Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10$^{−27and−30}$). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research

A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction

BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI

C-Peptide Increases Na,K-ATPase Expression via PKC- and MAP Kinase-Dependent Activation of Transcription Factor ZEB in Human Renal Tubular Cells

Replacement of proinsulin C-peptide in type 1 diabetes ameliorates nerve and kidney dysfunction, conditions which are associated with a decrease in Na,K-ATPase activity. We determined the molecular mechanism by which long term exposure to C-peptide stimulates Na,K-ATPase expression and activity in primary human renal tubular cells (HRTC) in control and hyperglycemic conditions.HRTC were cultured from the outer cortex obtained from patients undergoing elective nephrectomy. Ouabain-sensitive rubidium ((86)Rb(+)) uptake and Na,K-ATPase activity were determined. Abundance of Na,K-ATPase was determined by Western blotting in intact cells or isolated basolateral membranes (BLM). DNA binding activity was determined by electrical mobility shift assay (EMSA). Culturing of HRTCs for 5 days with 1 nM, but not 10 nM of human C-peptide leads to increase in Na,K-ATPase α(1)-subunit protein expression, accompanied with increase in (86)Rb(+) uptake, both in normal- and hyperglycemic conditions. Na,K-ATPase α(1)-subunit expression and Na,K-ATPase activity were reduced in BLM isolated from cells cultured in presence of high glucose. Exposure to1 nM, but not 10 nM of C-peptide increased PKCε phosphorylation as well as phosphorylation and abundance of nuclear ERK1/2 regardless of glucose concentration. Exposure to 1 nM of C-peptide increased DNA binding activity of transcription factor ZEB (AREB6), concomitant with Na,K-ATPase α(1)-subunit mRNA expression. Effects of 1 nM C-peptide on Na,K-ATPase α(1)-subunit expression and/or ZEB DNA binding activity in HRTC were abolished by incubation with PKC or MEK1/2 inhibitors and ZEB siRNA silencing.Despite activation of ERK1/2 and PKC by hyperglycemia, a distinct pool of PKCs and ERK1/2 is involved in regulation of Na,K-ATPase expression and activity by C-peptide. Most likely C-peptide stimulates sodium pump expression via activation of ZEB, a transcription factor that has not been previously implicated in C-peptide-mediated signaling. Importantly, only physiological concentrations of C-peptide elicit this effect

Using ecological and field survey data to establish a national list of the wild bee pollinators of crops

The importance of wild bees for crop pollination is well established, but less is known about which species contribute to service delivery to inform agricultural management, monitoring and conservation. Using sites in Great Britain as a case study, we use a novel qualitative approach combining ecological information and field survey data to establish a national list of crop pollinating bees for four economically important crops (apple, field bean, oilseed rape and strawberry). A traits data base was used to establish potential pollinators, and combined with field data to identify both dominant crop flower visiting bee species and other species that could be important crop pollinators, but which are not presently sampled in large numbers on crops flowers. Whilst we found evidence that a small number of common, generalist species make a disproportionate contribution to flower visits, many more species were identified as potential pollinators, including rare and specialist species. Furthermore, we found evidence of substantial variation in the bee communities of different crops. Establishing a national list of crop pollinators is important for practitioners and policy makers, allowing targeted management approaches for improved ecosystem services, conservation and species monitoring. Data can be used to make recommendations about how pollinator diversity could be promoted in agricultural landscapes. Our results suggest agri-environment schemes need to support a higher diversity of species than at present, notably of solitary bees. Management would also benefit from targeting specific species to enhance crop pollination services to particular crops. Whilst our study is focused upon Great Britain, our methodology can easily be applied to other countries, crops and groups of pollinating insects.LH was funded by NERC QMEE CDT. EJB was funded by a BBSRC Ph.D. studentship under grant BB/F016581/1. LB was was supported by the Scholarship Program of the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt, DBU, AZ 20014/302). AJC was funded by the BBSRC and Syngenta UK as part of a case award Ph.D. (grant no. 1518739). AE was funded by the Swiss National Science Foundation (grant number 405940-115642). DG and A-MK were funded by grant PCIN2014-145-C02-02 (MinECo; EcoFruit project BiodivERsA-FACCE2014-74). MG was supported by Establishing a UK Pollinator Monitoring and Research Partnership (PMRP) a collaborative project funded by Defra, the Welsh and Scottish Governments, JNCC and project partners’. GAdG was funded via research projects BO-11-011.01-051 and BO-43-011.06-007, commissioned by the Dutch Ministry of Agriculture, Nature and Food Quality. DK was funded by the Dutch Ministry of Economic Affairs (BO-11-011.01-011). AK-H was funded by the NKFIH project (FK123813), the Bolyai János Fellowship of the MTA, the ÚNKP-19-4-SZIE-3 New National Excellence Program of the Ministry for Innovation and Technology, and together with RF by the Hungarian Scientific Research Fund OTKA 101940. MM was funded by Waitrose & Partners, Fruition PO, and the University of Worcester. MM was funded by grant INIA-RTA2013-00139-C03-01 (MinECo and FEDER). BBP and RFS were funded by the UK Natural Environment Research Council as part of Wessex BESS (ref. NE/J014680/1). NJV was funded by the Walloon Region (Belgium) Direction générale opérationnelle de l’Agriculture, des Ressources naturelles et de l’Environnement (DGO3) for the "Modèle permaculturel" project on biodiversity in micro-farms, FNRS/FWO joint programme EOS — Excellence Of Science CliPS: Climate change and its impact on Pollination Services (project 30947854)". CW was funded by the Deutsche Forschungsgemeinschaft (DFG) (Project number 405945293). BW was funded by the Natural Environment Research Council (NERC) under research programme NE/N018125/1 ASSIST – Achieving Sustainable Agricultural Systems www.assist.ceh.ac.uk. TB and TO are supported by BBSRC, NERC, ESRC and the Scottish Government under the Global Food Security Programme (Grant BB/R00580X/1)

Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10−27and−30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research

The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project

© 2016 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd. The PREDICTS project—Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)—has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity

Physical activity initiated by employer induces improvements in a novel set of biomarkers of inflammation: an 8-week follow-up study

PURPOSE: We investigated the level of pro- and anti-inflammatory biomarkers before and after 8 weeks of unsupervised physical activity (PA) initiated by employer. METHODS: During autumn 2014, background data, blood samples and self-reported exercise level were collected from 76 men and 41 women in a Norwegian road maintenance company. Monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), leptin, adiponectin, p-selectin and CD40 ligand (CD40L) were analyzed. [Formula: see text] was measured in a subgroup of 50 subjects. RESULTS: With reference point of exercise ≤1 time/week, we found that participants who exercised 2–3 times/week had higher [Formula: see text] values (5.6 mL kg(−1) min(−1); 95% CI [1.3, 9.9]). MCP-1 was lower in those who exercised ≥ 4 times/week (−81.98 pg/ml [−142.9, −21.0]). IL-6 and p-selectin levels were lower in females who exercised ≥4 times/week (−1.04 pg/ml [−2.04, −0.03] and −13.75 ng/ml [−24.03, −3.48]). Leptin was lower in participants who exercised 2–3 times/week (−0.39 µg/ml ln [−0.68, −0.09]) and ≥4 times/week (−0.69 µg/ml ln [−1.10, −0.28]). During follow-up, [Formula: see text] increased (2.9 mL kg(−1) min(−1) [1.5, 4.3]), while p-selectin and CD40L decreased (−2.33 ng/ml [−3.78, −0.87] and 718.14 ng/ml [−1368, −68]). MCP-1 levels decreased among men (−32.70 pg/ml [−51.21, −14.19]). A joint analysis of all biomarkers (inversed adiponectin) showed that those who exercised ≥4 times/week at baseline had lower total levels of biomarkers and that total biomarker levels decreased during follow-up. CONCLUSIONS: Exercising several times a week was associated with less inflammation compared to exercising once a week or less. During the 8-week follow-up, total levels of biomarkers of inflammation improved. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00421-016-3533-5) contains supplementary material, which is available to authorized users

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressuressuch as habitat destruction, exploitation, pollution and introduction ofalien species. Existing global databases of species’ threat status or populationtime series are dominated by charismatic species. The collation of datasets withbroad taxonomic and biogeographic extents, and that support computation ofa range of biodiversity indicators, is necessary to enable better understanding ofhistorical declines and to project – and avert – future declines. We describe andassess a new database of more than 1.6 million samples from 78 countries representingover 28,000 species, collated from existing spatial comparisons oflocal-scale biodiversity exposed to different intensities and types of anthropogenicpressures, from terrestrial sites around the world. The database containsmeasurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35)biodiversity hotspots and 16 (of 17) megadiverse countries. The database containsmore than 1% of the total number of all species described, and more than1% of the described species within many taxonomic groups – including floweringplants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopteransand hymenopterans. The dataset, which is still being added to, istherefore already considerably larger and more representative than those usedby previous quantitative models of biodiversity trends and responses. The databaseis being assembled as part of the PREDICTS project (Projecting Responsesof Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk).We make site-level summary data available alongside this article. The full databasewill be publicly available in 2015

Renal effects of C-peptide in experimental type-1 diabetes mellitus [Elektronisk resurs]

The incidence and prevalence of diabetic nephropathy are increasing continuously, mainly due to the increase in type-2 diabetes. In contrast, the risk of diabetic nephropathy for the individual patient has decreased considerably in recent decades due to improved glycemic control, successful treatment of hypertension and hyperlipidemia and the use of renin angiotensin system inhibitors, which have protective effects beyond those on blood pressure. However, optimal glycemic control and normal blood pressure offer only incomplete protection from diabetic nephropathy. Thus, other factors are likely to be involved. In type-1 diabetes, one such factor may be proinsulin C-peptide. C-peptide has been thought to lack metabolic effects but in the past decade several studies have shown that C-peptide itself can be beneficial in preventing diabetic complications. The aims of the studies in this thesis have been to further evaluate the functional and morphological effects of C-peptide in the kidneys in experimental diabetes. Furthermore, the aim was to compare the C-peptide effects with those of an angiotensin concerting enzyme inhibitor (ACEI) and to evaluate the effects of combined C-peptide and ACEI treatment. Studies were performed in streptozotocin diabetic Sprague-Dawley and Wistar rats and the results demonstrate that C-peptide prevents or reduces diabetes-induced glomerular hyperfiltration by 17-42% (p<0.01) and urinary albumin excretion and urinary albumin/creatinine ratio. Furthermore, C-peptide reduces glomerular and renal hypertrophy by 19-32% (p<0.01), glomerular mesangial matrix fraction by 37% (p<0.001), glomerular expression of type-IV collagen by 42% (p<0.001) and prevents diabetes-induced overexpression of receptors for advanced glycation end products (RAGE). In addition, C-peptide and captopril are equally effective in preventing glomerular hyperfiltration, albuminuria and glomerular RAGE expression, besides having additive effects in lowering glomerular type-IV collagen by 90% (p<0.001) and glomerular filtration fraction (p<0.05). C-peptide does not affect renal blood flow significantly more than placebo. In conclusion, in experimental type-1 diabetes, C-peptide beneficially affects risk factors or manifestations of diabetic nephropathy such as glomerular hyperfiltration, albuminuria, glomerular hypertrophy, mesangial matrix expansion and glomerular expression of type-IV collagen and RAGE. There may also be potentially beneficial effects from combining Cpeptide and an ACEI in preventing this complication in type-1 diabetes