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Budburst models have mainly been developed to capture the processes of individual trees, and vary in their complexity and plant physiological realism. We evaluated how well eleven models capture the variation in budburst of birch and Norway spruce in Germany, Austria, the United Kingdom and Finland. The comparison was based on the models performance in relation to their underlying physiological assumptions with four different calibration schemes. The models were not able to accurately simulate the timing of budburst. In general the models overestimated the temperature effect, thereby the timing of budburst was simulated too early in the United Kingdom and too late in Finland. Among the better performing models were three models based on the growing degree day concept, with or without day length or chilling, and an empirical model based on spring temperatures. These models were also the models least influenced by the calibration data. For birch the best calibration scheme was based on multiple sites in either Germany or Europe, and for Norway spruce the best scheme included multiple sites in Germany or cold years of all sites. Most model and calibration combinations indicated greater bias with higher spring temperatures, mostly simulating earlier than observed budburst.

ObjectiveTranscriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.MethodsGlobal gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset.Results5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged.ConclusionsThese data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics. Electronic supplementary material The online version of this article (doi:10.1007/s10689-014-9728-1) contains supplementary material, which is available to authorized users.

Bark necrosis and resin flows in Norway spruce have increased in southern Sweden over the last few decades. Frost damage late in spring has been suggested as a possible cause, but other factors besides the climate may have contributed to the damage. The nutrient status influences the hardening processes and plants with poor nutritional conditions have an increased sensitivity to frost. In this study the sensitivity to frost of bark and the hardiness status of needles of Norway spruce were compared with the nutrient status at two sites with different soil fertility. The trees were 30-40 years old. The hardiness status of the bark and needles was negatively affected by low concentrations of P and Mg.

Bark lesions on beech are mostly caused by frost damage and/or insect and fungal infections. Liming, treatment with wood ash and N-fertilization were hypothesised to affect this type of damage. The frost sensitivity was measured as an index of injury, calculated from electrolytic leakage of bark samples. Samples were taken from the same trees in August and November at five sites. Two sites had been limed, one treated with wood ash and two had been fertilized with nitrogen, one of them with an additional phosphorous fertilization. Trees fertilized with nitrogen had significantly more lesions than trees from other treatments. The bark was more damaged at −20°C than at −10°C in both August and November at experimental conditions. No clear pattern in temperature sensitivity was detectable among sites or treatments approximately seven years after soil treatment. Trees with bark lesions seemed to be less able to withstand low temperatures.

Decline in pH and leakage of base cations have been recorded in beech forest soils in southern Sweden. This study investigated the influence of soil properties on frost sensitivity in beech bark and evaluated the effects on frost sensitivity of soil treatment with lime, wood ash or excessive N fertilization. Beech trees on five experimental sites were studied. The results indicated that beech trees subjected to a comparatively low C/N ratio and low concentration of nutrient elements in the mineral soil layer were predisposed to a higher sensitivity to frost. Seven years after treatment, no effects of N fertilization were detectable in the soil, but positive effects of liming were recorded. There were no obvious effects of bark ash amendments, owing to large differences among blocks at the site.

The roles of the two ldh genes of Enterococcus faecalis were studied using knockout mutants. Deletion of ldh-1 causes a metabolic shift from homolactic fermentation to ethanol, formate, and acetoin production, with a high level of formate production even under aerobic conditions. Ldh-2 plays only a minor role in lactate production.

Objective: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype. Despite relatively clear clinical features, OCCCs can be difficult to distinguish morphologically from other epithelial ovarian cancers. OCCC gene expression signatures capturing not only the morphology but also the biology of this tumor subtype have been described, and a previous study using comparative genomic hybridization showed that OCCCs are indeed heterogeneous. Still, only a few genes have been analyzed using gene sequencing techniques. In the present study we aimed to further characterize OCCCs and their histotype specific genetic changes using targeted sequencing of 60 well-established cancer genes. Increased knowledge about genetic aberrations in OCCCs may help to guide future development of targeted treatments and improve the outcome for these patients. Methods: Formalin fixed, paraffin-embedded (FFPE) tumor tissue was collected from 11 primary OCCCs, diagnosed at the Skane University Hospital, Lund, Sweden (1998-2013). One sample was excluded due to poor DNA quality. For the remaining 10 samples, 600 ng genomic DNA/sample was used for single strand targeted DNA sequencing using the SureSeq™ solid tumor panel consisting of 60 key genes involved in cancer evolution, including ovarian cancer. The panel covers all coding exons in the included genes, and is validated for research use on FFPE samples. The publicly available ENSEMBL database was used to classify the mutations according to severity across the genes. Serious mutations, defined as major non-conservative amino acid changes, splice or frameshift variants or changes in stop codons, affecting single nucleotide variations (SNVs) or insertions or deletions of DNA bases (indels) were used for further analyses. The mutation call cut-off was set to 20% and the reading depth ≥300x, and unsupervised hierarchical clustering of the tumor samples was performed. Results: >99% of the target bases had a 30x coverage across all samples, and the mean target coverage was 534x. Using the 20% cut-off, approximately 300 mutations were detected in the 60 genes across the 10 tumor samples. Unsupervised hierarchical clustering revealed two distinct clusters related to mutational load. Mutations in genes previously reported to be affected in OCCCs, such as ARID1A and ERBB2, were identified. Whereas ARID1A was mainly affected in one cluster, mutations in genes signifying a highly malignant phenotype, such as BRCA1 and BRCA2 dominated in the other. Genes in signaling pathways often affected in malignant tumors, as e.g. the RAS pathway, however, were unaffected. Other mutations detected in this dataset were ZFHX3 and KMT2C. KMT2C was the only highly mutated gene across both clusters. The clustering pattern was not related to age of FFPE blocks or tumor cell content. Conclusions: In the present study we show that OCCCs are genetically heterogeneous. The variation in mutation rate is in line with a previous publication, and points to differences in tumor biology that may be important for tumor behavior and thus patient outcome. The highly mutated genes may help in guiding trials of targeted treatments; the methyl transferase gene KMT2C, also known as MLL3, may potentially be one such target. Rearrangements of this gene are well-described in acute leukemias. Interestingly, KMT2C/MLL3 is also reported to be a mutational cancer driver gene in renal clear cell carcinomas according to the TCGA. Likewise, ZFHX3 has recently been reported in endometrial clear cell carcinomas. Despite the small size of this study it points to the well-established fact that ovarian cancer is not one single disease, and also confirms that even the rare OCCCs seem to harbor different biological features which may be of potential clinical importance. Citation Format: Jenny-Maria Jönsson, Nicolai Skovbjerg Arildsen, Anna Ebbesson, Sofia Westbom-Fremer, Anna Måsbäck, Susanne Malander, Mef Nilbert, Ingrid Hedenfalk. Targeted sequencing of ovarian clear cell carcinomas reveals intertumor heterogeneity and distinct clustering related to mutational load. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B12.

A warmer climate may increase the risk of attacks by insect pests on agricultural crops, and questions on how to adapt management practice have created a need for impact models. Phenological models driven by climate data can be used for assessing the potential distribution and voltinism of different insect species, but the quality of the simulations is influenced by a range of uncertainties. In this study, we model the temperature-dependent activity and development of the Colorado potato beetle, and analyse the influence of uncertainty associated with parameterization of temperature and day length response. We found that the developmental threshold has a major impact on the simulated number of generations per year. Little is known about local adaptations and individual variations, but the use of an upper and a lower developmental threshold gave an indication on the potential variation. The day length conditions triggering diapause are known only for a few populations. We used gridded observed temperature data to estimate local adaptations, hypothesizing that cold autumns can leave a footprint in the population genetics by low survival of individuals not reaching the adult stage before winter. Our study indicated that the potential selection pressure caused by climate conditions varies between European regions. Provided that there is enough genetic variation, a local adaption at the northern distribution limit would reduce the number of unsuccessful initiations and thereby increase the potential for spreading to areas currently not infested. The simulations of the impact model were highly sensitive to biases in climate model data, i.e. systematic deviations in comparison with observed weather, highlightening the need of improved performance of regional climate models. Even a moderate temperature increase could change the voltinism of Leptinotarsa decemlineata in Europe, but knowledge on agricultural practice and strategies for countermeasures is needed to evaluate changes in risk of attacks.

Wind is the dominant agent of damage in forests in Western Europe. Traditional winddamage models calculate a probability for damage or a critical wind speed at which damage occurs. However, in a dynamic vegetation model actual damage to stands and individual trees is needed to get a dynamical progression of the vegetation. We present a prototype for a new approach to modelling forest wind damage at the regional scale, which we incorporate within a dynamic vegetation model. The approach is based on knowledge from both empirical and mechanical models and calculates the damaged fraction of a cohort based on wind load and a sensitivity that depends on the current physical state and history of the cohort in relation to the ecosystem. The modelling concept has been developed, calibrated and evaluated for Swedish conditions but can be applicable to other similar areas with minor modification. Because of the stochastic nature of local wind load and the difficulty of describing the stand-level exposure, the ability to explain observed damage at stand level was low. Regional level variation in damage, which more depends on the wind load, was however explained reasonably well (R2 = 0.43). We suggest that this is a useful concept for evaluating alternatives of forest management under different climate scenarios in the process of adaptation to future storm-damage risks.

Scientific complexity and uncertainty is a key challenge for environmental risk governance and to understand how risks are framed and communicated is of utmost importance. The Baltic Sea ecosystem is stressed and exposed to different risks like eutrophication, overfishing, and hazardous chemicals. Based on an analysis of the Swedish newspaper Dagens Nyheter, this study discusses media representations of these risks. The results show that the reporting on the Baltic Sea has been fairly stable since the beginning of the 1990s. Many articles acknowledge several risks, but eutrophication receives the most attention and is also considered the biggest threat. Authorities, experts, organizations, and politicians are the dominating actors, while citizens and industry representatives are more or less invisible. Eutrophication is not framed in terms of uncertainty concerning the risk and consequences, but rather in terms of main causes.

A constructed lactate dehydrogenase (LDH)-negative mutant of Enterococcus faecalis V583 grows at the same rate as the wild type but ferments glucose to ethanol, formate, and acetoin. Microarray analysis showed that LDH deficiency had profound transcriptional effects: 43 genes in the mutant were found to be upregulated, and 45 were found to be downregulated. Most of the upregulated genes encode enzymes of energy metabolism or transport. By two-dimensional (2D) gel analysis, 45 differentially expressed proteins were identified. A comparison of transcriptomic and proteomic data suggested that for several proteins the level of expression is regulated beyond the level of transcription. Pyruvate catabolic genes, including the truncated ldh gene, showed highly increased transcription in the mutant. These genes, along with a number of other differentially expressed genes, are preceded by sequences with homology to binding sites for the global redox-sensing repressor, Rex, of Staphylococcus aureus . The data indicate that the genes are transcriptionally regulated by the NADH/NAD ratio and that this ratio plays an important role in the regulatory network controlling energy metabolism in E. faecalis .

Comparative study of user generated content on Swedish and UK online newspaper sites

In this study, we quantify the effect of uncertainties in climate projections on an impact model (IPS) that describes the temperature-dependent swarming and development of Ips typographus . Three forcing climate data sets (ensembles) were used: (1) E-Obs gridded observations, (2) ERA-40 reanalysis data downscaled by eight regional climate models (RCMs) and (3) regional scenarios from one RCM forced by seven GCM simulations representing SRES-A1B, for the period of 1961–2097. The IPS_RCM_ERA40 ensemble members, including IPS_RC3_ERA40 , were generally within the IPS_E-Obs confidence limits. The IPS model is however sensitive to the warming during spring and cooling during autumn, and deviations in simulated swarming were related to known climate model biases. The variation between the IPS_RCA3_GCM ensemble members was particularly high in regions where warmer summers (temperature increase from +2 °C to +4 °C) will induce an additional generation per year, for example a shift from one to two generations per year in south Scandinavia, and an increased frequency of three generations per year in central Europe. Impact assessments based on an ensemble of climate data gives more robust decision support than a single climate model approach because it allows a probabilistic assessment of the geographical areas experiencing a transition in biological response.

International audience; Natural disturbances play a key role in ecosystem dynamics and are important factors for sustainable forest ecosystem management. Quantitative models are frequently employed to tackle the complexities associated with disturbance processes. Here we review the wide variety of approaches to modelling natural disturbances in forest ecosystems, addressing the full spectrum of disturbance modelling from single events to integrated disturbance regimes. We applied a general, process-based framework founded in disturbance ecology to analyze modelling approaches for drought, wind, forest fires, insect pests and ungulate browsing. Modelling approaches were reviewed by disturbance agent and mechanism, and a set of general disturbance modelling concepts was deduced. We found that although the number of disturbance modelling approaches emerging over the last 15 years has increased strongly, statistical concepts for descriptive modelling are still largely prevalent over mechanistic concepts for explanatory and predictive applications. Yet, considering the increasing importance of disturbances for forest dynamics and ecosystem stewardship under anthropogenic climate change, the latter concepts are crucial tool for understanding and coping with change in forest ecosystems. Current challenges for disturbance modelling in forest ecosystems are thus (i) to overcome remaining limits in process understanding, (ii) to further a mechanistic foundation in disturbance modelling, (iii) to integrate multiple disturbance processes in dynamic ecosystem models for decision support in forest management, and (iv) to bring together scaling capabilities across several levels of organization with a representation of system complexity that captures the emergent behaviour of disturbance regimes.

Background The intake of dietary fibre has been shown to reduce the risk of developing diabetes mellitus. The aim of this study was to compare the effects of commercial rye whole-meal bread containing whole kernels and white wheat bread on the rate of gastric emptying and postprandial glucose response in healthy subjects. Methods Ten healthy subjects took part in a blinded crossover trial. Blood glucose level and gastric emptying rate (GER) were determined after the ingestion of 150 g white wheat bread or 150 g whole-meal rye bread on two different occasions after fasting overnight. The GER was measured using real-time ultrasonography, and was calculated as the percentage change in antral cross-sectional area 15 and 90 minutes after completing the meal. Results No statistically significant difference was found between the GER values or the blood glucose levels following the two meals when evaluated with the Wilcoxon signed rank sum test. Conclusion The present study revealed no difference in postprandial blood glucose response or gastric emptying after the ingestion of rye whole-meal bread compared with white wheat bread. Trial registration NCT00779298

Ecosystems on land, whether in a comparatively natural state or artificially constructed and managed, are a fundamental part of the environment in which most humans live. They also provide or help to control a variety of resources and intangible values vital to the health and economic conditions of human society (e.g. Costanza et al. 1997). These so-called ecosystem services, which are particularly important in a relatively populous region such as that of the Baltic Sea Basin, include the provision of food, fibre and wood products. Ecosystems also contribute to controlling water supplies, air and water quality, and conditions for the maintenance of biodiversity. Through their part in the Earth’s carbon, water and energy cycles they may ameliorate — or exacerbate — climate change.

Background and aims: Influence of sex hormones in ovarian cancer is of great interest, but study results are inconclusive. A majority of all ovarian cancers display high expression of sex hormone receptors, but the effect of endocrine treatment is limited. We assessed estrogen (ER) α and β, progesterone (PR), and androgen (AR) receptor expression in an ovarian cancer cohort in order to study the potential correlation between receptor expression and disease free survival. Expression of the genes encoding the respective receptors (ESR1, ESR2, PGR and AR), was further explored in molecular ovarian cancer subtypes. Methods: 140 ovarian cancers were collected in Sweden 1998-2000. A majority of the tumors were serous, high-grade and advanced stage. Immunohistochemical stainings for the receptors were evaluated on a tissue microarray, and dichotomized as either negative (10% stained cells). The 5-year disease free survival (DFS) was estimated and Cox regression was used for multivariable modelling. ESR1, ESR2, PGR and AR were analyzed using an independent dataset (n = 285 tumors). Progression free (PFS) and overall survival (OS) for high versus low gene expression was analyzed in the six molecular ovarian cancer subtypes, using the median as cut-off. Results: Immunohistochemical expression of PR and AR were both associated with increased 5-year DFS (p Gene expression analyses revealed higher mRNA levels of PGR in the molecular subtypes constituted of borderline and endometrioid tumors respectively (p Conclusions: This study indicates that PR and AR may serve as independent prognostic markers in subsets of ovarian cancer, with the best 5-year disease free survival seen with combined PR/AR positivity. Gene expression analysis of the corresponding genes revealed differences among the subtypes of ovarian cancer. This underlines the importance of stratifying tumors also based on molecular features when investigating prognostic markers. Larger, well defined study cohorts are needed to identify the best markers and to elucidate in which specific subtypes of ovarian cancer endocrine treatment may have a role. Citation Format: Jenny-Maria Jönsson, Nicolai Arildsen, Susanne Malander, Anna Måsbäck, Linda Werner Hartman, Mef Nilbert, Ingrid Hedenfalk. Sex hormone receptor expression affects ovarian cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1834. doi:10.1158/1538-7445.AM2015-1834

International audience; The sensitivity to frost in the living inner bark of trees have been hypothesised to be influenced by acid rain and N deposition through changes in nutrient balance and carbon metabolism. At the Skogaby experimental site, situated in southern Sweden, Norway spruce in control plots, plots fertilized with ammonium sulphate and plots fertilized with mineral nutrients except N were compared in this respect. Frost sensitivity was measured by electrolytic leakage and expressed as an index of injury. The results showed increased sensitivity to frost in the bark of trees treated with continuous applications of ammonium sulphate for 11 years. This was probably not only a direct effect of high nitrogen availability, but also caused by insufficient levels of other nutrients due to the rapid growth and changes in soil chemistry induced by the addition of ammonium sulphate. Mainly Mg and K seemed to be of importance for retaining a good frost resistance, supporting the hypothesis that nutrient imbalances increases the risk for development of frost related bark lesions in southern Sweden.; Effets d'un excès d'azote sur la sensibilité au froid de l'écorce interne de l'Epicéa. On a émis l'hypothèse selon laquelle la sensibilité au froid de la partie vivante interne de l'écorce des arbres serait influencée par les pluies acides et les dégâts azotés, par suite de changements de l'équilibre d'azote et du métabolisme du carbone. À la station expérimentale de Skogaby, située en Suède méridionale, on a comparé le comportement, sous cet angle, de l'épicéa dans un dispositif comportant des parcelles fertilisées avec divers nutrients à l'exclusion d'azote, ainsi que des parcelles témoins. La sensibilité au froid a été évaluée par des mesures de conductivité électrolitique, et exprimée par un indice de l'importance des dommages observés. Les résultats montrent une sensibilité accrue au froid de l'écorce des arbres traités d'une manière continue pendant 11 ans avec du sulfate d'ammoniac. Cela est probablement dû, non seulement à l'effet direct d'une importante disponibilité en azote, mais aussi à un niveau insuffisant de celle des autres nutrients, cela résultant d'une croissance plus rapide ainsi que de modifications des équilibres chimiques du sol induits par l'apport du sulfate d'ammoniac. Le rôle de Mg et K semble particulièrement important pour assurer une bonne résistance au froid, ce qui appuie l'hypothèse selon laquelle des déséquilibres entre nutrients augmentent le risque de lésions de l'écorce dans le sud de la Suède.

Light (LM) and transmission electron (TEM) microscopy were used to study previously specified ozone symptoms in the foliage of Norway spruce. The three youngest green needle generations from twenty mature trees in two stands on sites of different soil fertility at Asa, southern Sweden, were sampled in 1999. The critical dose of ozone, expressed as AOT40, was 6,362 ppb.h. LM showed ozone-specific symptoms: decreased chloroplast size with electron dense stroma advancing gradually from the outer to the inner cell layers, being most severe in the needle side facing the sky. The symptoms were expressed as ozone syndrome indices at the needle generation, tree and stand levels. The index had higher values at the low fertility site. TEM was used to confirm the LM results. The study shows that LM can be used for diagnosis of the impact of ozone on conifers in the field.

A sensitive, accurate, and straightforward way to determine basal and induced ethoxyresorufin O-deethylase (EROD) activities in gill filaments, using rainbow trout as model species, is described. Tip pieces of primary gill filaments were incubated in tissue culture plate wells containing HEPES-Cortland buffer supplemented with 7-ethoxyresorufin. Each well was sampled on two occasions, and resorufin concentrations were determined by measuring the fluorescence with a plate reader. EROD activity was calculated from the difference in resorufin concentration and the interval between the two samplings. EROD activity was found to be significantly induced by 6 h of exposure to waterborne beta-naphthoflavone (1 microM). EROD in gills was also induced by caging rainbow trout in a polluted river or by laboratory exposure of fish to water extracted from that river. There was no loss of EROD activity when gill tissue was kept in ice-cold buffer for up to 1 d, which promotes the use of the method for studying fish exposed in the wild. We propose this novel method as a way to monitor dioxin-like compounds in aquatic environments.

Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity, and inhibits platelet aggregation and is thus used in the treatment of peripheral vascular disease. It is transformed into at least seven phase I metabolites, of which two, M1 and M5, are active. The reduction of the keto group of pentoxifylline to a secondary alcohol in M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiral center. The aims of this study were: to develop HPLC methods to separate the enantiomers of M1, to investigate the kinetics of the reversible biotransformation of pentoxifylline to (R)- and (S)-M1 in hemolysed erythrocyte suspension, and to quantify the formation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oral administration of pentoxifylline to human volunteers. (R)- and (S)-M1 could be separated preparatively on a cellobiohydrolase column, while determination in blood or plasma was by HPLC after chiral derivatization with diacetyl-L-tartaric acid anhydride. The metabolism of pentoxifylline to (R)-M1 in suspensions of hemolysed erythrocytes followed simple Michaelis-Menten kinetics (K(m) = 11 mM), while that to (S)-M1 was best described by a two-enzyme model (K(m) = 1.1 and 132 mM). Studies with inhibitors indicated that the enzymes were of the carbonyl reductase type. At a therapeutic blood concentration of pentoxifylline, the calculated rate of formation of (S)-M1 is 15 times higher than that of the (R)-enantiomer. Back-conversion of M1 to pentoxifylline was 3-4 times faster for the (S)- than for the (R)-enantiomer. In vivo, the R:S plasma concentration ratio of M1 ranged from 0.010-0.025 after intravenous infusion of 300 or 600 mg of pentoxifylline, and from 0.019-0.037 after oral administration of 600 mg. The biotransformation of pentoxifylline to M1 was thus highly stereoselective in favor of the (S)-enantiomer both in vitro and in vivo.

Modern society is confronted with the grand challenge of coping with complex socio-environmental risks such as human-induced climate change and hazardous chemicals, typically characterized by scientific uncertainty, socio-political controversy, and ambiguity. This is true not least for the marine environment and for the Baltic Sea, one of the most polluted marine ecosystems in the world. This complexity may relate to multifaceted and uncertain sources and ecosystem responses, ambiguous and controversial scientific advice, or multi-level and multi-actor interactions and communication barriers. All in all, this challenges conventional risk assessment, risk management, and risk communication. Evidently, new strategies for coping with complexity seem to be a key prerequisite for sustainable governance of socio-ecological systems. The aim of this special issue is to describe and analyze the governance of complex socio-environmental risks with a focus on the Baltic Sea. Like the topic of interest, our approach is heterogeneous. The variability in topics and methodology of the individual articles are motivated by two underlying assumptions. First, we are convinced that methodologically pluralistic as well as inter- and trans-disciplinary approaches are required. This is linked to our second assumption that there are more profound differences between various risks than the conventional parameters (probability and harm) suggest, for example, the type and magnitude of impact, the degree of reversibility, and the form of complexity. Going back to Greek mythology, this can be exemplified with the risk and complexity connected with two well-known artifacts, the Sword of Damocles and Pandora’s Box. Clearly, the possible negative outcomes are quite extreme in both cases, but whereas Damocles’ dilemma can be relatively well captured by conventional risk assessment and management, the irreversibility in the case of Pandora’s Box requires new forms of analysis and governance, for example a precautionary approach. Although simplified, these cases are illustrative metaphors for two socio-environmental risks in the Baltic Sea, namely large-scale accidental oil spills and invasion of exotic species, respectively. Our point here is that governance of complex socio-environmental risk is context dependent and might require quite different approaches for various types of risks. The distinction between governing and governance may seem unproblematic, where the former primarily comprises command and control mechanisms and the latter a wide spectrum of actors influencing eventual outcomes. However, this distinction is quite complex, as leadership by governments may be required in order to structure participatory processes. For example, governmental organizations play leading roles in regulating marine transport and coordinating adaptation to climate change. Participatory processes and stakeholder involvement are on the other hand shown important for at least two reasons. First, knowledge not considered by science may fruitfully be brought into decision-making processes, as seen for example for time and place-bound fishermen’s knowledge on sizes and fluctuations of local fish stocks. Second, stakeholder participation in management processes may improve implementation by increasing legitimacy particularly when managing ambiguous risks. Risk management has traditionally been almost exclusively based on risk assessment in combination with economic implications. It is shown in this special issue that the relation between scientific knowledge and political decision-making is more complex than commonly thought. Ambiguity may be caused not only by stochastic components and knowledge gaps, but also by individual, social and contextual factors. It is clear that societies’ responses to various threats to the environment and to human health are not only based on tangible data on probabilities and level of harm, but also on how the risks are framed and communicated, how they relate to social and cultural norms and how the risks and effects are distributed among different groups of people. For example, risks related to consumption of fatty fish from the Baltic Sea with high concentrations of hazardous chemicals have to be balanced against positive health effect from eating fish and subjective values stemming from consumption of traditional food. In a rather different context, macro factors such as level of economic development and individual socio-economic status is shown to affect risk perceptions, and fertility rates in Russia seem to have been substantially affected by changes in how individuals have assessed future risks related to socio-economic conditions after the collapse of the Soviet Union. Complex risks and problems require a more sophisticated iterative approach to risk assessment and risk management than what traditional expert-driven approaches, often set out in policies, offer. This should naturally not be interpreted as an argument against science-based management. Science is central, but often needs to be complemented by academic perspectives from social sciences as well as the humanities. Furthermore, under scientific ignorance, science-based management fails and precautionary strategies, guiding the understanding of uncertainty, offer important complements. Likewise, aspects related to stakeholder participation, communication and increased involvement of civil society, and other concerned representatives all need to be addressed in many cases. We think that the improvement of risk governance in the Baltic Sea region requires moving from holistic perspectives and the formulation of an ecosystem-based approach in theory, to actual implementation in practice. There is a need to identify environmental risks, define appropriate levels of stakeholder involvement, assess needs for local knowledge, identify key actors and their respective interests, evaluate socio-economic impact and normative implications in particular problem areas in order to improve sector integration, and build a basis for a holistic, and often precautionary, ecosystem-based management approach.

International audience; Concentration of nutrients and balance between nutrients in trees can affect tree vitality, and are dependent on soil conditions and atmospheric deposition. The aim of this investigation was to survey the concentration of nutrients in beech bark and to look for relationships with the frost sensitivity of the bark. Beech trees with bark lesions were compared to undamaged beech trees on five experimental sites with control plots, plots treated with nitrogen, ash or lime. Trees treated with lime had increased Ca/Al ratio and decreased concentrations of Mn and B. Negative influence from N fertilization could be traced in the concentration of nutrients in the bark seven years after treatment, but the absence of new lesions indicated that the vigour of the trees has increased. The frost sensitivity was correlated to the nutrient content. Trees with lesions had higher concentrations of N and Al, indicating influence of soil acidity.; Influence de la composition en éléments minéraux de l'écorce en relation avec les traitements chimiques apportés au sol sur la sensibilité au froid du hêtre dans le sud de la Suède. La concentration et l'équilibre des éléments minéraux dans les arbres peut affecter leur vitalité et sont dépendants des conditions de sol et des dépôts atmosphériques. Le but de ce travail a été d'étudier la concentration des éléments minéraux dans l'écorce du hêtre et d'essayer de mettre en évidence des relations avec la sensibilité au froid des écorces. Les arbres avec des lésions au niveau de l'écorce étaient comparés avec des arbres indemnes dans cinq sites expérimentaux comprenant des placettes témoins et des placettes traitées avec apport d'azote, de cendres ou de chaux. Les arbres traités avec apport de chaux ont vu un accroissement du rapport Ca/Al et une décroissance de la concentration en manganèse et en bore. Une influence négative de la fertilisation azotée peut être retrouvée sur la concentration en éléments minéraux de l'écorce sept ans après le traitement. Mais l'absence de nouvelles lésions indique que la vigueur des arbres a été accrue. La sensibilité au froid a été correlée avec la teneur en éléments minéraux. Les arbres avec des lésions ont présenté une plus grande concentration en azote et en Al reflétant l'influence de l'acidité du sol.

Background: Ovarian cancers linked to Lynch syndrome represent a rare subset that typically present at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We aimed to identify molecular profiles of Lynch syndrome-associated ovarian cancer for application in refined diagnostics and targeted therapeutics. Methods: Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation (WG-DASL) was applied to 48 histopathologically matched ovarian cancers, which represented Lynch syndrome-associated tumors and sporadic tumors. The results were validated by application of an external ovarian cancer data set and by immunohistochemistry. Results: Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, predominantly involved in the mTOR and MAPK/ERK signaling pathways. Conclusion: The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to different tumorigenic routes and suggest that targets within the mTOR and MAPK/ERK signaling pathways may be relevant to consider for molecular diagnostics and targeted therapeutics. Citation Format: Jenny-Maria Jönsson, Katarina Bartuma, Mev Dominguez Valentin, Katja Harbst, Zoreh Ketabi, Susanne Malander, Mats Jönsson, Ana Carneiro, Anna Måsbäck, Göran Jönsson, Mef Nilbert. Distinct gene expression profiles in Lynch syndrome-associated ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A15.

Aim: Epithelial ovarian cancer is one of the most lethal female cancers. It is a heterogeneous group of neoplasms and the different histologic subtypes are thought to constitute separate disease entities. Efforts have been made to characterize ovarian cancers further and molecular subgroups that correlate to clinical features have been reported, but are still not in clinical use (Tothill et al., Clin Cancer Res, 2008). The subgroups, called C1-C6, represent serous and endometrioid ovarian tumors with the C1-C2 and C4-C5 subgroups characterizing high-grade serous tumors and correlated to a worse prognosis. The C3 and C6 subtypes represent borderline and low-grade tumors and show a favorable prognosis. We aimed to further outline and refine the genetic differences between malignant, benign and borderline ovarian tumors and to investigate similarities between ovarian cancer and the well described intrinsic subtypes of breast cancer (Perou et al., Nature, 2000). Materials and methods: Global gene expression profiling (Illumina HT-12 bead arrays) was applied to 72 fresh-frozen serous ovarian tumors (37 adenocarcinomas, 17 adenomas, 5 borderline tumors,13 biological replicates) collected in the ovarian tumor tissue biobank at Skane University Hospital, Sweden (2004-2011). We performed nearest centroid classification of our tumors for the molecular subtypes of ovarian cancer (“C-signatures”) as well as for the intrinsic subgroups of breast cancer (luminal A, luminal B, basal-like, normal-like, and HER2) using the genes from Hu et al. (BMC Genomics, 2006). The results were validated by performing nearest centroid classification of the intrinsic breast cancer subtypes and the C-signatures on the ovarian tumors in the Tothill cohort as well. Results: Our malignant tumors correlated significantly to the basal-like breast cancer subtype (p Conclusion: Both epithelial ovarian cancers and breast cancers are heterogeneous diseases, nevertheless they share many similarities such as hormonal influence and varying long-term prognosis. Our novel findings support a link between previously reported molecular subtypes in ovarian cancer and the well-established intrinsic subtypes of breast cancer, which could potentially be of use for further investigations of biomarkers in ovarian cancer and new thinking regarding the use of chemotherapeutic agents as well as targeted treatments. Citation Format: Jenny-Maria Jönsson, Mev Dominguez-Valentin, Ida Johansson, Siker Kimbung, Mats Jönsson, Anna Måsbäck, Susanne Malander, Mef Nilbert. Molecular subtyping of epithelial ovarian cancer reveals connections to intrinsic breast cancer subtypes. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B8.

The increase in height and weight and the age at the menarche have been determined in girls with idiopathic scoliosis and in age-matched normal girls. The scoliotic girls were classified according to the position of the curve. The menarche was found to occur significantly later in girls with either a thoracolumbar or a double primary curve than in the control group; it was also significantly later in those two groups combined than in the girls with a right convex thoracic curve. At the time of the menarche, the girls with a thoracolumbar or a double primary curve were significantly taller than those in the control group. The girls with a double primary curve, and these together with girls with a thoracolumbar curve, were also significantly taller than those with a right convex thoracic curve. Those in the control group were significantly heavier, and in some age groups significantly taller, than children born during the period 1953-1958 and providing earlier Swedish research data. The average age at the menarche did not differ from that for a normal population for this country. The observed differences between the group with a right convex thoracic curve and that with a thoracolumbar or a double primary curve indicate that the pathomechanism, and even the etiology, may vary with the form of idiopathic scoliosis.

Mammary asymmetry was estimated visually by different investigators in three series of scoliotic girls and in three control groups. The breasts of each girl were classified as being equal in size or as being obviously different in size, note being made of which breast was the larger. Breast asymmetry was significantly more common among the scoliotic than the normal girls. Moreover, the left breast was significantly more often larger in the scoliotic series of girls. On the other hand, there was no significant difference in the frequency of breast asymmetry in respect of the classifications according to curve type (right convex thoracic vs. other types) and to Cobb angle (35 degrees or less vs. more than 35 degrees).

Departing from previous theoretical and empirical studies on sustainable supply-chain management, we investigate organizational commitment (drivers and motivations) and capabilities (resources, str ...

The annual growth cycle of boreal trees is synchronized with seasonal changes in photoperiod and temperature. A warmer climate can lead to an earlier bud burst and increased risk of frost damage caused by temperature backlashes. In this study we analysed site- and provenance specific responses to interannual variation in temperature, using data from 18 Swedish and East-European provenances of Norway spruce (Picea abies), grown in three different sites in southern Sweden. The temperature sum requirements for bud burst, estimated from the provenance trials, were correlated with the provenance specific place of origin, in terms of latitudinal and longitudinal gradients. Frost damage had a significant effect on tree height development. Earlier timing of bud burst was linked to a higher risk of frost damage, with one of the sites being more prone to spring frost than the other two. The estimated provenance specific temperature sum requirements for bud burst were used to parametrize a temperature sum model of bud burst timing, which was then used together with the ensemble of gridded climate model data (RCP8.5) to assess the climate change impact on bud burst and associated risk of frost damage. In this respect, the simulated timing of bud burst and occurrence of frost events for the periods 2021–2050 and 2071–2100 were compared with 1989–2018. In response to a warmer climate, the total number of frost events in southern Sweden will decrease, while the number of frost events after bud burst will increase due to earlier bud burst timing. The provenance specific assessments of frost risk under climate change can be used for a selection of seed sources in Swedish forestry. In terms of selecting suitable provenances, knowledge on local climate conditions is of importance, as the gridded climate data may differ from local temperature conditions. A comparison with temperature logger data from ten different sites indicated that the gridded temperature data were a good proxy for the daily mean temperatures, but the gridded daily minimum temperatures tended to underestimate the local risk of frost events, in particular at the measurements 0.5 m above ground representing the height of newly established seedlings.