Vertical structure and physical processes of the Madden-Julian oscillation: exploring key model physics in climate simulations

Aimed at reducing deficiencies in representing the Madden-Julian oscillation (MJO) in general circulation models (GCMs), a global model evaluation project on vertical structure and physical processes of the MJO was coordinated. In this paper, results from the climate simulation component of this project are reported. It is shown that the MJO remains a great challenge in these latest generation GCMs. The systematic eastward propagation of the MJO is only well simulated in about one-fourth of the total participating models. The observed vertical westward tilt with altitude of the MJO is well simulated in good MJO models, but not in the poor ones. Damped Kelvin wave responses to the east of convection in the lower troposphere could be responsible for the missing MJO preconditioning process in these poor MJO models. Several process-oriented diagnostics were conducted to discriminate key processes for realistic MJO simulations. While large-scale rainfall partition and low-level mean zonal winds over the Indo-Pacific in a model are not found to be closely associated with its MJO skill, two metrics, including the low-level relative humidity difference between high and low rain events and seasonal mean gross moist stability, exhibit statistically significant correlations with the MJO performance. It is further indicated that increased cloud-radiative feedback tends to be associated with reduced amplitude of intraseasonal variability, which is incompatible with the radiative instability theory previously proposed for the MJO. Results in this study confirm that inclusion of air-sea interaction can lead to significant improvement in simulating the MJO.

Investigating the impact of defects on key stakeholders in the UK new housing sector

The UK house building sector is facing dual pressures to expand supply, along with delivering against tougher Building Regulations’ requirements, predominantly in the areas of sustainability. A review of current literature has highlighted that the pressures the UK house building industry is currently under may be having a negative impact on build quality, causing an increase in defects. A review and synthesis of the current defect literature with respect to new-build housing and the wider construction sector has found that the prevailing emphasis is limited to the classification, causes, pathology and statistical analysis of defects. There is thus a need to better understand the overall impact of individual defects on key stakeholders within the new-build housing defect detection and remediation process. As part of ongoing research to develop and verify a defect impact assessment rating system, this paper seeks to contribute to our understanding of the impact of individual defects from a key stakeholder perspective by undertaking the literature review and synthesis phase. The literature review identifies the three distinct, but interrelated, dominant impact factors: cost, disruption, and health and safety. By pulling the strands of defect literature together the theoretical lens and key stakeholder sampling strategy is formed as the basis for the subsequent impact weighting development phase.

Landscape connectivity: a key to effective habitat restoration in lowland agricultural landscapes

Landscape scale habitat restoration has the potential to reconnect habitats in fragmented landscapes. This study investigates landscape connectivity as a key to effective habitat restoration in lowland agricultural landscapes and applies these findings to transferable management recommendations. The study area is the Stonehenge World Heritage Site, UK, where landscape scale chalk grassland restoration has been implemented. Here, the ecological benefits of landscape restoration and the species, habitat and landscape characteristics that facilitate or impede the enhancement of biodiversity and landscape connectivity were investigated. Lepidoptera were used as indictors of restoration success and results showed restoration grasslands approaching the ecological conditions of the target chalk grassland habitat and increasing in biodiversity values within a decade. Restoration success is apparent for four species with a broad range of grass larval host plants (e.g. Melanargia galathea, Maniola jurtina) or with intermediate mobility (Polyommatus icarus). However, two species with specialist larval host plants and low mobility (Lysandra bellargus), are restricted to chalk grassland fragments. Studies of restoration grassland of different ages show that recent grassland restoration (1 or 2 years old) may reduce the functional isolation of chalk grassland fragments. A management experiment showed that mowing increases boundary following behaviour in two species of grassland Lepidoptera; Maniola jurtina and Zygaena filipendulae. Analysis of the landscape scale implications of the grassland restoration illustrates an increase in grassland habitat network size and in landscape connectivity, which is likely to benefit the majority of grassland associated Lepidoptera. Landscape and habitat variables can be managed to increase the success of restoration projects including the spatial targeting of receptor sites, vegetation structure and selection of seed source and management recommendations are provided that are transferrable to other species-rich grassland landscape scale restoration projects. Overall results show restoration success for some habitats and species within a decade. However, additional management is required to assist the re-colonisation of specialist species. Despite this, habitat restoration at the landscape scale can be an effective, long term approach to enhance butterfly biodiversity and landscape connectivity.

Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl

Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO−), polysulfides, and dinitrososulfite N-nitrosohydroxylamine-N-sulfonate (SULFI/NO), each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO− is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO− synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.

Biogeochemical cycles and biodiversity as key drivers of ecosystem services provided by soils

Soils play a pivotal role in major global biogeochemical cycles (carbon, nutrient and water), while hosting the largest diversity of organisms on land. Because of this, soils deliver fundamental ecosystem services, and management to change a soil process in support of one ecosystem service can either provide co-benefits to other services or can result in trade-offs. In this critical review, we report the state-of-the-art understanding concerning the biogeochemical cycles and biodiversity in soil, and relate these to the provisioning, regulating, supporting and cultural ecosystem services which they underpin. We then outline key knowledge gaps and research challenges, before providing recommendations for management activities to support the continued delivery of ecosystem services from soils. We conclude that although there are knowledge gaps that require further research, enough is known to start improving soils globally. The main challenge is in finding ways to share knowledge with soil managers and policy-makers, so that best-practice management can be implemented. A key element of this knowledge sharing must be in raising awareness of the multiple ecosystem services underpinned by soils, and the natural capital they provide. The International Year of Soils in 2015 presents the perfect opportunity to begin a step-change in how we harness scientific knowledge to bring about more sustainable use of soils for a secure global society.

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers.

Defining key structural determinants for the pro-osteogenic activity of flavonoids

Epidemiological studies suggest that fruits and vegetables may play a role in promoting bone growth and preventing age-related bone loss, attributable, at least in part, to phytochemicals such as flavonoids stimulating osteoblastogenesis. Through systematically screening the effect of flavonoids on the osteogenic differentiation of human mesenchymal stem cells in vitro, and correlating activity with chemical structure using comparative molecular field analysis, we have successfully identified important structural features which relate to their activity, as well as reliably predicting the activity of compounds with unknown activity. Contour maps emphasised the importance of electronegativity, steric bulk, and a 2-C-3-C double bond at the flavonoid C-ring, as well as overall electropositivity and reduced steric bulk at the flavonoid B-ring. These results support a role for certain flavonoids in promoting osteogenic differentiation, thus their potential for preventing skeletal deterioration, as well as providing a foundation for the lead optimisation of novel bone anabolics.

Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle

Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn/ mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn/ mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn/ mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn/ mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.

Surface termination of CePt5/Pt(111): the key to chemical inertness

The surface termination of CePt5/Pt(111) is determined experimentally by LEED-IV. In accordance with recent theoretical predictions, a dense Pt terminated surface is being found. Whereas the CePt5 volume lattice comprises Pt kagome layers, additional Pt atoms occupy the associated hole positions at the surface. This finding provides a natural explanation for the remarkable inertness of the CePt5 intermetallic. Implications of the structural relaxations determined by LEED-IV analysis are discussed with regard to observations by scanning tunneling microscopy and electron spectroscopies.

Biogeochemical cycles and biodiversity as key drivers of ecosystem services provided by soils

Soils play a pivotal role in major global biogeochemical cycles (carbon, nutrient, and water), while hosting the largest diversity of organisms on land. Because of this, soils deliver fundamental ecosystem services, and management to change a soil process in support of one ecosystem service can either provide co-benefits to other services or result in trade-offs. In this critical review, we report the state-of-the-art understanding concerning the biogeochemical cycles and biodiversity in soil, and relate these to the provisioning, regulating, supporting, and cultural ecosystem services which they underpin. We then outline key knowledge gaps and research challenges, before providing recommendations for management activities to support the continued delivery of ecosystem services from soils. We conclude that, although soils are complex, there are still knowledge gaps, and fundamental research is still needed to better understand the relationships between different facets of soils and the array of ecosystem services they underpin, enough is known to implement best practices now. There is a tendency among soil scientists to dwell on the complexity and knowledge gaps rather than to focus on what we do know and how this knowledge can be put to use to improve the delivery of ecosystem services. A significant challenge is to find effective ways to share knowledge with soil managers and policy makers so that best management can be implemented. A key element of this knowledge exchange must be to raise awareness of the ecosystems services underpinned by soils and thus the natural capital they provide. We know enough to start moving in the right direction while we conduct research to fill in our knowledge gaps. The lasting legacy of the International Year of Soils in 2015 should be for soil scientists to work together with policy makers and land managers to put soils at the centre of environmental policy making and land management decisions.

Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials

Background Appropriately conducted adaptive designs (ADs) offer many potential advantages over conventional trials. They make better use of accruing data, potentially saving time, trial participants, and limited resources compared to conventional, fixed sample size designs. However, one can argue that ADs are not implemented as often as they should be, particularly in publicly funded confirmatory trials. This study explored barriers, concerns, and potential facilitators to the appropriate use of ADs in confirmatory trials among key stakeholders. Methods We conducted three cross-sectional, online parallel surveys between November 2014 and January 2015. The surveys were based upon findings drawn from in-depth interviews of key research stakeholders, predominantly in the UK, and targeted Clinical Trials Units (CTUs), public funders, and private sector organisations. Response rates were as follows: 30(55 %) UK CTUs, 17(68 %) private sector, and 86(41 %) public funders. A Rating Scale Model was used to rank barriers and concerns in order of perceived importance for prioritisation. Results Top-ranked barriers included the lack of bridge funding accessible to UK CTUs to support the design of ADs, limited practical implementation knowledge, preference for traditional mainstream designs, difficulties in marketing ADs to key stakeholders, time constraints to support ADs relative to competing priorities, lack of applied training, and insufficient access to case studies of undertaken ADs to facilitate practical learning and successful implementation. Associated practical complexities and inadequate data management infrastructure to support ADs were reported as more pronounced in the private sector. For funders of public research, the inadequate description of the rationale, scope, and decision-making criteria to guide the planned AD in grant proposals by researchers were all viewed as major obstacles. Conclusions There are still persistent and important perceptions of individual and organisational obstacles hampering the use of ADs in confirmatory trials research. Stakeholder perceptions about barriers are largely consistent across sectors, with a few exceptions that reflect differences in organisations’ funding structures, experiences and characterisation of study interventions. Most barriers appear connected to a lack of practical implementation knowledge and applied training, and limited access to case studies to facilitate practical learning. Keywords: Adaptive designs; flexible designs; barriers; surveys; confirmatory trials; Phase 3; clinical trials; early stopping; interim analyses