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Recovering nutrients from organic materials to reduce artificial fertilizer inputs requires the implementation of processing technologies and can involve considerable logistics and transportation costs. Reducing such costs by directly applying organic materials to agricultural land can contribute to pollution due to potential contaminants and unbalanced nutrient ratios. Assessing the cost of increased recycling requires a spatially explicit approach because availability of organic materials, nutrient demand and agro-ecosystem properties vary spatially. A multi-objective model was developed to estimate the trade-offs between costs of nutrient recovery and improvements in nutrient distribution for a case study area in The Netherlands. The evaluated recovery processes included solid-liquid separation followed by reverse osmosis to recover nutrients from pig manure which was compared to a conventional process via hygienisation and export. Results indicate that, even in a nutrient saturated area, replacement potential of artificial nitrogen (N) and phosphorus (P) fertilizers through locally reclaimed nutrients is limited to about 17% N and 55% P. A cost optimum was found when about 48% of the initial pig manure quantities were processed via nutrient recovery and directed to land. Increasing manure processing for nutrient recovery led to a redistribution of nutrients and trace metals (zinc (Zn) and copper (Cu)), resulting in more localized concentration. Zn and Cu were enriched by about 8% and 2%, respectively, when maximizing nutrient recovery. Our generic model offers a methodology to assess the trade-offs between increased recycling and associated spatial effects to facilitate sustainable recycling infrastructures for achieving more circular agriculture.

Sensory-independent Ca

Cisplatin-induced ototoxicity in humans is more predominant in the cochlea than in the vestibule. Neither definite nor substantial vestibular dysfunction after cisplatin treatment has been consistently reported in the current literature. Inner ear hair cells seem to have intrinsic characteristics that make them susceptible to direct exposure to cisplatin. The existing literature suggests, however, that cisplatin might have different patterns of drug trafficking across the blood-labyrinth-barrier, or different degrees of cisplatin uptake to the hair cells in the cochlear and vestibular compartments. This review proposes an explanation for the preferential cochleotoxicity of cisplatin based on current evidence as well as the anatomy and physiology of the inner ear. The endocochlear potential, generated by the stria vascularis, acting as the driving force for hair cell mechanoelectrical transduction might also augment cisplatin entry into cochlear hair cells. Better understanding of the stria vascularis might shed new light on cochleotoxic mechanisms and inform the development of otoprotective interventions to moderate cisplatin associated ototoxicity.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics we screened 10,240 compounds, selecting those that protected against neomycin and gentamicin in zebrafish lateral-line hair cells and, when retested in mouse cochlear cultures, prevented gentamicin-induced death of outer hair cells (OHCs). Of 64 compounds that protected zebrafish hair cells, 8 protect OHCs from gentamicin in vitro. These hits share structural features and all block, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a known route of aminoglycoside entry into hair cells. Further characterisation of one of the strongest MET-channel blockers, UoS-7692, revealed it additionally protects against kanamycin and tobramycin, and does not abrogate the bactericidal activity of gentamicin. UoS-7692 behaves, like the aminoglycosides, as a permeant blocker of the MET channel, significantly reduces gentamicin-Texas Red loading into OHCs, and preserves lateral-line function in neomycin-treated zebrafish. Trans-tympanic injection of UoS-7692 protects mouse OHCs from furosemide-kanamycin exposure in vivo and partially preserves hearing. The results confirm the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides, and provide a series of hit compounds that will inform the design of future otoprotectants.

The substitution of biomass for fossil fuels in energy consumption is a measure to decrease the emissions of greenhouse gases and thereby mitigate global warming. During recent years, this has led to an increasing interest to use tree harvest residues as feedstock for bioenergy. An important concern related to the removal of harvesting residues is, however, the potential adverse effects on soil fertility caused by increased nutrient removal, relative to conventional stem-only harvesting. In the Netherlands this is a major concern, since most forests are located on poor sandy soils. To develop forest harvesting guidelines, we applied a mass balance approach comparing nutrient inputs by deposition and weathering with nutrient outputs by harvesting and leaching for various timber harvesting scenarios, including both stem-only harvesting and additional removal of tree tops and branches. A distinction was made in seven major tree species, six soil types (three sandy soils, loam, clay and peat soils) and nine regions, with clear variations in atmospheric deposition of phosphorus (P), calcium (Ca), magnesium (Mg) and potassium (K). For each region-tree-soil combination we calculated the maximum amounts that can be harvested such that the output of the nutrients Ca, Mg, K and P is balanced with the inputs. Results showed that at current harvesting rates, a negative balance of Ca, Mg, K or P is hardly calculated for the richer loamy to clayey soil types, while depletion can occur for the poorer sandy soils, particularly of P and K. Results are used to derive forest biomass harvesting guidelines, taking the uncertainties in the mass balance approach into account. The role of mitigating management approaches is also discussed.

In preparation of the Seventh Action Programme Nitrates Directive (2022-2025), an Environmental Impact Assessment at plan level (EIA) has been prepared, primarily assessing effects of measures on water quality. Special attention is paid to nitrate concentrations in the southern sand and loess area because the limit value of 50 mg L-1 for nitrate is exceeded in these areas on average. A first step in the calculation of effects is an assessment of the water quality in 2027 based on implemented policy measures and the expected development of the livestock population. According to this projection, the nitrate concentration in the southern sandy area will decrease by about 10 mg L-1 until 2027 as a result of measures taken in the 6th Action Programme. The effects of a reduction of fertilizer application, a broader crop rotation, the maximum application of catch crops and the establishment of fertilizer-free field margins were calculated with three different models. The reduction in nitrate concentration is calculated to be a few milligrams up to about 15 mg nitrate per liter under extreme assumptions. It is calculated that with the measures of the most far-reaching scenario the nitrate concentration in the southern sand area in 2027 will not exceed the limit value of 50 mg L-1, but is still exceeded in the loess area. Furthermore, it is calculated that on national average the nitrogen load on surface water from agricultural soils decreases by 6 - 13% and the phosphorus load by 1.2 – 4.4%. In a ‘Maximum Environmentally friendly Alternative’ scenario, just over 60% of WFD water bodies meet the nitrogen and phosphorus concentration standards in 2027. In 2027, a significant proportion of water bodies does not fully comply with standards for nutrient concentrations in surface water. The reduction in nutrient transport to surface water leads to a less than proportionate increase in the number of water bodies with a good quality status. Sustainable crop rotation schemes for arable crops on sandy and loess soils contribute to improving water quality. Their implementation has major implications for practice. Effects of the measures on emissions of ammonia (NH3), nitrous oxide (N2O), carbon dioxide (CO2), methane (CH4), and on improving biodiversity, the counteraction of desiccation and the reduction of flooding have been estimated based on expert judgement. The impacts of the possible measures are expected to be small (on a national scale). Ter voorbereiding op de invoering van het Zevende Actieprogramma Nitraatrichtlijn (2022-2025) is een milieueffectrapportage op planniveau opgesteld (PlanMER), waarbij vooral effecten van maatregelen op de waterkwaliteit zijn beoordeeld. Speciale aandacht gaat uit naar nitraatconcentraties in het zuidelijke zand- en lössgebied, omdat daar gebiedsgemiddeld de grenswaarde van 50 mg L-1 voor nitraat wordt overschreden. Een eerste stap in de berekening van effecten is een prognose van de waterkwaliteit in 2027, uitgaande van geïnstrumenteerd beleid en de voorziene ontwikkeling van de veestapel. Volgens deze prognose zal de nitraatconcentratie in het zuidelijke zandgebied tot 2027 met ca. 10 mg L-1 dalen als gevolg van in het 6e Actieprogramma genomen maatregelen. De effecten van verminderde mestgiften, ruimere bouwplannen, een maximale inzet van vanggewassen en de aanleg van bemestingsvrije perceelranden zijn met drie verschillende modellen berekend. De vermindering van de nitraatconcentratie wordt berekend op enkele milligrammen nitraat per liter tot ca. 15 mg L-1 bij extreme aannames. Berekend wordt dat met de maatregelen van het meest vergaande scenario in 2027 de grenswaarde van 50 mg L-1 voor nitraat niet meer overschreden wordt in het zuidelijke zandgebied, maar in het lössgebied nog wel. Verder is berekend dat de landelijk gemiddelde stikstofbelasting van het oppervlaktewater door landbouwgronden met 6-13% daalt en de fosforbelasting met 1,2-4,4%. In een scenario ‘Maximaal Milieuvriendelijk Alternatief’ voldoet in 2027 iets meer dan 60% van de KRW-waterlichamen aan de normen voor stikstof- en fosforconcentraties. In 2027 resteert in een aanzienlijk deel van de wateren nog een opgave om te voldoen aan normen voor nutriëntenconcentraties in oppervlaktewater. De daling van de uit- en afspoeling leidt tot een minder dan evenredige toename van het aantal waterlichamen met een goede kwaliteitsstatus. Duurzame bouwplannen voor de open teelten op zand- en lössgronden dragen bij aan het verbeteren van de waterkwaliteit. De invoering ervan heeft grote implicaties voor de praktijk. Effecten van de maatregelen op de emissies van ammoniak (NH3), lachgas (N2O), koolstofdioxide (CO2), methaan (CH4) en op biodiversiteit, verdroging en wateroverlast zijn geschat op basis van expertbeoordelingen. Naar verwachting zullen de effecten van de mogelijke maatregelen (op nationale schaal) gering zijn.

Key points Outer hair cells (OHCs) enhance the sensitivity and the frequency tuning of the mammalian cochlea.Similar to the primary sensory receptor, the inner hair cells (IHCs), the mature functional characteristics of OHCs are acquired before hearing onset.We found that OHCs, like IHCs, fire spontaneous Ca2+‐induced action potentials (APs) during immature stages of development, which are driven by CaV1.3 Ca2+ channels.We also showed that the development of low‐ and high‐frequency hair cells is differentially regulated during pre‐hearing stages, with the former cells being more strongly dependent on experience‐independent Ca2+ action potential activity. Abstract Sound amplification within the mammalian cochlea depends upon specialized hair cells, the outer hair cells (OHCs), which possess both sensory and motile capabilities. In various altricial rodents, OHCs become functionally competent from around postnatal day 7 (P7), before the primary sensory inner hair cells (IHCs), which become competent at about the onset of hearing (P12). The mechanisms responsible for the maturation of OHCs and their synaptic specialization remain poorly understood. We report that spontaneous Ca2+ activity in the immature cochlea, which is generated by CaV1.3 Ca2+ channels, differentially regulates the maturation of hair cells along the cochlea. Under near‐physiological recording conditions we found that, similar to IHCs, immature OHCs elicited spontaneous Ca2+ action potentials (APs), but only during the first few postnatal days. Genetic ablation of these APs in vivo, using CaV1.3−/− mice, prevented the normal developmental acquisition of mature‐like basolateral membrane currents in low‐frequency (apical) hair cells, such as I K,n (carried by KCNQ4 channels), I SK2 and I ACh (α9α10nAChRs) in OHCs and I K,n and I K,f (BK channels) in IHCs. Electromotility and prestin expression in OHCs were normal in CaV1.3−/− mice. The maturation of high‐frequency (basal) hair cells was also affected in CaV1.3−/− mice, but to a much lesser extent than apical cells. However, a characteristic feature in CaV1.3−/− mice was the reduced hair cell size irrespective of their cochlear location. We conclude that the development of low‐ and high‐frequency hair cells is differentially regulated during development, with apical cells being more strongly dependent on experience‐independent Ca2+ APs., Key points Outer hair cells (OHCs) enhance the sensitivity and the frequency tuning of the mammalian cochlea.Similar to the primary sensory receptor, the inner hair cells (IHCs), the mature functional characteristics of OHCs are acquired before hearing onset.We found that OHCs, like IHCs, fire spontaneous Ca2+‐induced action potentials (APs) during immature stages of development, which are driven by CaV1.3 Ca2+ channels.We also showed that the development of low‐ and high‐frequency hair cells is differentially regulated during pre‐hearing stages, with the former cells being more strongly dependent on experience‐independent Ca2+ action potential activity.

Impacts of climate change on European agricultural production, land use and the environment depend on its impact on crop yields. However, many impact studies assume that crop management remains unchanged in future scenarios, while farmers may adapt their sowing dates and cultivar thermal time requirements to minimize yield losses or realize yield gains. The main objective of this study was to investigate the sensitivity of climate change impacts on European crop yields, land use, production and environmental variables to adaptations in crops sowing dates and varieties' thermal time requirements. A crop, economic and environmental model were coupled in an integrated assessment modelling approach for six important crops, for 27 countries of the European Union (EU27) to assess results of three SRES climate change scenarios to 2050. Crop yields under climate change were simulated considering three different management cases; (i) no change in crop management from baseline conditions (NoAd), (ii) adaptation of sowing date and thermal time requirements to give highest yields to 2050 (Opt) and (iii) a more conservative adaptation of sowing date and thermal time requirements (Act). Averaged across EU27, relative changes in water-limited crop yields due to climate change and increased CO 2 varied between − 6 and + 21% considering NoAd management, whereas impacts with Opt management varied between + 12 and + 53%, and those under Act management between − 2 and + 27%. However, relative yield increases under climate change increased to + 17 and + 51% when technology progress was also considered. Importantly, the sensitivity to crop management assumptions of land use, production and environmental impacts were less pronounced than for crop yields due to the influence of corresponding market, farm resource and land allocation adjustments along the model chain acting via economic optimization of yields. We conclude that assumptions about crop sowing dates and thermal time requirements affect impact variables but to a different extent and generally decreasing for variables affected by economic drivers.

Phosphorus is an essential element to enhance the needed increase in crop production in the forthcoming century. On the other hand environmental losses of phosphorus cause eutrophication of surface waters. Both problems call for reliable models to predict the behaviour of phosphorus in agricultural soils. In this study the performances of five different sorption approaches were evaluated. The ultimate aim was to identify the most suitable concept for large scale predictions of P dynamics in soils, in terms of a high comparability between observations and predictions with a minimum amount of input data. The model results were compared with unique data from long term (10–15 years) experimental field studies of grassland including situations with P mining, equilibrium P fertilization and P surpluses and a pot experiment with P mining. The model performance was evaluated while using site specific constants and generic constants for adsorption and desorption. Three rate limited models (DPPS, INITIATOR and ANIMO) showed good performance when site specific constants were used but the performance of the equilibrium model (NEWS-Dynamic) was reasonably comparable. Model performance was better for experiments with a P surplus than for P mining and was also better for sandy soils as compared to clay and peat soils. However, long term desorption rates had to be calibrated for each application rate. The performance of all models declined when generic data were used. We conclude that none of the included models properly describe what happens when the soil changes its P status, considering that parameterization needs to be treatment-specific to obtain reliable predictions. Considering this flaw, models of intermediate complexity, including both equilibrium and rate limited sorption, and a limited data demand, like DPPS and INITIATOR, seem most suited for regional model application.

Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) – a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures.

Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell’s mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol itself in cochlear cultures and also to bind more tightly to the MET channel. At higher concentrations, both carvedilol and this derivative were toxic in cochlear cultures but not in zebrafish, suggesting a good therapeutic window under in vivo conditions.

Norrie disease (ND) is a rare, X-linked condition of visual and auditory impairment, often presenting with additional neurological features and developmental delays of varying severity. While all affected patients are born blind, or lose their vision in infancy, progressive sensorineural hearing loss develops in the majority of cases and is typically detected in the second decade of life. A range of additional symptoms of ND, such as seizure disorders, typically appear from a young age, but it is difficult to predict the range of symptoms ND patients will experience. After growing up without vision, hearing loss represents the greatest worry for many patients with ND, as they may lose the ability to participate in previously enjoyed activities or to communicate with others.Dual sensory loss has a physical, psychosocial and financial impact on both patients with ND and their families. Routine monitoring of the condition is required in order to identify, treat and provide support for emerging health problems, leading to a large burden of medical appointments. Many patients need to travel long distances to meet with specialists, representing a further burden on time and finances. Additionally, the rare nature of dual sensory impairment in children means that few clinical environments are designed to meet their needs. Dual Sensory clinics are multidisciplinary environments designed for sensory-impaired children and have been suggested to alleviate the impact of diseases involving sensory loss such as ND.Here, we discuss the diagnosis, monitoring and management of ND and the impact it has on paediatric patients and their caregivers. We describe the potential for dual sensory clinics to reduce disease burden through providing an appropriate clinical environment, access to multiple clinical experts in one visit, and ease of monitoring for patients with ND.

Changes in climate, technology, policy and prices affect agricultural and rural development. To evaluate whether this development is sustainable, impacts of these multiple drivers need to be assessed for multiple indicators. In a case study area in the Netherlands, a bio-economic farm model, an agent-based land-use change model, and a regional emission model have been used to simulate rural development under two plausible global change scenarios at both farm and landscape level. Results show that in this area, climate change will have mainly negative economic impacts (dairy gross margin, arable gross margin, economic efficiency, milk production) in the warmer and drier W+ scenario, while impacts are slightly positive in the G scenario with moderate climate change. Dairy farmers are worse off than arable farmers in both scenarios. Conversely, when the W+ scenario is embedded in the socio-economic Global Economy (GE) scenario, changes in technology, prices, and policy are projected to have a positive economic impact, more than offsetting the negative climate impacts. Important is, however, that environmental impacts (global warming, terrestrial and aquatic eutrophication) are largely negative and social impacts (farm size, number of farms, nature area, odour) are mixed. In the G scenario combined with the socio-economic Regional Communities (RC) scenario the average dairy gross margin in particular is negatively affected. Social impacts are similarly mixed as in the GE scenario, while environmental impacts are less severe. Our results suggest that integrated assessments at farm and landscape level can be used to guide decision-makers in spatial planning policies and climate change adaptation. As there will always be trade-offs between economic, social, and environmental impacts stakeholders need to interact and decide upon most important directions for policies. This implies a choice between production and income on the one hand and social and environmental services on the other hand. (C) 2015 Elsevier Ltd. All rights reserved.

In view of the prevalence of sensorineural hearing defects in an ageing population, the development of protocols to generate cochlear hair cells and their associated sensory neurons as tools to further our understanding of inner ear development are highly desirable. We report herein a robust protocol for the generation of both vestibular and cochlear hair cells from human pluripotent stem cells which represents an advance over currently available methods that have been reported to generate vestibular hair cells only. Generating otic organoids from human pluripotent stem cells using a three-dimensional culture system, we show formation of both types of sensory hair cells bearing stereociliary bundles with active mechano-sensory ion channels. These cells share many morphological characteristics with their in vivo counterparts during embryonic development of the cochlear and vestibular organs and moreover demonstrate electrophysiological activity detected through single-cell patch clamping. Collectively these data represent an advance in our ability to generate cells of an otic lineage and will be useful for building models of the sensory regions of the cochlea and vestibule.

Outer hair cells (OHCs) are highly specialized sensory cells conferring the fine tuning and high sensitivity of the mammalian cochlea to acoustic stimuli. Here, by genetically manipulating spontaneous Ca2+signallingin vivo, through a period of early postnatal development, we find that the refinement of OHC afferent innervation is regulated by complementary spontaneous Ca2+signals originating in OHCs and non-sensory cells. OHCs fire spontaneous Ca2+spikes during a narrow period of immature development. Simultaneously, waves of Ca2+activity in the non-sensory greater epithelial ridge act, via ATP-induced activation of P2X receptors, to synchronize OHC firing, resulting in the refinement of their afferent innervation. In the absence of connexin channels Ca2+waves are impaired, leading to a reduction in the number of ribbon synapses and afferent fibres on OHCs. We propose that the correct maturation of the afferent connectivity in OHCs requires experience-independent Ca2+signals from sensory and non-sensory cells.

Spatially detailed information on agricultural nitrogen (N) budgets is relevant to identify regions where there is a need for a reduction in inputs in view of various forms of N pollution. However, at the scale of the European Union, there is a lack of consistent, reliable, high spatial resolution data necessary for the calculation of regional N losses. To gain insight in the reduction in uncertainty achieved by using higher spatial resolution input data. This was done by comparing spatially disaggregated agricultural N budgets for Denmark for the period 2000–2010, generated by two versions of the European scale model Integrator, a version using high spatial resolution national data for Denmark (Integrator-DK) and a version using available data at the EU scale (Integrator-EU). Results showed that the national N fluxes in the N budgets calculated by the two versions of the model were within 1–5% for N inputs by fertilizer and manure excretion, but inputs by N fixation and N mineralisation differed by 50–100% and N uptake also differed by ca 25%, causing a difference in N leaching and runoff of nearly 50%. Comparison with an independently derived Danish national budget appeared generally to be better with Integrator-EU results in 2000 but with Integrator-DK results in 2010. However, the spatial distribution of manure distribution and N losses from Integrator-DK were closer to observed distributions than those from Integrator-EU. We conclude that close attention to local agronomic practices is needed when using a leaching fraction approach and that for effective support of environmental policymaking, Member States need to collect or submit high spatial resolution agricultural data to Eurostat.

Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red–conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem.

The ability of cochlear hair cells to convert sound into receptor potentials relies on the mechanoelectrical transducer (MET) channels present in their stereociliary bundles. There is strong evidence implying that transmembrane channel-like protein (TMC) 1 contributes to the pore-forming subunit of the mature MET channel, yet its expression is delayed (~>P5 in apical outer hair cells, OHCs) compared to the onset of mechanotransduction (~P1). Instead, the temporal expression of TMC2 coincides with this onset, indicating that it could be part of the immature MET channel. We investigated MET channel properties from OHCs of homo- and heterozygous Tmc2 knockout mice. In the presence of TMC2, the MET channel blocker dihydrostreptomycin (DHS) had a lower affinity for the channel, when the aminoglycoside was applied extracellularly or intracellularly, with the latter effect being more pronounced. In Tmc2 knockout mice OHCs were protected from aminoglycoside ototoxicity during the first postnatal week, most likely due to their small MET current and the lower saturation level for aminoglycoside entry into the individual MET channels. DHS entry through the MET channels of Tmc2 knockout OHCs was lower during the first than in the second postnatal week, suggestive of a developmental change in the channel pore properties independent of TMC2. However, the ability of TMC2 to modify the MET channel properties strongly suggests it contributes to the pore-forming subunit of the neonatal channel. Nevertheless, we found that TMC2, different from TMC1, is not necessary for OHC development. While TMC2 is required for mechanotransduction in mature vestibular hair cells, its expression in the immature cochlea may be an evolutionary remnant.

Several dairy farms in the Netherlands aim at reducing environmental impacts by improving the internal nutrient cycle (INC) on their farm by optimizing the use of available on-farm resources. This study evaluates the environmental performance of selected INC farms in the Northern Friesian Woodlands in comparison to regular benchmark farms using a Life Cycle Assessment. Regular farms were selected on the basis of comparability in terms of milk production per farm and per hectare, soil type and drainage conditions. In addition, the environmental impacts of INC farming at landscape level were evaluated with the integrated modelling system INITIATOR, using spatially explicit input data on animal numbers, land use, agricultural management, meteorology and soil, assuming that all farms practised the principle of INC farming. Impact categories used at both farm and landscape levels were global warming potential, acidification potential and eutrophication potential. Additional farm level indicators were land occupation and non-renewable energy use, and furthermore all farm level indicators were also expressed per kg fat and protein corrected milk. Results showed that both on-farm and off-farm non-renewable energy use was significantly lower at INC farms as compared with regular farms. Although nearly all other environmental impacts were numerically lower, both on-farm and off-farm, differences were not statistically significant. Nitrogen losses to air and water decreased by on average 5 to 10% when INC farming would be implemented for the whole region. The impact of INC farming on the global warming potential and eutrophication potential was, however, almost negligible (

Context - This paper describes the environmental consequences of agricultural adaptation on eutrophication of the nearby ecological network for a study area in the Netherlands. More specifically, we explored (i) likely responses of farmers to changes in climate, technology, policy, and markets; (ii) subsequent changes in nitrogen (N) emissions in responses to farmer adaptations; and (iii) to what extent the emitted N was deposited in nearby nature reserves, in view of the potential impacts on plant species diversity and desired nature targets. Methods - For this purpose, a spatially-explicit study at landscape level was performed by integrating the environmental model INITIATOR, the farm model FSSIM, and the land-use model RULEX. We evaluated two alternative scenarios of change in climate, technology, policy, and markets for 2050: one in line with a ‘global economy’ (GE) storyline and the other in line with a ‘regional communities’ (RC) storyline. Results - Results show that the GE storyline resulted in a relatively strong increase in agricultural production compared to the RC storyline. Despite the projected conversions of agricultural land to nature (as part of the implementation of the National Ecological Network), we project an increase in N losses and N deposition due to N emissions in the study area of about 20 %. Even in the RC storyline, with a relatively modest increase in agricultural production and a larger expansion of the nature reserve, the N losses and deposition remain at the current level, whereas a reduction is required. Conclusions - We conclude that more ambitious green policies are needed in view of nature protection.

A series of environmental policies have been implemented in the European Union (EU) to decrease nitrogen (N) emissions from agriculture. The Nitrates Directive (ND) is one of the main policies; it aims to reduce nitrate leaching from agriculture through a number of measures. A study was carried out to quantify the effects of the ND in the EU-27 on the leaching and runoff of nitrate (NO3(-)) to groundwater and surface waters, and on the emissions of ammonia (NH3), nitrous oxide (N2O), nitrogen oxides (NO(x)) and dinitrogen (N2) to the atmosphere. We formulated a scenario with and a scenario without implementation of the ND. The model MITERRA-Europe was used to calculate N emissions on a regional level in the EU-27 for the period 2000-2008. The calculated total N loss from agriculture in the EU-27 was 13 Mton N in 2008, with 53% as N2, 22% as NO3, 21% as NH3, 3% as N2O, and 1% as NO(x). The N emissions and leaching in the EU-27 slightly decreased in the period 2000-2008. Total emissions in the EU in 2008 were smaller with implementation of the ND than without the ND, by 3% for NH3, 6% for N2O, 9% for NO(x), and 16% for N leaching and runoff in 2008. However, regional differences were large. The lower emissions with ND were mainly due to the lower N inputs by fertilizers and manures. In conclusion, implementation of the ND decreased both N leaching losses to ground and surface waters, and gaseous emissions to the atmosphere. It is expected that the ND will result in a further decrease in N emissions in EU-27 in the near future, because the implementation of the measures for the ND is expected to become more strict.

This paper quantifies the efficiency of emission control measures in agriculture at landscape scale on the N deposition and critical N load exceedances in Natura 2000 sites. The model INITIATOR2 was run with spatially explicit farm data to predict atmospheric emissions of ammonia. These emissions were input of an atmospheric transport model to assess the N deposition in the Natura 2000 sites. Using the Dutch province of Overijssel as a case study, calculations for the year 2006 show that only 35% of the N deposition in the Natura 2000 sites were caused by agricultural NH3 emissions within the province. Comparatively most cost-efficient measures were low-emission application, followed by measures to reduce the protein content in feed. Relocating farms out of the Natura 2000 sites was very cost inefficient. Since critical N depositions of the Natura 2000 sites in Overijssel are largely exceeded in more than 90% of the area, the evaluated abatement measures were, however, not effective to reduce the area exceeding critical loads when only applied within the province Overijssel. Reductions of N deposition to a level below critical loads can only be achieved with the support of national and international emission reductions.

Ototoxicity refers to damage of inner ear structures (i.e., the cochlea and vestibule) and their function (hearing and balance) following exposure to specific in-hospital medications (i.e., aminoglycoside antibiotics, platinum-based drugs), as well as a variety of environmental or occupational exposures (e.g., metals and solvents). This review provides a narrative derived from relevant papers describing factors contributing to (or increasing the risk of) aminoglycoside and cisplatin-induced ototoxicity. We also review current strategies to protect against ototoxicity induced by these indispensable pharmacotherapeutic treatments for life-threatening infections and solid tumors. We end by highlighting several interventional strategies that are currently in development, as well as the diverse challenges that still need to be overcome to prevent drug-induced hearing loss.

Key points The transduction of sound into electrical signals occurs at the hair bundles atop sensory hair cells in the cochlea, by means of mechanosensitive ion channels, the mechano‐electrical transducer (MET) channels.The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli.In this study we used a mouse model (Snell's waltzer) for hereditary deafness in humans that has a mutation in the gene encoding an unconventional myosin, myosin VI, which is present in the hair bundles.We found that in the absence of myosin VI the MET current fails to acquire its characteristic adaptation as the hair bundles develop.We propose that myosin VI supports the acquisition of adaptation by removing key molecules from the hair bundle that serve a temporary, developmental role. Abstract Mutations in Myo6, the gene encoding the (F‐actin) minus end‐directed unconventional myosin, myosin VI, cause hereditary deafness in mice (Snell's waltzer) and humans. In the sensory hair cells of the cochlea, myosin VI is expressed in the cell bodies and along the stereocilia that project from the cells’ apical surface. It is required for maintaining the structural integrity of the mechanosensitive hair bundles formed by the stereocilia. In this study we investigate whether myosin VI contributes to mechano‐electrical transduction. We report that Ca2+‐dependent adaptation of the mechano‐electrical transducer (MET) current, which serves to keep the transduction apparatus operating within its most sensitive range, is absent in outer and inner hair cells from homozygous Snell's waltzer mutant mice, which fail to express myosin VI. The operating range of the MET channels is also abnormal in the mutants, resulting in the absence of a resting MET current. We found that cadherin 23, a component of the hair bundle's transient lateral links, fails to be downregulated along the length of the stereocilia in maturing Myo6 mutant mice. MET currents of heterozygous littermates appear normal. We propose that myosin VI, by removing key molecules from developing hair bundles, is required for the development of the MET apparatus and its Ca2+‐dependent adaptation., Key points The transduction of sound into electrical signals occurs at the hair bundles atop sensory hair cells in the cochlea, by means of mechanosensitive ion channels, the mechano‐electrical transducer (MET) channels.The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli.In this study we used a mouse model (Snell's waltzer) for hereditary deafness in humans that has a mutation in the gene encoding an unconventional myosin, myosin VI, which is present in the hair bundles.We found that in the absence of myosin VI the MET current fails to acquire its characteristic adaptation as the hair bundles develop.We propose that myosin VI supports the acquisition of adaptation by removing key molecules from the hair bundle that serve a temporary, developmental role.

The transduction of sound into electrical signals depends on mechanically sensitive ion channels in the stereociliary bundle. The molecular composition of this mechanoelectrical transducer (MET) channel is not yet known. Transmembrane channel-like protein isoforms 1 (TMC1) and 2 (TMC2) have been proposed to form part of the MET channel, although their exact roles are still unclear. Using Beethoven (Tmc1(Bth/Bth)) mice, which have an M412K point mutation in TMC1 that adds a positive charge, we found that Ca(2+) permeability and conductance of the MET channel of outer hair cells (OHCs) were reduced. Tmc1(Bth/Bth) OHCs were also less sensitive to block by the permeant MET channel blocker dihydrostreptomycin, whether applied extracellularly or intracellularly. These findings suggest that the amino acid that is mutated in Bth is situated at or near the negatively charged binding site for dihydrostreptomycin within the permeation pore of the channel. We also found that the Ca(2+) dependence of the operating range of the MET channel was altered by the M412K mutation. Depolarization did not increase the resting open probability of the MET current of Tmc1(Bth/Bth) OHCs, whereas raising the intracellular concentration of the Ca(2+) chelator BAPTA caused smaller increases in resting open probability in Bth mutant OHCs than in wild-type control cells. We propose that these observations can be explained by the reduced Ca(2+) permeability of the mutated MET channel indirectly causing the Ca(2+) sensor for adaptation, at or near the intracellular face of the MET channel, to become more sensitive to Ca(2+) influx as a compensatory mechanism.In the auditory system, the hair cells convert sound-induced mechanical movement of the hair bundles atop these cells into electrical signals through the opening of mechanically gated ion channels at the tips of the bundles. Although the nature of these mechanoelectrical transducer (MET) channels is still unclear, recent studies implicate transmembrane channel-like protein isoform 1 (TMC1) channels in the mammalian cochlea. Using a mutant mouse model (Beethoven) for progressive hearing loss in humans (DFNA36), which harbors a point mutation in the Tmc1 gene, we show that this mutation affects the MET channel pore, reducing its Ca(2+) permeability and its affinity for the permeant blocker dihydrostreptomycin. A number of phenomena that we ascribe to Ca(2+)-dependent adaptation appear stronger, in compensation for the reduced Ca(2+) entry.

Supplementary Material, SMART2 Model description, Conversion pH and nitrate concentration for the Plant diversity Indicator, Areal distribution of soil-vegetation combinations, Input data, Details on the derivation of deposition and hydrology scenarios Nitrogen and sulphur deposition scenarios. (DOCX 578 kb)

A geostatistical model was developed and applied to predict six soil properties and soil horizon thickness for mineral A, B and C soil horizons at the European scale and quantify the associated prediction uncertainties. The soil properties are pH, organic carbon content, organic nitrogen content, clay and sand contents and bulk density. The geostatistical model takes a regression cokriging approach, in which correlations between soil properties and across soil horizons are taken into account. Non-stationarities in the means and variances are represented by mapping units of the generalised European soil and land cover maps. The model was calibrated using the combined WISE, SPADE 1 and EFSDB databases, which jointly contain approximately 3600 soil profiles, irregularly distributed over Europe. The resulting model showed for most soil properties strong dependencies on soil type and land cover, moderate correlations between soil property residuals, strong correlations across horizons, and moderate spatial correlation of regression residuals. Kriging predictions and simulations were made on a 5 km by 5 km grid. Uncertainties in the resulting maps are large, particularly in under-sampled parts of Europe and in strata with large spatial variation. We conclude that geostatistical prediction and simulation are useful techniques to quantify uncertainties in soil property maps at the European scale, but that many more observations are required to fully exploit the relationship with explanatory variables and improve mapping accuracy. One important advantage of the techniques used is that they yield a full probabilistic model, as required by Monte Carlo uncertainty propagation analyses of spatially distributed dynamic models that use soil properties as uncertain input. In particular, the results of this study have been used to analyse how uncertainty in soil properties propagate through terrestrial greenhouse gas emission models.

The global animal food chain has a large contribution to the global anthropogenic greenhouse gas (GHG) emissions, but its share and sources vary highly across the world. However, the assessment of GHG emissions from livestock production is subject to various uncertainties, which have not yet been well quantified at large spatial scale. We assessed the uncertainties in the relations between animal production (milk, meat, egg) and the CO2, CH4, and N2O emissions in Africa, Latin America and the European Union, using the MITERRA-Global model. The uncertainties in model inputs were derived from time series of statistical data, literature review or expert knowledge. These model inputs and parameters were further divided into nine groups based on type of data and affected greenhouse gas. The final model output uncertainty and the uncertainty contribution of each group of model inputs to the uncertainty were quantified using a Monte Carlo approach, taking into account their spatial and cross-correlation. GHG emissions and their uncertainties were determined per livestock sector, per product and per emission source category. Results show large variation in the GHG emissions and their uncertainties for different continents, livestock sectors products or source categories. The uncertainty of total GHG emissions from livestock sectors is higher in Africa and Latin America than in the European Union. The uncertainty of CH4 emission is lower than that for N2O and CO2. Livestock parameters, CH4 emission factors and N emission factors contribute most to the uncertainty in the total model output. The reliability of GHG emissions from livestock sectors is relatively high (low uncertainty) at continental level, but could be lower at country level.

The integrated modelling system INITIATOR was applied to a landscape in the northern part of the Netherlands to assess current nitrogen fluxes to air and water and the impact of various agricultural measures on these fluxes, using spatially explicit input data on animal numbers, land use, agricultural management, meteorology and soil. Average model results on NH(3) deposition and N concentrations in surface water appear to be comparable to observations, but the deviation can be large at local scale, despite the use of high resolution data. Evaluated measures include: air scrubbers reducing NH(3) emissions from poultry and pig housing systems, low protein feeding, reduced fertilizer amounts and low-emission stables for cattle. Low protein feeding and restrictive fertilizer application had the largest effect on both N inputs and N losses, resulting in N deposition reductions on Natura 2000 sites of 10% and 12%, respectively.

This paper summarizes current knowledge on the impacts of changes of nitrogen (Nr) use in agriculture on the global warming potential (GWP) by its impact on carbon dioxide (CO2), nitrous oxide (N2O) and methane (CH4) emissions from agricultural and terrestrial nonagricultural systems and from aquatic and marine ecosystems. Ranges in ‘N induced exchange factors’, giving responses of CO2–C, N2O–N and CH4–C exchange per kg N input, are presented for all ecosystems. Using these factors, a quantification is made of CO2, N2O and CH4 exchange (emissions or uptake) induced by the use of Nr in agriculture at European scale for the year 2000. This includes: (i) direct impacts in the agricultural systems due to Nr inputs by fertilizer and manure and NH3 deposition and (ii) indirect impacts due to Nr leaching and NH3 deposition caused by agriculture on terrestrial, aquatic and marine ecosystems. Results show that the increase in GWP caused by elevated N2O emission due to Nr use in agriculture is completely counteracted by elevated carbon sequestration in nonagricultural systems. Nr effects on biodiversity, eutrophication and human health, however, need to be considered when considering the overall impacts of Nr use in agriculture.

Nitrous oxide (N2O) emission from agricultural land is an important component of the total annual greenhouse gas (GHG) budget. In addition, uncertainties associated with agricultural N2O emissions are large. The goals of this work were (i) to quantify the uncertainties of modelled N2O emissions caused by model input uncertainty at point and landscape scale (i.e. resolution), and (ii) to identify the main sources of input uncertainty at both scales. For the Dutch western fen meadow landscape, we performed a Monte Carlo uncertainty propagation analysis using the INITIATOR model. The Monte Carlo analysis used novel and state-of-the-art methods for estimating and simulating continuous-numerical and categorical input variables, handling spatial and cross-correlations and analyzing spatial aggregation effects. Spatial auto- and cross-correlation of uncertain numerical inputs that are spatially variable were represented by the linear model of coregionalization. Bayesian Maximum Entropy was used to quantify the uncertainty of spatially variable categorical model inputs. Stochastic sensitivity analysis was used to analyze the contribution of groups of uncertain inputs to the uncertainty of the N2O emission at point and landscape scale. The average N2O emission at landscape scale had a mean of 20.5 kg N2O-N ha(-1) yr(-1) and a standard deviation of 10.7 kg N2O-N ha(-1) yr(-1), producing a relative uncertainty of 52%. At point scale, the relative error was on average 78%, indicating that upscaling decreases uncertainty. Soil inputs and denitrification and nitrification inputs were the main sources of uncertainty in N2O emission at point scale. At landscape scale, uncertainty in soil inputs averaged out and uncertainty in denitrification and nitrification inputs was the dominant source of uncertainty. This was partly because these inputs were assumed constant across areas with the same soil type and land use, which is probably not very realistic. Experiments at landscape scale are needed to assess the spatial variability of these fractions and analyze how a more realistic representation influences the uncertainty budget at landscape scale. This research confirms that results from uncertainty analyses are often scale dependent and that results for one scale cannot directly be extrapolated to other scales. (C) 2010 Elsevier B.V. All rights reserved.

A European Union (EU-27) wide N2O emission estimate for the agricultural sector is presented, using the INTEGRATOR model, combined with detailed GIS-based environmental data and farming data. INTEGRATOR links various modules, calculating NH3, NOx, N2O, CO2, and CH4 emissions from housing and manure storage systems, agricultural and non-agricultural soils and surface waters, while accounting for the interaction between agricultural and non-agricultural systems through an emission-deposition model for NH3 and NOx. This study is limited to N2O emissions from housing and manure storage systems and agricultural soils. All emissions are based on N2O emission factors which depend on environment (weather and soil conditions), land use (grassland, arable land, crop residues), and management (type of manure and fertilizer, etc). We assessed the plausibility by a comparison of calculated present nitrous oxide emissions at country level with those derived by more simple emission factor approaches and detailed ecosystem models. The model was used to assess the impact of various farming practice packages to mitigate N2O emissions. For the agricultural sector of the EU-27, a total N2O emission of 347 kton N2O-N is calculated for the year 2000, which is comparable to other estimates. The overall achievable reduction in N2O emissions with the evaluated mitigation measures is about 25%. For the EU-27, the most effective measures are balanced fertilization and maximum manure application, but this is highly variable per country.

Field observations and experimental data of effects of nitrogen (N) deposition on plant species diversity have been used to derive empirical critical N loads for various ecosystems. The great advantage of such an approach is the inclusion of field evidence, but there are also restrictions, such as the absence of explicit criteria regarding significant effects on the vegetation, and the impossibility to predict future impacts when N deposition changes. Model approaches can account for this. In this paper, we review the possibilities of static and dynamic multispecies models in combination with dynamic soil–vegetation models to (1) predict plant species composition as a function of atmospheric N deposition and (2) calculate critical N loads in relation to a prescribed protection level of the species composition. The similarities between the models are presented, but also several important differences, including the use of different indicators for N and acidity and the prediction of individual plant species vs. plant communities. A summary of the strengths and weaknesses of the various models, including their validation status, is given. Furthermore, examples are given of critical load calculations with the model chains and their comparison with empirical critical N loads. We show that linked biogeochemistry–biodiversity models for N have potential for applications to support European policy to reduce N input, but the definition of damage thresholds for terrestrial biodiversity represents a major challenge. There is also a clear need for further testing and validation of the models against long-term monitoring or long-term experimental data sets and against large-scale survey data. This requires a focused data collection in Europe, combing vegetation descriptions with variables affecting the species diversity, such as soil acidity, nutrient status and water availability. Finally, there is a need for adaptation and upscaling of the models beyond the regions for which dose–response relationships have been parameterized, to make them generally applicable.

This article describes two different visualisation instruments that can be used for awareness raising and educational purposes: Nitrogenius and the N-visualisation tool. Both instruments aim to convey the complex interactions that occur in the nitrogen (N) cycle and the need for integrated measures when aiming to reduce N-related environmental problems such as eutrophication, acidification or global warming. Nitrogenius was developed in the year 2000. This four-player computer “game” focuses on the Dutch N problems caused by N2O, NH3 and NOx emissions as well as nitrate in surface and ground water. Underlying the glossy user interface is a set of comprehensive models and a database with potential measures that were considered to be feasible at the time. Since 2000, the model has been used for educational purposes annually at Wageningen University. About 150 MSc students played the game, with the aim to solve the N-related problems in the Netherlands. This article analyses these games, and presents the surprising correlation for the period 2000-2007 with the actual environmental trends in the Netherlands. The second tool is an N- visualisation tool that was developed in 2007. This tool provides both a historic overview of the nitrogen issue and demonstrates the effect of seven potential measures on the world wide N cycle. The effects of increased biomass use and intensification of agriculture are examples of included measures. The net effect on global warming, food availability and biodiversity are output parameters of this instrument. The calculations and assumptions underlying this tool are easily accessible through an open source spreadsheet. This tool was used in 2008 and 2009 at Wageningen University for educational purposes. The pros and cons of both games for awareness raising and educational purposes will be discussed

We assessed the involvement of harmonin-b, a submembranous protein containing PDZ domains, in the mechanoelectrical transduction machinery of inner ear hair cells. Harmonin-b is located in the region of the upper insertion point of the tip link that joins adjacent stereocilia from different rows and that is believed to gate transducer channel(s) located in the region of the tip link's lower insertion point. In Ush1cdfcr-2J/dfcr-2J mutant mice defective for harmonin-b, step deflections of the hair bundle evoked transduction currents with altered speed and extent of adaptation. In utricular hair cells, hair bundle morphology and maximal transduction currents were similar to those observed in wild-type mice, but adaptation was faster and more complete. Cochlear outer hair cells displayed reduced maximal transduction currents, which may be the consequence of moderate structural anomalies of their hair bundles. Their adaptation was slower and displayed a variable extent. The latter was positively correlated with the magnitude of the maximal transduction current, but the cells that showed the largest currents could be either hyperadaptive or hypoadaptive. To interpret our observations, we used a theoretical description of mechanoelectrical transduction based on the gating spring theory and a motor model of adaptation. Simulations could account for the characteristics of transduction currents in wild-type and mutant hair cells, both vestibular and cochlear. They led us to conclude that harmonin-b operates as an intracellular link that limits adaptation and engages adaptation motors, a dual role consistent with the scaffolding property of the protein and its binding to both actin filaments and the tip link component cadherin-23. Electronic supplementary material The online version of this article (doi:10.1007/s00424-009-0711-x) contains supplementary material, which is available to authorized users.

In this study, we present estimated ranges in carbon (C) sequestration per kg nitrogen (N) addition in above-ground biomass and in soil organic matter for forests and heathlands, based on: (i) empirical relations between spatial patterns of carbon uptake and influencing environmental factors including nitrogen deposition (forests only), (ii) 15N field experiments, (iii) long-term low-dose N fertilizer experiments and (iv) results from ecosystem models. The results of the various studies are in close agreement and show that above-ground accumulation of carbon in forests is generally within the range 15–40 kg C/kg N. For heathlands, a range of 5–15 kg C/kg N has been observed based on low-dose N fertilizer experiments. The uncertainty in C sequestration per kg N addition in soils is larger than for above-ground biomass and varies on average between 5 and 35 kg C/kg N for both forests and heathlands. All together these data indicate a total carbon sequestration range of 5–75 kg C/kg N deposition for forest and heathlands, with a most common range of 20–40 kg C/kg N. Results cannot be extrapolated to systems with very high N inputs, nor to other ecosystems, such as peatlands, where the impact of N is much more variable, and may range from C sequestration to C losses.

Hair cells in the inner ear provide the basis for the exquisite hearing capabilities of mammals. These cells transduce sound-induced displacements of their mechanosensitive hair bundle into electrical currents within a fraction of a millisecond and with nanometer fidelity. Excitatory displacements of the hair cell's bundle tense tip links that open transducer channels. These channels are located either at one or at both ends of the links, where the latter possibility was thought to compromise sensitivity via negative cooperativity, and discarded for quantitatively describing the transduction process. Here, we show instead that this series mode of activation accurately explains measured transduction in hair cells. It enhances both sensitivity and dynamic range of hair cell transduction, by one channel that is extremely sensitive at small displacements while the other responds best to larger stimuli. Our results provide a new framework for exploring the dynamics of hair cell activation.

The process based model SMART–SUMO–WATBAL was applied to 166 intensive monitoring forest plots of mid- and high-latitude Europe to evaluate the effects of expected future changes in carbon dioxide concentration, temperature, precipitation and nitrogen deposition on forest growth (net annual increment). These results were used in the large-scale forest scenario model EFISCEN (European Forest Information SCENario model) to upscale impacts of environmental change and to combine these results with adapted forest management. Because of the few plots available, Mediterranean countries were excluded from analyses. Results are presented for 109 million ha in 23 European countries. We predict significant impacts of environmental change on mid- and high-latitude European forests. Under a no climate change scenario, an increased fellings scenario assumed wood demand to increase from 3.8 to 5.3 m3 ha−1 yr−1 between 2000 and 2010, maintaining growing stock volumes at around 170 m3 ha−1. In 2100 it was thus possible to cut 50% more under intensive management than current felling level. Climate change increased this possibility to 90% (from 3.8 to 7.2 m3 ha−1 yr−1). The growing stock in 2100 increased to 279 m3 ha−1 under base felling level and no environmental change, but under environmental change, the rise was up to 381 m3 ha−1 in 2100. The average carbon stock of whole tree biomass was 72 Mg ha−1 carbon in 2005 and it increased to a predicted 104 Mg ha−1 carbon in 2100 under no environmental change and base fellings. Environmental change enhanced the build up of carbon stocks to up to 143 Mg ha−1 carbon in 2100. An average 35–40% higher increment is thus foreseen for 2100 compared to a no environmental change scenario (both under base fellings). The largest relative growth rate change is foreseen for the Nordic countries, with up to 75% growth increase. The impact of environmental change on C stock change in trees is as significant as the impact of forest management.