222 research outputs found
The Claims Culture: A Taxonomy of Industry Attitudes
This paper presents an analysis of a familiar aspect of construction industry culture that we have dubbed 'the claims culture'. This is a culture of contract administration that lays a strong emphasis on the planning and management of claims. The principal elements of the analysis are two sets of distinctions. The first comprises economic and occupational orders, referring to two kinds of control that are exercised over the construction process; predicated respectively on economic ownership and occupational competence. The second refers to contrasting attitudes towards relationships and problem solving within these orders: respectively 'distributive' and 'integrative'. The concepts of economic and occupational order entail further sub-categories. The various attitudes associated with these categories and sub-categories are described. They are assessed as to their consequences for change initiatives in the industry
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Closure Strategy for a Waste Disposal Facility with Multiple Waste Types and Regulatory Drivers at the Nevada Test Site
The U.S. Department of Energy, National Security Administration Nevada Site Office (NNSA/NSO) is planning to close the 92-Acre Area of the Area 5 Radioactive Waste Management Site (RWMS) at the Nevada Test Site (NTS), which is about 65 miles northwest of Las Vegas, Nevada. Closure planning for this facility must take into account the regulatory requirements for a diversity of waste streams, disposal and storage configurations, disposal history, and site conditions. This paper provides a brief background of the Area 5 RWMS, identifies key closure issues, and presents the closure strategy. Disposals have been made in 25 shallow excavated pits and trenches and 13 Greater Confinement Disposal (GCD) boreholes at the 92-Acre Area since 1961. The pits and trenches have been used to dispose unclassified low-level waste (LLW), low-level mixed waste (LLMW), and asbestiform waste, and to store classified low-level and low-level mixed materials. The GCD boreholes are intermediate-depth disposal units about 10 feet (ft) in diameter and 120 ft deep. Classified and unclassified high-specific activity LLW, transuranic (TRU), and mixed TRU are disposed in the GCD boreholes. TRU waste was also disposed inadvertently in trench T-04C. Except for three disposal units that are active, all pits and trenches are operationally covered with 8-ft thick alluvium. The 92-Acre Area also includes a Mixed Waste Disposal Unit (MWDU) operating under Resource Conservation and Recovery Act (RCRA) Interim Status, and an asbestiform waste unit operating under a state of Nevada Solid Waste Disposal Site Permit. A single final closure cover is envisioned over the 92-Acre Area. The cover is the evapotranspirative-type cover that has been successfully employed at the NTS. Closure, post-closure care, and monitoring must meet the requirements of the following regulations: U.S. Department of Energy Order 435.1, Title 40 Code of Federal Regulations (CFR) Part 191, Title 40 CFR Part 265, Nevada Administrative Code (NAC) 444.743, RCRA requirements as incorporated into NAC 444.8632, and the Federal Facility Agreement and Consent Order (FFACO). A grouping of waste disposal units according to waste type, location, and similarity in regulatory requirements identified six closure units: LLW Unit, Corrective Action Unit (CAU) 111 under FFACO, Asbestiform LLW Unit, Pit 3 MWDU, TRU GCD Borehole Unit, and TRU Trench Unit. The closure schedule of all units is tied to the closure schedule of the Pit 3 MWDU under RCRA
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Closure Strategy for a Waste Disposal Facility with Multiple Waste Types and Regulatory Drivers at the Nevada Test Site
The U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office (NNSA/NSO) plans to close the waste and classified material storage cells in the southeast quadrant of the Area 5 Radioactive Waste Management Site (RWMS), informally known as the '92-Acre Area', by 2011. The 25 shallow trenches and pits and the 13 Greater Confinement Disposal (GCD) borings contain various waste streams including low-level waste (LLW), low-level mixed waste (LLMW), transuranic (TRU), mixed transuranic (MTRU), and high specific activity LLW. The cells are managed under several regulatory and permit programs by the U.S. Department of Energy (DOE) and the Nevada Division of Environmental Protection (NDEP). Although the specific closure requirements for each cell vary, 37 closely spaced cells will be closed under a single integrated monolayer evapotranspirative (ET) final cover. One cell will be closed under a separate cover concurrently. The site setting and climate constrain transport pathways and are factors in the technical approach to closure and performance assessment. Successful implementation of the integrated closure plan requires excellent communication and coordination between NNSA/NSO and the regulators
Continuous flexibility analysis of SARS-CoV-2 spike prefusion structures
Using a new consensus-based image-processing approach together with principal component analysis, the flexibility and conformational dynamics of the SARS-CoV-2 spike in the prefusion state have been analysed. These studies revealed concerted motions involving the receptor-binding domain (RBD), N-terminal domain, and subdomains 1 and 2 around the previously characterized 1-RBD-up state, which have been modeled as elastic deformations. It is shown that in this data set there are not well defined, stable spike conformations, but virtually a continuum of states. An ensemble map was obtained with minimum bias, from which the extremes of the change along the direction of maximal variance were modeled by flexible fitting. The results provide a warning of the potential image-processing classification instability of these complicated data sets, which has a direct impact on the interpretability of the results.The authors would like to acknowledge financial support from
CSIC (PIE/COVID-19 No. 202020E079), the Comunidad de
Madrid through grant CAM (S2017/BMD-3817), the Spanish
Ministry of Science and Innovation through projects SEV
2017-0712, FPU-2015/264 and PID2019-104757RB-I00/AEI/
FEDER, the Instituto de Salud Carlos III [PT17/0009/0010
(ISCIII-SGEFI/ERDF)], and the European Union and
Horizon 2020 through grants INSTRUCT–ULTRA
(INFRADEV-03-2016-2017, Proposal 731005), EOSC Life
(INFRAEOSC-04-2018, Proposal 824087), HighResCells
(ERC-2018-SyG, Proposal 810057), IMpaCT (WIDESPREAD-
03-2018, Proposal 857203), CORBEL
(INFRADEV-1-2014-1, Proposal 654248) and EOSC–Synergy
(EINFRA-EOSC-5, Proposal 857647). HDT and BF were
supported by NIH grant GM125769 and JSM was supported
by NIH grant R01-AI12752
Ultraviolet A Radiation and COVID‐19 Deaths in the USA with replication studies in England and Italy
An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors
The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction
Nanoparticle display of prefusion coronavirus spike elicits S1-focused cross-reactive antibody response against diverse coronavirus subgenera
Multivalent antigen display is a fast-growing area of interest toward broadly protective vaccines. Current nanoparticle-based vaccine candidates demonstrate the ability to confer antibody-mediated immunity against divergent strains of notably mutable viruses. In coronaviruses, this work is predominantly aimed at targeting conserved epitopes of the receptor binding domain. However, targeting conserved non-RBD epitopes could limit the potential for antigenic escape. To explore new potential targets, we engineered protein nanoparticles displaying coronavirus prefusion-stabilized spike (CoV_S-2P) trimers derived from MERS-CoV, SARS-CoV-1, SARS-CoV-2, hCoV-HKU1, and hCoV-OC43 and assessed their immunogenicity in female mice. Monotypic SARS-1 nanoparticles elicit cross-neutralizing antibodies against MERS-CoV and protect against MERS-CoV challenge. MERS and SARS nanoparticles elicit S1-focused antibodies, revealing a conserved site on the S N-terminal domain. Moreover, mosaic nanoparticles co-displaying distinct CoV_S-2P trimers elicit antibody responses to distant cross-group antigens and protect male and female mice against MERS-CoV challenge. Our findings will inform further efforts toward the development of pan-coronavirus vaccines
Africa’s response to the COVID-19 pandemic : A review of the nature of the virus, impacts and implications for preparedness
Background: COVID-19 continues to wreak havoc in different countries across the world, claiming thousands of lives, increasing morbidity and disrupting lifestyles. The global scientific community is in urgent need of relevant evidence, to understand the challenges and knowledge gaps, as well as the opportunities to contain the spread of the virus. Considering the unique socio-economic, demographic, political, ecological and climatic contexts in Africa, the responses which may prove to be successful in other regions may not be appropriate on the continent. This paper aims to provide insight for scientists, policy makers and international agencies to contain the virus and to mitigate its impact at all levels. Methods: The Affiliates of the African Academy of Sciences (AAS), came together to synthesize the current evidence, identify the challenges and opportunities to enhance the understanding of the disease. We assess the potential impact of this pandemic and the unique challenges of the disease on African nations. We examine the state of Africa’s preparedness and make recommendations for steps needed to win the war against this pandemic and combat potential resurgence. Results: We identified gaps and opportunities among cross-cutting issueswhich must be addressed or harnessed in this pandemic. Factors such as the nature of the virus and the opportunities for drug targeting, point of care diagnostics, health surveillance systems, food security, mental health, xenophobia and gender-based violence, shelter for the homeless, water and sanitation, telecommunications challenges, domestic regional coordination and financing. Conclusion: Based on our synthesis of the current evidence, while there are plans for preparedness in several African countries, there are significant limitations. A multi-sectoral efforts from the science, education, medical, technology, communication, business, and industry sectors, as well as local communities, must work collaboratively to assist countries in order to win this fight
SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness
A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity1. This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy
Engineered immunogens to elicit antibodies against conserved coronavirus epitopes
Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing residues 815-823 adjacent to the fusion peptide, are highly conserved across sarbecoviruses and are recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current and emergent viruses. Here we employ computational modeling to design scaffolded immunogens that display the spike 815-823 peptide and the stem helix epitopes without the distracting and immunodominant receptor binding domain. These engineered proteins bind with high affinity and specificity to the mature and germline versions of previously identified broadly protective human antibodies. Epitope scaffolds interact with both sera and isolated monoclonal antibodies with broadly reactivity from individuals with pre-existing SARS-CoV-2 immunity. When used as immunogens, epitope scaffolds elicit sera with broad betacoronavirus reactivity and protect as “boosts” against live virus challenge in mice, illustrating their potential as components of a future pancoronavirus vaccine
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