Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

Aims/hypothesis: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. 
 Methods: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10^{−4 were followed up in 3,750 additional patients with type 1 diabetes from seven studies.} 
 Results: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10^{−8). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.} 
 Conclusions/interpretation: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Functional Consequences of Splicing of the Antisense Transcript COOLAIR on FLC Transcription

Antisense transcription is widespread in many genomes; however, how much is functional is hotly debated. We are investigating functionality of a set of long noncoding antisense transcripts, collectively called COOLAIR, produced at Arabidopsis FLOWERING LOCUS C (FLC). COOLAIR initiates just downstream of the major sense transcript poly(A) site and terminates either early or extends into the FLC promoter region. We now show that splicing of COOLAIR is functionally important. This was revealed through analysis of a hypomorphic mutation in the core spliceosome component PRP8. The prp8 mutation perturbs a cotranscriptional feedback mechanism linking COOLAIR processing to FLC gene body histone demethylation and reduced FLC transcription. The importance of COOLAIR splicing in this repression mechanism was confirmed by disrupting COOLAIR production and mutating the COOLAIR proximal splice acceptor site. Our findings suggest that altered splicing of a long noncoding transcript can quantitatively modulate gene expression through cotranscriptional coupling mechanisms.

Origin of British and Irish mammals: disparate post-glacial colonisation and species introductions

Global climate changes during the Quaternary reveal much about broader evolutionary effects of environmental change. Detailed regional studies reveal how evolutionary lineages and novel communities and ecosystems, emerge through glacial bottlenecks or from refugia. There have been significant advances in benthic imaging and dating, particularly with respect to the movements of the British (Scottish) and Irish ice sheets and associated changes in sea level during and after the Last Glacial Maximum (LGM). Ireland has been isolated as an island for approximately twice as long as Britain with no evidence of any substantial, enduring land bridge between these islands after ca 15 kya. Recent biogeographical studies show that Britain's mammal community is akin to those of southern parts of Scandinavia, The Netherlands and Belgium, but the much lower mammal species richness of Ireland is unique and needs explanation. Here, we consider physiographic, archaeological, phylogeographical i.e. molecular genetic, and biological evidence comprising ecological, behavioural and morphological data, to review how mammal species recolonized western Europe after the LGM with emphasis on Britain and, in particular, Ireland. We focus on why these close neighbours had such different mammal fauna in the early Holocene, the stability of ecosystems after LGM subject to climate change and later species introductions.

There is general concordance of archaeological and molecular genetic evidence where data allow some insight into history after the LGM. Phylogeography reveals the process of recolonization, e.g. with respect to source of colonizers and anthropogenic influence, whilst archaeological data reveal timing more precisely through carbon dating and stratigraphy. More representative samples and improved calibration of the ‘molecular clock’ will lead to further insights with regards to the influence of successive glaciations. Species showing greatest morphological, behavioural and ecological divergence in Ireland in comparison to Britain and continental Europe, were also those which arrived in Ireland very early in the Holocene either with or without the assistance of people. Cold tolerant mammal species recolonized quickly after LGM but disappeared, potentially as a result of a short period of rapid warming. Other early arrivals were less cold tolerant and succumbed to the colder conditions during the Younger Dryas or shortly after the start of the Holocene (11.5 kya), or the area of suitable habitat was insufficient to sustain a viable population especially in larger species. Late Pleistocene mammals in Ireland were restricted to those able to colonize up to ca 15 kya, probably originating from adjacent areas of unglaciated Britain and land now below sea level, to the south and west (of Ireland). These few, early colonizers retain genetic diversity which dates from before the LGM. Late Pleistocene Ireland, therefore, had a much depleted complement of mammal species in comparison to Britain.

Mammal species, colonising predominantly from southeast and east Europe occupied west Europe only as far as Britain between ca 15 and 8 kya, were excluded from Ireland by the Irish and Celtic Seas. Smaller species in particular failed to colonise Ireland. Britain being isolated as an island from ca. 8 kya has similar species richness and composition to adjacent lowland areas of northwest continental Europe and its mammals almost all show strongest genetic affinity to populations in neighbouring continental Europe with a few retaining genotypes associated with earlier, western lineages.

The role of people in the deliberate introduction of mammal species and distinct genotypes is much more significant with regards to Ireland than Britain reflecting the larger species richness of the latter and its more enduring land link with continental Europe. The prime motivation of early people in moving mammals was likely to be resource driven but also potentially cultural; as elsewhere, people exploring uninhabited places introduced species for food and the materials they required to survive. It is possible that the process of introduction of mammals to Ireland commenced during the Mesolithic and accelerated with Neolithic people. Irish populations of these long established, introduced species show some unique genetic variation whilst retaining traces of their origins principally from Britain but in some cases, Scandinavia and Iberia. It is of particular interest that they may retain genetic forms now absent from their source populations. Further species introductions, during the Bronze and late Iron Ages, and Viking and Norman invasions, follow the same pattern but lack the time for genetic divergence from their source populations. Accidental introductions of commensal species show considerable genetic diversity based on numerous translocations along the eastern Atlantic coastline. More recent accidental and deliberate introductions are characterised by a lack of genetic diversity other than that explicable by more than one introduction.

The substantial advances in understanding the postglacial origins and genetic diversity of British and Irish mammals, the role of early people in species translocations, and determination of species that are more recently introduced, should inform policy decisions with regards to species and genetic conservation. Conservation should prioritise early, naturally recolonizing species and those brought in by early people reflecting their long association with these islands. These early arrivals in Britain and Ireland and associated islands show genetic diversity that may be of value in mitigating anthropogenic climate change across Europe. In contrast, more recent introductions are likely to disturb ecosystems greatly, lead to loss of diversity and should be controlled. This challenge is more severe in Ireland where the number and proportion of invasive species from the 19th century to the present has been greater than in Britain.

Contaminants in surface water and sediments around the Tynagh Mine, Galway, Ireland.

A former silver mine in Tynagh, Co. Galway, Ireland is one of the most contaminated mine sites in Europe with maximum concentrations of Zn, As, Pb, Mn, Ni, Cu, and Cd far exceeding guideline values for water and sediment. The aims of this research were to 1) further assess the contamination, particularly metals, in surface water and sediment around the site, and 2) determine if the contamination has increased 10 years after the Environmental Protection Agency Ireland (EPAI) identified off-site contamination. Site pH is alkaline to neutral because CaCO3-rich sediment and rock material buffer the exposed acid generating sulphide-rich ore. When this study was compared to the previous EPAI study conducted 10 years earlier, it appeared that further weathering of exposed surface sediment had increased concentrations of As and other potentially toxic elements. Water samples from the tailings ponds and adjacent Barnacullia Stream had concentrations of Al, Cd, Mn, Zn and Pb above guideline values. Lead and Zn concentrations from the tailings pond sediment were 16 and 5 times higher, respectively, than concentrations reported 10 years earlier. Pb and Zn levels in most sediment samples exceeded the Expert Group (EGS) guidelines of 1000 and 5000 mg/kg, respectively. Arsenic concentrations were as high as 6238 mg/kg in the tailings ponds sediment, which is 62 and 862 times greater than the EGS and Canadian Soil Quality Guidelines (CSQG), respectively. Cadmium, Cu, Fe, Mn, Pb and Zn concentrations in water and sediment were above guideline values downstream of the site. Additionally, Fe, Mn and organic matter (OM) were strongly correlated and correlated to Zn, Pb, As, Cd, Cu and Ni in stream sediment. Therefore, the nearby Barnacullia Stream is also a significant pathway for contaminant transport to downstream areas. Further rehabilitation of the site may decrease the contamination around the area.

Single vocal cord irradiation:a competitive treatment strategy in early glottic cancer

INTRODUCTION: The treatment of choice for early glottic cancer is still being debated; ultimately it relies on the functional outcome. This paper reports on a novel sparing 4D conformal technique for single vocal cord irradiation (SVCI).

MATERIAL AND METHODS: The records of 164 T1a patients with SCC of the vocal cord, irradiated in the Erasmus MC between 2000 and 2008, were analyzed for local control and overall survival. The quality of life was determined by EORTC H&N35 questionnaires. Also the VHI (voice handicap index), and the TSH (thyroid stimulating hormone) blood levels, were established. On-line image guided SVCI, using cone beam CT or stereotactic radiation therapy (SRT) techniques, were developed.

RESULTS: A LC rate at five-years of 93% and a VHI of 12.7 (0-63) was determined. It appeared feasible to irradiate one vocal cord within 1-2mm accuracy. This way sparing of the contralateral (CL) vocal cord and CL normal tissues, could be achieved.

CONCLUSIONS: Given the accuracy (1-2mm) and small volume disease (CTV limited to one vocal cord), for the use of stereotactic RT techniques SVCI with large fraction sizes is currently being investigated in clinic. It is argued that hypofractionated SVCI can be a competitive alternative to laser surgery.

The chromosome 3q25 locus associated with fetal adiposity is not associated with childhood adiposity

Increased newborn adiposity is associated with later adverse metabolic outcomes. Previous genome-wide association studies (GWAS) demonstrated strong association of a locus on chromosome 3 (3q25.31) with newborn sum of skinfolds, a measure of overall adiposity. Whether this locus is associated with childhood adiposity is unknown. Genotype and sum of skinfolds data were available for 293 children at birth and age 2, and for 350 children at birth and age 6 from a European cohort (Belfast, UK) who participated in the Hyperglycemia and Adverse Pregnancy Outcome GWAS. We examined single nucleotide polymorphisms (SNPs) at the 3q25.31 locus associated with newborn adiposity. Linear regression analyses under an additive genetic model adjusting for maternal body mass index were performed. In both cohorts, a positive association was observed between all SNPs and sum of skinfolds at birth (P=2.3 × 10(-4), β=0.026 and P=4.8 × 10(-4), β=0.025). At the age of 2 years, a non-significant negative association was observed with sum of skinfolds (P=0.06; β =-0.015). At the age of 6 years, there was no evidence of association (P=0.86; β=0.002). The 3q25.31 locus strongly associated with newborn adiposity had no significant association with childhood adiposity suggesting that its impact may largely be limited to fetal fat accretion.

The main-belt comets: The Pan-STARRS1 perspective

We analyze a set of 760 475 observations of 333 026 unique main-belt objects obtained by the Pan-STARRS1(PS1) survey telescope between 2012 May 20 and 2013 November 9, a period during which PS1 discoveredtwo main-belt comets, P/2012 T1 (PANSTARRS) and P/2013 R3 (Catalina-PANSTARRS). PS1 cometdetection procedures currently consist of the comparison of the point spread functions (PSFs) of movingobjects to those of reference stars, and the flagging of objects that show anomalously large radial PSFwidths for human evaluation and possible observational follow-up. Based on the number of missed discoveryopportunities among comets discovered by other observers, we estimate an upper limit comet discoveryefficiency rate of 70% for PS1. Additional analyses that could improve comet discovery yields infuture surveys include linear PSF analysis, modeling of trailed stellar PSFs for comparison to trailed movingobject PSFs, searches for azimuthally localized activity, comparison of point-source-optimized photometryto extended-source-optimized photometry, searches for photometric excesses in objects withknown absolute magnitudes, and crowd-sourcing. Analysis of the discovery statistics of the PS1 surveyindicates an expected fraction of 59 MBCs per 106 outer main-belt asteroids (corresponding to a totalexpected population of 140 MBCs among the outer main-belt asteroid population with absolute magnitudesof 12 < HV < 19:5), and a 95% confidence upper limit of 96 MBCs per 106 outer main-belt asteroids(corresponding to a total of 230 MBCs), assuming a detection efficiency of 50%. We note howeverthat significantly more sensitive future surveys (particularly those utilizing larger aperture telescopes)could detect many more MBCs than estimated here. Examination of the orbital element distribution ofall known MBCs reveals an excess of high eccentricities (0:1 < e < 0:3) relative to the background asteroidpopulation. Theoretical calculations show that, given these eccentricities, the sublimation rate for atypical MBC is orders of magnitude larger at perihelion than at aphelion, providing a plausible physicalexplanation for the observed behavior of MBCs peaking in observed activity strength near perihelion.These results indicate that the overall rate of mantle growth should be slow, consistent with observationalevidence that MBC activity can be sustained over multiple orbit passages.

The European Union funded NEOShield project: A global approach to near-Earth object impact threat mitigation

Although discussions are underway within the Action Team 14 of the United Nations COPUOS, there is currently no concerted international plan addressing the impact threat from near-Earth objects (NEOs) and how to organize, prepare and implement mitigation measures. We report on a new international project to address impact hazard mitigation issues, being the subject of a proposal submitted to the European Commission in response to the 2011 FP7 Call "Prevention of impacts from near-Earth objects on our planet". Our consortium consists of 13 research institutes, universities, and industrial partners from 6 countries and includes leading US and Russian space organizations. The primary aim of the project, NEOShield, is to investigate in detail the three most promising mitigation techniques: the kinetic impactor, blast deflection,and the gravity tractor, and devise feasible demonstration missions. Furthermore, we will investigate options for an international strategy for implementation when an actual impact threat arises. The NEOShield project was formally accepted by the European Commission on 17 November 2011 and funded with a total of 5.8 million Euros for a period of 3.5 years. The kick-off meeting took place at the DLR Institute of Planetary Research, Berlin, in January 2012. In this paper we present a brief overview of the planned scope of the project.

Bactericidal efficacy of atmospheric pressure non-thermal plasma (APNTP) against the ESKAPE pathogens

The emergence of multidrug-resistant pathogens within the clinical environment is presenting a mounting problem in hospitals worldwide. The 'ESKAPE' pathogens (Enterococcusfaecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) have been highlighted as a group of causative organisms in a majority of nosocomial infections, presenting a serious health risk due to widespread antimicrobial resistance. The stagnating pipeline of new antibiotics requires alternative approaches to the control and treatment of nosocomial infections. Atmospheric pressure nonthermal plasma (APNTP) is attracting growing interest as an alternative infection control approach within the clinical setting. This study presents a comprehensive bactericidal assessment of an in-house-designed APNTP jet both against biofilms and planktonic bacteria of the ESKAPE pathogens. Standard plate counts and the XTT metabolic assay were used to evaluate the antibacterial effect of APNTP, with both methods demonstrating comparable eradication times. APNTP exhibited rapid antimicrobial activity against all of the ESKAPE pathogens in the planktonic mode of growth and provided efficient and complete eradication of ESKAPE pathogens in the biofilm mode of growth within 360 s, with the exception of A. baumannii where a >4log reduction in biofilm viability was observed. This demonstrates its effectiveness as a bactericidal treatment against these pathogens and further highlights its potential application in the clinical environment for the control of highly antimicrobial-resistant pathogens.

Seasonal and geographical differences in aflatoxin exposures in Senegal

The aim of the study was to determine the geographical and seasonal variations in aflatoxin dietary exposure levels in adults from Senegal. A total of 168 adults (50% male) were recruited from three districts: Nioro du Rip (n=90), located in the Sudan Savannah agro-ecological zone where rainfall is sufficient for groundnut growth; Saint-Louis (n=40) and Mboro (n=38), located in the Sahel zone where groundnuts are produced under irrigated conditions. Diet information and samples were collected at groundnut harvest and post-harvest seasons. Plasma aflatoxin-albumin adducts (AF-alb) and total aflatoxin in household groundnut samples were measured by ELISA and a quantitative thin layer chromatography method, respectively. The blood AF-alb geometric mean was 45.7 pg/mg albumin (range 5.5-588.2 pg/mg). Nioro du Rip had a higher AF-alb level at harvest than Saint-Louis and Mboro (80.0 vs 15.6 and 33.3 pg/mg, P<0.001). Similar trends were observed at post-harvest (P<0.05). Seasonal trends were not consistent across the districts as Nioro du Rip had a higher AF-alb level at harvest than post-harvest (80.0 vs 58.6 pg/mg, P=0.026), whereas Saint-Louis had a higher level at post-harvest than harvest (25.6 vs 15.6 pg/mg, P=0.032). It is clear that aflatoxin exposure is prevalent in adults from Senegal and that season and geographical location are strong determinants of aflatoxin exposure.

A biogeography-based optimization algorithm with mutation strategies for model parameter estimation of solar and fuel cells

Mathematical models are useful tools for simulation, evaluation, optimal operation and control of solar cells and proton exchange membrane fuel cells (PEMFCs). To identify the model parameters of these two type of cells efficiently, a biogeography-based optimization algorithm with mutation strategies (BBO-M) is proposed. The BBO-M uses the structure of biogeography-based optimization algorithm (BBO), and both the mutation motivated from the differential evolution (DE) algorithm and the chaos theory are incorporated into the BBO structure for improving the global searching capability of the algorithm. Numerical experiments have been conducted on ten benchmark functions with 50 dimensions, and the results show that BBO-M can produce solutions of high quality and has fast convergence rate. Then, the proposed BBO-M is applied to the model parameter estimation of the two type of cells. The experimental results clearly demonstrate the power of the proposed BBO-M in estimating model parameters of both solar and fuel cells.

Galleria mellonella as a novel in vivo model for assessment of the toxicity of 1-alkyl-3-methylimidazolium chloride ionic liquids

The larval form of the Greater Wax Moth (Galleria mellonella) was evaluated as a model system for the study of the acute in vivo toxicity of 1-alkyl-3-methylimidazolium chloride ionic liquids. 24-h median lethal dose (LD50) values for nine of these ionic liquids bearing alkyl chain substituents ranging from 2 to 18 carbon atoms were determined. The in vivo toxicity of the ionic liquids was found to correlate directly with the length of the alkyl chain substituent, and the pattern of toxicity observed was in accordance with previous studies of ionic liquid toxicity in other living systems, including a characteristic toxicity ‘cut-off’ effect. However, G. mellonella appeared to be more susceptible to the toxic effects of the ionic liquids tested, possibly as a result of their high body fat content. The results obtained in this study indicate that G. mellonella represents a sensitive, reliable and robust in vivo model organism for the evaluation of ionic liquid toxicity.

Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma

Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10-2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A-T haplotype from rs963248-rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only one control (P = 0.015). This SNP is located in the 3'-UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.

Epidermolysis bullosa:evidence for linkage to genetic markers on chromosome 1 in a family with the autosomal dominant simplex form

DNA from members of a three-generation pedigree of Irish origin, displaying an autosomal dominant simplex form of epidermolysis bullosa of the epidermolytic, simplex, or Koebner variety (EBS2), was analyzed for linkage with a set of markers derived from the long arm of chromosome 1. Two-point analysis revealed positive lod scores for five of these markers, AT3 (Z = 2.107, theta = 0), APOA2 (Z = 1.939, theta = 0.15), D1S66 (Z = 1.204, theta = 0), D1S13 (Z = 1.026, theta = 0.15), and D1S65 (Z = 0.329, theta = 0.15). Multilocus analysis, incorporating the markers D1S19, D1S16, D1S13, APOA2, D1S66, AT3, and D1S65, resulted in a lod score of 3 maximizing at AT3. These data strongly support previous tentative indications of linkage between EBS2 and genetic markers on the long arm of chromosome 1.

PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21

Prostate cancer development and progression are associated with alterations in expression and function of elements of cytokine networks, some of which can activate multiple signaling pathways. Protein inhibitor of activated signal transducers and activators of transcription (PIAS)1, a regulator of cytokine signaling, may be implicated in the modulation of cellular events during carcinogenesis. This study was designed to investigate the functional significance of PIAS1 in models of human prostate cancer. We demonstrate for the first time that PIAS1 protein expression is significantly higher in malignant areas of clinical prostate cancer specimens than in normal tissues, thus suggesting a growth-promoting role for PIAS1. Expression of PIAS1 was observed in the majority of tested prostate cancer cell lines. In addition, we investigated the mechanism by which PIAS1 might promote prostate cancer and found that down-regulation of PIAS1 leads to decreased proliferation and colony formation ability of prostate cancer cell lines. This decrease correlates with cell cycle arrest in the G0/G1 phase, which is mediated by increased expression of p21(CIP1/WAF1). Furthermore, PIAS1 overexpression positively influences cell cycle progression and thereby stimulates proliferation, which can be mechanistically explained by a decrease in the levels of cellular p21. Taken together, our data reveal an important new role for PIAS1 in the regulation of cell proliferation in prostate cancer.