Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm

Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dualenergy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a metaanalysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10-8) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10-9). The gene-based association test suggested an association between MEF2C and forearm BMD ( p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Hierarchically structured porous poly(2-oxazoline) hydrogels

A new method for fabricating hydrogels with intricate control over hierarchical 3D porosity using micro-fiber porogens is presented. Melt electrospinning writing of poly(ε-caprolactone) is used to create the sacrificial template leading to hierarchical structuring consisting of pores inside the denser poly(2-oxazoline) hydrogel mesh. This versatile approach provides new opportunities to create well-defined multilevel control over interconnected pores with diameters in the lower micrometer range inside hydrogels with potential applications as cell scaffolds with tunable diffusion and transport of, e.g. nutrients, growth factors or therapeutics.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

Suggestive linkage of the parathyroid receptor type 1 to osteoporosis

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < -2.5) and low BMD relative to an age- and gender-matched cohort (Z score < -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH-related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. Sixty-four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7-3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL-1α (MLS 1.4), IL-4 (MLS 1.2), and IL-6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband-wise ascertainment, also showed evidence of linkage (p ≤0.05) at markers close to or within the candidate genes IL- 1α, PTHR1, IL-6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.

Risk analysis of prostate cancer in PRACTICAL, a multinational consortium, using 25 known prostate cancer susceptibility loci

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS).We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived agespecific absolute risks of developing prostate cancer by PRS stratum and family history. Results The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact:We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

Not “just words”: Exposure to homophobic epithets leads to dehumanizing and physical distancing from gay men

We examined whether homophobic epithets (e.g., faggot) function as labels of deviance for homosexuals that contribute to their dehumanization and physical distance. Across two studies, participants were supraliminally (Study 1) and subliminally (Study 2) exposed to a homophobic epithet, a category label, or a generic insult. Participants were then asked to associate human related and animal-related words to homosexuals and heterosexuals. Results showed that after exposure to a homophobic epithet, compared with a category label or a generic insult, participants associated less human-related words with homosexuals, indicating dehumanization. In Study 2, we also assessed the effect of a homophobic epithet on physical distance from a target group member and found that homophobic epithets led to greater physical distancing of a gay man. These findings indicate that homophobic epithets foster dehumanization and avoidance of gay people, in ways that other insults or labels do not.

Counter-figures : An Essay on Antimetaphoric Resistance: Paul Celan's Poetry and Poetics at the Limits of Figurality

Titled "An Essay on Antimetaphoric Resistance", the dissertation investigates what is here being called "Counter-figures": a term which has in this context a certain variety of applications. Any other-than-image or other-than-figure, anything that cannot be exhausted by figuration (and that is, more or less, anything at all, except perhaps the reproducible images and figures themselves) can be considered "counter-figurative" with regard to the formation of images and figures, ideas and schemas, "any graven image, or any likeness of any thing". Singularity and radical alterity, as well as temporality and its peculiar mode of uniqueness are key issues here, and an ethical dimension is implied by, or intertwined with, the aesthetic. In terms borrowed from Paul Celan's "Meridian" speech, poetry may "allow the most idiosyncratic quality of the Other, its time, to participate in the dialogue". This connection between singularity, alterity and temporality is one of the reasons why Celan so strongly objects to the application of the traditional concept of metaphor to poetry. As Celan says, "carrying over [übertragen]" by metaphor may imply an unwillingness to "bear with [mittragen]" and to "endure [ertragen]" the poem. The thesis is divided into two main parts. The first consists of five distinct prolegomena which all address the mentioned variety of applications of the term "counter-figures", and especially the rejection or critique of either metaphor (by Aristotle, for instance) or the concept of metaphor (defined by Aristotle, and sometimes deemed "anti-poetic" by both theorists and poets). Even if we restrict ourselves to the traditional rhetorico-poetical terms, we may see how, for instance, metonymy can be a counter-figure for metaphor, allegory for symbol, and irony for any single trope or for any piece of discourse at all. The limits of figurality may indeed be located at these points of intersection between different types of tropes or figures, and even between figures or tropes and the "non-figurative trope" or "pseudo-figure" called catachresis. The second part, following on from the open-ended prolegomena, concentrates on Paul Celan's poetry and poetics. According to Celan, true poetry is "essentially anti-metaphoric". I argue that inasmuch as we are willing to pay attention to the "will" of the poetic images themselves (the tropes and metaphors in a poem) to be "carried ad absurdum", as Celan invites us to do, we may find alternative ways of reading poetry and approaching its "secret of the encounter", precisely when the traditional rhetorical instruments, and especially the notion of metaphor, become inapplicable or suspicious — and even where they still seem to impose themselves.

Breastmilk-saliva interactions boost innate immunity by regulating the oral microbiome in early infancy

Introduction Xanthine oxidase (XO) is distributed in mammals largely in the liver and small intestine, but also is highly active in milk where it generates hydrogen peroxide (H2O2). Adult human saliva is low in hypoxanthine and xanthine, the substrates of XO, and high in the lactoperoxidase substrate thiocyanate, but saliva of neonates has not been examined. Results Median concentrations of hypoxanthine and xanthine in neonatal saliva (27 and 19 μM respectively) were ten-fold higher than in adult saliva (2.1 and 1.7 μM). Fresh breastmilk contained 27.3±12.2 μM H2O2 but mixing baby saliva with breastmilk additionally generated >40 μM H2O2, sufficient to inhibit growth of the opportunistic pathogens Staphylococcus aureus and Salmonella spp. Oral peroxidase activity in neonatal saliva was variable but low (median 7 U/L, range 2–449) compared to adults (620 U/L, 48–1348), while peroxidase substrate thiocyanate in neonatal saliva was surprisingly high. Baby but not adult saliva also contained nucleosides and nucleobases that encouraged growth of the commensal bacteria Lactobacillus, but inhibited opportunistic pathogens; these nucleosides/bases may also promote growth of immature gut cells. Transition from neonatal to adult saliva pattern occurred during the weaning period. A survey of saliva from domesticated mammals revealed wide variation in nucleoside/base patterns. Discussion and Conclusion During breast-feeding, baby saliva reacts with breastmilk to produce reactive oxygen species, while simultaneously providing growth-promoting nucleotide precursors. Milk thus plays more than a simply nutritional role in mammals, interacting with infant saliva to produce a potent combination of stimulatory and inhibitory metabolites that regulate early oral–and hence gut–microbiota. Consequently, milk-saliva mixing appears to represent unique biochemical synergism which boosts early innate immunity.

Three Sides of a Wall : Obstacles and Border States in Paul Auster's Novels

Tutkielmani käsittelee yhdysvaltalaisen kirjailijan Paul Austerin (s. 1947) romaanituotannossa esiintyviä esteitä ja rajatiloja. Erityisesti olen kiinnostunut siitä, miten Auster liittää nämä "marginaalitilat" amerikkalaiseen vapauden ja laajentumisen ideologiaan sekä kieleen ja kirjoittamiseen. Austerin romaaneissa esteiden ja rajatilojen käsittely voidaan jakaa kolmeen vaiheeseen. Ensimmäisessä vaiheessa henkilöt ovat vahvojen esteiden rajoittamia tai rakentavat niitä itse. Rajoittuneisuus ei kuitenkaan aina tunnu häiritsevän heitä - itse asiassa monet päähenkilöistä tuntevat itsensä onnellisiksi tai vähintäänkin tyytyväisiksi joutuessaan esteen takia pysähdyttämään vapaan liikkeensä. Toisessa vaiheessa henkilöt pyrkivät ylittämään tai rikkomaan esteen päästäkseen toiselle puolelle. Kuten amerikkalaiset esi-isänsä aikoinaan, he etsivät rajatonta, laajaa ja tyhjää tilaa - "suurta tuntematonta" valloitettavakseen. Tällaisen tilan kohdatessaan he joutuvat kuitenkin usein epävarmuuden valtaan. Kolmas vaihe on tutkielmani kannalta tärkein: välitila, josta käytän työssäni nimitystä "in-betweenity". Tähän vaiheeseen päästään kulkemalla ensin kahden muun vaiheen kautta. Juuri tietoisuus näistä kahdesta muusta vaiheesta synnyttää tämän kolmannen tilan, eräänlaisen rajatilan, jossa tajutaan sekä esteiden että esteettömyyden tärkeys. Tämä välitila on Austerille tyypillinen tila, joka kertoo paitsi amerikkalaisen unelman paradoksaalisuudesta myös (kaunokirjallisen) kielenkäytön prosessista. Monet Austerin kirjojen muurin rakentajista tai purkajista voidaan nähdä kirjailijahahmoina, joiden omituinen suhde esteisiin ja rajoihin kumpuaa juuri siitä rajatilasta, jonka asukkaita he kielentaiteilijoina väistämättä ovat. Tällaisen tilan/tilattomuuden kuvaaminen tekee Austerista oman postmodernin aikamme tärkeän kirjailijan - kirjailijan, joka sen sijaan, että pyrkisi eroon paradokseista, sijoittaa hahmonsa niiden sisään. Rajoihin ja esteisiin liittyvä problematiikka ei kuitenkaan ole pelkästään nykyajan ongelma vaan kysymys, joka ihmisen toisaalta rajoja kaipaavan toisaalta rajattomuutta kaipaavan luonteen vuoksi säilyy aina ajankohtaisena. Avainsanat: Paul Auster, este, muuri, raja, Yhdysvallat

Konstruktiivisen linjakkuuden perusteita etsimässä : Systemaattinen analyysi John Biggsin esittämistä yliopisto-opetuksen lähtökohdista

The aim of this study is to explore by systematic textual analysis the crucial conceptions of constructive alignment and to reconstruct the concept of constructive alignment and examine the relation between conceptual relationships in John Biggs’s texts. In this study, I have also analyzed the presuppositions of the concept of constructive alignment and its possible implications. The research material includes Biggs’s (1996b; 2003) article entitled Enhancing Teaching through Constructive Alignment and book entitled Teaching for Quality Learning at University. The primary purpose of the systematic textual analysis is to reconstruct concepts and gain access to a new or more profound understanding of the concepts. The main purpose of the constructive alignment is to design a teaching system that supports and encourages students to adopt a deep approach learning. At the center of the constructive alignment are two concepts: constructivism in learning and alignment in teaching. A tension was detected between these concepts. Biggs assumes that students’ learning activities are primed by the teaching. Because of this it is not important what the teacher does. At the same time he emphasizes that teaching interacts with learning. The teacher’s task is to support student’s appropriate learning activities. On the basis of the analysis, I conclude these conceptions are not mutually exclusive. Interaction between teaching and learning has an effect on student’s learning activities. The most essential benefit of the model of constructive alignment is that Biggs brings together and considers teaching at the same level with learning. A weakness of Biggs’s model relates to the theoretical basis and positions of the concept of constructive alignment. There are some conflicts between conceptions of epistemology in Biggs’s texts. In addition, Biggs writes about constructivism also as conceptions of epistemology, but doesn’t consider implications of that position or what follows or doesn’t follow from that commitment. On the basis of the analysis, I suggest that constructivism refers in Biggs’s texts rather to constructivism in learning than philosophical constructivism. In light of this study, constructive alignment doesn´t lead to philosophical constructivism. That’s why constructive alignment stays out of idealism. Biggs’s way of thinking about teachers possibility to confronting students’ misconceptions and evaluate and assess students’ constructions support a realist purpose in terms of philosophical stance. Realism does not drift toward general problems of relativism, like lack of criteria for assessing or evaluate these constructions.