Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Ruumiillinen esine, materiaalinen suku : Tutkimus Pyhä Anna itse kolmantena -aiheisista keskiajan puuveistoksista Suomessa

Embobied Object, Material Family. Late-Medieval Wood Sculptures Depicting Saint Anne with the Virgin and Child in Finland Saint Anne, the mother of the Virgin Mary, was one of the most popular saints in Western Europe in the late Middle Ages. She was often depicted with two other figures, the Virgin and the Christ Child (Anna Selbdritt). The dissertation examines the polychrome wood sculptures showing this motif, with a special focus on those remaining in Finland. It investigates the meanings these sculptures had to their observers in the fifteenth-century Finland. The study sheds light to important material heritage which is little known and offers new insights into the cult and imagery of the holy grandmother. Methodologically the study is based on iconology and post-formalist art history, and it appropriates concepts such as spatiality, sanctity, corporeality, and gender. Taking a comparative approach it knits together larger tendencies and local people and incidents. By conflating methodological domains it renews the ways how fragmentary wood sculptures, lacking documentary written sources, can be contextually interpreted and comprehended. The sculptures are analyzed from three angles. Firstly, the study explores the sculptures by focusing on their materiality and facture, which is to consider them as records of their own making. The analysis provides new information concerning the quantity, location, and current condition of the sculptures and it also elucidates problems regarding attribution, dating, display, and craftsmanship. The book presents the results of the empirical study of 45 Saint Anne groups; these works are individually described in the large Appendix. Secondly, the works are contextualized to the specific historical conditions in which they were observed. The study discusses closely the circumstances in the Turku Cathedral around the shrine of Saint Anne, the popular belief, and the piety of individual persons. The sculptures, deemed as the embodiments of the holy characters, interacted with the devotees. Thirdly, the works are examined within the wider theological and ideological currents of the era centered on the body and Incarnation. Saint Anne with the Virgin and Child motif demonstrated the Carnal Trinity, the motherly side of the Holy Trinity. The dissertation argues that Saint Anne was interpreted as the female counterpart or, in a mythical sense, wife of God. Furthermore, the Child s implicit, simultaneous presence as a suffering or dead man imbues the sculptures with a sense of the Passion, thus associating them with the pietà and the Mater dolorosa motifs. The naked Christ Child underlines him as the offering and, eventually, the Eucharistic wafer. The study suggests that the sculptures mediate continuity and the bloodline between the generations by the intertwined and repeated gestures, clothing and positions of the portrayed figures. Regardless of the ostensible homeliness of the sculptures, so readily reiterated by earlier scholars, these sculptures represented creation and birth through the carnal yet holy mothers.

Fernando Pessoan ortonyymi ja heteronyymit modernistis-romanttisena myyttinä

Tutkimuksessani selvitän portugalilaisrunoilija Fernando Pessoan (1888-1935) heteronyymejä ja ortonyymiä modernistis-romanttisena myyttinä. Myytin piirteet paljastuivat Pessoan omia kirjoituksia ja runoja tutkimalla ja käyttämällä apuna Pessoa-tutkimusta. Tutkimusaineistonani ovat Pessoa-ortonyymin Mensagem-runoelma ja ”Autopsykografia”-runo, Álvaro de Campoksen vuonna 1917 Portugal Futurista –lehdessä julkaistu ”Ultimatum”-runomanifesti, Alberto Caeiron ”Guardador de Rebanhos”-runosikermä sekä Ricardo Reisin ”Oodit”-kokonaisuuteen kuuluvat runot: n:ro 59 ”Acima da verdade estão os deuses” (”Totuuden yläpuolella ovat jumalat”, 1914), n:ro 66 ”Olho os campos, Neera” (”Katson peltoja, Neera”, 1917), n:ro 181 ”Amo o que vejo” (”Rakastan sitä mitä näen”, 1934), n:ro 175 ”Estas só. Ninguem o sabe.” (”Olet yksin. Kukaan ei tiedä sitä”, 1933). Tutkimuksessani romanttisen runouden keskeisinä piirteinä pidetään uskoa taiteilijaneroon (geniukseen), mimeettiseen illuusioon (taide tavoittelee ulkoisen todellisuuden toisintamista mahdollisimman autenttisena) ja tekijän ja kokijan eli subjektin ja objektin erottamiseen toisistaan. Käsitänkin modernin runon tutkimuksessani hylänneen monia entisiä käsityksiä ja vastakkainasetteluja muun muassa tekijän ja ulkopuolisen maailman, mielen ja kielen välillä. Näitä moderneja ”rikkomuksia” identifioin ja määrittelen Pessoan heteronyymien runoudessa. Tutkimukseni apukäsitteitä ovat vilpittömyys ja autenttisuus, jotka kuvaavat runoilijan suhdetta itseensä ja muihin ja joita on pohtinut mm. Lionel Trilling teoksessaan Sincerity and authencity. Romanttisessa runoudessa suhde yhteisöön muodostui ensisijaisesti suhteessa omaan itseen, yhtenäiseen minuuteen nojaavan vilpittömyyden kautta, modernissa runoudessa hajanaisuutta ja yksilön suhdetta myös yhteisöön korostavan autenttisuuden avulla. Tutkimuksessani havaitsin, että Pessoa on jo tuotantonsa alusta lähtien kehittänyt tietoisesti modernistis-romanttista myyttiä – päätelmää tukivat niin Pessoan omat kirjoitukset kuin runoanalyysini. Pessoa ennusti ensimmäisen kerran romanttiseen nerotaiteilijaan vertautuvaa ”supra-Camõesia” ”A nova poesia Portuguesa Sociologicamente considerada” –esseessään vuonna 1912. Campoksen ”Ultimatum”-manifestissa puhuja uskoi muutaman useita kymmeniä persoonallisuuksia hallitsevan ”Synteesi-Ihmisen” tai ”supra-Camõesin” ilmestymiseen. ”Synteesi-Ihmisen” oli määrä palauttaa kukoistukseensa lamaantuneessa tilassa ollut Portugalin kirjallisuus uuteen kukoistukseensa. Eräänlaisen perustan koko myytille loi vuotta ennen Pessoan kuolemaa julkaistu Mensagem (suom. Viesti), jossa runoilija esittää saudosistisen ja sebastianistisen perustan. Teixeira de Pascoaesin kehittämä saudosismi näkyy Mensagemissa uskona Portugalin valtion perustajien ja laajentajien – löytöretkeilijöiden – edustamaan voittoisaan lusofoniseen mentaliteettiin, jonka Pessoa asettaa niin kansakunnan, runoilijan kuin ihmisen ihanteeksi. Toinen Mensagemissa esiintyvä myytin rakennusaine on sebastianismi eli usko kuningas Sebastianin (1554-1578) paluuseen. ”Synteesi-Ihminen”/”supra-Camões” oli reinkarnoitunut Sebastian, jonka piti palauttaa kansa ja kulttuuri kukoistukseensa lusofonisen valloittajamentaliteetin avulla. ”Autopsykografia”-runossaan Pessoa esittää puolestaan runoilijaa koskevan modernin poetiikan ongelmineen: esittävyyteen perustuva taide etäännyttää kokijan – taiteilijan – aina väistämättä ensimmäisestä, spontaanista ja luonnollisesta kokemuksesta ja tekee hänestä teeskentelijän ja simulakrumien (Baudrillard), toisen tason merkityksen tuottajan. ”Autopsykografian” moderni poetiikka koskee myös lukijaa, joka ei tavoita runoilijan välittämää merkitystä vaan kolmannen tason merkityksen. ”Autopsykografian” runous- ja ihmiskäsitys on moderni: runoilija on ammattimainen teeskentelijä, lähtökohtaisesti vilpillinen ja epäautenttinen. Pessoa ja Campos edustavat Pessoan objektiivisia heteronyymejä ja myytin modernia puolta. Pessoan subjektiiviset heteronyymit Reis ja Caeiro täydentävät objektiviisia, modernin ihmisen ahdistusta ja levottomuutta ilmaisseita Pessoaa ja Camposta ollen luonteeltaan romanttisia vilpittömyyden kannattajia. Caeiro arvosti näköaistia yli muiden aistien. Hänen tavoitteenaan oli katsoa aina kuin ensimmäistä kertaa, spontaanisti ja välittömästi kuin lapsi. Reis puolestaan korosti harmoniaa jumalten, ihmisten ja luonnon välillä ja uskoi kohtuullisiin aistinautintoihin. Molemmat muodostivat Pessoan myytin romanttisen puolen yhteisessä halussaan hylätä sosiaaliset roolit ja opetukset ja palata kohti yksilöllistä minää. Vilpittömyys ja autenttisuus ovat Caeiron ja Reisin ohjeita runoilijalle ja ihmiselle. Objektiiviset ja subjektiiviset heteronyymit yhdessä muodostavat modernistis-romanttisen myytin, joka kokonaisuudessaan on looginen: objektiiviset heteronyymit esittivät teeskentelyn, vilpillisyyden ja moderniuden ongelmat; subjektiiviset tarjosivat ratkaisua niihin, poisopettelua sosiaalisista rooleista ja rohkeutta mennä kohti omaa yksilöllistä minuutta.

Glass Formation in the Ternary Sulphate System, K2S04-Na2S04-ZnS04

Glasses have been prepared by conventional quenching techniques in the ternary sulphate system KzSO4-Na2SO4-ZnSO4, in the range 30-80 % ZnS04. The proportions of alkali sulphates in the glass have been varied widely. The glass formation region has been delineated and densities, refractive indices and microhardnesses have been measured. The heat capacities of the glasses have been measured over a wide range of temperature by differential scanning calorimetry. The effect of composition on molar volume, molar polarization and glass transition have been explained on the basis of a random close-packing model.

Use of CLIMEX modelling to identify prospective areas for exploration to find new biological control agents for prickly acacia

Selection of biocontrol agents that are adapted to the climates in areas of intended release demands a thorough analysis of the climates of the source and release sites. We present a case study that demonstrates how use of the CLIMEX software can improve decision making in relation to the identification of prospective areas for exploration for agents to control the woody weed, prickly acacia Acacia nilotica ssp. indica in the arid areas of north Queensland.

Two sympatric spotted gum species are molecularly homogeneous.

Large fruited spotted gum eucalypt Corymbia henryi occurs sympatrically with small fruited spotted gum Corymbia citriodora subspecies variegata over a large portion of its range on the east coast of Australia. The two taxa are interfertile, have overlapping flowering times and share a common set of insect and vertebrate pollinators. Previous genetic analysis of both taxa from two geographically remote sites suggested that the two were morphotypes rather than genetically distinct species. In this study we further explore this hypothesis of genic species by expanding sampling broadly through their sympatric locations and examine local-scale spatial genetic structure in stands that differ in species and age composition. Delineation of populations at five microsatellite loci, using an individual-based approach and Bayesian modelling, as well as clustering of individuals based on allele frequencies showed the two species to be molecularly homogeneous. Genetic structure aligned largely with geographic areas of origin, and followed an isolation-by-distance model, where proximal populations were generally less differentiated than more distant ones. At the stand level, spotted gums also generally showed little structure consistent with the high levels of gene flow inferred across the species range. Disturbances in the uniformity of structuring were detected, however, and attributed to localised events giving rise to even aged stands, probably due to regeneration from a few individuals following fire.

Lone-pair interactionsnext term in previous termmolecules

Theoretically calculated previous termlone-pairnext term splittings in H2O2, H2S2, N2H4, P2H4, glyoxal and dithioglyoxal have been compared with experimental values. Potential functions for rotation and the effect of geometry relaxation on rotomer energies have also been examined.

Studio portrait of Cora Berliner with her mother and sister; Hannover Portraits Family

Digital Image

Human papillomavirus infection and vaccination: Awareness and knowledge of HPV and acceptability of HPV vaccine among mothers of teenage daughters in Weihai, Shandong, China

In preparation for the introduction of human papillomavirus (HPV) vaccine, we investigated awareness and knowledge of HPV/HPV vaccine and potential acceptability to HPV vaccine among mothers with a teenage daughter in Weihai, Shandong, China. A cross-sectional survey was conducted in 2013 with a sample of 1850 mothers who had a daughter (aged 9–17 years) attending primary, junior and senior high schools. In the final sample (N = 1578, response rate 85.30%), awareness of HPV was reported by 305 (19.32%) mothers. Awareness varied significantly by daughter’s age (P<0.01), mother’s education level (P<0.01), mother’s occupation (P<0.01), household income (P<0.01) and residence type (P<0.01). Knowledge about HPV/HPV vaccine was poor with a mean total score of 3.56 (SD = 2.40) out of a possible score of 13. Mothers with a higher education level reported higher levels of knowledge (P = 0.02). Slightly more than one-fourth (26.49%) of mothers expressed their potential acceptability of HPV vaccine for their daughters. Acceptability increased along with increased daughters’ age (P<0.01), household income (P<0.01) and knowledge level (P<0.01). House wives and unemployed mothers had the highest acceptability (P<0.01). The most common reasons for not accepting HPV vaccination were “My daughter is too young to have risk of cervical cancer (30.95%)”, “The vaccine has not been widely used, and the decision will be made after it is widely used (24.91%)”, “Worry about the safety of the vaccine (22.85%)”. Awareness and knowledge of HPV/HPV vaccines are poor and HPV vaccine acceptability is low among these Chinese mothers. These results may help inform appropriate health education programs in this population.

Bacterial Community Structure in the Hindgut of Wild and Captive Dugongs (Dugong dugon)

Dugongs (Dugong dugon) are marine mammals that obtain nutrients through hindgut fermentation of seagrass, however, the microbes responsible have not been identified. This study used denaturing gradient gel electrophoresis (DGGE) and 454-pyrosequencing to profile hindgut bacterial communities in wild dugongs. Faecal samples obtained from 32 wild dugongs representing four size/maturity classes, and two captive dugongs fed on cos lettuce were screened using DGGE. Partial 16S rRNA gene profiles of hindgut bacteria from wild dugong calves and juveniles were grouped together and were different to those in subadults and adults. Marked differences between hindgut bacterial communities of wild and captive dugongs were also observed, except for a single captive whose profile resembled wild adults following an unsuccessful reintroduction to the wild. Pyrosequencing of hindgut communities in two wild dugongs confirmed the stability of bacterial populations, and Firmicutes (average 75.6% of Operational Taxonomic Units [OTUs]) and Bacteroidetes (19.9% of OTUs) dominated. Dominant genera were Roseburia, Clostridium, and Bacteroides. Hindgut microbial composition and diversity in wild dugongs is affected by ontogeny and probably diet. In captive dugongs, the absence of the dominant bacterial DNA bands identified in wild dugongs is probably dependent upon prevailing diet and other captive conditions such as the use of antibiotics. This study represents a first step in the characterisation of a novel microbial ecosystem-the marine hindgut of Sirenia.

Population dynamics of Thaumastocoris peregrinus in Eucalyptus plantations of South Africa

Thaumastocoris peregrinus is a sap-sucking insect that infests non-native Eucalyptus plantations in Africa, New Zealand, South America and parts of Southern Europe, in addition to street trees in parts of its native range of Australia. In South Africa, pronounced fluctuations in the population densities have been observed. To characterise spatiotemporal variability in T. peregrinus abundance and the factors that might influence it, we monitored adult population densities at six sites in the main eucalypt growing regions of South Africa. At each site, twenty yellow sticky traps were monitored weekly for 30 months, together with climatic data. We also characterised the influence of temperature on growth and survival experimentally and used this to model how temperature may influence population dynamics. T. peregrinus was present throughout the year at all sites, with annual site-specific peaks in abundance. Peaks occurred during autumn (February-April) for the Pretoria site, summer (November-January) for the Zululand site and spring (August-October) for the Tzaneen, Sabie and Piet Retief monitoring sites. Temperature (both experimental and field-collected), humidity and rainfall were mostly weakly, or not at all, associated with population fluctuations. It is clear that a complex interaction of these and other factors (e.g. host quality) influence population fluctuations in an annual, site specific cycle. The results obtained not only provide insights into the biology of T. peregrinus, but will also be important for future planning of monitoring and control programs using semiochemicals, chemical insecticides or biological control agents. © 2014 Springer-Verlag Berlin Heidelberg.

Population dynamics of Thaumastocoris peregrinus in Eucalyptus plantations of South Africa

Thaumastocoris peregrinus is a sap-sucking insect that infests non-native Eucalyptus plantations in Africa, New Zealand, South America and parts of Southern Europe, in addition to street trees in parts of its native range of Australia. In South Africa, pronounced fluctuations in the population densities have been observed. To characterise spatiotemporal variability in T. peregrinus abundance and the factors that might influence it, we monitored adult population densities at six sites in the main eucalypt growing regions of South Africa. At each site, twenty yellow sticky traps were monitored weekly for 30 months, together with climatic data. We also characterised the influence of temperature on growth and survival experimentally and used this to model how temperature may influence population dynamics. T. peregrinus was present throughout the year at all sites, with annual site-specific peaks in abundance. Peaks occurred during autumn (February–April) for the Pretoria site, summer (November–January) for the Zululand site and spring (August–October) for the Tzaneen, Sabie and Piet Retief monitoring sites. Temperature (both experimental and field-collected), humidity and rainfall were mostly weakly, or not at all, associated with population fluctuations. It is clear that a complex interaction of these and other factors (e.g. host quality) influence population fluctuations in an annual, site specific cycle. The results obtained not only provide insights into the biology of T. peregrinus, but will also be important for future planning of monitoring and control programs using semiochemicals, chemical insecticides or biological control agents.

Grid interfacing of a photovoltaic system using a chain cell converter

With the rapid development of photovoltaic system installations and increased number of grid connected power systems, it has become imperative to develop an efficient grid interfacing instrumentation suitable for photovoltaic systems ensuring maximum power transfer. The losses in the power converter play an important role in the overall efficiency of a PV system. Chain cell converter is considered to be efficient as compared to PWM converters due to lower switching losses, modularized circuit layout, reduced voltage rating of the converter switches, reduced EMI. The structure of separate dc sources in chain cell converter is well suited for photovoltaic systems as there will b several separate PV modules in the PV array which can act as an individual dc source. In this work, a single phase multilevel chain cell converter is used to interface the photovoltaic array to a single phase grid at a frequency of 50Hz. Control algorithms are developed for efficient interfacing of the PV system with grid and isolating the PV system from grid under faulty conditions. Digital signal processor TMS320F 2812 is used to implement the control algorithms developed and for the generation of other control signals.