Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. © 2011 Duncan et al.

A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways

Background: Changing perspectives on the natural history of celiac disease (CD), new serology and genetic tests, and amended histological criteria for diagnosis cast doubt on past prevalence estimates for CD. We set out to establish a more accurate prevalence estimate for CD using a novel serogenetic approach.Methods: The human leukocyte antigen (HLA)-DQ genotype was determined in 356 patients with 'biopsy-confirmed' CD, and in two age-stratified, randomly selected community cohorts of 1,390 women and 1,158 men. Sera were screened for CD-specific serology.Results: Only five 'biopsy-confirmed' patients with CD did not possess the susceptibility alleles HLA-DQ2.5, DQ8, or DQ2.2, and four of these were misdiagnoses. HLA-DQ2.5, DQ8, or DQ2.2 was present in 56% of all women and men in the community cohorts. Transglutaminase (TG)-2 IgA and composite TG2/deamidated gliadin peptide (DGP) IgA/IgG were abnormal in 4.6% and 5.6%, respectively, of the community women and 6.9% and 6.9%, respectively, of the community men, but in the screen-positive group, only 71% and 75%, respectively, of women and 65% and 63%, respectively, of men possessed HLA-DQ2.5, DQ8, or DQ2.2. Medical review was possible for 41% of seropositive women and 50% of seropositive men, and led to biopsy-confirmed CD in 10 women (0.7%) and 6 men (0.5%), but based on relative risk for HLA-DQ2.5, DQ8, or DQ2.2 in all TG2 IgA or TG2/DGP IgA/IgG screen-positive subjects, CD affected 1.3% or 1.9%, respectively, of females and 1.3% or 1.2%, respectively, of men. Serogenetic data from these community cohorts indicated that testing screen positives for HLA-DQ, or carrying out HLA-DQ and further serology, could have reduced unnecessary gastroscopies due to false-positive serology by at least 40% and by over 70%, respectively.Conclusions: Screening with TG2 IgA serology and requiring biopsy confirmation caused the community prevalence of CD to be substantially underestimated. Testing for HLA-DQ genes and confirmatory serology could reduce the numbers of unnecessary gastroscopies. © 2013 Anderson et al.; licensee BioMed Central Ltd.

Cohort profile: Andhra Pradesh Children and Parents Study (APCAPS)

The Andhra Pradesh Children and Parents Study (APCAPS) was originally established to study the long-term effects of early-life undernutrition on risk of cardiovascular disease. Its aims were subsequently expanded to include trans-generational influences of other environmental and genetic factors on chronic diseases in rural India. It builds on the Hyderabad Nutrition Trial (HNT) conducted in 1987–90 to compare the effects on birthweight of a protein-calorie supplement for pregnant women and children. The index children of HNT and their mothers were retraced and examined in 2003–05, and the children re-examined as young adults aged 18–21 years in 2009–10. The cohort was expanded to include both parents and siblings of the index children in a recently completed follow-up conducted in 2010–12 (N = ∼6225 out of 10 213 participants). Recruitment of the remaining residents of these 29 villages (N = ∼55 000) in Ranga Reddy district of Andhra Pradesh is now under way. Extensive data on socio-demographic, lifestyle, medical, anthropometric, physiological, vascular and body composition measures, DNA, stored plasma, and assays of lipids and inflammatory markers on APCAPS participants are available. Details of how to access these data are available from the corresponding author.

HLA-DR/DQ haplotype in rheumatoid arthritis: Novel allelic associations in UK Caucasians

Objective. To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA). Methods. HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method. Results. Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRβ molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident. Conclusion. These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region.

Tule, rakkaani! : Naisen ja miehen välisestä etiikasta kirjallisuuden rakkauskuvauksissa

Tutkin väitöskirjassani naisen ja miehen välistä rakkautta ja naisen ja miehen välisen rakkauden kuvauksia kirjallisuudessa ranskalaisen filosofin Luce Irigarayn samuuden järjestyksen kritiikin ja sukupuolieron etiikan valossa. Osoitan ensinnäkin, kuinka Platonin Pidoissa, Percy Bysshe Shelleyn Epipsychidionissa (1821) ja Barbara Cartlandin Liekehtivässä lumessa (1975) kuvataan rakkautta kahden rakastavaisen yhteensulautumiseksi - tutkin millaisia haltuunottamisen ja sulauttamisen muotoja rakastavaisten välillä näissä teoksissa tulee esille. Toiseksi osoitan, kuinka Laulujen laulussa, Dian kreivittären 1100-luvulla kirjoittamassa lyriikassa ja Guillevicin runokokoelmasta Trouées (1981) löytyvässä sikermässä Ylistyslaulu kuvataan rakkautta kahden toisiinsa palautumattoman rakastavaisen väliseksi suhteeksi - syvennyn näistä teoksista löytyviin kuvauksiin toista ihmettelevästä kohtaamisesta, toisen huomioonottavasta puhuttelemisesta ja toista hyväilevästä koskettamisesta. Tutkimukseni keskiössä on siis rakastavaisten välinen etiikka eli kysymykset siitä, kuinka rakastavaisten välinen suhde voisi toteutua ilman että kumpikaan pyrkisi haltuunottamaan toista. Objektivoivan analyysin sijaan tutkimusmenetelmänäni on rakkaudellinen vuoropuhelu niin valitsemieni kaunokirjallisten teosten kuin Irigarayn filosofiankin kanssa. Seuraan tässä Irigarayn ja toisen ranskalaisen ajattelijan Hélène Cixous'n työskentelytapoja - heidän mukaansa pysähtyvä ja kuulosteleva asenne on pyrkivää ja tarttuvaa otetta hedelmällisempi niin inhimillistä toista kuin kirjallistakin toista lähestyttäessä, sillä sen avulla toinen voi säilyttää liikkuvuutensa, arvaamattomuutensa ja vapautensa. Työni tulokset ovat johtopäätösten sijaan avauksia. Jatkan tutkimuksessani Irigarayn työtä ulottamalla hänen samuuden järjestyksen kritiikkinsä ja sukupuolieron etiikan hahmottelunsa kirjallisuudentutkimuksen alueelle. Irigarayta seuraten ajattelen uudelleen naisen ja miehen, henkisen ja ruumiillisen, aistimellisen ja transsendentaalisen välisiä suhteita. Tehtävänämme ei ole muodostaa rakkauden teoriaa tai rakastavaisten välisen etiikan ohjelmaa, vaan tutkia mitä etiikka merkitsee ja voisi merkitä rakkauden alueella.

Phylogeography of the pharaoh cuttle Sepia pharaonis based on partial mitochondrial 16S sequence data

The pharaoh cuttle Sepia pharaonis Ehrenberg, 1831 (Mollusca: Cephalopoda: Sepiida) is a broadly distributed species of substantial fisheries importance found from east Africa to southern Japan. Little is known about S. pharaonis phylogeography, but evidence from morphology and reproductive biology suggests that Sepia pharaonis is actually a complex of at least three species. To evaluate this possibility, we collected tissue samples from Sepia pharaonis from throughout its range. Phylogenetic analyses of partial mitochondrial 16S sequences from these samples reveal five distinct clades: a Gulf of Aden/Red Sea clade, a northern Australia clade, a Persian Gulf/Arabian Sea clade, a western Pacific clade (Gulf of Thailand and Taiwan) and an India/Andaman Sea clade. Phylogenetic analyses including several Sepia species show that S. pharaonis sensu lato may not be monophyletic. We suggest that "S. pharaonis" may consist of up to five species, but additional data will be required to fully clarify relationships within the S. pharaonis complex.

Neuronal oscillations in gamma- and alpha-frequency bands: from object representations to sensory awareness

The synchronization of neuronal activity, especially in the beta- (14-30 Hz) /gamma- (30 80 Hz) frequency bands, is thought to provide a means for the integration of anatomically distributed processing and for the formation of transient neuronal assemblies. Thus non-stimulus locked (i.e. induced) gamma-band oscillations are believed to underlie feature binding and the formation of neuronal object representations. On the other hand, the functional roles of neuronal oscillations in slower theta- (4 8 Hz) and alpha- (8 14 Hz) frequency bands remain controversial. In addition, early stimulus-locked activity has been largely ignored, as it is believed to reflect merely the physical properties of sensory stimuli. With human neuromagnetic recordings, both the functional roles of gamma- and alpha-band oscillations and the significance of early stimulus-locked activity in neuronal processing were examined in this thesis. Study I of this thesis shows that even the stimulus-locked (evoked) gamma oscillations were sensitive to high-level stimulus features for speech and non-speech sounds, suggesting that they may underlie the formation of early neuronal object representations for stimuli with a behavioural relevance. Study II shows that neuronal processing for consciously perceived and unperceived stimuli differed as early as 30 ms after stimulus onset. This study also showed that the alpha band oscillations selectively correlated with conscious perception. Study III, in turn, shows that prestimulus alpha-band oscillations influence the subsequent detection and processing of sensory stimuli. Further, in Study IV, we asked whether phase synchronization between distinct frequency bands is present in cortical circuits. This study revealed prominent task-sensitive phase synchrony between alpha and beta/gamma oscillations. Finally, the implications of Studies II, III, and IV to the broader scientific context are analysed in the last study of this thesis (V). I suggest, in this thesis that neuronal processing may be extremely fast and that the evoked response is important for cognitive processes. I also propose that alpha oscillations define the global neuronal workspace of perception, action, and consciousness and, further, that cross-frequency synchronization is required for the integration of neuronal object representations into global neuronal workspace.

Portrait of Isaak Meyerhof; Hildesheim, Germany.

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Ptesculentoside, a novel norsesquiterpene glucoside from the Australian bracken fern Pteridium esculentum.

A novel norsesquiterpene glucoside ptesculentoside has been isolated from the Australian bracken Pteridium esculentum, together with the known bracken carcinogen ptaquiloside and lesser amounts of caudatoside. The structure of ptesculentoside is determined by analysis of 1D and 2D NMR spectra, and via its conversion into previously known pterosin G.

The use of heat-sums to predict harvest dates following potassium chlorate (KClO3) application in longan.

The ability to initiate and manipulate flowering with KClO3 allows flowering of longan, to be triggered outside of the normal flowering season (July-September) in Australia. Fruit maturity following normal flowering will occur approximately six-eight months (180-220 days) from flowering, depending on variety. Out of season flowering will result in differing times to maturity due to different temperature regimes during the maturity period. Knowing how long fruit will take to mature from different KClO3 application dates is potentially a valuable tool for growers to use as it would allow them to time their applications with market opportunities, e.g. Chinese New Year, periods of low volumes or periods of high prices. A simple heat-sum calculation was shown to reliably quantify fruit maturity periods, 2902 and 3432 growing degree days for Kohala and Biew Kiew respectively. Growers can use heat-sum as a predictive tool to allow for efficient planning of harvesting, packaging and freight requirements.

Portrait of Ludwig Oelsner Portraits Men

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Portrait of Isaak Meyerhof; Hildesheim, Germany.

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Reproduction of painting by Frieda Ruelf of Rabbi Dr. Isaac Ruelf Portraits; Men

Signed by the artist bottom right

Combined Jewish Philanthropies (Boston, Mass.) records, undated, 1865-1989 (bulk 1942-1979)

The Combined Jewish Philanthropies (CJP) of Boston, Massachusetts is the oldest federated Jewish philanthropy in the United States. The current incarnation of CJP was formed in 1960, when two separate federated philanthropies – the Combined Jewish Appeal and Associated Jewish Philanthropies – merged to create a single organization dedicated to serving the needs of Boston’s Jewish community. CJP’s records contain the history of several other organizations, from the forerunners of the current Federation to the Jewish institutions supported by CJP. Their beginnings can be traced to the founding of the United Hebrew Benevolent Association (UHBA) in 1864 at the Pleasant Street Synagogue (now Temple Israel.) This collection contains meeting minutes, correspondence, photographs, scrapbooks, financial documents and ledgers, appeal information, publicity, programs, brochures and other written documents relating CJP’s history.

In search of Gustav: The story of the Lilienfeld (later Lynfield) family covering the last 200 years 1800-1920

This is the first of three books about the history of Geoffrey Lynfield's family. It is about four Lilienfeld brothers--Geoffrey Lynfield's grandfather and his brothers. They were born in the Jewish enclave of Marburg and ended up in South Africa when and where the first diamonds were discovered. The manuscript also includes photographs and documents.