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.

Co-culture of Notochordal Cells with Nucleus pulposus and Annulus fibrosus cells under normoxia and hypoxia

Introduction Notochordal cells (NC) are shifted back into focus due to their apparent action of activating other disc cells via indirect release of yet unknown factors into the medium (conditioned medium = CM).1,2 Recent evidence confirms the results from the late 1990s.3,4 Here, we test porcine (p) NC cultured in 3D and the influence of adding serum or using serum-free medium onto the culture on NC cells and its stimulating effects for subsequent coculture with primary bovine (b) nucleus pulposus (bNPC) and annulus fibrous cells (bAFC). Materials and Methods Primary pNC, bNPC, and bAFC were isolated from porcine tails (< 6-12 months age) or bovine tails (∼1 year age), which were obtained from the food chain (N = 4 repeats) within 4 hours postmortem. All cells were seeded into 1.2% alginate, each with a density of 4 × 106/mL. NC were then either cultured for 7 days in serum free medium (SFM = Dulbecco modified eagle medium [DMEM] supplied with ITS+, 50 µg/mL vitamin C and nonessential amino acids) or DMEM + 10% fetal calf serum (FCS). CM was produced from NC collecting 4 mL SFM and keeping approximately 30 beads for 7 days. Then, a coculture was set up in SFM for 14 days using indirect cell-cell contact (culture insert, high density pore, 0.4 µm) using a 50:50% ratio5 of pNC:bNP or bAF, or by addition of CM, respectively. The cell activity, glycosaminoglycan per DNA (GAG/DNA) ratio, and real-time RT-PCR of IVD relevant genes were monitored. Mass spectrometry was performed on the SFM and the cocultured medium as well as the CM of the pNC to identify possible key cytokines to the stimulatory effects. Results The results for cell activity confirmed that pNC are highly responsive on the nutritional condition in the culture (K-W test, p = 0.048) after 7 days of coculture. bNPC and bAFC did not respond significantly different to coculture or addition of CM with respect to cell activity. However, GAG/DNA ratio of pNC was significantly upregulated if they were initially pre-exposed to FCS and in coculture with bNPC after 14 days, for both normoxia and hypoxia (K-W, p = 0.03). The bNPC were stimulated by both, 1:1 coculture with pNC but also by addition of CM only, which resulted in approximately 200% increased GAG/DNA values relative to the day 0 state. However, this doubling of the GAG/DNA ratio was nonsignificant after 14 days. The aggrecan/collagen type 2 ratio as quantified from real-time RT-PCR pointed to a beneficial state of the bNPC if cultured either in indirect coculture with pNC or by the addition of CM (Fig. 1). The mass spectrometric analysis of the CM revealed that there was connecting tissue growth factor present (CTGF) among the cytokine CLC11, a cytokine that has been found to be expressed in skeletal tissues including bone marrow and chondrocytes among other factors that might have immunoregulatory and cell proliferative functions.

Mountains and climate chance. A global concern

Mountains are among the regions most affected by climate change. The implications of climate change will reach far beyond mountain areas, as the contributions in the present publication prepared for the Conference of the Parties to the United Nations Framework Convention on Climate Change (COP 20) in Lima 2014 show. Themes discussed are water, glaciers and permafrost, hazards, biodiversity, food security and economy. The case studies included show that concrete adaptive action has been taken in many mountain areas of the world. The publication concludes with a series of recommendations for sustainable mountain development in the face of climate change.

Mountains and climate change: A global concern

Mountains are among the regions most affected by climate change. The implications of climate change will reach far beyond mountain areas, as the contributions in the present publication prepared for the Conference of the Parties to the United Nations Framework Convention on Climate Change (COP 20) in Lima 2014 show. Themes discussed are water, glaciers and permafrost, hazards, biodiversity, food security and economy. The case studies included show that concrete adaptive action has been taken in many mountain areas of the world. The publication concludes with a series of recommendations for sustainable mountain development in the face of climate change.

The geography of large-scale land acquisitions: Analysing socio-ecological patterns of target contexts in the global South

This paper analyses local geographical contexts targeted by transnational large-scale land acquisitions (>200 ha per deal) in order to understand how emerging patterns of socio-ecological characteristics can be related to processes of large-scale foreign investment in land. Using a sample of 139 land deals georeferenced with high spatial accuracy, we first analyse their target contexts in terms of land cover, population density, accessibility, and indicators for agricultural potential. Three distinct patterns emerge from the analysis: densely populated and easily accessible croplands (35% of land deals); remote forestlands with lower population densities (34% of land deals); and moderately populated and moderately accessible shrub- or grasslands (26% of land deals). These patterns are consistent with processes described in the relevant case study literature, and they each involve distinct types of stakeholders and associated competition over land. We then repeat the often-cited analysis that postulates a link between land investments and target countries with abundant so-called “idle” or “marginal” lands as measured by yield gap and available suitable but uncultivated land; our methods differ from the earlier approach, however, in that we examine local context (10-km radius) rather than countries as a whole. The results show that earlier findings are disputable in terms of concepts, methods, and contents. Further, we reflect on methodologies for exploring linkages between socioecological patterns and land investment processes. Improving and enhancing large datasets of georeferenced land deals is an important next step; at the same time, careful choice of the spatial scale of analysis is crucial for ensuring compatibility between the spatial accuracy of land deal locations and the resolution of available geospatial data layers. Finally, we argue that new approaches and methods must be developed to empirically link socio-ecological patterns in target contexts to key determinants of land investment processes. This would help to improve the validity and the reach of our findings as an input for evidence-informed policy debates.

Strategy and Action Plan for Sustainable Land Management in the High Pamir and Pamir-Alai Mountains

This Strategy and Action Plan was written within the framework of the project on Sustainable Land Management in the High Pamir and Pamir-Alai Mountains (PALM). PALM is an integrated transboundary initiative of the governments of the Kyrgyz Republic and the Republic of Tajikistan. It aims to address the interlinked problems of land degradation and poverty within a region that is one of Central Asia’s crucial sources of freshwater and a location of biodiversity hotspots. The project is executed by the Committee on Environment Protection in Tajikistan and the National Center for Mountain Regions Development in Kyrgyzstan, with fi nancial support from the Global Environment Facility (GEF) and other donors. The United Nations Environment Programme (UNEP) is the GEF Implementing Agency for the project, and the United Nations University (UNU) is the International Executing Agency. This Strategy and Action Plan integrates the work of three main teams of experts, namely the Pamir-Alai Transboundary Strategy and Action Plan (PATSAP) team, the Legal Task Forces, and a team of Natural Disaster Risk specialists. The PATSAP team was coordinated by the Centre for Development and Environment (CDE), University of Bern, Switzerland. The Legal Task Force was led by the Australian Centre for Agriculture and Law of the University of New England (UNE), and responsibility for the Natural Disaster Risk assessment was with the Central- Asian Institute of Applied Geosciences (CAIAG) in Bishkek, Kyrgyzstan. The development of the strategy took place from June 2009 to October 2010. The activities included fi eld study tours for updating the information base with fi rst-hand information from the local level, coordination meetings with actors from the region, and two multi-level stakeholder forums conducted in Khorog and Osh to identify priorities and to collect ideas for concrete action plans. The baseline information collected for the Strategy and Action Plan has been compiled by the experts and made available as reports1. A joint multi-level stakeholder forum was conducted in Jirgitol, Tajikistan, for in-depth discussion of the transboundary aspects. In August 2010, the draft Strategy and Action Plan was distributed among local, national, and international actors for consultation, and their comments were discussed at feedback forums in Khorog and Bishkek. This Strategy and Action Plan is intended as a recommendation. Nevertheless, it proposes concrete mechanisms for implementing the proposed sustainable land management (SLM) activities: The Regional Natural Resources Governance Framework provides the legal and policy concepts, principles, and regulatory requirements needed to create an enabling environment for SLM in the High Pamir and Pamir-Alai region at the transboundary, national, and local levels. The priority directions outlined provide a framework for the elaboration of rayon-level strategies and for strategies on specifi c topics (forestry, livestock, etc.), as well as for further development of government programmes and international projects. The action plans may serve as a pool of concrete ideas, which can be taken up by diff erent institutions and in smaller or larger projects. Finally, this document provides a basis for the elaboration and signing of targeted cooperation agreements on land use and management between the leaders of Osh oblast (Kyrgyz Republic), Gorno Badakhshan Autonomous Oblast, and Jirgitol rayon (Republic of Tajikistan).

An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei

Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug action or targeting.

First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension.

UNLABELLED This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, ≥160 mm Hg; 24-hour systolic pressure, ≥135 mm Hg; and ≥3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mm Hg for all patients and 179.3±16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were -11.6±25.3 and -6.6±18.0 mm Hg for all patients (P<0.001 for both) and -20.3±22.8 and -8.9±16.9 mm Hg for those with severe hypertension (P<0.001 for both). Renal denervation was associated with low rates of adverse events. After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01534299.

Land system science and sustainable development of the earth system: A global land project perspective

Land systems are the result of human interactions with the natural environment. Understanding the drivers, state, trends and impacts of different land systems on social and natural processes helps to reveal how changes in the land system affect the functioning of the socio-ecological system as a whole and the tradeoff these changes may represent. The Global Land Project has led advances by synthesizing land systems research across different scales and providing concepts to further understand the feedbacks between social-and environmental systems, between urban and rural environments and between distant world regions. Land system science has moved from a focus on observation of change and understanding the drivers of these changes to a focus on using this understanding to design sustainable transformations through stakeholder engagement and through the concept of land governance. As land use can be seen as the largest geo-engineering project in which mankind has engaged, land system science can act as a platform for integration of insights from different disciplines and for translation of knowledge into action.

Global diversity, population stratification and selection of human copy number variation

In order to explore the diversity and selective signatures of duplication and deletion human copy number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single nucleotide variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

Ethical considerations for a global concept of sustainable land use

The paper gives an overview of current land husbandry problems in different agro-ecological zones of the world. It then lists four ethical principles, conceived at the global level, needed to achieve sustainable land use (SLU). Finally, it develops guidelines which can be used to facilitate a more effective implementation and realization of SLU. In the year of the UN Conference on Environment and Development (UNCED), such recommendations are important for improving the competence of political and economic decision-makers in taking action at national and international levels.

Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage.

Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.