Spectrin promotes the association of F-actin with the cytoplasmic surface of the human erythrocyte membrane

We studied the binding of actin to the erythrocyte membrane by a novel application of falling ball viscometry. Our approach is based on the notion that if membranes have multiple binding sites for F-actin they will be able to cross-link and increase the viscosity of actin. Spectrin- and actin-depleted inside-out vesicles reconstituted with purified spectrin dimer or tetramer induce large increases in the viscosity of actin. Comparable concentrations of spectrin alone, inside-out vesicles alone, inside-out vesicles plus heat-denatured spectrin dimmer or tetramer induce large increases in the viscosity of actin. Comparable concentrations of spectrin alone, inside-out vesicles alone, inside-out plus heat denatured spectrin, ghosts, or ghosts plus spectrin have no effect on the viscosity of actin. Centrifugation experiments show that the amount of actin bound to the inside-out vesicles is enhanced in the presence of spectrin. The interactions detected by low-shear viscometry reflect actin interaction with membrane- bound spectrin because (a) prior removal of band 4.1 and ankyrin (band 2.1, the high- affinity membrane attachment site for spectrin) reduces both spectrin binding to the inside-out vesicles and their capacity to stimulate increase in viscosity of actin in the presence of spectrin + actin are inhibited by the addition of the water-soluble 72,000- dalton fragment of ankyrin, which is known to inhibit spectrin reassociation to the membrane. The increases in viscosity of actin induced by inside-out vesicles reconstituted with purified spectrin dimer or tetramer are not observed when samples are incubated at 0 degrees C. This temperature dependence may be related to the temperature-dependent associations we observe in solution studies with purified proteins: addition of ankyrin inhibits actin cross-linking by spectrin tetramer plus band 4.1 at 0 degrees C, and enhances it at 32 degrees C. We conclude (a) that falling ball viscometry can be used to assay actin binding to membranes and (b) that spectrin is involved in attaching actin filaments or oligomers to the cytoplasmic surface of the erythrocyte membrane

Can patterns of urban biodiversity be predicted using simple measures of green infrastructure?

Urban species and habitats provide important ecosystem services such as summertime cooling, recreation, and pollination at a variety of scales. Many studies have assessed how biodiversity responds to urbanization, but little work has been done to try and create recommendations that can be easily applied to urban planning, design and management practice. Urban planning often operates at broad spatial scales, typically using relatively simplistic targets for land cover mix to influence biodiversity and ecosystem service provision. Would more complicated, but still easily created, prescriptions for urban vegetation be beneficial? Here we assess the importance of vegetation measures (percentage vegetation cover, tree canopy cover and variation in canopy height) across four taxonomic groups (bats, bees, hoverflies and birds) at multiple spatial scales (100, 250, 500, 1000 m) within a major urban area (Birmingham, the United Kingdom). We found that small-scale (100–250-m radius) measures of vegetation were important predictors for hoverflies and bees, and that bats were sensitive to vegetation at a medium spatial-scale (250–500 m). In contrast, birds responded to vegetation characteristics at both small (100 m) and large (1000 m) scales. Vegetation cover, tree cover and variation in canopy height were expected to decrease with built surface cover; however, only vegetation height showed this expected trend. The results indicate the importance of relatively small patches of vegetation cover for supporting urban biodiversity, and show that relatively simple measures of vegetation characteristics can be useful predictors of species richness (or activity density, in the case of bats). They also highlight the danger of relying upon percentage built surface cover as an indicator of urban biodiversity potential

The characteristics of summer sub-hourly rainfall over the southern UK in a high-resolution convective permitting model

Flash flooding is often caused by sub-hourly rainfall extremes. Here, we examine southern UK sub-hourly 10 min rainfall from Met Office state-of-the-art convective-permitting model simulations for the present and future climate. Observational studies have shown that the duration of rainfall can decrease with temperature in summer in some regions. The duration decrease coincides with an intensification of sub-hourly rainfall extremes. This suggests that rainfall duration and sub-hourly rainfall intensity may change in future under climate change with important implications for future changes in flash flooding risk. The simulations show clear intensification of sub-hourly rainfall, but we fail to detect any decrease in rainfall duration. In fact, model results suggest the opposite with a slight (probably insignificant) lengthening of both extreme and non-extreme rainfall events in the future. The lengthening is driven by rainfall intensification without clear changes in the shape of the event profile. Other metrics are also examined, including the relationship between intense 10 min rainfall and temperature, and return levels changes; all are consistent with results found for hourly rainfall. No evaluation of model performance at the sub-hourly timescale is possible, highlighting the need for high-quality sub-hourly observations. Such sub-hourly observations will advance our understanding of the future risks of flash flooding

Compound wind and rainfall extremes: Drivers and future changes over the UK and Ireland

\ua9 2024The co-occurrence of wind and rainfall extremes can yield larger impacts than when either hazard occurs in isolation. This study assesses compound extremes produced by Extra-tropical cyclones (ETCs) during winter from two perspectives. Firstly, we assess ETCs with extreme footprints of wind and rainfall; footprint severity is measured using the wind severity index (WSI) and rain severity index (RSI) which account for the intensity, duration, and area of either hazard. Secondly, we assess local co-occurrences of 6-hourly wind and rainfall extremes within ETCs. We quantify the likelihood of compound extremes in these two perspectives and characterise a number of their drivers (jet stream, cyclone tracks, and fronts) in control (1981–2000) and future (2060–2081, RCP8.5) climate simulations from a 12-member ensemble of local convection-permitting 2.2 km climate projections over the UK and Ireland. Simulations indicate an increased probability of ETCs producing extremely severe WSI and RSI in the same storm in the future, occurring 3.6 times more frequently (every 5 years compared to every 18 years in the control). This frequency increase is mainly driven by increased rainfall intensities, pointing to a predominantly thermodynamic driver. However, future winds also increase alongside a strengthened jet stream, while a southward displaced jet and cyclone track in these events leads to a dynamically-enhanced increase in temperature. This intensifies rainfall in line with Clausius-Clapeyron, and potentially wind speeds due to additional latent heat energy. Future simulations also indicate an increase in the land area experiencing locally co-occurring wind and rainfall extremes; largely explained by increased rainfall within warm and cold fronts, although the relative increase is highest near cold fronts suggesting increased convective activity. These locally co-occurring extremes are more likely in storms with severe WSI and RSI, but not exclusively so as local co-occurrence requires the coincidence of separate drivers within ETCs. Overall, our results reveal many contributing factors to compound wind and rainfall extremes and their future changes. Further work is needed to understand the uncertainty in the future response by sampling additional climate models

PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer's disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies

Compound wind and rainfall extremes: Drivers and future changes over the UK and Ireland

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordData availability: Wind and rainfall data is freely available. Other data can be made available upon reasonable request.The co-occurrence of wind and rainfall extremes can yield larger impacts than when either hazard occurs in isolation. This study assesses compound extremes produced by Extra-tropical cyclones (ETCs) during winter from two perspectives. Firstly, we assess ETCs with extreme footprints of wind and rainfall; footprint severity is measured using the wind severity index (WSI) and rain severity index (RSI) which account for the intensity, duration, and area of either hazard. Secondly, we assess local co-occurrences of 6-hourly wind and rainfall extremes within ETCs. We quantify the likelihood of compound extremes in these two perspectives and characterise a number of their drivers (jet stream, cyclone tracks, and fronts) in control (1981-2000) and future (2060-2081, RCP8.5) climate simulations from a 12-member ensemble of local convection-permitting 2.2 km climate projections over the UK and Ireland. Simulations indicate an increased probability of ETCs producing extremely severe WSI and RSI in the same storm in the future, occurring 3.6 times more frequently (every 5 years compared to every 18 years in the control). This frequency increase is mainly driven by increased rainfall intensities, pointing to a predominantly thermodynamic driver. However, future winds also increase alongside a strengthened jet stream, while a southward displaced jet and cyclone track in these events leads to a dynamically-enhanced increase in temperature. This intensifies rainfall in line with Clausius-Clapeyron, and potentially wind speeds due to additional latent heat energy. Future simulations also indicate an increase in the land area experiencing locally co-occurring wind and rainfall extremes; largely explained by increased rainfall within warm and cold fronts, although the relative increase is highest near cold fronts suggesting increased convective activity. These locally co-occurring extremes are more likely in storms with severe WSI and RSI, but not exclusively so as local co-occurrence requires the coincidence of separate drivers within ETCs. Overall, our results reveal many contributing factors to compound wind and rainfall extremes and their future changes. Further work is needed to understand the uncertainty in the future response by sampling additional climate models.Natural Environment Research Council (NERC)Joint UK BEIS/Defra Hadley Centre Climate ProgrammeEuropean Union Horizon 202

Large-scale dynamics moderate impact-relevant changes to organised convective storms

Larger organised convective storms (mesoscale-convective systems) can lead to major flood events in Europe. Here we assess end-of-century changes to their characteristics in two convection-permitting climate simulations from the UK Met Office and ETH-Zürich that both use the high Representative Concentration Pathway 8.5 scenario but different approaches to represent atmospheric changes with global warming and different models. The UK Met Office projections indicate more frequent, smaller, and slower-moving storms, while ETH-Zürich projections show fewer, larger, and faster-moving storms. However, both simulations show increases to peak precipitation intensity, total precipitation volume, and temporal clustering, suggesting increasing risks from mesoscale-convective systems in the future. Importantly, the largest storms that pose increased flood risks are projected to increase in frequency and intensity. These results highlight that understanding large-scale dynamical drivers as well as the thermodynamical response of storms is essential for accurate projections of changes to storm hazards, needed for future climate adaptation

Microservice Transition and its Granularity Problem: A Systematic Mapping Study

Microservices have gained wide recognition and acceptance in software industries as an emerging architectural style for autonomic, scalable, and more reliable computing. The transition to microservices has been highly motivated by the need for better alignment of technical design decisions with improving value potentials of architectures. Despite microservices' popularity, research still lacks disciplined understanding of transition and consensus on the principles and activities underlying "micro-ing" architectures. In this paper, we report on a systematic mapping study that consolidates various views, approaches and activities that commonly assist in the transition to microservices. The study aims to provide a better understanding of the transition; it also contributes a working definition of the transition and technical activities underlying it. We term the transition and technical activities leading to microservice architectures as microservitization. We then shed light on a fundamental problem of microservitization: microservice granularity and reasoning about its adaptation as first-class entities. This study reviews state-of-the-art and -practice related to reasoning about microservice granularity; it reviews modelling approaches, aspects considered, guidelines and processes used to reason about microservice granularity. This study identifies opportunities for future research and development related to reasoning about microservice granularity.Comment: 36 pages including references, 6 figures, and 3 table

From Monolith to Microservices: A Classification of Refactoring Approaches

While the recently emerged Microservices architectural style is widely discussed in literature, it is difficult to find clear guidance on the process of refactoring legacy applications. The importance of the topic is underpinned by high costs and effort of a refactoring process which has several other implications, e.g. overall processes (DevOps) and team structure. Software architects facing this challenge are in need of selecting an appropriate strategy and refactoring technique. One of the most discussed aspects in this context is finding the right service granularity to fully leverage the advantages of a Microservices architecture. This study first discusses the notion of architectural refactoring and subsequently compares 10 existing refactoring approaches recently proposed in academic literature. The approaches are classified by the underlying decomposition technique and visually presented in the form of a decision guide for quick reference. The review yielded a variety of strategies to break down a monolithic application into independent services. With one exception, most approaches are only applicable under certain conditions. Further concerns are the significant amount of input data some approaches require as well as limited or prototypical tool support.Comment: 13 pages, 4 tables, 2 figures, Software Engineering Aspects of Continuous Development and New Paradigms of Software Production and Deployment, First International Workshop, DEVOPS 2018, Chateau de Villebrumier, France, March 5-6, 2018, Revised Selected Paper