Participation de l'endocarde dans les malformations cardiaques du syndrome Holt-Oram

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

John Holt, 1923-85

Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries

Several studies have demonstrated an association between polycystic ovary syndrome (PCOS) and the dinucleotide repeat microsatellite marker D19S884, which is located in intron 55 of the fibrillin-3 (FBN3) gene. Fibrillins, including FBN1 and 2, interact with latent transforming growth factor (TGF)-β-binding proteins (LTBP) and thereby control the bioactivity of TGFβs. TGFβs stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, features feasibly influenced by abnormal fibrillin expression. To examine a possible role of fibrillins in PCOS, particularly FBN3, we undertook tagging and functional single nucleotide polymorphism (SNP) analysis (32 SNPs including 10 that generate non-synonymous amino acid changes) using DNA from 173 PCOS patients and 194 controls. No SNP showed a significant association with PCOS and alleles of most SNPs showed almost identical population frequencies between PCOS and control subjects. No significant differences were observed for microsatellite D19S884. In human PCO stroma/cortex (n = 4) and non-PCO ovarian stroma (n = 9), follicles (n = 3) and corpora lutea (n = 3) and in human ovarian cancer cell lines (KGN, SKOV-3, OVCAR-3, OVCAR-5), FBN1 mRNA levels were approximately 100 times greater than FBN2 and 200–1000-fold greater than FBN3. Expression of LTBP-1 mRNA was 3-fold greater than LTBP-2. We conclude that FBN3 appears to have little involvement in PCOS but cannot rule out that other markers in the region of chromosome 19p13.2 are associated with PCOS or that FBN3 expression occurs in other organs and that this may be influencing the PCOS phenotype.

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Solis-Cohen family papers, 1808-1990.

Correspondence, diaries, acount books, pamphlets, and other personal and professional materials pertaining to Jacob da Silva Solis and his descendents.

Surface motions and intraplate continental deformation in Alaska driven by mantle flow

The degree to which the lithosphere and mantle are coupled and contribute to surface deformation beneath continental regions remains a fundamental question in the field of geodynamics. Here we use a new approach with a surface deformation field constrained by GPS, geologic, and seismicity data, together with a lithospheric geodynamic model, to solve for tractions inferred to be generated by mantle convection that (1) drive extension within interior Alaska generating southward directed surface motions toward the southern convergent plate boundary, (2) result in accommodation of the relative motions between the Pacific and North America in a comparatively small zone near the plate boundary, and (3) generate the observed convergence within the North American plate interior in the Mackenzie mountains in northwestern Canada. The evidence for deeper mantle influence on surface deformation beneath a continental region suggests that this mechanism may be an important contributing driver to continental plate assemblage and breakup.

Joint modeling of lithosphere and mantle dynamics: Evaluation of constraints from global tomography models

With the advances in technology, seismological theory, and data acquisition, a number of high-resolution seismic tomography models have been published. However, discrepancies between tomography models often arise from different theoretical treatments of seismic wave propagation, different inversion strategies, and different data sets. Using a fixed velocity-to-density scaling and a fixed radial viscosity profile, we compute global mantle flow models associated with the different tomography models and test the impact of these for explaining surface geophysical observations (geoid, dynamic topography, stress, and strain rates). We use the joint modeling of lithosphere and mantle dynamics approach of Ghosh and Holt (2012) to compute the full lithosphere stresses, except that we use HC for the mantle circulation model, which accounts for the primary flow-coupling features associated with density-driven mantle flow. Our results show that the seismic tomography models of S40RTS and SAW642AN provide a better match with surface observables on a global scale than other models tested. Both of these tomography models have important similarities, including upwellings located in Pacific, Eastern Africa, Iceland, and mid-ocean ridges in the Atlantic and Indian Ocean and downwelling flows mainly located beneath the Andes, the Middle East, and central and Southeast Asia.

An address delivered on the occasion of the funeral of the Rev. William James

Address

The type I antifreeze protein gene family in Pleuronectidae

Antifreeze proteins (AFPs) protect marine teleosts from freezing in icy seawater by binding to nascent ice crystals and preventing their growth. It has been suggested that the gene dosage for AFPs in fish reflects the degree of exposure to harsh winter climates. The starry flounder, _Platichthys stellatus_, has been chosen to examine this relationship because it inhabits a range of the Pacific coast from California to the Arctic. This flatfish is presumed to produce type I AFP, which is an alanine-rich, amphipathic alpha-helix. Genomic DNA from four starry flounder was Southern blotted and probed with a cDNA of a winter flounder liver AFP. The hybridization signal was consistent with a gene family of approximately 40 copies. Blots of DNA from other starry flounder indicate that California fish have far fewer gene copies whereas Alaska fish have far more. This analysis is complicated by the fact that there are three different type I AFP isoforms. The first is expressed in the liver and secreted into circulation, the second is a larger hyperactive dimer also thought to be expressed in the liver, and the third is expressed in peripheral tissues. To evaluate the contribution of these latter two isoforms to the overall gene signal on Southern blots, hybridization probes for the three isoforms were isolated from starry flounder DNA by genomic cloning. Two clones revealed linkage of genes for different isoforms, and this was confirmed by genomic Southern blotting, where hybridization patterns indicated that the majority of genes were present in tandem repeats. The sequence and diversity of all three isoforms was sampled in the starry flounder genome by PCR. All coding sequences derived for the skin and liver isoforms were consistent with the proposed structure-function relationships for this AFP, where the flat hydrophobic side of the helix is conserved for ice binding. There was greater sequence diversity in the skin and hyperactive isoforms than in the liver isoform, suggesting that the latter evolved recently from one of the other two. The genomic PCR primers are currently being used to sample isoform diversity in related right-eyed flounders to test this hypothesis.

William Herschel Telescope observations of distant comets

We present results from broad-band V- and R-filter observations obtained at the 4.2-m William Herschel Telescope on La Palma on 2002 July 12-14. A total of six comets were imaged, and their heliocentric distances ranged from 2.8 to 6.1 au. The comets observed were 43P/Wolf-Harrington, 129P/Shoemaker-Levy 3, 133P/Elst-Pizarro, 143P/Kowal-Mrkos, P/1998 U4 (Spahr) and P/2001 H5 (NEAT). A detailed surface brightness profile analysis indicates that three of the targeted comets (43P/Wolf-Harrington, 129P/Shoemaker-Levy 3 and P/1998 U4) were visibly active, and the remaining three comets were stellar in appearance. Further analysis shows that for the three `stellar-like' comets the possible coma contribution to the observed flux does not exceed 12.2 per cent, and in the case of comet 143P/Kowal-Mrkos the coma contribution is expected to be as low as 1 per cent, and so the resulting photometry most likely represents that of the projected nucleus surface. Effective radii for the inactive comets range from 1.02 to 4.56 km, and the effective radius upper limits for the active comets range from 1.94 to 4.15 km. We assume an albedo and phase coefficient of 0.04 and 0.035 mag deg-1, respectively, with the exception of comets 133P/Elst-Pizarro and 143P/Kowal-Mrkos for which phase coefficients were previously measured. These values are compared with previous measurements, and for comet 43P/Wolf-Harrington we find that the nucleus axial ratio a/b could be as large as 2.44. For the active comets we measured dust production levels in terms of the Af? quantity. Spectral gradients were extracted for two of the inactive comets from their measured broad-band colour indices, and compared with the rest of the comet population for which (V-R) colour and spectral gradient values exist. We find a spectral gradient for 143P/Kowal-Mrkos of 9.9 +/- 8.1 per cent/100 nm, which is very typical of Jupiter-family comets, the majority of which have reflectivity gradients in the range 0-13 per cent (100 nm)-1. The spectral gradient for comet 133P/Elst-Pizarro is amongst the bluest yet measured. We measure a (V-R) colour index value of 0.14 +/- 0.11 for the nucleus of 133P/Elst-Pizarro which is considerably lower than previous measurements. A possible explanation for this difference is considered.

The persistent activity of Jupiter-family comets at 3-7 AU

We present an analysis of comet activity based on the Spitzer Space Telescope component of the Survey of the Ensemble Physical Properties of Cometary Nuclei. We show that the survey is well suited to measuring the activity of Jupiter-family comets at 3-7 AU from the Sun. Dust was detected in 33 of 89 targets (37 ± 6%), and we conclude that 21 comets (24 ± 5%) have morphologies that suggest ongoing or recent cometary activity. Our dust detections are sensitivity limited, therefore our measured activity rate is necessarily a lower limit. All comets with small perihelion distances (q <1.8 AU) are inactive in our survey, and the active comets in our sample are strongly biased to post-perihelion epochs. We introduce the quantity ɛfρ, intended to be a thermal emission counterpart to the often reported Afρ, and find that the comets with large perihelion distances likely have greater dust production rates than other comets in our survey at 3-7 AU from the Sun, indicating a bias in the discovered Jupiter-family comet population. By examining the orbital history of our survey sample, we suggest that comets perturbed to smaller perihelion distances in the past 150 yr are more likely to be active, but more study on this effect is needed.

When terror hits home: Identity Fused Americans who saw Boston bombing victims as “family” provided aid

When tragedy strikes a group, only some group members characteristically rush to the aid of the victims. What motivates the altruism of these exceptional individuals? Here, we provide one set of answers based on data collected before and shortly after the 15 April 2013, Boston Marathon bombings. The results of three studies indicated that Americans who were strongly “fused” with their country were especially inclined to provide various forms of support to the bombing victims. Moreover, the degree to which participants reported perceiving fellow Americans as psychological kin statistically mediated links between fusion and pro-group outcomes. Together, these findings shed new light on relationships between personal and group identity, cognitive representations of group members, and personally costly, pro-group actions.