaging in Drosophila melanogaster, we investigate how patterned cell shape changes promote tissue bending during early embryogenesis. We find that the transcription factors Twist and Snail combinatorially regulate a multicellular pattern of lateral F-actin density that differs from the previously described Myosin-2 gradient. This F-actin pattern correlates with whether cells apically constrict, stretch or maintain their shape. We show that the Myosin-2 gradient and F-actin depletion do not depend on force transmission, suggesting that transcriptional activity is required to create these patterns. The Myosin-2 gradient width results from a gradient in RhoA activation that is refined through the balance between RhoGEF2 and the RhoGAP C-GAP. Our experimental results and simulations of a 3D elastic shell model show that tuning gradient width regulates tissue curvature.

Dynamics of hydraulic and contractile wave-mediated fluid transport during Drosophila oogenesis.

From insects to mice, oocytes develop within cysts alongside nurse-like sister germ cells. Prior to fertilization, the nurse cells' cytoplasmic contents are transported into the oocyte, which grows as its sister cells regress and die. Although critical for fertility, the biological and physical mechanisms underlying this transport process are poorly understood. Here, we combined live imaging of germline cysts, genetic perturbations, and mathematical modeling to investigate the dynamics and mechanisms that enable directional and complete cytoplasmic transport in Drosophila melanogaster egg chambers. We discovered that during "nurse cell (NC) dumping" most cytoplasm is transported into the oocyte independently of changes in myosin-II contractility, with dynamics instead explained by an effective Young-Laplace law, suggesting hydraulic transport induced by baseline cell-surface tension. A minimal flow-network model inspired by the famous two-balloon experiment and motivated by genetic analysis of a myosin mutant correctly predicts the directionality, intercellular pattern, and time scale of transport. Long thought to trigger transport through "squeezing," changes in actomyosin contractility are required only once NC volume has become comparable to nuclear volume, in the form of surface contractile waves that drive NC dumping to completion. Our work thus demonstrates how biological and physical mechanisms cooperate to enable a critical developmental process that, until now, was thought to be mainly biochemically regulated.

Dimensions of invasiveness: Links between local abundance, geographic range size, and habitat breadth in Europe's alien and native floras.

Understanding drivers of success for alien species can inform on potential future invasions. Recent conceptual advances highlight that species may achieve invasiveness via performance along at least three distinct dimensions: 1) local abundance, 2) geographic range size, and 3) habitat breadth in naturalized distributions. Associations among these dimensions and the factors that determine success in each have yet to be assessed at large geographic scales. Here, we combine data from over one million vegetation plots covering the extent of Europe and its habitat diversity with databases on species' distributions, traits, and historical origins to provide a comprehensive assessment of invasiveness dimensions for the European alien seed plant flora. Invasiveness dimensions are linked in alien distributions, leading to a continuum from overall poor invaders to super invaders-abundant, widespread aliens that invade diverse habitats. This pattern echoes relationships among analogous dimensions measured for native European species. Success along invasiveness dimensions was associated with details of alien species' introduction histories: earlier introduction dates were positively associated with all three dimensions, and consistent with theory-based expectations, species originating from other continents, particularly acquisitive growth strategists, were among the most successful invaders in Europe. Despite general correlations among invasiveness dimensions, we identified habitats and traits associated with atypical patterns of success in only one or two dimensions-for example, the role of disturbed habitats in facilitating widespread specialists. We conclude that considering invasiveness within a multidimensional framework can provide insights into invasion processes while also informing general understanding of the dynamics of species distributions.

Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial.

BACKGROUND: Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. METHODS: This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. FINDINGS: Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). INTERPRETATION: Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. FUNDING: UK National Institute for Health and Care Research.

The Great Oxidation Event preceded a Paleoproterozoic "snowball Earth".

The inability to resolve the exact temporal relationship between two pivotal events in Earth history, the Paleoproterozoic Great Oxidation Event (GOE) and the first "snowball Earth" global glaciation, has precluded assessing causality between changing atmospheric composition and ancient climate change. Here we present temporally resolved quadruple sulfur isotope measurements (δ34S, ∆33S, and ∆36S) from the Paleoproterozoic Seidorechka and Polisarka Sedimentary Formations on the Fennoscandian Shield, northwest Russia, that address this issue. Sulfides in the former preserve evidence of mass-independent fractionation of sulfur isotopes (S-MIF) falling within uncertainty of the Archean reference array with a ∆36S/∆33S slope of -1.8 and have small negative ∆33S values, whereas in the latter mass-dependent fractionation of sulfur isotopes (S-MDF) is evident, with a ∆36S/∆33S slope of -8.8. These trends, combined with geochronological constraints, place the S-MIF/S-MDF transition, the key indicator of the GOE, between 2,501.5 ± 1.7 Ma and 2,434 ± 6.6 Ma. These are the tightest temporal and stratigraphic constraints yet for the S-MIF/S-MDF transition and show that its timing in Fennoscandia is consistent with the S-MIF/S-MDF transition in North America and South Africa. Further, the glacigenic part of the Polisarka Formation occurs 60 m above the sedimentary succession containing S-MDF signals. Hence, our findings confirm unambiguously that the S-MIF/S-MDF transition preceded the Paleoproterozoic snowball Earth. Resolution of this temporal relationship constrains cause-and-effect drivers of Earth's oxygenation, specifically ruling out conceptual models in which global glaciation precedes or causes the evolution of oxygenic photosynthesis.

The influence of biofertilizers on leaf economics spectrum traits in a herbaceous crop.

Microbial inoculations or 'biofertilizers' represent novel contributions to sustainable agriculture. While belowground mechanisms surrounding how biofertilizers enhance crop production are well described, their role in aboveground trait expression remains less well explored. We quantified infraspecific variation in leaf economics spectrum (LES) traits in response to 10 biofertilizer treatments in basil (Ocimum basiclicum) cultivated under hydroponic conditions. Multiple physiological (i.e. maximum photosynthesis rates (A), dark respiration (R), and leaf-level light compensation points) and morphological (i.e. leaf mass per area (LMA) and leaf thickness) traits varied significantly across microbial treatments. Following treatments, basil plants differentiated from one another along an infraspecific LES, with certain plants expressing more resource-acquiring LES trait values (i.e. high A, R, leaf N, and low LMA), versus others that expressed the opposite suite of resource-conserving LES trait values. Infraspecific trait covariation largely matched LES patterns observed among plants globally. Bivariate and multivariate trait analyses further revealed that certain treatments-namely those including closely related Bacillus and Brevibacillus species strains-increased leaf resource capture traits such as A and leaf N. Biofertilizers influence plant performance through a role in moderating infraspecific leaf trait variation, thereby suggesting aboveground leaf traits may be used to diagnose optimal biofertilizer formulations in basil and other crops.

International Analysis of Sources and Human Health Risk Associated with Trace Metal Contaminants in Residential Indoor Dust.

People spend increasing amounts of time at home, yet the indoor home environment remains understudied in terms of potential exposure to toxic trace metals. We evaluated trace metal (and metalloid) concentrations (As, Cu, Cr, Mn, Ni, Pb, and Zn) and health risks in indoor dust from homes from 35 countries, along with a suite of potentially contributory residential characteristics. The objective was to determine trace metal source inputs and home environment conditions associated with increasing exposure risk across a range of international communities. For all countries, enrichments compared to global crustal values were Zn > Pb > Cu > As > Cr > Ni; with the greatest health risk from Cr, followed by As > Pb > Mn > Cu > Ni > Zn. Three main indoor dust sources were identified, with a Pb-Zn-As factor related to legacy Pb sources, a Zn-Cu factor reflecting building materials, and a Mn factor indicative of natural soil sources. Increasing home age was associated with greater Pb and As concentrations (5.0 and 0.48 mg/kg per year of home age, respectively), as were peeling paint and garden access. Therefore, these factors form important considerations for the development of evidence-based management strategies to reduce potential risks posed by indoor house dust. Recent findings indicate neurocognitive effects from low concentrations of metal exposures; hence, an understanding of the home exposome is vital.

Syntaxins 6 and 8 facilitate tau into secretory pathways.

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer's disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells. Similarly, we showed the syntaxin 6 (STX6), part of the same SNARE family as STX8 also facilitated tau release. STX6 was previously genetically linked to progressive supranuclear palsy (PSP), a tauopathy. Finally, we demonstrated that the transmembrane domain of STX6 is required and sufficient to mediate tau secretion. The differential role of STX6 and STX8 in alternative secretory pathways suggests the association of tau with different secretory processes. Taken together, both syntaxins, STX6 and STX8, may contribute to AD and PSP pathogenesis by mediating release of tau from cells and facilitating pathology spreading.

ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis.

Lysyl oxidase (LOX) and LOX-like (LOXL) proteins are copper-dependent metalloenzymes with well-documented roles in tumor metastasis and fibrotic diseases. The mechanism by which copper is delivered to these enzymes is poorly understood. In this study, we demonstrate that the copper transporter ATP7A is necessary for the activity of LOX and LOXL enzymes. Silencing of ATP7A inhibited LOX activity in the 4T1 mammary carcinoma cell line, resulting in a loss of LOX-dependent mechanisms of metastasis, including the phosphorylation of focal adhesion kinase and myeloid cell recruitment to the lungs, in an orthotopic mouse model of breast cancer. ATP7A silencing was also found to attenuate LOX activity and metastasis of Lewis lung carcinoma cells in mice. Meta-analysis of breast cancer patients found that high ATP7A expression was significantly correlated with reduced survival. Taken together, these results identify ATP7A as a therapeutic target for blocking LOX- and LOXL-dependent malignancies.

Development of an international Delphi survey to establish core outcome domains for trials in adults with glomerular disease.

Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making.

Carbon concentration in the world's trees across climatic gradients.

Wood carbon (C) concentration is a key wood trait that varies widely among tree species, but our understanding of the factors governing this trait is limited, despite reason to hypothesize that wood C varies systematically across environmental gradients. We compiled a novel database of 1145 geo-referenced wood C observations from 415 species, to elucidate climate correlates of wood C concentrations, and test if these relationships differ across tissue types and major taxonomic divisions (i.e. angiosperms vs gymnosperms). Climate variables, including mean annual temperature (MAT) and precipitation and temperature seasonality, are significantly correlated with wood C concentrations. Relationships between wood C and these variables differ across tissue types and taxonomic divisions, yet there is a negative relationship between wood C and MAT that exists across all tissues and species groups. Wood C concentrations in trees are influenced by climate, with experimental evidence (albeit scant) indicating that climate-driven changes in lignin concentrations likely govern these relationships. Our study presents among the first lines of evidence indicating that wood C concentrations are correlated with environmental conditions, thereby enhancing our understanding of the potential adaptive significance of wood C variation in trees.

The leaf economics spectrum's morning coffee: plant size-dependent changes in leaf traits and reproductive onset in a perennial tree crop.

BACKGROUND AND AIMS: Size-dependent changes in plant traits are an important source of intraspecific trait variation. However, there are few studies that have tested if leaf trait co-variation and/or trade-offs follow a within-genotype leaf economics spectrum (LES) related to plant size and reproductive onset. To our knowledge, there are no studies on any plant species that have tested whether or not the shape of a within-genotype LES that describes how traits covary across whole plant sizes, is the same as the shape of a within-genotype LES that represents environmentally driven trait plasticity. METHODS: We quantified size-dependent variation in eight leaf traits in a single coffee genotype (Coffea arabica var. Caturra) in managed agroecosystems with different environmental conditions (light and fertilization treatments), and evaluated these patterns with respect to reproductive onset. We also evaluated if trait covariation along a within-genotype plant-size LES differed from a within-genotype environmental LES defined with trait data from coffee growing in different environmental conditions. KEY RESULTS: Leaf economics traits related to resource acquisition - maximum photosynthetic rates (A) and mass-based leaf nitrogen (N) concentrations - declined linearly with plant size. Structural traits - leaf mass, leaf thickness, and leaf mass per unit area (LMA) - and leaf area increased with plant size beyond reproductive onset, then declined in larger plants. Three primary LES traits (mass-based A, leaf N and LMA) covaried across a within-genotype plant-size LES, with plants moving towards the 'resource-conserving' end of the LES as they grow larger; in coffee these patterns were nearly identical to a within-genotype environmental LES. CONCLUSIONS: Our results demonstrate that a plant-size LES exists within a single genotype. Our findings indicate that in managed agroecosystems where resource availability is high the role of reproductive onset in driving within-genotype trait variability, and the strength of covariation and trade-offs among LES traits, are less pronounced compared with plants in natural systems. The consistency in trait covariation in coffee along both plant-size and environmental LES axes indicates strong constraints on leaf form and function that exist within plant genotypes.

Does a health crisis change how we value health?

General population health state values are used in healthcare resource allocation, including health technology assessment. We examine whether UK general population health valuations changed during the COVID-19 pandemic. Ratings of EQ-5D-5L health states 11111 (no problems), 55555 (extreme problems), and dead were collected in a UK general population survey during the pandemic (April-May 2020) using the 0 = worst imaginable health, 100 = best imaginable health visual analog scale (EQ-VAS). Ratings for 55555 were transformed to a full health = 1, dead = 0 scale. Responses were compared to similar data collected pre-pandemic (2018). After propensity score matching to minimize sample differences, EQ-VAS responses were analyzed using Tobit regressions. On the 0-100 scale, 11111 was rated on average 8.67 points lower, 55555 rated 9.56 points higher, and dead rated 7.45 points lower post-pandemic onset compared to pre-pandemic. On the full health = 1, dead = 0 scale, 55555 values were 0.09 higher post-pandemic onset. There was evidence of differential impacts of COVID-19 by gender, age, and ethnicity, although only age impacted values on the 1-0 scale. COVID-19 may have affected how people value health. It is unknown whether the effect is large enough to have policy relevance, but caution should be taken in assuming pre-COVID-19 values are unchanged.

Effectiveness of Dementia Care Mapping™ to reduce agitation in care home residents with dementia: an open-cohort cluster randomised controlled trial.

OBJECTIVES: Agitation is common and problematic in care home residents with dementia. This study investigated the (cost)effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation in this population. METHOD: Pragmatic, cluster randomised controlled trial with cost-effectiveness analysis in 50 care homes, follow-up at 6 and 16 months and stratified randomisation to intervention (n = 31) and control (n = 19). Residents with dementia were recruited at baseline (n = 726) and 16 months (n = 261). Clusters were not blinded to allocation. Three DCM cycles were scheduled, delivered by two trained staff per home. Cycle one was supported by an external DCM expert. Agitation (Cohen-Mansfield Agitation Inventory (CMAI)) at 16 months was the primary outcome. RESULTS: DCM was not superior to control on any outcomes (cross-sectional sample n = 675: 287 control, 388 intervention). The adjusted mean CMAI score difference was -2.11 points (95% CI -4.66 to 0.44, p = 0.104, adjusted ICC control = 0, intervention 0.001). Sensitivity analyses supported the primary analysis. Incremental cost per unit improvement in CMAI and QALYs (intervention vs control) on closed-cohort baseline recruited sample (n = 726, 418 intervention, 308 control) was £289 and £60,627 respectively. Loss to follow-up at 16 months in the original cohort was 312/726 (43·0%) mainly (87·2%) due to deaths. Intervention dose was low with only a quarter of homes completing more than one DCM cycle. CONCLUSION: No benefits of DCM were evidenced. Low intervention dose indicates standard care homes may be insufficiently resourced to implement DCM. Alternative models of implementation, or other approaches to reducing agitation should be considered.

Ultra-Low Molecular Weight Photoswitchable Hydrogelators.

Two photoswitchable arylazopyrozoles form hydrogels at a concentration of 1.2 % (w/v). With a molecular weight of 258.28 g mol-1 , these are the lowest known molecular weight hydrogelators that respond reversibly to light. Photoswitching of the E- to the Z-form by exposure to 365 nm light results in a macroscopic gel→sol transition; nearly an order of magnitude reduction in the measured elastic and loss moduli. In the case of the meta-arylazopyrozole, cryogenic transmission electron microscopy suggests that the 29±7 nm wide sheets in the E-gel state narrow to 13±2 nm upon photoswitching to the predominantly Z-solution state. Photoswitching for meta-arylazopyrozole is reversible through cycles of 365 nm and 520 nm excitation with little fatigue. The release of a rhodamine B dye encapsulated in gels formed by the arylazopyrozoles is accelerated more than 20-fold upon photoswitching with 365 nm light, demonstrating these materials are suitable for light-controlled cargo release.

Tension, contraction and tissue morphogenesis.

D'Arcy Thompson was a proponent of applying mathematical and physical principles to biological systems, an approach that is becoming increasingly common in developmental biology. Indeed, the recent integration of quantitative experimental data, force measurements and mathematical modeling has changed our understanding of morphogenesis - the shaping of an organism during development. Emerging evidence suggests that the subcellular organization of contractile cytoskeletal networks plays a key role in force generation, while on the tissue level the spatial organization of forces determines the morphogenetic output. Inspired by D'Arcy Thompson's On Growth and Form, we review our current understanding of how biological forms are created and maintained by the generation and organization of contractile forces at the cell and tissue levels. We focus on recent advances in our understanding of how cells actively sculpt tissues and how forces are involved in specific morphogenetic processes.

Actomyosin-based tissue folding requires a multicellular myosin gradient.

Tissue folding promotes three-dimensional (3D) form during development. In many cases, folding is associated with myosin accumulation at the apical surface of epithelial cells, as seen in the vertebrate neural tube and the Drosophila ventral furrow. This type of folding is characterized by constriction of apical cell surfaces, and the resulting cell shape change is thought to cause tissue folding. Here, we use quantitative microscopy to measure the pattern of transcription, signaling, myosin activation and cell shape in the Drosophila mesoderm. We found that cells within the ventral domain accumulate different amounts of active apical non-muscle myosin 2 depending on the distance from the ventral midline. This gradient in active myosin depends on a newly quantified gradient in upstream signaling proteins. A 3D continuum model of the embryo with induced contractility demonstrates that contractility gradients, but not contractility per se, promote changes to surface curvature and folding. As predicted by the model, experimental broadening of the myosin domain in vivo disrupts tissue curvature where myosin is uniform. Our data argue that apical contractility gradients are important for tissue folding.

Effect of polar amino acid incorporation on Fmoc-diphenylalanine-based tetrapeptides.

Peptide hydrogels show great promise as extracellular matrix mimics due to their tuneable, fibrous nature. Through incorporation of polar cationic, polar anionic or polar neutral amino acids into the Fmoc-diphenylalanine motif, we show that electrostatic charge plays a key role in the properties of the subsequent gelators. Specifically, we show that an inverse relationship exists for biocompatibility in the solution state versus the gel state for cationic and anionic peptides. Finally, we use tethered bilayer lipid membrane (tBLM) experiments to suggest a likely mode of cytotoxicity for tetrapeptides which exhibit cytotoxicity in the solution state.

Exploring self-report and proxy-report quality-of-life measures for people living with dementia in care homes.

PURPOSE: There are many validated quality-of-life (QoL) measures designed for people living with dementia. However, the majority of these are completed via proxy-report, despite indications from community-based studies that consistency between proxy-reporting and self-reporting is limited. The aim of this study was to understand the relationship between self- and proxy-reporting of one generic and three disease-specific quality-of-life measures in people living with dementia in care home settings. METHODS: As part of a randomised controlled trial, four quality-of-life measures (DEMQOL, EQ-5D-5L, QOL-AD and QUALID) were completed by people living with dementia, their friends or relatives or care staff proxies. Data were collected from 726 people living with dementia living in 50 care homes within England. Analyses were conducted to establish the internal consistency of each measure, and inter-rater reliability and correlation between the measures. RESULTS: Residents rated their quality of life higher than both relatives and staff on the EQ-5D-5L. The magnitude of correlations varied greatly, with the strongest correlations between EQ-5D-5L relative proxy and staff proxy. Internal consistency varied greatly between measures, although they seemed to be stable across types of participants. There was poor-to-fair inter-rater reliability on all measures between the different raters. DISCUSSION: There are large differences in how QoL is rated by people living with dementia, their relatives and care staff. These inconsistencies need to be considered when selecting measures and reporters within dementia research.