Intracisternal delivery of NFκB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment.

We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFκB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic kainic acid (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self-complementary AAV2/9 (scAAV2/9) delivery in the adult rat cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, AAV2/9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFκB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the CD11b marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug-induced or transgenic disease models. However, further improvements are required to enhance viral particles penetration into the brain

On the growth kinetics of Ni(Pt) silicide thin films

We report on the effect of Pt on the growth kinetics of δ-Ni2Si and Ni 1−xPtxSi thin films formed by solid phase reaction of a Ni(Pt) alloyed thin film on Si(100). The study was performed by real-time Rutherford backscattering spectrometry examining the silicide growth rates for initial Pt concentrations of 0, 1, 3, 7, and 10 at. % relative to the Ni content. Pt was found to exert a drastic effect on the growth kinetics of both phases. δ-Ni2Si growth is slowed down tremendously, which results in the simultaneous growth of this phase with Ni 1−xPtxSi. Activation energies extracted for the Ni 1−xPtxSi growth process exhibit an increase from Ea = 1.35 ± 0.06 eV for binary NiSi to Ea = 2.7 ± 0.2 eV for Ni 1−xPtxSi with an initial Pt concentration of 3 at. %. Further increasing the Pt content to 10 at. % merely increases the activation energy for Ni 1−xPtxSi growth to Ea = 3.1 ± 0.5 eV

Cost-benefit analysis of BIM-enabled design clash detection and resolution

Building Information Modelling (BIM) is increasingly deployed as part of the processes in Architecture, Engineering and Construction (AEC) industry projects. While the benefits of BIM have been extensively proclaimed, explicit justification in terms of direct cost savings for BIM implementation on real-life projects, particularly for clash detection BIM workstream, are not well documented. This paper proposes and demonstrates a methodology to prove how BIM-based clash detection leads to cost savings. A schema is developed based on literature review and industrial expertise to quantify cost savings achieved by the utilisation of BIM-based clash detection and resolution. This paper provides validation of the proposed schema on a major infrastructure project. The developed schema includes the categorisation of identified clashes based on stakeholder involvement and required actions. The validation used the estimated cost of clashes were those not resolved before site operations took place. This schema simplifies both the categorisation and cost estimation of clashes in design. Estimated savings yielded 20% of contract value using the schema, for the multi-million-dollar project case study, thus extending evidence of BIM savings and benefits. The schema improves the existing process and valorises clash detection, thus allowing stakeholders to conduct a cost-benefit analysis. In addition, the categorisation methodology allows prioritising on the most costly clashes, and draw lessons learnt for further projects. This schema opens the path towards a systematic methodology to appraise the benefits of different BIM uses or processes

Public Benefits of Undeveloped Lands on Urban Outskirts: Non-Market Valuation Studies and their Role in Land Use Plans

Over the past three decades, the economics profession has developed methods for estimating the public benefits of green spaces, providing an opportunity to incorporate such information into land-use planning. While federal regulations routinely require such estimates for major regulations, the extent to which they are used in local land use plans is not clear. This paper reviews the literature on public values for lands on urban outskirts, not just to survey their methods or empirical findings, but to evaluate the role they have played--or have the potential to play-- in actual land use plans. Based on interviews with authors and representatives of funding agencies and local land trusts, it appears that academic work has had a mixed reception in the policy world. Reasons for this include a lack of interest in making academic work accessible to policy makers, emphasizing revealed preference methods which are inconsistent with policy priorities related to nonuse values, and emphasis on benefit-cost analyses. Nevertheless, there are examples of success stories that illustrate how such information can play a vital role in the design of conservation policies. Working Paper 07-2

What Price Recreation in Finland?—A Contingent Valuation Study of Non-Market Benefits of Public Outdoor Recreation Areas

Basic services in Finnish national parks and state-owned recreation areas have traditionally been publicly financed and thus free of charge for users. Since the benefits of public recreation are not captured by market demand, government spending on recreation services must be motivated in some other way. Here, we elicit people’s willingness to pay (WTP) for services in the country’s state-owned parks to obtain an estimate of the value of outdoor recreation in monetary terms. A variant of the Tobit model is used in the econometric analysis to examine the WTP responses elicited by a payment card format. We also study who the current users of recreation services are in order to enable policymakers to anticipate the redistribution effects of a potential implementation of user fees. Finally, we discuss the motives for WTP, which reveal concerns such as equity and ability to pay that are relevant for planning public recreation in general and for the introduction of fees in particular

Controlling for Observed and Unobserved Site Characteristics in RUM Models of Recreation Demand

Recreation demand models are typically plagued by limited information on site attributes. If these unobserved site attributes are correlated with the observed characteristics and/or the travel cost variable, the resulting parameter estimates are likely to be biased. We develop a Bayesian approach to estimating a model that incorporates a full set of alternative-speci c constants, insulating the key travel cost parameter from the in uence of unobservables. The proposed posterior simulator can be used in the mixed logit framework in which some parameters of the conditional utility function are random. We apply the estimation procedures to data from the Iowa Lakes Project.Hatch Act and State of Iowa, the Iowa Department of Natural Resources and the U.S. Environmental Protection Agency's Science to Achieve Results (STAR) program.Grant R830818.http://ajae.oxfordjournals.org/hb201

Stratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning

Quantitative or qualitative differences in immunity may drive clinical severity in COVID-19. Although longitudinal studies to record the course of immunological changes are ample, they do not necessarily predict clinical progression at the time of hospital admission. Here we show, by a machine learning approach using serum pro-inflammatory, anti-inflammatory and anti-viral cytokine and anti-SARS-CoV-2 antibody measurements as input data, that COVID-19 patients cluster into three distinct immune phenotype groups. These immune-types, determined by unsupervised hierarchical clustering that is agnostic to severity, predict clinical course. The identified immune-types do not associate with disease duration at hospital admittance, but rather reflect variations in the nature and kinetics of individual patient's immune response. Thus, our work provides an immune-type based scheme to stratify COVID-19 patients at hospital admittance into high and low risk clinical categories with distinct cytokine and antibody profiles that may guide personalized therapy. Developing predictive methods to identify patients with high risk of severe COVID-19 disease is of crucial importance. Authors show here that by measuring anti-SARS-CoV-2 antibody and cytokine levels at the time of hospital admission and integrating the data by unsupervised hierarchical clustering/machine learning, it is possible to predict unfavourable outcome

On Combining Stated Preferences and Revealed Preferences Approaches to Evaluate Environmental Resources Having a Recreational Use

This work aims at analysing the value of recreational water uses for the Idro Lake (Lombardy, Northern Italy), which has been experiencing dramatic fluctuations in its levels in recent years, due to excessive productive withdrawal that affected recreational uses. It estimates the economic benefits deriving from recreational uses, by considering the current recreational demand and the hypothetical one obtained by considering an “improved quality” scenario. Through an on-site survey, we built a panel dataset. Following Whitehead et al. (2000) and Hanley et al. (2003) we get welfare estimates by combining SP and RP responses. The present CS is estimated in €134 per individual, whilst the increase in CS is estimated in €173 per individual. These figures can be confronted with the economic value of competitive uses and with the clean up costs, respectively, to infer some policy indications

Techno-Ecological Synergy: A Framework for Sustainable Engineering

Even though the importance of ecosystems in sustaining all human activities is well-known, methods for sustainable engineering fail to fully account for this role of nature. Most methods account for the demand for ecosystem services, but almost none account for the supply. Incomplete accounting of the very foundation of human well-being can result in perverse outcomes from decisions meant to enhance sustainability and lost opportunities for benefiting from the ability of nature to satisfy human needs in an economically and environmentally superior manner. This paper develops a framework for understanding and designing synergies between technological and ecological systems to encourage greater harmony between human activities and nature. This framework considers technological systems ranging from individual processes to supply chains and life cycles, along with corresponding ecological systems at multiple spatial scales ranging from local to global. The demand for specific ecosystem services is determined from information about emissions and resource use, while the supply is obtained from information about the capacity of relevant ecosystems. Metrics calculate the sustainability of individual ecosystem services at multiple spatial scales and help define necessary but not sufficient conditions for local and global sustainability. Efforts to reduce ecological overshoot encourage enhancement of life cycle efficiency, development of industrial symbiosis, innovative designs and policies, and ecological restoration, thus combining the best features of many existing methods. Opportunities for theoretical and applied research to make this framework practical are also discussed