Comparison of different normalised LCIA results and their feasibility in communication

Purpose

The purpose of this study was to answer the following three questions: (1) What are the reference values of normalisation for Finnish production and Finnish consumption and how do they differ from the European reference values?, (2) How do these differences influence the interpretation of normalised LCIA results?, and (3) How can normalised LCIA results be made more comprehensible to non-LCA experts with the help of communication material?

Methods

Finnish reference values for normalisation were calculated on the basis of the Finnish environmentally extended input–output model and ReCiPe LCIA method. The influence of different normalised results on the interpretation of LCIA was assessed based on an LCA study of print products. LCA communication material (product-specific fact sheets) was developed by organising workshops and interviews with stakeholders in the paper and printing industry.

Results and discussion

A comparison of the production based Finnish reference values to the European reference values shows that Finland contributes roughly 1 % to the European values in all impact categories except in the fossil depletion category where the contribution is 3 %. The order of magnitude of the impact categories varies depending on the reference system used for normalisation, which influences the interpretation of LCIA results. The normalised results were made more comprehensible by developing fact sheets including background information and guidance for interpretation of the LCIA results.

Conclusions

The interpreter of normalised LCIA results does not usually have the information to estimate how the chosen reference system influences the results. A sensitivity analysis with different reference values may help to highlight this effect. When communicating to non-LCA-practitioners, LCIA results need to be connected to a wider context, which can be achieved by using normalisation to give an idea of the order of magnitude of the results. However, the harmfulness of the impact categories in relation to each other cannot be judged on the basis of the normalised results, which seems to be a difficult concept for non-LCA-practitioners to understand.     

Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor

Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.     

Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results.     

Regulatory subunit B'gamma of protein phosphatase 2A prevents unnecessary defense reactions under low light in Arabidopsis

Light is an important environmental factor that modulates acclimation strategies and defense responses in plants. We explored the functional role of the regulatory subunit B'γ (B'γ) of protein phosphatase 2A (PP2A) in light-dependent stress responses of Arabidopsis (Arabidopsis thaliana). The predominant form of PP2A consists of catalytic subunit C, scaffold subunit A, and highly variable regulatory subunit B, which determines the substrate specificity of PP2A holoenzymes. Mutant leaves of knockdown pp2a-b'γ plants show disintegration of chloroplasts and premature yellowing conditionally under moderate light intensity. The cell-death phenotype is accompanied by the accumulation of hydrogen peroxide through a pathway that requires CONSTITUTIVE EXPRESSION OF PR GENES5 (CPR5). Moreover, the pp2a-b'γ cpr5 double mutant additionally displays growth suppression and malformed trichomes. Similar to cpr5, the pp2a-b'γ mutant shows constitutive activation of both salicylic acid- and jasmonic acid-dependent defense pathways. In contrast to cpr5, however, pp2a-b'γ leaves do not contain increased levels of salicylic acid or jasmonic acid. Rather, the constitutive defense response associates with hypomethylation of DNA and increased levels of methionine-salvage pathway components in pp2a-b'γ leaves. We suggest that the specific B'γ subunit of PP2A is functionally connected to CPR5 and operates in the basal repression of defense responses under low irradiance.     

Indirect modulation of the intracellular c-Di-GMP level in Shewanella oneidensis MR-1 by MxdA

The GGDEF domain protein MxdA, which is important for biofilm formation in Shewanella oneidensis MR-1, was hypothesized to possess diguanylate cyclase activity. Here, we demonstrate that while MxdA controls the cellular level of c-di-GMP in S. oneidensis, it modulates the c-di-GMP pool indirectly.     

The α-glucuronidase Agu1 from <Emphasis Type="Italic">Schizophyllum commune</Emphasis> is a member of a novel glycoside hydrolase family (GH115)

Schizophyllum commune produces an α-glucuronidase that is active on polymeric xylan, while the ascomycete α-glucuronidases are only active on xylan oligomers. In this study, we have identified the gene (agu1) encoding this enzyme and confirmed the functionality by overexpression of the gene in S. commune and degradation of aldopentauronic acids, (MeGlcA)³-Xyl₄, in the cultivation medium of the transformants. Expression analysis demonstrated that agu1 is not co-regulated with the predominant xylanase-encoding gene (xynA) of S. commune. The detailed sequence analysis of Agu1 demonstrated that this gene belongs to a novel glycoside hydrolase family (GH115) that also contains candidate genes from ascomycete fungi and bacteria. Phylogenetic analysis showed that the fungal GH115 α-glucuronidases are distinctly separate from the prokaryotic clade and distributed over three branches. The identification of putative genes encoding this enzyme in industrial fungi, such as Aspergillus oryzae and Hypocrea jecorina, will provide a starting point for further analysis of the importance of this enzyme for the hydrolysis of plant biomass.     

Association of Serum 25-Hydroxyvitamin D with Lifestyle Factors and Metabolic and Cardiovascular Disease Markers: Population-Based Cross-Sectional Study (FIN-D2D)

Objectives

Low serum 25-hydroxyvitamin D (25OHD) level has been associated with an increased risk of several chronic diseases. Our aim was to determine lifestyle and clinical factors that are associated with 25OHD level and to investigate connection of 25OHD level with metabolic and cardiovascular disease markers.

Design

In total, 2868 Finnish men and women aged 45–74 years participated in FIN-D2D population-based health survey in 2007. Participants that had a serum sample available (98.4%; n = 2822) were included in this study. 25OHD was measured with chemiluminescent microparticle immunoassay method.

Results

The mean 25OHD level was 58.2 nmol/l in men (n = 1348) and 57.1 nmol/l in women (n = 1474). Mean 25OHD level was lower in the younger age groups than in the older ones (p<0.0001 both in men and women). This study confirmed that low physical activity (p<0.0001 both in men and women), smoking (p = 0.0002 in men and p = 0.03 in women) and high BMI (p<0.0001 in women) are factors that independently associate with low 25OHD level. Of the metabolic and cardiovascular disease markers high triglyceride concentration (p = 0.02 in men and p = 0.001 in women) and high apolipoprotein B/apolipoprotein A1 ratio (p = 0.04 in men and p = 0.03 in women) were independently associated with low 25OHD level.

Conclusions

Higher age did not predict lower 25OHD level in this study population of aged 45–74 years which may derive from a healthy life-style of “active pensioners”. Low physical activity and smoking came up as independent lifestyle factors associated with low 25OHD level. Defining the molecular mechanisms behind the associations of 25OHD with low physical activity and smoking are important objective in future studies. The association of 25OHD with BMI, high triglyceride concentration and apolipoprotein B/apolipoprotein A1 ratio may be related to the role of vitamin D in inflammation, but more detailed studies are needed.     

Comparison of solution-based exome capture methods for next generation sequencing

Background

Techniques enabling targeted re-sequencing of the protein coding sequences of the human genome on next generation sequencing instruments are of great interest. We conducted a systematic comparison of the solution-based exome capture kits provided by Agilent and Roche NimbleGen. A control DNA sample was captured with all four capture methods and prepared for Illumina GAII sequencing. Sequence data from additional samples prepared with the same protocols were also used in the comparison.

Results

We developed a bioinformatics pipeline for quality control, short read alignment, variant identification and annotation of the sequence data. In our analysis, a larger percentage of the high quality reads from the NimbleGen captures than from the Agilent captures aligned to the capture target regions. High GC content of the target sequence was associated with poor capture success in all exome enrichment methods. Comparison of mean allele balances for heterozygous variants indicated a tendency to have more reference bases than variant bases in the heterozygous variant positions within the target regions in all methods. There was virtually no difference in the genotype concordance compared to genotypes derived from SNP arrays. A minimum of 11× coverage was required to make a heterozygote genotype call with 99% accuracy when compared to common SNPs on genome-wide association arrays.

Conclusions

Libraries captured with NimbleGen kits aligned more accurately to the target regions. The updated NimbleGen kit most efficiently covered the exome with a minimum coverage of 20×, yet none of the kits captured all the Consensus Coding Sequence annotated exons.     

Genetic association for renal traits among participants of African ancestry reveals new loci for renal function

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m²), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10⁻⁷) and FNDC1 (p-value = 3.0×10⁻⁷) for UACR, and KCNQ1 with eGFR (p = 3.6×10⁻⁶). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.     

Dementia and oral health among subjects aged 75 years or older

doi: 10.1111/j.1741‐2358.2010.00396.x Dementia and oral health among subjects aged 75 years or older Objective: To study the association between diagnosed dementia and oral health, focusing on the type of dementia, among an elderly population aged 75 years or older. Background: Elderly people with dementia are at risk from oral diseases, but to date, only a few studies have analysed the association between type of dementia and oral health, and their results are inconclusive. Materials and methods: This cross‐sectional study is based on the Geriatric multi‐disciplinary strategy (Gems) study that included 76 demented and 278 non‐demented subjects. The data were collected by means of an interview and an oral clinical examination. The type of dementia was diagnosed according to DSM‐IV criteria. Poisson’s and logistic regression models were used to determine relative risks (RR), odds ratios (OR) and 95% confidence limits (CI). Results: Our results showed that patients with Alzheimer’s disease and those with other types of dementia had an increased likelihood of having carious teeth, teeth with deep periodontal pockets, and poor oral and denture hygiene, compared with non‐demented persons. The results showed that the type of dementia does not seem to be an essential determinant of oral health. Conclusions: Among the elderly aged 75 years or older, patients with Alzheimer’s disease or other types of dementia are at increased risk of poor oral health and poor oral hygiene.