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Pollinators benefit from increasing floral resources in agricultural landscapes, which could be an underexplored co‐benefit of mass‐flowering crop cultivation. However, the impacts of mass‐flowering crops on pollinator communities are complex and appear to be context‐dependent, mediated by factors such as crop flowering time and the availability of other flower resources in the landscape. A synthesis of research is needed to develop management recommendations for effective pollinator conservation in agroecosystems.By combining 22 datasets from 13 publications conducted in nine temperate countries (20 European, 2 North American), we investigated if mass‐flowering crop flowering time (early or late season), bloom state (during or after crop flowering) and extent of non‐crop habitat cover in the landscape moderated the effect of mass‐flowering crop cover on wild pollinator abundance and species richness in mass‐flowering crop and non‐crop habitats.During bloom, wild bee abundance and richness are negatively related to mass‐flowering crop cover. Dilution effects were predominant in crop habitats and early in the season, except for bumblebees, which declined with mass‐flowering crop cover irrespective of habitat or season. Late in the season and in non‐crop habitats, several of these negative relationships were either absent or reversed. Late‐season mass‐flowering crop cover is positively related to honeybee abundance in crop habitats and to other bee abundance in non‐crop habitats. These results indicate that crop‐adapted species, like honeybees, move to forage and concentrate on late‐season mass‐flowering crops at a time when flower availability in the landscape is limited, potentially alleviating competition for flower resources in non‐crop habitats. We found no evidence of pollinators moving from mass‐flowering crop to non‐crop habitats after crop bloom.Synthesis and applications: Our results confirm that increasing early‐season mass‐flowering crop cover dilutes wild pollinators in crop habitats during bloom. We find that dilution effects were absent late in the season. While mass‐flowering crop cultivation alone is unlikely to be sufficient for maintaining pollinators, as part of carefully designed diverse crop rotations or mixtures combined with the preservation of permanent non‐crop habitats, it might provide valuable supplementary food resources for pollinators in temperate agroecosystems, particularly later in the season when alternative flower resources are scarce. [ABSTRACT FROM AUTHOR]

A multiple-hole die for the production of single large blocks of polystyrene foam with carbon dioxide as blowing agent was developed. First, single-hole die experiments were carried out with different hole sizes (2.0, 1.0, and 0.50 mm). Using these single-hole dies dimensionally-stable foam was produced with a density of 31 kg [m.sup.-3] and an open cell structure. Next, the hole diameter and hole distances for a newly constructed multiple-hole die were chosen on basis of the radial expansion in the single-hole die experiments. Tests with the multiple-hole die showed that the seven strings could melt together forming one large string with a diameter of about 20 mm and a density of 50 kg [m.sup.-3]. Therefore, the concept of using a multiple-hole die for producing single large blocks of polystyrene was proven. However, larger block sizes were not possible because of the limited capabilities of the extruder. POLYM. ENG. SCI., 51:2328-2334, 2011. © 2011 Society of Plastics Engineers, INTRODUCTION Polystyrene (PS) foams are widely used as packaging materials and as heat insulators in the construction industry. They have a low density, a low thermal conductivity, and a relatively [...]

In reproductive swards, stems can act as a barrier that affects the grazing behaviour of ruminant livestock. The barrier effect of stems is closely associated with both the force required to fracture the stems and the density of these stems (in combination, these make up grazing resistance), and these factors need to be considered when making predictions about the forage intake of ruminants grazing reproductive pastures. Differences in grazing resistance between sward canopy layers of different grass species are thought to affect bite dimensions, but data are scarce. In this study, we assessed the grazing resistance for three canopy layers of seven tropical grass species. Species differed significantly in grazing resistance for every canopy layer, with a general ranking order for grazing resistance, in ascending order: Cenchrus ciliaris (' American' buffel), Digitaria milanjiana (' Jarra' finger grass), Setaria surgens (annual pigeon grass), Setaria sphacelata (' Narok' setaria), Dichanthium sericeum ( Queensland bluegrass), Chloris gayana (' Callide' Rhodes grass). In the top canopy layer, grazing resistance did not appear to create a barrier for any of the species, but in the bottom canopy layer, it did for all species. Species also differed in the relative contribution of fracture force and density to grazing resistance. The results highlight the importance of managing the grazing systems to minimize the barrier effect of the stems, which can be done by controlling the phenological stage of the pasture and the grass species and animal size used in the system. [ABSTRACT FROM AUTHOR]

The intake of forage grasses by grazing ruminants is closely related to the mechanical fracture properties of grasses. The relationship between the tensile fracture properties of grasses and foraging behaviour is of particular importance in tropical reproductive swards composed of both stems and leaves. This study (i) quantified and compared the tensile fracture properties of stems and leaves of seven tropical grass species and (ii) provided insight into the underlying plant traits that explain differences in fracture properties between species. Fracture force, tensile strength, fracture energy and toughness of stems (in various phenological stages) and leaves were measured and compared among five introduced tropical grasses ( Cenchrus ciliaris, Chloris gayana, Digitaria milanjiana, Megathyrsus maximus (syn. Panicum maximum), Setaria sphacelata) and two native tropical grasses ( Setaria surgens and Dichanthium sericeum). Species differed significantly in fracture force and fracture energy, with stems and leaves of C. ciliaris and S. surgens requiring less force and energy to fracture and stems and leaves of M. maximus and S. sphacelata requiring more force and energy to fracture in comparison with the other species. Differences in tensile strength and toughness were less pronounced. The differences among species in fracture force and energy mainly resulted from differences in cross-sectional area of plant parts rather than from differences in tensile strength and toughness. [ABSTRACT FROM AUTHOR]

Nitrogen deposition and climate change have been identified as major threats to the biodiversity of semi-natural grasslands. Their relative contribution to recent biodiversity loss is however not fully understood, and may depend on local site conditions such as soil type, which hampers efforts to prevent further decline. We used data from >900 permanent plots in semi-natural grasslands in Dutch roadsides to investigate whether trends in plant diversity and community composition (2004-2020) could be explained by: (1) nitrogen deposition (NH x and NO y ) and climate change (winter degree days and summer drought), (2) the interactive effect of nitrogen deposition and climate change, and (3) the interactive effect of nitrogen deposition and climate change with soil type. Overall we observed a decline in plant diversity and an increased dominance of tall species and grasses. These changes were linked to winter warming, but not to changes in summer drought and nitrogen deposition. The effect of winter warming was more pronounced in areas with higher NO y deposition, but was consistent across different soil types. Our results suggest that winter warming will become an important driver of plant diversity loss by altering competitive interactions, which could have major repercussions for other trophic levels and ecosystem services. Future conservation and restoration of grassland biodiversity therefore requires management regimes that are adapted to winter warming., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To increase pollinator populations, international policy targets minimum levels of seminatural habitat cover, but it is unknown whether improving the quality of existing habitats could bring similar benefits without the need of reducing cropland area. Using data we collected in 26 Italian agricultural landscapes during the entire flying season, we explored the relative importance of habitat quantity (seminatural habitat cover) and quality (flower availability) on pollinator densities in seminatural habitats. We obtained transect-based counts and estimated the effect of habitat quantity (proportion of seminatural habitat) and quality (flower cover and richness) on wild bee and hoverfly densities. We used the relationships revealed in the data to simulate pollinator population sizes in landscapes with varying habitat quantity and quality. Wild bee densities were only related to flower availability, whereas hoverfly densities were additionally related to seminatural habitat cover. We found that in complex agricultural landscapes (above 15% seminatural habitat cover), improving habitat quality increased pollinator populations more effectively than increasing habitat quantity. However, increasing habitat quantity was by far the most effective approach for boosting pollinator populations in simple landscapes., (© 2024 The Author(s). Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Background: Maximizing the effectiveness of natural pest control requires a detailed understanding of how service delivery is affected by natural enemy community diversity and composition. Many studies have investigated the effects of natural enemy abundance and species richness on pest control. Studies examining the effects of evenness and species identity are fewer and have produced inconsistent results. Here we test the effects of arthropod predator community evenness and species identity on natural pest control by exposing aphid (Sitobion avenae) colonies in experimental cages to arthropod predator communities that had the same abundance and species richness but differed in evenness and dominant species., Results: We found that the identity of the most dominant species in the arthropod predator community predominantly drove the pest control efficiency. However, additional to the effects of species identity, we also found a causal positive relationship between the evenness of arthropod predator communities and the suppression of pest growth., Conclusion: Our results provide support for the hypothesis that ecosystem service provision is generally a function of the abundance and efficiency of the most dominant species of the service-providing groups. This could partly explain why management practices aiming at promoting abundance of natural enemies often have mixed effects on pest control. Our results also demonstrate that diversity components such as evenness have important additional effects. However, in real-world ecosystems these effects may be obscured because evenness is generally confounded with abundance or species richness in natural enemy predator communities. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Purpose: Despite new treatment options, melanoma continues to have an unfavorable prognosis. DNA damage response (DDR) inhibitors are a promising drug class, especially in combination with chemotherapy (CT) or radiotherapy (RT). Manipulating DNA damage repair during RT is an opportunity to exploit the genomic instability of cancer cells and may lead to radiosensitizing effects in tumors that could improve cancer therapy., Methods: A panel of melanoma-derived cell lines of different origin were used to investigate toxicity-related clonogenic survival, cell death, and cell cycle distribution after treatment with a kinase inhibitor (KI) against ATM (AZD0156) or ATR (VE-822, berzosertib), irradiation with 2 Gy, or a combination of KI plus ionizing radiation (IR). Two fibroblast cell lines generated from healthy skin tissue were used as controls., Results: Clonogenic survival indicated a clear radiosensitizing effect of the ATM inhibitor (ATMi) AZD0156 in all melanoma cells in a synergistic manner, but not in healthy tissue fibroblasts. In contrast, the ATR inhibitor (ATRi) VE-822 led to additive enhancement of IR-related toxicity in most of the melanoma cells. Both inhibitors mainly increased cell death induction in combination with IR. In healthy fibroblasts, VE-822 plus IR led to higher cell death rates compared to AZD0156. A significant G2/M block was particularly induced in cancer cells when combining AZD0156 with IR., Conclusion: ATMi, in contrast to ATRi, resulted in synergistic radiosensitization regarding colony formation in melanoma cancer cells, while healthy tissue fibroblasts were merely affected with respect to cell death induction. In connection with an increased number of melanoma cells in the G2/M phase after ATMi plus IR treatment, ATMi seems to be superior to ATRi in melanoma cancer cell treatments when combined with RT., (© 2022. The Author(s).)

Agricultural expansion and intensification have boosted global food production but have come at the cost of environmental degradation and biodiversity loss. Biodiversity-friendly farming that boosts ecosystem services, such as pollination and natural pest control, is widely being advocated to maintain and improve agricultural productivity while safeguarding biodiversity. A vast body of evidence showing the agronomic benefits of enhanced ecosystem service delivery represent important incentives to adopt practices enhancing biodiversity. However, the costs of biodiversity-friendly management are rarely taken into account and may represent a major barrier impeding uptake by farmers. Whether and how biodiversity conservation, ecosystem service delivery, and farm profit can go hand in hand is unknown. Here, we quantify the ecological, agronomic, and net economic benefits of biodiversity-friendly farming in an intensive grassland-sunflower system in Southwest France. We found that reducing land-use intensity on agricultural grasslands drastically enhances flower availability and wild bee diversity, including rare species. Biodiversity-friendly management on grasslands furthermore resulted in an up to 17% higher revenue on neighboring sunflower fields through positive effects on pollination service delivery. However, the opportunity costs of reduced grassland forage yields consistently exceeded the economic benefits of enhanced sunflower pollination. Our results highlight that profitability is often a key constraint hampering adoption of biodiversity-based farming and uptake critically depends on society's willingness to pay for associated delivery of public goods such as biodiversity.

Ecological intensification has been proposed as an alternative paradigm for intensive agriculture to boost yield sustainably through utilizing ecosystem services. A prerequisite to achieving this is to understand the relations between multiple ecosystem services and production, while taking growth conditions such as nutrient availability into consideration. Here, we conducted a pot-field experiment to study the interactive effects of soil organic matter (SOM) content and arbuscular mycorrhizal fungi (AMF) inoculation on the production of raspberry (Rubus idaeus L.) under four levels of fertilizer application. Raspberry flower number, fruit number and yield only significantly increased with fertilizer inputs but were not impacted by SOM content or AMF inoculation. Fruit set and single berry weight were influenced by both SOM content and AMF inoculation, in complex three-way interactions with fertilizer application. Fruit set of AMF inoculated plants increased with fertilizer inputs in low SOM soils, but decreased with fertilizer inputs under high SOM soils, with the highest fruit set occurring at no fertilizer inputs. In low SOM soils, the relation between single berry weight and fertilizer application was more pronounced in inoculated plants than in non-inoculated plants, while in high SOM soils the relative benefits of AMF inoculation on single berry weight decreased with increasing fertilizer inputs. We attribute the lack of effects of AMF inoculation and SOM content on flower number, fruit number and yield mainly to potential tradeoffs between the experimental variables that all influence resource uptake by plant root systems. Our results suggest that potentially beneficial effects of AMF and SOM can be offset by each other, probably driven by the dynamic relations between AMF and the host plants. The findings reveal fundamental implications for managing AMF inoculation and SOM management simultaneously in real-world agricultural systems., Competing Interests: The authors have declared that no competing interests exist.

Seventy five percent of the world's food crops benefit from insect pollination. Hence, there has been increased interest in how global change drivers impact this critical ecosystem service. Because standardized data on crop pollination are rarely available, we are limited in our capacity to understand the variation in pollination benefits to crop yield, as well as to anticipate changes in this service, develop predictions, and inform management actions. Here, we present CropPol, a dynamic, open, and global database on crop pollination. It contains measurements recorded from 202 crop studies, covering 3,394 field observations, 2,552 yield measurements (i.e., berry mass, number of fruits, and fruit density [kg/ha], among others), and 47,752 insect records from 48 commercial crops distributed around the globe. CropPol comprises 32 of the 87 leading global crops and commodities that are pollinator dependent. Malus domestica is the most represented crop (32 studies), followed by Brassica napus (22 studies), Vaccinium corymbosum (13 studies), and Citrullus lanatus (12 studies). The most abundant pollinator guilds recorded are honey bees (34.22% counts), bumblebees (19.19%), flies other than Syrphidae and Bombyliidae (13.18%), other wild bees (13.13%), beetles (10.97%), Syrphidae (4.87%), and Bombyliidae (0.05%). Locations comprise 34 countries distributed among Europe (76 studies), North America (60), Latin America and the Caribbean (29), Asia (20), Oceania (10), and Africa (7). Sampling spans three decades and is concentrated on 2001-2005 (21 studies), 2006-2010 (40), 2011-2015 (88), and 2016-2020 (50). This is the most comprehensive open global data set on measurements of crop flower visitors, crop pollinators and pollination to date, and we encourage researchers to add more datasets to this database in the future. This data set is released for non-commercial use only. Credits should be given to this paper (i.e., proper citation), and the products generated with this database should be shared under the same license terms (CC BY-NC-SA)., (© 2021 The Ecological Society of America.)

(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

Background: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein., Methods: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×10 10 viral particles (low dose) or 1×10 11 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule., Results: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 212 to 354), regardless of vaccine dose or age group, and reached 96% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3., Conclusions: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.)., (Copyright © 2021 Massachusetts Medical Society.)

Objective: To assess long-term outcomes of amputation in patients with long-standing therapy-resistant complex regional pain syndrome type I (CRPS-I)., Design: Partly cross-sectional, partly longitudinal study., Subjects: Patients who had amputation of a limb due to long-standing, therapy-resistant CRPS-I, at the University Medical Centre Groningen, The Netherlands, between May 2000 and September 2015 (n = 53) were invited to participate., Methods: Participants were interviewed in a semi-structured way regarding mobility, pain, recurrence of CRPS-I, quality of life, and prosthesis use. Those who reported recurrence of CRPS-I underwent physical examination., Results: A total of 47 patients (median age at time of amputation, 41.0 years; 40 women) participated. Longitudinal evaluation was possible in 17 participants. Thirty-seven participants (77%) reported an important improvement in mobility (95% confidence interval (95% CI) 63; 87%). An important reduction in pain was reported by 35 participants (73%; 95% CI 59; 83%). CRPS-I recurred in 4 of 47 participants (9%; 95% CI 3; 20%), once in the residual limb and 3 times in another limb. At the end of the study of the 35 participants fitted with a lower limb prosthesis, 24 were still using the prosthesis. Longitudinal evaluation showed no significant deteriorations., Conclusion: Amputation can be considered as a treatment for patients with long-standing, therapy-resistant CRPS-I. Amputation can increase mobility and reduce pain, thereby improving the quality of patients' lives. However, approximately one-quarter of participants reported deteriorations in intimacy and self-confidence after the amputation.

Agricultural intensification and associated loss of high-quality habitats are key drivers of insect pollinator declines. With the aim of decreasing the environmental impact of agriculture, the 2014 EU Common Agricultural Policy (CAP) defined a set of habitat and landscape features (Ecological Focus Areas: EFAs) farmers could select from as a requirement to receive basic farm payments. To inform the post-2020 CAP, we performed a European-scale evaluation to determine how different EFA options vary in their potential to support insect pollinators under standard and pollinator-friendly management, as well as the extent of farmer uptake.A structured Delphi elicitation process engaged 22 experts from 18 European countries to evaluate EFAs options. By considering life cycle requirements of key pollinating taxa (i.e. bumble bees, solitary bees and hoverflies), each option was evaluated for its potential to provide forage, bee nesting sites and hoverfly larval resources.EFA options varied substantially in the resources they were perceived to provide and their effectiveness varied geographically and temporally. For example, field margins provide relatively good forage throughout the season in Southern and Eastern Europe but lacked early-season forage in Northern and Western Europe. Under standard management, no single EFA option achieved high scores across resource categories and a scarcity of late season forage was perceived.Experts identified substantial opportunities to improve habitat quality by adopting pollinator-friendly management. Improving management alone was, however, unlikely to ensure that all pollinator resource requirements were met. Our analyses suggest that a combination of poor management, differences in the inherent pollinator habitat quality and uptake bias towards catch crops and nitrogen-fixing crops severely limit the potential of EFAs to support pollinators in European agricultural landscapes. Policy Implications . To conserve pollinators and help protect pollination services, our expert elicitation highlights the need to create a variety of interconnected, well-managed habitats that complement each other in the resources they offer. To achieve this the Common Agricultural Policy post-2020 should take a holistic view to implementation that integrates the different delivery vehicles aimed at protecting biodiversity (e.g. enhanced conditionality, eco-schemes and agri-environment and climate measures). To improve habitat quality we recommend an effective monitoring framework with target-orientated indicators and to facilitate the spatial targeting of options collaboration between land managers should be incentivised., (© 2020 The Authors. Journal of Applied Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by a few dominant species or rely on high richness remains unclear. Using a global database from 89 studies (with 1475 locations), we partition the relative importance of species richness, abundance, and dominance for pollination; biological pest control; and final yields in the context of ongoing land-use change. Pollinator and enemy richness directly supported ecosystem services in addition to and independent of abundance and dominance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Molecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology. Targeting interleukin-2 (IL2) receptors on activated T-cells using positron emission tomography (PET) with N-(4-[ 18 F]fluorobenzoyl)-interleukin-2 ([ 18 F]FB-IL2) could be such a strategy. This paper describes the challenging translation of the partly manual labeling of [ 18 F]FB-IL2 for preclinical studies into an automated procedure following Good Manufacturing Practices (GMP), resulting in a radiopharmaceutical suitable for clinical use., Methods: The preclinical synthesis of [ 18 F]FB-IL2 was the starting point for translation to a clinical production method. To overcome several challenges, major adaptations in the production process were executed. The final analytical methods and production method were validated and documented. All data with regards to the quality and safety of the final drug product were documented in an investigational medicinal product dossier., Results: Restrictions in the [ 18 F]FB-IL2 production were imposed by hardware configuration of the automated synthesis equipment and by use of disposable cassettes. Critical steps in the [ 18 F]FB-IL2 production comprised the purification method, stability of recombinant human IL2 and the final formulation. With the GMP compliant production method, [ 18 F]FB-IL2 could reliably be produced with consistent quality complying to all specifications., Conclusions: To enable the use of [ 18 F]FB-IL2 in clinical studies, a fully automated GMP compliant production process was developed. [ 18 F]FB-IL2 is now produced consistently for use in clinical studies.

Background: Amputation for longstanding therapy resistant complex regional pain syndrome type-I (CRPS-I) is controversial. Reported results are inconsistent. It is assumed that psychological factors play a role in CRPS-I., Objective: To explore which psychological factors prior to amputation are associated with poor outcomes after amputation in the case of longstanding therapy resistant CRPS-I., Methods: Between May 2008 and August 2015, 31 patients with longstanding therapy resistant CRPS-I were amputated. Before the amputation 11 psychological factors were assessed. In 2016, participants had a structured interview by telephone and filled out questionnaires to assess their outcome. In case of a perceived recurrence of CRPS-I a physician visited the patient to examine the symptoms. Associations between psychological factors and poor outcomes were analysed., Results: Four of the 11 psychological factors were associated with poor outcomes. Regression analyses showed that change in the worst pain in the past week was associated with poor social support (B = 0.3, 95% confidence interval: 0.1;0.6) and intensity of pain before amputation (B = 2.0, 95% confidence interval 0.9;3.0). Patients who reported important improvements in mobility (n = 23) had significantly higher baseline resilience (median 79) compared to those (n = 8) who did not report it (median 69)(Mann-Whitney U, Z = -2.398, p = 0.015). Being involved in a lawsuit prior to amputation was associated with a recurrence in the residual limb (Bruehl criteria). A psychiatric history was associated with recurrence somewhere else (Bruehl criteria)., Conclusion: Poor outcomes of amputation in longstanding therapy resistant CPRS-1 are associated with psychological factors. Outstanding life events are not associated with poor outcome although half of the participants had experienced outstanding life events., Competing Interests: The authors have declared that no competing interests exist.

The current worldwide pollinator decline is caused by the interplay of different drivers. Several strategies have been undertaken to counteract or halt this decline, one of which is the implementation of wildflower fields. These supplementary flowers provide extra food resources and have proven their success in increasing pollinator biodiversity and abundance. Yet such landscape alterations could also alter the host-pathogen dynamics of pollinators, which could affect the populations. In this study, we investigated the influence of sown wildflower fields on the prevalence of micro-parasites and viruses in the wild bumble bee Bombus pascuorum, one of the most abundant bumble bee species in Europe and the Netherlands. We found that the effect of sown wildflower fields on micro-parasite prevalence is affected by the composition of the surrounding landscape and the size of the flower field. The prevalence of micro-parasites increases with increasing size of sown wildflower fields in landscapes with few semi-natural landscape elements. This effect was not observed in landscapes with a high amount of semi-natural landscape elements. We elaborate on two mechanisms which can support these findings: (1) "transmission hot spots" within the altered flower-networks, which could negatively impact hosts experiencing an increased exposure; (2) improved tolerance of the hosts, withstanding higher parasite populations.

Background: Inappropriate prescribing is a well-known clinical problem in nursing home residents, but few interventions have focused on reducing inappropriate medication use., Objective: To examine successful discontinuation of inappropriate medication use and to improve prescribing in nursing home residents., Design: Pragmatic cluster randomized controlled trial, with clustering by elder care physicians and their wards. (ClinicalTrials.gov: NCT01876095)., Setting: 59 Dutch nursing home wards for long-term care., Patients: Residents with a life expectancy greater than 4 weeks who consented to treatment with medication., Intervention: Multidisciplinary Multistep Medication Review (3MR) consisting of an assessment of the patient perspective, medical history, critical appraisal of medications, a meeting between the treating elder care physician and the pharmacist, and implementation of medication changes., Measurements: Successful discontinuation of use of at least 1 inappropriate drug (that is, without relapse or severe withdrawal symptoms) and clinical outcomes (neuropsychiatric symptoms, cognitive function, and quality of life) after 4 months of follow-up., Results: Nineteen elder care physicians (33 wards) performed the 3MR, and 16 elder care physicians (26 wards) followed standard procedures. A total of 426 nursing home residents (233 in the intervention group and 193 in the control group) were followed for an average of 144 days (SD, 21). In an analysis of all participants, use of at least 1 inappropriate medication was successfully discontinued for 91 (39.1%) residents in the intervention group versus 57 (29.5%) in the control group (adjusted relative risk, 1.37 [95% CI, 1.02 to 1.75]). Clinical outcomes did not deteriorate between baseline and follow-up., Limitations: The 3MR was done only once. Some withdrawal symptoms or relapses may have been missed., Conclusion: The 3MR is effective in discontinuing inappropriate medication use in frail nursing home residents without a decline in their well-being., Primary Funding Source: Netherlands Organisation for Health Research and Development.

Mass-flowering crops (MFCs) are increasingly cultivated and might influence pollinator communities in MFC fields and nearby semi-natural habitats (SNHs). Across six European regions and 2 years, we assessed how landscape-scale cover of MFCs affected pollinator densities in 408 MFC fields and adjacent SNHs. In MFC fields, densities of bumblebees, solitary bees, managed honeybees and hoverflies were negatively related to the cover of MFCs in the landscape. In SNHs, densities of bumblebees declined with increasing cover of MFCs but densities of honeybees increased. The densities of all pollinators were generally unrelated to the cover of SNHs in the landscape. Although MFC fields apparently attracted pollinators from SNHs, in landscapes with large areas of MFCs they became diluted. The resulting lower densities might negatively affect yields of pollinator-dependent crops and the reproductive success of wild plants. An expansion of MFCs needs to be accompanied by pollinator-supporting practices in agricultural landscapes., (© 2016 The Authors Ecology Letters published by CNRS and John Wiley & Sons Ltd.)

Land-use change and global warming are important factors driving bee decline, but it is largely unknown whether these drivers have resulted in changes in the life-history traits of bees. Recent studies have shown a stronger population decline of large- than small-bodied bee species, suggesting there may have been selective pressure on large, but not on small species to become smaller. Here we test this hypothesis by analyzing trends in bee body size of 18 Dutch species over a 147-year period using specimens from entomological collections. Large-bodied female bees shrank significantly faster than small-bodied female bees (6.5% and 0.5% respectively between 1900 and 2010). Changes in temperature during the flight period of bees did not influence the size-dependent shrinkage of female bees. Male bees did not shrink significantly over the same time period. Our results could imply that under conditions of declining habitat quantity and quality it is advantageous for individuals to be smaller. The size and sex-dependent responses of bees point towards an evolutionary response but genetic studies are required to confirm this. The declining body size of the large bee species that currently dominate flower visitation of both wild plants and insect-pollinated crops may have negative consequences for pollination service delivery.

Wild and managed bees are well documented as effective pollinators of global crops of economic importance. However, the contributions by pollinators other than bees have been little explored despite their potential to contribute to crop production and stability in the face of environmental change. Non-bee pollinators include flies, beetles, moths, butterflies, wasps, ants, birds, and bats, among others. Here we focus on non-bee insects and synthesize 39 field studies from five continents that directly measured the crop pollination services provided by non-bees, honey bees, and other bees to compare the relative contributions of these taxa. Non-bees performed 25-50% of the total number of flower visits. Although non-bees were less effective pollinators than bees per flower visit, they made more visits; thus these two factors compensated for each other, resulting in pollination services rendered by non-bees that were similar to those provided by bees. In the subset of studies that measured fruit set, fruit set increased with non-bee insect visits independently of bee visitation rates, indicating that non-bee insects provide a unique benefit that is not provided by bees. We also show that non-bee insects are not as reliant as bees on the presence of remnant natural or seminatural habitat in the surrounding landscape. These results strongly suggest that non-bee insect pollinators play a significant role in global crop production and respond differently than bees to landscape structure, probably making their crop pollination services more robust to changes in land use. Non-bee insects provide a valuable service and provide potential insurance against bee population declines.

Species distribution models (SDM) are increasingly used to understand the factors that regulate variation in biodiversity patterns and to help plan conservation strategies. However, these models are rarely validated with independently collected data and it is unclear whether SDM performance is maintained across distinct habitats and for species with different functional traits. Highly mobile species, such as bees, can be particularly challenging to model. Here, we use independent sets of occurrence data collected systematically in several agricultural habitats to test how the predictive performance of SDMs for wild bee species depends on species traits, habitat type, and sampling technique. We used a species distribution modeling approach parametrized for the Netherlands, with presence records from 1990 to 2010 for 193 Dutch wild bees. For each species, we built a Maxent model based on 13 climate and landscape variables. We tested the predictive performance of the SDMs with independent datasets collected from orchards and arable fields across the Netherlands from 2010 to 2013, using transect surveys or pan traps. Model predictive performance depended on species traits and habitat type. Occurrence of bee species specialized in habitat and diet was better predicted than generalist bees. Predictions of habitat suitability were also more precise for habitats that are temporally more stable (orchards) than for habitats that suffer regular alterations (arable), particularly for small, solitary bees. As a conservation tool, SDMs are best suited to modeling rarer, specialist species than more generalist and will work best in long-term stable habitats. The variability of complex, short-term habitats is difficult to capture in such models and historical land use generally has low thematic resolution. To improve SDMs' usefulness, models require explanatory variables and collection data that include detailed landscape characteristics, for example, variability of crops and flower availability. Additionally, testing SDMs with field surveys should involve multiple collection techniques.

There is compelling evidence that more diverse ecosystems deliver greater benefits to people, and these ecosystem services have become a key argument for biodiversity conservation. However, it is unclear how much biodiversity is needed to deliver ecosystem services in a cost-effective way. Here we show that, while the contribution of wild bees to crop production is significant, service delivery is restricted to a limited subset of all known bee species. Across crops, years and biogeographical regions, crop-visiting wild bee communities are dominated by a small number of common species, and threatened species are rarely observed on crops. Dominant crop pollinators persist under agricultural expansion and many are easily enhanced by simple conservation measures, suggesting that cost-effective management strategies to promote crop pollination should target a different set of species than management strategies to promote threatened bees. Conserving the biological diversity of bees therefore requires more than just ecosystem-service-based arguments.

Evidence for declining populations of both wild and managed bees has raised concern about a potential global pollination crisis. Strategies to mitigate bee loss generally aim to enhance floral resources. However, we do not really know whether loss of preferred floral resources is the key driver of bee decline because accurate assessment of host plant preferences is difficult, particularly for species that have become rare. Here we examine whether population trends of wild bees in The Netherlands can be explained by trends in host plants, and how this relates to other factors such as climate change. We determined host plant preference of bee species using pollen loads on specimens in entomological collections that were collected before the onset of their decline, and used atlas data to quantify population trends of bee species and their host plants. We show that decline of preferred host plant species was one of two main factors associated with bee decline. Bee body size, the other main factor, was negatively related to population trend, which, because larger bee species have larger pollen requirements than smaller species, may also point toward food limitation as a key factor driving wild bee loss. Diet breadth and other potential factors such as length of flight period or climate change sensitivity were not important in explaining twentieth century bee population trends. These results highlight the species-specific nature of wild bee decline and indicate that mitigation strategies will only be effective if they target the specific host plants of declining species.

Declines in insect pollinators across Europe have raised concerns about the supply of pollination services to agriculture. Simultaneously, EU agricultural and biofuel policies have encouraged substantial growth in the cultivated area of insect pollinated crops across the continent. Using data from 41 European countries, this study demonstrates that the recommended number of honeybees required to provide crop pollination across Europe has risen 4.9 times as fast as honeybee stocks between 2005 and 2010. Consequently, honeybee stocks were insufficient to supply >90% of demands in 22 countries studied. These findings raise concerns about the capacity of many countries to cope with major losses of wild pollinators and highlight numerous critical gaps in current understanding of pollination service supplies and demands, pointing to a pressing need for further research into this issue.

In Europe, agri-environmental schemes (AES) have been introduced in response to concerns about farmland biodiversity declines. Yet, as AES have delivered variable results, a better understanding of what determines their success or failure is urgently needed. Focusing on pollinating insects, we quantitatively reviewed how environmental factors affect the effectiveness of AES. Our results suggest that the ecological contrast in floral resources created by schemes drives the response of pollinators to AES but that this response is moderated by landscape context and farmland type, with more positive responses in croplands (vs. grasslands) located in simple (vs. cleared or complex) landscapes. These findings inform us how to promote pollinators and associated pollination services in species-poor landscapes. They do not, however, present viable strategies to mitigate loss of threatened or endangered species. This indicates that the objectives and design of AES should distinguish more clearly between biodiversity conservation and delivery of ecosystem services., (© 2013 John Wiley & Sons Ltd/CNRS.)

Biodiversity continues to decline, despite the implementation of international conservation conventions and measures. To counteract biodiversity loss, it is pivotal to know how conservation actions affect biodiversity trends. Focussing on European farmland species, we review what is known about the impact of conservation initiatives on biodiversity. We argue that the effects of conservation are a function of conservation-induced ecological contrast, agricultural land-use intensity and landscape context. We find that, to date, only a few studies have linked local conservation effects to national biodiversity trends. It is therefore unknown how the extensive European agri-environmental budget for conservation on farmland contributes to the policy objectives to halt biodiversity decline. Based on this review, we identify new research directions addressing this important knowledge gap., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Several pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-kappaB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev., Methodology/principal Findings: By applying a selection based on in vivo protein-protein interaction assays of compounds from a combinatorial chemical library followed by virtual screening, we have developed small molecules that efficiently antagonize the Ubc13-Uev1 protein-protein interaction, inhibiting the enzymatic activity of the heterodimer. In mammalian cells, they inhibit lysine 63-type polyubiquitylation of PCNA, inhibit activation of NF-kappaB by TNF-alpha and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells., Conclusions/significance: This is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications.

The zinc-coordinated protein motifs known as RING-finger domains, present on a class of ubiquitin ligases (E3's), recruit ubiquitin-conjugating enzymes (E2s), tethering them to substrate proteins for covalent modification with ubiquitin. Each RING-finger domain can recruit different E2s, and these interactions are frequently selective, in that certain RING-finger domains associate preferentially with certain E2s. This selectivity acquires particular biological relevance when the recruited E2s exert specialized functions. We have explored the determinants that specify the presence or absence of experimentally detectable interaction between two RING-finger domains, those on RNF11 and RNF103, and two E2s, UBC13, a specialized E2 that catalyzes ubiquitin chain elongation through Lys63 of ubiquitin, and UbcH7, which mediates polyubiquitylation through Lys48. Through the iterative use of computational predictive tools and experimental validations, we have found that these interactions and their selectivity are partly governed by the combinations of electrostatic interactions linking specific residues of the contact interfaces. Our analysis also predicts that the main determinants of selectivity of these interactions reside on the RING-finger domains, rather than on the E2s. The application of some of these rules of interaction selectivity has permitted us to experimentally manipulate the selectivity of interaction of the RING-finger domain-E2 pairs under study., ((c) 2008 Wiley-Liss, Inc.)

The heterodimeric ubiquitin conjugating enzyme (E2) UBC13-UEV mediates polyubiquitylation through lysine 63 of ubiquitin (K63), rather than lysine 48 (K48). This modification does not target proteins for proteasome-dependent degradation. Searching for potential regulators of this variant polyubiquitylation we have identified four proteins, namely RNF8, KIA00675, KF1, and ZNRF2, that interact with UBC13 through their RING finger domains. These domains can recruit, in addition to UBC13, other E2s that mediate canonical (K48) polyubiquitylation. None of these RING finger proteins were known previously to recruit UBC13. For one of these proteins, RNF8, we show its activity as a ubiquitin ligase that elongates chains through either K48 or K63 of ubiquitin, and its nuclear co-localization with UBC13. Thus, our screening reveals new potential regulators of non-canonical polyubiquitylation., ((c) 2005 Wiley-Liss, Inc.)