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Showing papers by "Memorial University of Newfoundland published in 2012"


Journal ArticleDOI
TL;DR: In this paper, the authors develop a framework for ecosystem services research and practice, addressing three challenges: (1) non-material values are ill suited to characterization using monetary methods; (2) it is difficult to unequivocally link particular changes in socioecological systems to cultural benefits; and (3) cultural benefits are associated with many services, not just cultural ES.
Abstract: A focus on ecosystem services (ES) is seen as a means for improving decisionmaking. In the research to date, the valuation of the material contributions of ecosystems to human well-being has been emphasized, with less attention to important cultural ES and nonmaterial values. This gap persists because there is no commonly accepted framework for eliciting less tangible values, characterizing their changes, and including them alongside other services in decisionmaking. Here, we develop such a framework for ES research and practice, addressing three challenges: (1) Nonmaterial values are ill suited to characterization using monetary methods; (2) it is difficult to unequivocally link particular changes in socioecological systems to particular changes in cultural benefits; and (3) cultural benefits are associated with many services, not just cultural ES. There is no magic bullet, but our framework may facilitate fuller and more socially acceptable integrations of ES information into planning and management.

867 citations


Journal ArticleDOI
Lam C. Tsoi1, Sarah L. Spain1, Sarah L. Spain2, Jo Knight1  +212 moreInstitutions (52)
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

786 citations



Journal ArticleDOI
TL;DR: The results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes, and that a-DMRs may initiate at an earlier age.
Abstract: Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

664 citations


Journal ArticleDOI
TL;DR: More studies are needed to definitively conclude that vitamin D can offer preventive and therapeutic benefits across a wide range of physiological states and chronic nonskeletal disorders.
Abstract: Significant controversy has emerged over the last decade concerning the effects of vitamin D on skeletal and nonskeletal tissues. The demonstration that the vitamin D receptor is expressed in virtually all cells of the body and the growing body of observational data supporting a relationship of serum 25-hydroxyvitamin D to chronic metabolic, cardiovascular, and neoplastic diseases have led to widespread utilization of vitamin D supplementation for the prevention and treatment of numerous disorders. In this paper, we review both the basic and clinical aspects of vitamin D in relation to nonskeletal organ systems. We begin by focusing on the molecular aspects of vitamin D, primarily by examining the structure and function of the vitamin D receptor. This is followed by a systematic review according to tissue type of the inherent biological plausibility, the strength of the observational data, and the levels of evidence that support or refute an association between vitamin D levels or supplementation and maternal/child health as well as various disease states. Although observational studies support a strong case for an association between vitamin D and musculoskeletal, cardiovascular, neoplastic, and metabolic disorders, there remains a paucity of large-scale and long-term randomized clinical trials. Thus, at this time, more studies are needed to definitively conclude that vitamin D can offer preventive and therapeutic benefits across a wide range of physiological states and chronic nonskeletal disorders.

650 citations


Journal ArticleDOI
Richard Anney1, Lambertus Klei2, Dalila Pinto3, Dalila Pinto4, Joana Almeida, Elena Bacchelli5, Gillian Baird6, Nadia Bolshakova1, Sven Bölte7, Patrick Bolton8, Thomas Bourgeron9, Thomas Bourgeron10, Sean Brennan1, Jessica Brian3, Jillian P. Casey11, Judith Conroy11, Catarina Correia12, Catarina Correia13, Christina Corsello14, Emily L. Crawford15, Maretha de Jonge16, Richard Delorme, Eftichia Duketis7, Frederico Duque, Annette Estes17, Penny Farrar18, Bridget A. Fernandez19, Susan E. Folstein20, Eric Fombonne21, John R. Gilbert20, Christopher Gillberg22, Joseph T. Glessner23, Andrew Green11, Jonathan Green24, Stephen J. Guter25, Elizabeth A. Heron1, Richard Holt18, Jennifer L. Howe3, Gillian Hughes1, Vanessa Hus14, Roberta Igliozzi, Suma Jacob25, Graham Kenny1, Cecilia Kim23, Alexander Kolevzon4, Vlad Kustanovich, Clara Lajonchere, Janine A. Lamb24, Miriam Law-Smith1, Marion Leboyer10, Ann Le Couteur26, Bennett L. Leventhal27, Bennett L. Leventhal28, Xiao-Qing Liu29, Frances Lombard1, Catherine Lord30, Linda Lotspeich31, Sabata C. Lund15, Tiago R. Magalhaes13, Tiago R. Magalhaes12, Carine Mantoulan32, Christopher J. McDougle33, Christopher J. McDougle34, Nadine M. Melhem2, Alison K. Merikangas1, Nancy J. Minshew2, Ghazala Mirza18, Jeff Munson17, Carolyn Noakes3, Gudrun Nygren22, Katerina Papanikolaou35, Alistair T. Pagnamenta18, Barbara Parrini, Tara Paton3, Andrew Pickles24, David J. Posey33, Fritz Poustka7, Jiannis Ragoussis18, Regina Regan11, Wendy Roberts3, Kathryn Roeder36, Bernadette Rogé32, Michael Rutter37, Sabine Schlitt7, Naisha Shah11, Val C. Sheffield38, Latha Soorya4, Inês Sousa18, Vera Stoppioni, Nuala Sykes18, Raffaella Tancredi, Ann P. Thompson39, Susanne Thomson15, Ana Tryfon4, John Tsiantis35, Herman van Engeland16, John B. Vincent3, Fred R. Volkmar40, Jacob A. S. Vorstman16, Simon Wallace18, Kirsty Wing18, Kerstin Wittemeyer18, Shawn Wood2, Danielle Zurawiecki4, Lonnie Zwaigenbaum41, Anthony J. Bailey42, Agatino Battaglia, Rita M. Cantor43, Hilary Coon44, Michael L. Cuccaro20, Geraldine Dawson45, Geraldine Dawson46, Sean Ennis11, Christine M. Freitag7, Daniel H. Geschwind43, Jonathan L. Haines47, Sabine M. Klauck48, William M. McMahon44, Elena Maestrini5, Judith Miller44, Judith Miller23, Anthony P. Monaco49, Anthony P. Monaco18, Stanley F. Nelson43, John I. Nurnberger33, Guiomar Oliveira, Jeremy R. Parr26, Margaret A. Pericak-Vance20, Joseph Piven45, Gerard D. Schellenberg23, Stephen W. Scherer3, Astrid M. Vicente13, Astrid M. Vicente12, Thomas H. Wassink38, Ellen M. Wijsman17, Catalina Betancur50, Catalina Betancur51, Catalina Betancur52, Joseph D. Buxbaum4, Edwin H. Cook25, Louise Gallagher1, Michael Gill1, Joachim Hallmayer31, Andrew D. Paterson3, James S. Sutcliffe15, Peter Szatmari39, Veronica J. Vieland53, Hakon Hakonarson23, Bernie Devlin2 
Trinity College, Dublin1, University of Pittsburgh2, University of Toronto3, Icahn School of Medicine at Mount Sinai4, University of Bologna5, Guy's and St Thomas' NHS Foundation Trust6, Goethe University Frankfurt7, King's College London8, Pasteur Institute9, University of Paris10, University College Dublin11, Instituto Gulbenkian de Ciência12, University of Lisbon13, University of Michigan14, Vanderbilt University15, Utrecht University16, University of Washington17, University of Oxford18, Memorial University of Newfoundland19, University of Miami20, McGill University21, University of Gothenburg22, University of Pennsylvania23, University of Manchester24, University of Illinois at Chicago25, Newcastle University26, New York University27, Nathan Kline Institute for Psychiatric Research28, University of Manitoba29, Cornell University30, Stanford University31, University of Toulouse32, Indiana University33, Harvard University34, National and Kapodistrian University of Athens35, Carnegie Mellon University36, Medical Research Council37, University of Iowa38, McMaster University39, Yale University40, University of Alberta41, University of British Columbia42, University of California, Los Angeles43, University of Utah44, University of North Carolina at Chapel Hill45, Autism Speaks46, Veterans Health Administration47, German Cancer Research Center48, Tufts University49, Pierre-and-Marie-Curie University50, Centre national de la recherche scientifique51, French Institute of Health and Medical Research52, Ohio State University53
TL;DR: Stage 2 of the Autism Genome Project genome-wide association study is reported, adding 1301 ASD families and bringing the total to 2705 families analysed, and it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

353 citations


Journal ArticleDOI
TL;DR: Those with elevated %BF are at increased risk of developing cardiometabolic disease despite having a normal BMI, and future development of adequate screening tools to identify these individuals is crucial to the prevention of obesity-associated disease.
Abstract: Background and aims Nearly 25% of normal weight individuals display abnormal metabolic profiles associated with obesity. As a wide range in body fat percentage (%BF) exists for BMI-defined normal weight individuals, we investigated whether elevated %BF (determined using DXA) was associated with cardiometabolic dysregulation among 977 normal weight subjects (192 men, 785 women) from the Canadian province of Newfoundland and Labrador. Methods and results BMI and %BF were measured after a 12-h fasting period. Cardiometabolic abnormalities considered included elevated triglyceride, glucose and hsCRP levels, decreased HDL cholesterol, insulin resistance, and hypertension. Subjects were classified as metabolically healthy (0 or 1 cardiometabolic abnormality) or abnormal (≥2 cardiometabolic abnormalities) and divided into sex-specific %BF tertiles as follows: low (≤15.2% men, ≤29.7% women), medium (15.3–20.7%% men, 29.8–34.9%% women) and high (≥20.8% men, ≥35.0% women). The prevalence of the metabolically abnormal phenotype was higher among medium and high %BF subjects (12.0% and 19.5%, respectively) compared to the low group (7.4%; p Conclusion Our findings indicate that those with elevated %BF are at increased risk of developing cardiometabolic disease despite having a normal BMI. Future development of adequate screening tools to identify these individuals is crucial to the prevention of obesity-associated disease.

335 citations


Journal ArticleDOI
TL;DR: In this article, the authors present a dis- tribution of high-resolution glaciologically self-consistent deglacial histories for the North American ice com- plex calibrated against a large set of RSL, marine limit, and geodetic data.

324 citations


Journal ArticleDOI
TL;DR: Fifteen additional rare missense variants in CARD14 are described, their distribution in seven psoriasis cohorts, and their effects on NF-kB activation and the transcriptome of keratinocytes, to contribute to the understanding of the genetic basis of Psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.
Abstract: Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10−6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw∗0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.

305 citations


Journal ArticleDOI
TL;DR: A hemizygous SHANK1 deletion is identified that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning, and the discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHank1 deletions provides a possible contributory model for the male gender bias in autism.
Abstract: Recent studies have highlighted the involvement of rare ( 15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.

295 citations


Journal ArticleDOI
TL;DR: The authors in this paper show that the combination of very low target population productivity, nonselective fishing gear, economics that favor population liquidation and a very weak regulatory regime makes deep-sea fisheries unsustainable with very few exceptions.

Journal ArticleDOI
Lisette Stolk1, John R. B. Perry2, John R. B. Perry3, Daniel I. Chasman4  +195 moreInstitutions (54)
TL;DR: A meta-analysis of 22 genome-wide association studies in 38,968 women of European descent identified 13 loci newly associated with age at natural menopause, including genes implicated in DNA repair, immune function and immune function.
Abstract: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Journal ArticleDOI
TL;DR: The results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation.
Abstract: Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32-81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10(-04) to 7.8 × 10(-42) , α(corr) = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging.

Journal ArticleDOI
TL;DR: In this paper, the role of the Internal Revenue Service (IRS) monitoring in corporate tax avoidance has been investigated. And the authors show that tax enforcement is more effective than tax avoidance.
Abstract: We extend research on the determinants of corporate tax avoidance to include the role of Internal Revenue Service (IRS) monitoring. Our evidence from large samples implies that U.S. public firms undertake less aggressive tax positions when tax enforcement is stricter. Reflecting its first-order economic impact on firms, our coefficient estimates imply that raising the probability of an IRS audit from 19 percent (the 25th percentile in our data) to 37 percent (the 75th percentile) increases their cash effective tax rates, on average, by nearly two percentage points, which amounts to a 7 percent increase in cash effective tax rates. These results are robust to controlling for firm size and time, which determine our primary proxy for IRS enforcement, in different ways; specifying several alternative dependent and test variables; and confronting potential endogeneity with instrumental variables and panel data estimations, among other techniques. JEL Classifications: M40; G34; G32; H25.

Journal ArticleDOI
TL;DR: Use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome and the recent evidence on blood pressure targets for patients with hypertension and diabetes are reviewed and continue to recommend a blood pressure target of less than 130/80 mm Hg.

Journal ArticleDOI
TL;DR: In this paper, the authors used electron paramagnetic resonance (EPR) spectroscopy to determine the bioaccessibility of five millet varieties (kodo, finger, proso, foxtail and pearl) under physiological conditions.

Journal ArticleDOI
Andrea D. Coviello1, Robin Haring2, Melissa Wellons3, Dhananjay Vaidya4, Terho Lehtimäki, Sarah Keildson5, Kathryn L. Lunetta1, Chunyan He6, Myriam Fornage7, Vasiliki Lagou5, Massimo Mangino8, N. Charlotte Onland-Moret9, Brian H. Chen10, Joel Eriksson11, Melissa Garcia12, Yongmei Liu13, Annemarie Koster12, Kurt Lohman13, Leo-Pekka Lyytikäinen, Ann-Kristin Petersen12, Jennifer Prescott14, Lisette Stolk14, Liesbeth Vandenput11, Andrew R. Wood, Wei Vivian Zhuang1, Aimo Ruokonen15, Anna-Liisa Hartikainen16, Anneli Pouta16, Stefania Bandinelli16, Reiner Biffar, Georg Brabant2, David G. Cox17, David G. Cox18, Yuhui Chen5, Steven R. Cummings19, Luigi Ferrucci12, Marc J. Gunter20, Susan E. Hankinson14, Susan E. Hankinson21, Hannu Martikainen16, Albert Hofman22, Georg Homuth2, Thomas Illig23, John-Olov Jansson11, Andrew D. Johnson1, David Karasik14, Magnus Karlsson24, Johannes Kettunen25, Johannes Kettunen26, Douglas P. Kiel23, Peter Kraft, Jingmin Liu26, Östen Ljunggren14, Mattias Lorentzon11, M. Maggio27, Marcello Ricardo Paulista Markus28, Dan Mellström11, Iva Miljkovic29, Daniel B. Mirel2, Sarah C. Nelson30, Laure Morin Papunen16, Petra H.M. Peeters9, Inga Prokopenko5, Leslie J. Raffel31, Martin Reincke32, Alexander P. Reiner33, Kathryn M. Rexrode14, Fernando Rivadeneira14, Stephen M. Schwartz34, David S. Siscovick27, Nicole Soranzo8, Nicole Soranzo35, Doris Stöckl32, Shelley S. Tworoger14, André G. Uitterlinden14, André G. Uitterlinden22, Carla H. van Gils9, Ramachandran S. Vasan1, H.-Erich Wichmann32, Guangju Zhai36, Guangju Zhai8, Shalender Bhasin1, Martin Bidlingmaier34, Stephen J. Chanock12, Immaculata De Vivo14, Tamara B. Harris12, David J. Hunter14, Mika Kähönen, Simin Liu10, Pamela Ouyang4, Tim D. Spector8, Yvonne T. van der Schouw9, Jorma Viikari37, Henri Wallaschofski2, Mark I. McCarthy5, Timothy M. Frayling, Anna Murray, Steve Franks18, Marjo-Riitta Järvelin16, Marjo-Riitta Järvelin18, Frank De Jong14, Olli T. Raitakari37, Alexander Teumer22, Claes Ohlsson11, Joanne M. Murabito1, John R. B. Perry5, John R. B. Perry15, John R. B. Perry8 
TL;DR: Evidence of sex-differentiated genetic influences on sex steroid hormone-binding globulin is found and the importance of considering these features when estimating complex trait variance is highlighted.
Abstract: Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5x10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained similar to 15.6% and similar to 8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Journal ArticleDOI
TL;DR: In this paper, the authors considered a susceptible-infected-susceptible (SIS) reaction-diffusion model, where the rates of disease transmission and recovery are assumed to be spatially heterogeneous and temporally periodic and the total population number is constant.
Abstract: In this paper, we consider a susceptible–infected–susceptible (SIS) reaction–diffusion model, where the rates of disease transmission and recovery are assumed to be spatially heterogeneous and temporally periodic and the total population number is constant. We introduce a basic reproduction number and establish threshold-type results on the global dynamics in terms of . In particular, we obtain the asymptotic properties of with respect to the diffusion rate dI of the infected individuals, which exhibit the delicate influence of the time-periodic heterogeneous environment on the extinction and persistence of the infectious disease. Our analytical results suggest that the combination of spatial heterogeneity and temporal periodicity tends to enhance the persistence of the disease.

Journal ArticleDOI
TL;DR: A switched reluctance motor (SRM) has been developed as one of the possible candidates of rare-earth-free electric motors and it is found that competitive power of 50-kW rating and efficiency of 95% are achieved.
Abstract: A switched reluctance motor (SRM) has been developed as one of the possible candidates of rare-earth-free electric motors. A prototype machine has been built and tested. It has competitive dimensions, torque, power, and efficiency with respect to the 50-kW interior permanent magnet synchronous motor employed in the hybrid electric vehicles (Toyota Prius 2003). It is found that competitive power of 50-kW rating and efficiency of 95% are achieved. The prototype motor provided 85% of the target torque. Except the maximum torque, the most speed-torque region is found to be covered by the test SRM. The cause of discrepancy in the measured and calculated torque values is examined. An improved design is attempted, and a new experimental switched reluctance machine is designed and built for testing. The results are given in this paper.

Journal ArticleDOI
TL;DR: In this article, the authors describe the theory and practice of restorative justice with the aim of defining this distinctive paradigm, in comparison to other forms of discipline, as one that uniquely emphasizes social engagement over social control.
Abstract: In the ongoing effort of designing school contexts in support of proactive discipline, a range of practices and theoretical frameworks have been advanced, from behaviorist approaches to social and emotional learning. This article describes the theory and practice of restorative justice with the aim of defining this distinctive paradigm, in comparison to other forms of discipline, as one that uniquely emphasizes social engagement over social control. In so doing, a responsive regulatory framework supports pedagogy, praxis, and discipline such that relational school cultures are nurtured; wherein, behavior is understood in social context, individuals are recognized as being part of a social web of relations, and building, maintaining, and repairing relationships become priorities. This focus on developing rich and embedded relational ecologies finds its strength through nurturing motivational bonds of belonging that support individual development and social responsibility. This is distinct from formal insti...

Journal ArticleDOI
TL;DR: This paper identified two categories of corporate responses grounded in different temporal perspectives: focused and integrated, and discussed the implications of this categorization for research on corporate environmentalism and time in organizational theory.
Abstract: Prior research often categorizes corporate environmental responses on a spectrum that ranges from reactive to proactive. Such research subordinates the role of time, yet time is central to organizational responses to environmental issues such as climate change. In this paper, we study five oil and gas firms and inductively develop a framework of corporate responses to climate change that explicitly acknowledges the role of time. The framework identifies two categories of corporate responses grounded in different temporal perspectives: focused and integrated. We discuss the implications of this categorization for research on corporate environmentalism and time in organizational theory.

Journal ArticleDOI
TL;DR: This paper found that tax aggressive U.S. public firms are less likely to commit accounting fraud than non-aggressive firms, and applied factor analysis to identify tax avoidance with a common factor extracted from the underlying proxies and match on propensity scores.
Abstract: There are competing arguments and mixed prior evidence on whether firms that are aggressive in their financial reporting exhibit more or less tax aggressiveness. Our research contributes to resolving this issue by examining the association between aggressive tax reporting and the incidence of alleged accounting fraud. Relying on several proxies for tax aggressiveness to triangulate our evidence, we generally find that tax aggressive U.S. public firms are less likely to commit accounting fraud. However, we caution that our results are sensitive to how tax aggressiveness is measured. More specifically, four (two) of the five (three) proxies for firms’ effective tax rates (book-tax differences) load positively (negatively) during the 1981-2001 period, implying that fraud firms are less tax aggressiveness. Our inferences persist when we isolate the 1995-2001 period in which accounting impropriety steeply rose and corporate tax compliance steeply fell. Moreover, we continue to find that tax aggressive firms are less apt to fraudulently manipulate their financial statements when we apply factor analysis to identify tax avoidance with a common factor extracted from the underlying proxies and match on propensity scores to ensure that the fraud and non-fraud samples have very similar non-tax characteristics.

Journal ArticleDOI
TL;DR: The study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer and selected the most statistically significant single nucleotide polymorphisms for replication using ten independent studies.
Abstract: Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.

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TL;DR: This report presents clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3.
Abstract: The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.

Journal ArticleDOI
TL;DR: This review provides an overview of experimental evidence that has led to the current understanding of the role of calcium signaling in death and dysfunction following TBI.
Abstract: Cell death and dysfunction after traumatic brain injury (TBI) is caused by a primary phase, related to direct mechanical disruption of the brain, and a secondary phase which consists of delayed events initiated at the time of the physical insult. Arguably, the calcium ion contributes greatly to the delayed cell damage and death after TBI. A large, sustained influx of calcium into cells can initiate cell death signaling cascades, through activation of several degradative enzymes, such as proteases and endonucleases. However, a sustained level of intracellular free calcium is not necessarily lethal, but the specific route of calcium entry may couple calcium directly to cell death pathways. Other sources of calcium, such as intracellular calcium stores, can also contribute to cell damage. In addition, calcium-mediated signal transduction pathways in neurons may be perturbed following injury. These latter types of alterations may contribute to abnormal physiology in neurons that do not necessarily die after a traumatic episode. This review provides an overview of experimental evidence that has led to our current understanding of the role of calcium signaling in death and dysfunction following TBI.

Journal ArticleDOI
TL;DR: In this paper, a geometric capacitary analysis based on space dualities is presented for the Morrey spaces in harmonic analysis over the Euclidean spaces, which addresses several fundamental aspects of functional analysis and potential theory.
Abstract: Through a geometric capacitary analysis based on space dualities, this paper addresses several fundamental aspects of functional analysis and potential theory for the Morrey spaces in harmonic analysis over the Euclidean spaces.

Journal ArticleDOI
TL;DR: Of the 615 ASD cases analyzed on both SNP and CGH arrays, it was found that 13,572 of 21,346 of the CNVs were exclusively detected by the CGH array, which serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection.
Abstract: The identification of rare inherited and de novo copy number variations (CNVs) in human subjects has proven a productive approach to highlight risk genes for autism spectrum disorder (ASD). A variety of microarrays are available to detect CNVs, including single-nucleotide polymorphism (SNP) arrays and comparative genomic hybridization (CGH) arrays. Here, we examine a cohort of 696 unrelated ASD cases using a high-resolution one-million feature CGH microarray, the majority of which were previously genotyped with SNP arrays. Our objective was to discover new CNVs in ASD cases that were not detected by SNP microarray analysis and to delineate novel ASD risk loci via combined analysis of CGH and SNP array data sets on the ASD cohort and CGH data on an additional 1000 control samples. Of the 615 ASD cases analyzed on both SNP and CGH arrays, we found that 13,572 of 21,346 (64%) of the CNVs were exclusively detected by the CGH array. Several of the CGH-specific CNVs are rare in population frequency and impact previously reported ASD genes (e.g., NRXN1, GRM8, DPYD), as well as novel ASD candidate genes (e.g., CIB2, DAPP1, SAE1), and all were inherited except for a de novo CNV in the GPHN gene. A functional enrichment test of gene-sets in ASD cases over controls revealed nucleotide metabolism as a potential novel pathway involved in ASD, which includes several candidate genes for follow-up (e.g., DPYD, UPB1, UPP1, TYMP). Finally, this extensively phenotyped and genotyped ASD clinical cohort serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection.

Journal ArticleDOI
TL;DR: The results suggest that EGCG ester derivatives with anti-inflammatory potentials may be useful in preventing/treating inflammation-mediated diseases and health conditions.

Journal ArticleDOI
12 Jan 2012-Nature
TL;DR: It is reported that mouse IgA+ plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types.
Abstract: The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.

Journal ArticleDOI
Jillian P. Casey1, Tiago R. Magalhaes2, Tiago R. Magalhaes3, Judith Conroy1, Regina Regan1, Naisha Shah1, Richard Anney4, Denis C. Shields1, Brett S. Abrahams5, Joana Almeida, Elena Bacchelli6, Anthony J. Bailey7, Gillian Baird8, Agatino Battaglia, Tom Berney9, Nadia Bolshakova4, Patrick Bolton10, Thomas Bourgeron11, Sean Brennan4, Phil Cali12, Catarina Correia2, Catarina Correia3, Christina Corsello13, Marc N. Coutanche14, Geraldine Dawson15, Geraldine Dawson16, Maretha de Jonge17, Richard Delorme, Eftichia Duketis18, Frederico Duque, Annette Estes19, Penny Farrar14, Bridget A. Fernandez20, Susan E. Folstein21, Suzanne Foley14, Eric Fombonne22, Christine M. Freitag18, John R. Gilbert21, Christopher Gillberg23, Joseph T. Glessner24, Jonathan Green25, Stephen J. Guter12, Hakon Hakonarson24, Richard Holt14, Gillian Hughes4, Vanessa Hus13, Roberta Igliozzi, Cecilia Kim24, Sabine M. Klauck26, Alexander Kolevzon27, Janine A. Lamb28, Marion Leboyer29, Ann Le Couteur9, Bennett L. Leventhal30, Bennett L. Leventhal31, Catherine Lord13, Sabata C. Lund32, Elena Maestrini6, Carine Mantoulan33, Christian R. Marshall34, Helen McConachie9, Christopher J. McDougle35, Jane McGrath4, William M. McMahon36, Alison K. Merikangas4, Judith Miller36, Fiorella Minopoli6, Ghazala Mirza14, Jeff Munson19, Stanley F. Nelson37, Gudrun Nygren23, Guiomar Oliveira, Alistair T. Pagnamenta14, Katerina Papanikolaou38, Jeremy R. Parr9, Barbara Parrini, Andrew Pickles28, Dalila Pinto34, Joseph Piven15, David J. Posey35, Annemarie Poustka26, Fritz Poustka18, Jiannis Ragoussis14, Bernadette Rogé33, Michael Rutter10, Ana Filipa Sequeira2, Ana Filipa Sequeira3, Latha Soorya27, Inês Sousa14, Nuala Sykes14, Vera Stoppioni, Raffaella Tancredi, Maïté Tauber33, Ann P. Thompson39, Susanne Thomson32, John Tsiantis38, Herman van Engeland17, John B. Vincent34, Fred R. Volkmar40, Jacob A. S. Vorstman17, Simon Wallace14, Kai Wang24, Thomas H. Wassink41, Kathy White14, Kirsty Wing14, Kerstin Wittemeyer42, Brian L. Yaspan32, Lonnie Zwaigenbaum43, Catalina Betancur29, Joseph D. Buxbaum27, Rita M. Cantor37, Edwin H. Cook12, Hilary Coon36, Michael L. Cuccaro21, Daniel H. Geschwind5, Jonathan L. Haines32, Joachim Hallmayer44, Anthony P. Monaco14, John I. Nurnberger35, Margaret A. Pericak-Vance21, Gerard D. Schellenberg24, Stephen W. Scherer34, James S. Sutcliffe32, Peter Szatmari39, Veronica J. Vieland45, Ellen M. Wijsman19, Andrew Green1, Michael Gill4, Louise Gallagher4, Astrid M. Vicente2, Astrid M. Vicente3, Sean Ennis1 
TL;DR: A large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD highlights the applicability of HH mapping in complex disorders such as ASD and offers an alternative approach to the analysis of genome-wide association data.
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.