The Regulatory Framework for Nanomaterials at a Global Level: SAICM and WTO Insights

The regulation of nanomaterials is being discussed at various levels. This article offers a historical description of governmental activities concerning the safety of nanomaterials at the United Nations (UN) level since 2006, with a focus on the UN Strategic Approach to International Chemicals Management (SAICM). The outcomes of the SAICM process were a nanospecific resolution and the addition of new activities on nanotechnologies and manufactured nanomaterials to the SAICM’s Global Plan of Action. The article discusses the implications of these decisions for multilateral environmental agreements. In addition, it studies the consequences of the regulation of nanotechnologies activities on trade governance, in particular the relationship between the SAICM to the legally binding World Trade Organization (WTO) agreements (notably the General Agreement on Tariffs and Trade and the Agreement on Technical Barriers to Trade). The article concludes that the SAICM decisions on manufactured nanomaterials are compatible with WTO law.

The Host Nonsense-Mediated mRNA Decay Pathway Restricts Mammalian RNA Virus Replication

In addition to classically defined immune mechanisms, cell-intrinsic processes can restrict virus infection and have shaped virus evolution. The details of this virus-host interaction are still emerging. Following a genome-wide siRNA screen for host factors affecting replication of Semliki Forest virus (SFV), a positive-strand RNA (+RNA) virus, we found that depletion of nonsense-mediated mRNA decay (NMD) pathway components Upf1, Smg5, and Smg7 led to increased levels of viral proteins and RNA and higher titers of released virus. The inhibitory effect of NMD was stronger when virus replication efficiency was impaired by mutations or deletions in the replicase proteins. Consequently, depletion of NMD components resulted in a more than 20-fold increase in production of these attenuated viruses. These findings indicate that a cellular mRNA quality control mechanism serves as an intrinsic barrier to the translation of early viral proteins and the amplification of +RNA viruses in animal cells.

Nonsense-mediated mRNA decay (NMD) restricts replication of mammalian RNA viruses

A genome-wide siRNA screen against host factors that affect the infection of Semliki Forest virus (SFV), a positive-strand (+)RNA virus, revealed that components of the nonsense-mediated mRNA decay (NMD) pathway restrict early, post-entry steps of the infection cycle. In HeLa cells and primary human fibroblasts, knockdown of UPF1, SMG5 and SMG7 leads to increased levels of viral proteins and RNA and to higher titers of released virus. The inhibitory effect of NMD was stronger when the efficiency of virus replication was impaired by mutations or deletions in the replicase proteins. Accordingly, impairing NMD resulted in a more than 20-fold increased production of these attenuated viruses. Our data suggest that intrinsic features of genomic and sub-genomic viral mRNAs, most likely the extended 3'-UTR length, make them susceptible to NMD. The fact that SFV replication is entirely cytoplasmic strongly suggests that degradation of the viral RNA occurs through the exon junction complex (EJC)-independent mode of NMD. Collectively, our findings uncover a new biological function for NMD as an intrinsic barrier to the translation of early viral proteins and the amplification of (+)RNA viruses in animal cells. Thus, in addition to its role in mRNA surveillance and post-transcriptional gene regulation, NMD also contributes to protect cells from RNA viruses.

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers

Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders1, 2. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin3, 4 and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure5 and neurocognitive impairment6. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

Excited-State Structure, Vibrations, and Nonradiative Relaxation of Jet-Cooled 5-Fluorocytosine

The S0 → S1 vibronic spectrum and S1 state nonradiative relaxation of jet-cooled keto-amino 5-fluorocytosine (5FCyt) are investigated by two-color resonant two-photon ionization spectroscopy at 0.3 and 0.05 cm–1 resolution. The 000 rotational band contour is polarized in-plane, implying that the electronic transition is 1ππ*. The electronic transition dipole moment orientation and the changes of rotational constants agree closely with the SCS-CC2 calculated values for the 1ππ* (S1) transition of 5FCyt. The spectral region from 0 to 300 cm–1 is dominated by overtone and combination bands of the out-of-plane ν1′ (boat), ν2′ (butterfly), and ν3′ (HN–C6H twist) vibrations, implying that the pyrimidinone frame is distorted out-of-plane by the 1ππ* excitation, in agreement with SCS-CC2 calculations. The number of vibronic bands rises strongly around +350 cm–1; this is attributed to the 1ππ* state barrier to planarity that corresponds to the central maximum of the double-minimum out-of-plane vibrational potentials along the ν1′, ν2′, and ν3′ coordinates, which gives rise to a high density of vibronic excitations. At +1200 cm–1, rapid nonradiative relaxation (knr ≥ 1012 s–1) sets in, which we interpret as the height of the 1ππ* state barrier in front of the lowest S1/S0 conical intersection. This barrier in 5FCyt is 3 times higher than that in cytosine. The lifetimes of the ν′ = 0, 2ν1′, 2ν2′, 2ν1′ + 2ν2′, 4ν2′, and 2ν1′ + 4ν2′ levels are determined from Lorentzian widths fitted to the rotational band contours and are τ ≥ 75 ps for ν′ = 0, decreasing to τ ≥ 55 ps at the 2ν1′ + 4ν2′ level at +234 cm–1. These gas-phase lifetimes are twice those of S1 state cytosine and 10–100 times those of the other canonical nucleobases in the gas phase. On the other hand, the 5FCyt gas-phase lifetime is close to the 73 ps lifetime in room-temperature solvents. This lack of dependence on temperature and on the surrounding medium implies that the 5FCyt nonradiative relaxation from its S1 (1ππ*) state is essentially controlled by the same ∼1200 cm–1 barrier and conical intersection both in the gas phase and in solution.

Minimum carbon payment along an aridity gradient for dryland afforestation in non annex I countries with stochastic weather and prices

Recent findings demonstrate that trees in deserts are efficient carbon sinks. It remains however unknown whether the Clean Development Mechanism will accelerate the planting of trees in Non Annex I dryland countries. We estimated the price of carbon at which a farmer would be indifferent between his customary activity and the planting of trees to trade carbon credits, along an aridity gradient. Carbon yields were simulated by means of the CO2FIX v3.1 model for Pinus halepensis with its respective yield classes along the gradient (Arid – 100mm to Dry Sub Humid conditions – 900mm). Wheat and pasture yields were predicted on somewhat similar nitrogen-based quadratic models, using 30 years of weather data to simulate moisture stress. Stochastic production, input and output prices were afterwards simulated on a Monte Carlo matrix. Results show that, despite the high levels of carbon uptake, carbon trading by afforesting is unprofitable anywhere along the gradient. Indeed, the price of carbon would have to raise unrealistically high, and the certification costs would have to drop significantly, to make the Clean Development Mechanism worthwhile for non annex I dryland countries farmers. From a government agency's point of view the Clean Development Mechanism is attractive. However, such agencies will find it difficult to demonstrate “additionality”, even if the rule may be somewhat flexible. Based on these findings, we will further discuss why the Clean Development Mechanism, a supposedly pro-poor instrument, fails to assist farmers in Non Annex I dryland countries living at minimum subsistence level.

Capability of E-Bike Tourism in Switzerland

AIM OF PAPER AND RESEARCH QUESTIONS The primary aim of this investigation was to examine, if tourism in Switzerland can be stimulated by focusing on e-bike offers. Switzerland is an attractive and manifold country for bike tourism. However, there are plenty of hilly and steep areas, where the topography is quite demanding and cycling is predestined to ambitious sportsperson. Less performance-oriented bike tourists are possibly discouraged by the challenges of the landscape. E-bikes seem to be a reasonable alterna-tive to enable less trained person to attend bike tours in steeper regions as well as to keep heterogeneous groups together. E-bikes are already popular in Switzerland for daily routes as the journey to work, but they are not very common in the tour-istic context. The presented investigation evaluates the current standing of supply and demand for e-bike tourism and asks for opportunities and threats in the future development. LITERTURE REVIEW The existing frameworks to analyse capability in the field of sport tourism are limited, because of the broad variation of sports and tourism types. Still several conceptions are valuable to evaluate the opportunities of e-bike tourism in Switzer-land. According to Higham and Hinch (2009) the potential of touristic products and destinations always depends on the interaction among the factors place, people and activity. Standeven and de Knop (1999) support this position by identify-ing the experience of place as a key component of the sport tourism experience. Bull (2005) assumes that place not only affects experience. In his opinion, the specific spatially located resources are even crucial for the existence of nature sports. He identifies four factors determining the attraction of touristic products or destination, as physical characteristics, accessibility and infrastructural arrangements, political and economic resources as well as cultural and perceptual aspects. Concerning the demand side (people) the contemporary research is guided by an individual psychological focus delivering mainly results about motives and the decision making process (e.g. Görtz & Hürten, 2011). RESEARCH DESIGN AND DATA ANALYSIS The presented study is based on a between method triangulation, consisting of qualitative interviews with important stake-holders on the supply side and a cross sectional survey on the demand side. Qualitative interviews were conducted with the first provider of touristic e-bike routes and with the manager of the leading e-bike rental company in Switzerland. The interviews were evaluated by qualitative content analysis according to Mayring (2008). The survey covered a randomized sample of 748 adult persons and focused on interests and needs of potential consumers. The concluding potentials analy-sis combined the results of the interviews and the survey with the findings of literature research. As central outcome the strengths, weaknesses, opportunities and threats were evaluated and presented by SWOT-analysis. RESULTS Results showed that the development of e-bike tourism in Switzerland was not initiated by tourism promoter, but by an innovative e-bike producer. However, also for the manufacturer the fit between landscape (place), product (activity) and visitors (people) was the crucial criterion. The first e-bike tours were offered in a demanding and rural region, in order that the experience of place was able to promote a positive overall experience. Due to the success of the first touristic e-bike products, several tourism regions started to extend their portfolio with e-bike offers. To date a nationwide network for signalised e-bike tours, rental stations and changing stations for rechargeable batteries is established. Despite the attractive offer, the demand is only moderate. The obtained results of the consumer survey pointed at a certain barrier to use e-bikes for tourism activities. The most substantial barrier is the missing affinity for bike tourism in general. Another notable group considering themselves as “fit enough for normal bike tourism”. Nevertheless 55% of the respondent are interested in tour-istic e-bike products. Looking only at people with e-bike tourism experience, even 92% are interested in further activities. DISCUSSION AN CONCLUSION The current study findings are encouraging because they suggest a superior suitability and an attractive level of e-bike tourism products in Switzerland. The results of the consumer survey indicate an increasing demand for e-bike tourism. The investigation also points at some risks, as the rivalry for bike tourism or the raised safety hazard because of the increased driving speed. Summing up, the results support the conclusion, that e-bike tourism will become more important in the com-ing years. However, to reach the goal relevant trends as the requirement for customised offers must be considered and marketing activities are supposed to be extended. REFERENCES Bull, C. (2005). Sport tourism resource analysis. In J. Higham (Ed.), Sport tourism destination: Issues, opportunities and analysis (pp. 25-38). Amsterdam: Elsevier Butterworth-Heinemann. Görtz, M., & D. Hürten (2011). Motive der Radurlauber, psychografische Merkmale und Reiseverhalten. In A. Dreyer, E. Miglbauer & R. Mühlnickel (Hrsg.), Radtourismus. Entwicklungen, Potenziale, Perspektiven (S. 36-43). München: Olden-bourg. Higham, J., & Hinch, T. (2009). Sport and Tourism. Globalization, Mobility and Identity. Amsterdam: Butterworth-Heinemann. Mayring, P. (2008). Qualitative Inhaltsanalyse. Grundlagen und Techniken (10. Aufl.). Weinheim: Beltz Verlag. Standeven, J., & De Knop, P. (1999). Sport Tourism. Campaign: Human Kinetics.

Economic benefits and costs of Sustainable Land Management Technologies: An analysis of WOCAT's global data

Perceived profitability is a key factor in explaining farmers' decision to adopt or not adopt sustainable land management (SLM) technologies. Despite this importance, relatively little is known about the economics of SLM. This paper contributes to the literature by analysing data on costs and perceived cost/benefit ratios of SLM technologies. Data are taken from the World Overview of Conservation Approaches and Technologies technology database and cover 363 case studies conducted in a variety of countries between 1990 and 2012. Based on an in-depth descriptive analysis, we determine what costs accrue to local stakeholders and assess perceived short-term and long-term cost/benefit ratios. Our results show that a large majority of the technologies in our sample are perceived as being profitable: 73% were perceived to have a positive or at least neutral cost/benefit ratio in the short term, while 97% were perceived to have a positive or very positive cost/benefit ratio in the long term. An additional empirical analysis confirms that economic factors are key determinants of land users' decisions to adopt or not adopt SLM technologies. We conclude that a wide range of existing SLM practices generate considerable benefits not only for land users, but for other stakeholders as well. High initial investment costs associated with some practices may, however, constitute a barrier to their adoption; short-term support for land users can help to promote these practices where appropriate.

Sharing evidence of sustainable land management impacts

Ensuring sustainable use of natural resources is crucial for maintaining the basis for our livelihoods. With threats from climate change, disputes over water, biodiversity loss, competing claims on land, and migration increasing worldwide, the demands for sustainable land management (SLM) practices will only increase in the future. For years already, various national and international organizations (GOs, NGOs, donors, research institutes, etc.) have been working on alternative forms of land management. And numerous land users worldwide – especially small farmers – have been testing, adapting, and refining new and better ways of managing land. All too often, however, the resulting SLM knowledge has not been sufficiently evaluated, documented and shared. Among other things, this has often prevented valuable SLM knowledge from being channelled into evidence-based decision-making processes. Indeed, proper knowledge management is crucial for SLM to reach its full potential. Since more than 20 years, the international WOCAT network documents and promotes SLM through its global platform. As a whole, the WOCAT methodology comprises tools for documenting, evaluating, and assessing the impact of SLM practices, as well as for knowledge sharing, analysis and use for decision support in the field, at the planning level, and in scaling up identified good practices. In early 2014, WOCAT’s growth and ongoing improvement culminated in its being officially recognized by the UNCCD as the primary recommended database for SLM best practices. Over the years, the WOCAT network confirmed that SLM helps to prevent desertification, to increase biodiversity, enhance food security and to make people less vulnerable to the effects of climate variability and change. In addi- tion, it plays an important role in mitigating climate change through improving soil organic matter and increasing vegetation cover. In-depth assessments of SLM practices from desertification sites enabled an evaluation of how SLM addresses prevalent dryland threats. The impacts mentioned most were diversified and enhanced production and better management of water and soil degradation, whether through water harvesting, improving soil moisture, or reducing runoff. Among others, favourable local-scale cost-benefit relationships of SLM practices play a crucial role in their adoption. An economic analysis from the WOCAT database showed that land users perceive a large majority of the technologies as having benefits that outweigh costs in the long term. The high investment costs associated with some practices may constitute a barrier to adoption, however, where appropriate, short-term support for land users can help to promote these practices. The increased global concerns on climate change, disaster risks and food security redirect attention to, and trigger more funds for SLM. To provide the necessary evidence-based rationale for investing in SLM and to reinforce expert and land users assessments of SLM impacts, more field research using inter- and transdisciplinary approaches is needed. This includes developing methods to quantify and value ecosystem services, both on-site and off-site, and assess the resilience of SLM practices, as currently aimed at within the EU FP7 projects CASCADE and RECARE.

ABCB5 Identifies Immunoregulatory Dermal Cells

Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5(+) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5(+) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy.

Emergence of acquired HIV-1 drug resistance has almost been stopped in Switzerland - a 15 year prospective cohort analysis

BACKGROUND  Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level. METHODS  We included 11,084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of at least one major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on patient's risk of harboring drug resistant viruses. RESULTS  The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of three-class resistance decreased from 9.0% to 4.4% and was always <0.4% for patients who initiated ART after 2006. Most patients actively participating in the SHCS in 2013 with drug resistant viruses initiated ART before 1999 (59.8%). Nevertheless, in 2013, 94.5% of patients who initiated ART before 1999 had good remaining treatment options based on Stanford algorithm. CONCLUSION  HIV-1 drug resistance among ART-experienced patients in Switzerland is a well-controlled relic from the pre-combination ART era. Emergence of drug resistance can be virtually stopped with new potent therapies and close monitoring.

siRNA mediated knockdown of tissue factor expression in pigs for xenotransplantation.

Acute vascular rejection (AVR), in particular microvascular thrombosis, is an important barrier to successful pig-to-primate xenotransplantation. Here, we report the generation of pigs with decreased tissue factor (TF) levels induced by small interfering (si)RNA-mediated gene silencing. Porcine fibroblasts were transfected with TF-targeting small hairpin (sh)RNA and used for somatic cell nuclear transfer. Offspring were analyzed for siRNA, TF mRNA and TF protein level. Functionality of TF downregulation was investigated by a whole blood clotting test and a flow chamber assay. TF siRNA was expressed in all twelve liveborn piglets. TF mRNA expression was reduced by 94.1 ± 4.7% in TF knockdown (TFkd) fibroblasts compared to wild-type (WT). TF protein expression in PAEC stimulated with 50 ng/mL TNF-α was significantly lower in TFkd pigs (mean fluorescence intensity TFkd: 7136 ± 136 vs. WT: 13 038 ± 1672). TF downregulation significantly increased clotting time (TFkd: 73.3 ± 8.8 min, WT: 45.8 ± 7.7 min, p < 0.0001) and significantly decreased thrombus formation compared to WT (mean thrombus coverage per viewing field in %; WT: 23.5 ± 13.0, TFkd: 2.6 ± 3.7, p < 0.0001). Our data show that a functional knockdown of TF is compatible with normal development and survival of pigs. TF knockdown could be a valuable component in the generation of multi-transgenic pigs for xenotransplantation.