Systemic absorption and metabolism of drugs in the small intestine, metabolism by the liver as well as excretion by the kidney are key determinants of efficacy and safety for therapeutic candidates. ...However, these systemic responses of applied substances lack in most
in vitro
assays. In this study, a microphysiological system maintaining the functionality of four organs over 28 days in co-culture has been established at a minute but standardized microsystem scale. Preformed human intestine and skin models have been integrated into the four-organ-chip on standard cell culture inserts at a size 100 000-fold smaller than their human counterpart organs. A 3D-based spheroid, equivalent to ten liver lobules, mimics liver function. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. A peristaltic on-chip micropump ensures pulsatile media flow interconnecting the four tissue culture compartments through microfluidic channels. A second microfluidic circuit ensures drainage of the fluid excreted through the kidney epithelial cell layer. This four-organ-chip system assures near to physiological fluid-to-tissue ratios. In-depth metabolic and gene analysis revealed the establishment of reproducible homeostasis among the co-cultures within two to four days, sustainable over at least 28 days independent of the individual human cell line or tissue donor background used for each organ equivalent. Lastly, 3D imaging two-photon microscopy visualised details of spatiotemporal segregation of the two microfluidic flows by proximal tubule epithelia. To our knowledge, this study is the first approach to establish a system for
in vitro
microfluidic ADME profiling and repeated dose systemic toxicity testing of drug candidates over 28 days.
We established a microfluidic four-organ-chip for interconnected long-term co-culture of human intestine (1), liver (2), skin (3) and kidney (4) equivalents.
The knowledge about potential climate change impacts on forests is continuously expanding and some changes in growth, drought induced mortality and species distribution have been observed. However ...despite a significant body of research, a knowledge and communication gap exists between scientists and non-scientists as to how climate change impact scenarios can be interpreted and what they imply for European forests. It is still challenging to advise forest decision makers on how best to plan for climate change as many uncertainties and unknowns remain and it is difficult to communicate these to practitioners and other decision makers while retaining emphasis on the importance of planning for adaptation.
In this paper, recent developments in climate change observations and projections, observed and projected impacts on European forests and the associated uncertainties are reviewed and synthesised with a view to understanding the implications for forest management. Current impact assessments with simulation models contain several simplifications, which explain the discrepancy between results of many simulation studies and the rapidly increasing body of evidence about already observed changes in forest productivity and species distribution. In simulation models uncertainties tend to cascade onto one another; from estimating what future societies will be like and general circulation models (GCMs) at the global level, down to forest models and forest management at the local level.
Individual climate change impact studies should not be uncritically used for decision-making without reflection on possible shortcomings in system understanding, model accuracy and other assumptions made. It is important for decision makers in forest management to realise that they have to take long-lasting management decisions while uncertainty about climate change impacts are still large. We discuss how to communicate about uncertainty – which is imperative for decision making – without diluting the overall message. Considering the range of possible trends and uncertainties in adaptive forest management requires expert knowledge and enhanced efforts for providing science-based decision support.
•Uncertainty is inherent to climate change impact assessments.•Extreme events are only weakly represented in many assessments.•The range of possible impacts has so far been underestimated in most studies.•Some general trends are common to all climate projections.•Guidance is needed to interpret state-of-the-art knowledge and give helpful advice.
Over the last decades, the natural disturbance is increasingly putting pressure on European forests. Shifts in disturbance regimes may compromise forest functioning and the continuous provisioning of ...ecosystem services to society, including their climate change mitigation potential. Although forests are central to many European policies, we lack the long‐term empirical data needed for thoroughly understanding disturbance dynamics, modeling them, and developing adaptive management strategies. Here, we present a unique database of >170,000 records of ground‐based natural disturbance observations in European forests from 1950 to 2019. Reported data confirm a significant increase in forest disturbance in 34 European countries, causing on an average of 43.8 million m3 of disturbed timber volume per year over the 70‐year study period. This value is likely a conservative estimate due to under‐reporting, especially of small‐scale disturbances. We used machine learning techniques for assessing the magnitude of unreported disturbances, which are estimated to be between 8.6 and 18.3 million m3/year. In the last 20 years, disturbances on average accounted for 16% of the mean annual harvest in Europe. Wind was the most important disturbance agent over the study period (46% of total damage), followed by fire (24%) and bark beetles (17%). Bark beetle disturbance doubled its share of the total damage in the last 20 years. Forest disturbances can profoundly impact ecosystem services (e.g., climate change mitigation), affect regional forest resource provisioning and consequently disrupt long‐term management planning objectives and timber markets. We conclude that adaptation to changing disturbance regimes must be placed at the core of the European forest management and policy debate. Furthermore, a coherent and homogeneous monitoring system of natural disturbances is urgently needed in Europe, to better observe and respond to the ongoing changes in forest disturbance regimes.
Shifts in forest disturbance regimes may compromise the continuous provisioning of ecosystem services to society. Although forests in Europe are central to many policies, empirical data for understanding disturbance dynamics are lacking. We present a unique database of >170,000 ground‐based natural disturbance records in European forests from 1950 to 2019. Disturbances significantly increase over the study period, damaging on average 43.8 million m3 of timber volume per year. This is likely a conservative estimate due to under‐reporting. We estimated the magnitude of unreported damages to be between 8.6 and 18.3 million m3/year.
This study compiles and summarizes the existing knowledge about observed and projected impacts of climate change on forests in Europe. Forests will have to adapt not only to changes in mean climate ...variables but also to increased variability with greater risk of extreme weather events, such as prolonged drought, storms and floods. Sensitivity, potential impacts, adaptive capacity, and vulnerability to climate change are reviewed for European forests. The most important potential impacts of climate change on forest goods and services are summarized for the Boreal, Temperate Oceanic, Temperate Continental, Mediterranean, and mountainous regions. Especially in northern and western Europe the increasing atmospheric CO
2 content and warmer temperatures are expected to result in positive effects on forest growth and wood production, at least in the short–medium term. On the other hand, increasing drought and disturbance risks will cause adverse effects. These negative impacts are very likely to outweigh positive trends in southern and eastern Europe. From west to east, the drought risk increases. In the Mediterranean regions productivity is expected to decline due to strongly increased droughts and fire risks.
Adaptive capacity consists of the inherent adaptive capacity of trees and forest ecosystems and of socio-economic factors determining the capability to implement planned adaptation. The adaptive capacity in the forest sector is relatively large in the Boreal and the Temperate Oceanic regions, more constrained by socio-economic factors in the Temperate Continental, and most limited in the Mediterranean region where large forest areas are only extensively managed or unmanaged.
Potential impacts and risks are best studied and understood with respect to wood production. It is clear that all other goods and services provided by European forests will also be impacted by climate change, but much less knowledge is available to quantify these impacts. Understanding of adaptive capacity and regional vulnerability to climate change in European forests is not well developed and requires more focussed research efforts. An interdisciplinary research agenda integrated with monitoring networks and projection models is needed to provide information at all levels of decision making, from policy development to the management unit.
Where are Europe's last primary forests? Sabatini, Francesco Maria; Burrascano, Sabina; Keeton, William S. ...
Diversity & distributions,
October 2018, Volume:
24, Issue:
9/10
Journal Article
Peer reviewed
Open access
Aim: Primary forests have high conservation value but are rare in Europe due to historic land use. Yet many primary forest patches remain unmapped, and it is unclear to what extent they are ...effectively protected. Our aim was to (1) compile the most comprehensive European-scale map of currently known primary forests, (2) analyse the spatial determinants characterizing their location and (3) locate areas where so far unmapped primary forests likely occur. Location: Europe. Methods: We aggregated data from a literature review, online questionnaires and 32 datasets of primary forests. We used boosted regression trees to explore which biophysical, socio-economic and forest-related variables explain the current distribution of primary forests. Finally, we predicted and mapped the relative likelihood of primary forest occurrence at a 1-km resolution across Europe. Results: Data on primary forests were frequently incomplete or inconsistent among countries. Known primary forests covered 1.4 Mha in 32 countries (0.7% of Europe's forest area). Most of these forests were protected (89%), but only 46% of them strictly. Primary forests mostly occurred in mountain and boreal areas and were unevenly distributed across countries, biogeographical regions and forest types. Unmapped primary forests likely occur in the least accessible and populated areas, where forests cover a greater share of land, but wood demand historically has been low. Main conclusions: Despite their outstanding conservation value, primary forests are rare and their current distribution is the result of centuries of land use and forest management. The conservation outlook for primary forests is uncertain as many are not strictly protected and most are small and fragmented, making them prone to extinction debt and human disturbance. Predicting where unmapped primary forests likely occur could guide conservation efforts, especially in Eastern Europe where large areas of primary forest still exist but are being lost at an alarming pace.
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•The MOC allows integration of biological barriers into dynamic multi-tissue systems.•A human primary intestinal and a liver model were combined in a microfluidic system.•Liver and ...skin models were co-cultured in endothelialized multi-organ-chips.•Oral treatment of co-cultures was modeled by apical application to intestinal tissue.
Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called “human-on-a-chip” concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air–liquid interface for the skin model during their co-culture with the liver equivalents respectively at 1/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver–skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance – troglitazone – to the chip-based co-cultures.
Ceccherini et al.1 quantify change using map pixel counts, rather than using a statistically rigorous sampling approach that is more appropriate for the estimation of area change7. ...although ...Ceccherini et al.1 considered false positives (incorrect detection of forest loss) in their sample analyses, they did not consider false negatives (undetected forest loss). ...analyses, which address both omission and commission errors, offer accurate and unbiased results of forest change. ...sample reference data tailored to the specific purpose of a given study can be used to discriminate proportions of loss due to natural disturbances within the overall forest loss rates12. ...we are confident that natural disturbances were not correctly excluded. ...information and knowledge are crucial to develop science-based, climate-smart forestry strategies18 to ensure that European forests continue to be an important carbon sink and a key ecosystem service provider in relation to the protection of biodiversity and the development of the bioeconomy. https://doi.org/10.1038/s41586-021-03292-x Received: 3 July 2020 Accepted: 26 January 2021 Published online: 28 April 2021 Check for updates Acknowledgements We thank G. Ceccherini and co-authors for immediately making available all original material, processing codes and results of their study upon request.
Summary
Increasing the amount of carbon stored in harvested wood products (HWPs) is an internationally recognized measure to mitigate climate change. Several approaches and tiers of methods may be ...used to analyze the contribution of HWP in terms of greenhouse gas emissions and removals at a regional and national level. The Intergovernmental Panel on Climate Change (IPCC) provides guidelines on three tiers of methods for estimating annual carbon stock changes in the carbon pool of HWPs. These tiers mostly differ by the availability of input data and the level of HWP aggregation. In this case study for the Czech Republic, we have applied the production approach and alternative tiers of accounting methods, which are described in the IPCC guidelines, including the default method (tier 2) and the most advanced method (tier 3). We used country‐specific data and material flow analysis to trace the carbon flow over the entire forest‐based sector, including only the domestic harvest and the primary and secondary wood products manufactured within the country. The results of this study show that the carbon stored in the HWP pool could be underestimated if simpler methods and default values nonspecific to the country are applied. At the national level, applying the tier 3 method resulted in a 15.8% higher annual carbon inflow in the pool of HWPs compared to the tier 2 IPCC default method. This means that the advanced method reveals an apparently higher carbon sink in HWPs. A documented increase of carbon storage might bring additional credits to reporting countries, and, more important, it could promote the use of long‐life HWPs to mitigate climate change.
In July 2016, the European Commission (EC) published a legislative proposal for incorporating greenhouse gas emissions and removals due to Land Use, Land Use Change and Forestry (LULUCF) into its ...2030 Climate and Energy Framework. The Climate and Energy Framework aims at a total emission reduction of 40% by 2030 for all sectors together as part of the Paris Agreement. The LULUCF proposal regulates a “no debit” target for LULUCF (Forests and Agricultural soils), and regulates the accounting of any additional mitigation potential that might be expected of it. We find that the forest share of the LULUCF sector can achieve much more than what is in the regulation now. We elaborate a strategy for unlocking European Union (EU) forests and forest sector potential based on the concept of “climate smart forestry” (CSF). We find that to-date, European policy has not firmly integrated forest potential into the EU climate policy framework. Nor have climate objectives been firmly integrated into those of the forest and forest sector at either the EU or national level. Yet a wide range of measures can be applied to provide positive incentives for more firmly integrating these climate objectives into the forest and forest sector framework. With the right set of incentives in place at EU and Member States levels, we find the current literature supports the view that the EU has the potential to achieve an additional combined mitigation impact through CSF of 441 Mt CO2/year by 2050. In addition, CSF, through reducing and/or removing greenhouse gas emissions, adapting and building forest resilience, and sustainably increasing forest productivity and incomes, tackles multiple policy goals.
We reviewed the experimental evidence for long-term carbon (C) sequestration in soils as consequence of specific forest management strategies. Utilization of terrestrial C sinks alleviates the burden ...of countries which are committed to reducing their greenhouse gas emissions. Land-use changes such as those which result from afforestation and management of fast-growing tree species, have an immediate effect on the regional rate of C sequestration by incorporating carbon dioxide (CO
2) in plant biomass. The potential for such practices is limited in Europe by environmental and political constraints. The management of existing forests can also increase C sequestration, but earlier reviews found conflicting evidence regarding the effects of forest management on soil C pools. We analyzed the effects of harvesting, thinning, fertilization application, drainage, tree species selection, and control of natural disturbances on soil C dynamics. We focused on factors that affect the C input to the soil and the C release via decomposition of soil organic matter (SOM). The differentiation of SOM into labile and stable soil C fractions is important. There is ample evidence about the effects of management on the amount of C in the organic layers of the forest floor, but much less information about measurable effects of management on stable C pools in the mineral soil. The C storage capacity of the stable pool can be enhanced by increasing the productivity of the forest and thereby increasing the C input to the soil. Minimizing the disturbances in the stand structure and soil reduces the risk of unintended C losses. The establishment of mixed species forests increases the stability of the forest and can avoid high rates of SOM decomposition. The rate of C accumulation and its distribution within the soil profile differs between tree species. Differences in the stability of SOM as a direct species effect have not yet been reported.
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