Conference and workshop on modelling global land use implications in the environmental assessment of biofuels

Background, Aims and Scope  On 4–5 June 2007, an international conference was held in Copenhagen. It provided an interdisciplinary forum where economists and geographers met with LCA experts to discuss the challenges of modelling the ultimate land use changes caused by an increased demand for biofuels. Main Features  The main feature of the conference was the cross-breeding of experience from the different approaches to land use modelling: The field of LCA could especially benefit from economic modelling in the identification of marginal crop production and the resulting expansion of the global agricultural area. Furthermore, the field of geography offers insights in the complexity behind new land cultivation and practical examples of where this is seen to occur on a regional scale. Results  Results presented at the conference showed that the magnitude and location of land use changes caused by biofuels demand depend on where the demand arises. For instance, mandatory blending in the EU will increase land use both within and outside of Europe, especially in South America. A key learning for the LCA society was that the response to a change in demand for a given crop is not presented by a single crop supplier or a single country, but rather by responses from a variety of suppliers of several different crops in several countries. Discussion  The intensification potential of current and future crop and biomass production was widely discussed. It was generally agreed that some parts of the third world hold large potentials for intensification, which are not realised due to a number of barriers resulting in so-called yield gaps. Conclusions  Modelling the global land use implications of biofuels requires an interdisciplinary approach optimally integrating economic, geographical, biophysical, social and possibly other aspects in the modelling. This interdisciplinary approach is necessary but also difficult due to different perspectives and mindsets in the different disciplines. Recommendations and Perspectives  The concept of a location dependent marginal land use composite should be introduced in LCA of biofuels and it should be acknowledged that the typical LCA assumption of linear substitution is not necessarily valid. Moreover, fertiliser restrictions/accessibility should be included in land use modelling and the relation between crop demand and intensification should be further explored. In addition, environmental impacts of land use intensification should be included in LCA, the powerful concept of land use curves should be further improved, and so should the modelling of diminishing returns in crop production.     

Use of low‐dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator‐controlled cohort study

At standard doses used for schizophrenia or bipolar disorder, quetiapine has been associated with weight gain and increased levels of triglycerides, to­tal cholesterol and low‐density lipoprotein (LDL) cholesterol, which are risk factors for cardiovascular morbidity and mortality. However, this drug is also commonly used off‐label at low doses for anxiolytic or hypnotic purposes, and its cardiovascular safety at these doses is unknown. We aimed to assess the risk of major adverse cardiovascular events with use of low‐dose quetiapine compared to use of Z‐drug hypnotics in a nationwide, active comparator‐controlled cohort study. The cohort included new users of either drugs in Denmark from 2003 to 2017, aged 18‐85 years, without history of ischemic stroke, myocardial infarction, cancer, and severe mental illness. The main outcome was the occurrence of major adverse cardiovascular events, defined as non‐fatal myocardial infarction or ischemic stroke, or death from cardiovascular causes. Selective serotonin reuptake inhibitors (SSRIs) were used as an alternative comparator in sensitivity analyses. Altogether, we compared 60,566 low‐dose quetiapine users with 454,567 Z‐drug users, followed for 890,198 person‐years in intent‐to‐treat analysis, and 330,334 person‐years in as‐treated analysis. In intention‐to‐treat analysis, low‐dose quetiapine was associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR=1.13, 95% CI: 1.02‐1.24, p=0.014) and cardiovascular death (aHR=1.26, 95% CI: 1.11‐1.43, p<0.001). In as‐treated analysis, continuous low‐dose quetiapine use was associated with increased risk of major adverse cardiovascular events (aHR=1.52, 95% CI: 1.35‐1.70, p<0.001), non‐fatal ischemic stroke (aHR=1.37, 95% CI: 1.13‐1.68, p=0.002) and cardiovascular death (aHR=1.90, 95% CI: 1.64‐2.19, p<0.001). The risk of major adverse cardiovascular events was greater in women (aHR=1.28, p=0.02) and those aged ≥65 years at initiation (aHR=1.24, p<0.001). Compared to SSRIs, low‐dose quetiapine use was associated with an increased risk of major adverse cardiovascular events (aHR=1.42, p<0.001), non‐fatal ischemic stroke (aHR=1.27, p=0.0028) and cardiovascular death (aHR=1.72, p<0.001). So, we conclude that the use of low‐dose quetiapine is associated with an increased risk of major adverse cardiovascular events, especially in women and the elderly. On the basis of these findings, we suggest that use of off‐label low‐dose quetiapine for sedative or hypnotic purposes should be discouraged.     

Soil–atmosphere exchange of N2O, CO2 and CH4 along a slope of an evergreen broad-leaved forest in southern China

At most sites the magnitude of soil-atmosphere exchange of nitrous dioxide (N₂O), carbon dioxide (CO₂) and methane (CH₄) was estimated based on a few chambers located in a limited area. Topography has been demonstrated to influence the production and consumption of these gases in temperate ecosystems, but this aspect has often been ignored in tropical areas. In this study, we investigated spatial variability of the net fluxes of these gases along a 100 m long slope of a evergreen broadleaved forest in southern China over a whole year. We expected that the lower part of slope would release more N₂O and CO₂, but take up less atmospheric CH₄ than the upper part due to different availability of water and nutrients. Our results showed that the soil moisture (Water Filled Pore Space, WFPS) decreased along the slope from bottom to top as we expected, but among the three gases only N₂O emissions followed this pattern. Annual means of WFPS ranged from 27.7% to 52.7% within the slope, and annual emissions of N₂O ranged from 2.0 to 4.4 kg N ha^?1 year^?1, respectively. These two variables were highly and positively correlated across the slope. Neither potential rates of net N mineralization and nitrification, nor N₂O emissions in the laboratory incubated soils varied with slope positions. Soil CO₂ release and CH₄ uptake appeared to be independent on slope position in this study. Our results suggested that soil water content and associated N₂O emissions are likely to be influenced by topography even in a short slope, which may need to be taken into account in field measurements and modelling.     

Ubiquitin-specific Protease 11 (USP11) Deubiquitinates Hybrid Small Ubiquitin-like Modifier (SUMO)-Ubiquitin Chains to Counteract RING Finger Protein 4 (RNF4)

Ring finger protein 4 (RNF4) is a SUMO-targeted ubiquitin E3 ligase with a pivotal function in the DNA damage response (DDR). SUMO interaction motifs (SIMs) in the N-terminal part of RNF4 tightly bind to SUMO polymers, and RNF4 can ubiquitinate these polymers in vitro. Using a proteomic approach, we identified the deubiquitinating enzyme ubiquitin-specific protease 11 (USP11), a known DDR-component, as a functional interactor of RNF4. USP11 can deubiquitinate hybrid SUMO-ubiquitin chains to counteract RNF4. SUMO-enriched nuclear bodies are stabilized by USP11, which functions downstream of RNF4 as a counterbalancing factor. In response to DNA damage induced by methyl methanesulfonate, USP11 could counteract RNF4 to inhibit the dissolution of nuclear bodies. Thus, we provide novel insight into cross-talk between ubiquitin and SUMO and uncover USP11 and RNF4 as a balanced SUMO-targeted ubiquitin ligase/protease pair with a role in the DDR.     

Inhibitor scaffold for the histone lysine demethylase KDM4C (JMJD2C)

The human histone demethylases of the KDM4 (JMJD2) family have been associated to diseases such as prostate and breast cancer, as well as X-linked mental retardation. Therefore, these enzymes are considered oncogenes and their selective inhibition might be a possible therapeutic approach to treat cancer. Here we describe a heterocyclic ring system library screened against the histone demethylase KDM4C (JMJD2C) in the search for novel inhibitory scaffolds. A 4-hydroxypyrazole scaffold was identified as an inhibitor of KDM4C; this scaffold could be employed in the further development of novel therapeutics, as well as for the elucidation of the biological roles of KDM4C on epigenetic regulation.     

Mutation of fungal endoglucanases into glycosynthases and characterization of their acceptor substrate specificity

Humicola insolens mutant Cel7B E197A is a powerful endo-glycosynthase displaying an acceptor substrate specificity restricted to β-d-glucosyl, β-d-xylosyl, β-d-mannosyl and β-d-glucosaminyl in +1 subsite. Our aim was to extend this substrate specificity to β-d-N-acetylglucosaminyl, in order to get access to a wider array of oligosaccharidic structures obtained through glycosynthase assisted synthesis. In a first approach a trisaccharide bearing a β-d-N-acetylglucosaminyl residue was docked at the +1 subsite of H. insolens Cel7B, indicating that the mutation of only one residue, His209, could lead to the expected wider acceptor specificity. Three H. insolens Cel7B glycosynthase mutants (H209A, H209G and H209A/A211T) were produced and expressed in Aspergillus oryzae. In parallel, sequence alignment investigations showed that several cellulases from family GH7 display an alanine residue instead of histidine at position 209. Amongst them, Trichoderma reesei Cel7B, an endoglucanase sharing the highest degree of sequence identity with Humicola Cel7B, was found to naturally accept a β-d-N-acetylglucosaminyl residue at +1 subsite. The T. reesei Cel7B mutant nucleophile E196A was produced and expressed in Saccharomyces cerevisiae, and its activity as glycosynthase, together with the H. insolens glycosynthase mutants, was evaluated toward various glycosidic acceptors.     

Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations

Mast cells are inflammatory cells that play key roles in health and disease. They are distributed in all tissues and appear in two main phenotypes, connective tissue and mucosal mast cells, with differing capacities to release inflammatory mediators. A metabolic profiling approach was used to obtain a more comprehensive understanding of the ability of mast cell phenotypes to produce eicosanoids and other lipid mediators. A total of 90 lipid mediators (oxylipins) were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS), representing the cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 (CYP) metabolic pathways. In vitro-derived murine mucosal-like mast cells (MLMC) and connective tissue-like mast cells (CTLMC) exhibited distinct mRNA expression patterns of enzymes involved in oxylipin biosynthesis. Oxylipins produced by 5-LO and COX pathways were the predominant species in both phenotypes, with 5-LO products constituting 90 ± 2% of the CTLMCs compared with 58 ± 8% in the MLMCs. Multivariate analyses demonstrated that CTLMCs and MLMCs secrete differing oxylipin profiles at baseline and following calcium ionophore stimulation, evidencing specificity in both a time- and biosynthetic pathway-dependent manner. In addition to the COX-regulated prostaglandin PGD₂ and 5-LO-regulated cysteinyl-leukotrienes (e.g., LTC₄), several other mediators evidenced phenotype-specificity, which may have biological implications in mast cell-mediated regulation of inflammatory responses.     

Detecting multivariate differentially expressed genes

Background  

Gene expression is governed by complex networks, and differences in expression patterns between distinct biological conditions may therefore be complex and multivariate in nature. Yet, current statistical methods for detecting differential expression merely consider the univariate difference in expression level of each gene in isolation, thus potentially neglecting many genes of biological importance.