Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Background: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. Methods: We aim to identify genetic risk factors by a “trio-based” exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Results: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Conclusions: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD

Mortality Attributable to Low Levels of Education in the United States

BackgroundEducational disparities in U.S. adult mortality are large and have widened across birth cohorts. We consider three policy relevant scenarios and estimate the mortality attributable to: (1) individuals having less than a high school degree rather than a high school degree, (2) individuals having some college rather than a baccalaureate degree, and (3) individuals having anything less than a baccalaureate degree rather than a baccalaureate degree, using educational disparities specific to the 1925, 1935, and 1945 cohorts.MethodsWe use the National Health Interview Survey data (1986–2004) linked to prospective mortality through 2006 (N=1,008,949), and discrete-time survival models, to estimate education- and cohort-specific mortality rates. We use those mortality rates and data on the 2010 U.S. population from the American Community Survey, to calculate annual attributable mortality estimates.ResultsIf adults aged 25–85 in the 2010 U.S. population experienced the educational disparities in mortality observed in the 1945 cohort, 145,243 deaths could be attributed to individuals having less than a high school degree rather than a high school degree, 110,068 deaths could be attributed to individuals having some college rather than a baccalaureate degree, and 554,525 deaths could be attributed to individuals having anything less than a baccalaureate degree rather than a baccalaureate degree. Widening educational disparities between the 1925 and 1945 cohorts result in a doubling of attributable mortality. Mortality attributable to having less than a high school degree is proportionally similar among women and men and among non-Hispanic blacks and whites, and is greater for cardiovascular disease than for cancer.ConclusionsMortality attributable to low education is comparable in magnitude to mortality attributable to individuals being current rather than former smokers. Existing research suggests that a substantial part of the association between education and mortality is causal. Thus, policies that increase education could significantly reduce adult mortality

Rising arterial stiffness with accumulating comorbidities associates with heart failure with preserved ejection fraction

Aims: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular–vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. Methods and results: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near‐normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = −0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e′) on echocardiography (r = −0.307, P = 0.014). Conclusions: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at‐risk intermediate phenotypes (e.g. pre‐HFpEF) before overt HFpEF occurs

Production, purification, and characterization of recombinant hFSH glycoforms for functional studies

Previously, our laboratory demonstrated the existence of a β-subunit glycosylation-deficient human FSH glycoform, hFSH21. A third variant, hFSH18, has recently been detected in FSH glycoforms isolated from purified pituitary hLH preparations. Human FSH21 abundance in individual female pituitaries progressively decreased with increasing age. Hypo-glycosylated glycoform preparations are significantly more active than fully-glycosylated hFSH preparations. The purpose of this study was to produce, purify and chemically characterize both glycoform variants expressed by a mammalian cell line. Recombinant hFSH was expressed in a stable GH3 cell line and isolated from serum-free cell culture medium by sequential, hydrophobic and immunoaffinity chromatography. FSH glycoform fractions were separated by Superdex 75 gel-filtration. Western blot analysis revealed the presence of both hFSH18 and hFSH21 glycoforms in the low molecular weight fraction, however, their electrophoretic mobilities differed from those associated with the corresponding pituitary hFSH variants. Edman degradation of FSH21/18 -derived β-subunit before and after peptide-N-glycanase F digestion confirmed that it possessed a mixture of both mono-glycosylated FSHβ subunits, as both Asn7 and Asn24 were partially glycosylated. FSH receptor-binding assays confirmed our previous observations that hFSH21/18 exhibits greater receptor-binding affinity and occupies more FSH binding sites when compared to fully-glycosylated hFSH24. Thus, the age-related reduction in hypo-glycosylated hFSH significantly reduces circulating levels of FSH biological activity that may further compromise reproductive function. Taken together, the ability to express and isolate recombinant hFSH glycoforms opens the way to study functional differences between them both in vivo and in vitro

Polarimetry and Unification of Low-Redshift Radio Galaxies

We have made high-quality measurements of the polarization spectra of 13 FR II radio galaxies and taken polarization images for 11 of these with the Keck telescopes. Seven of the eight narrow-line radio galaxies (NLRG) are polarized, and six of the seven show prominent broad Balmer lines in polarized light. The broad lines are also weakly visible in total flux. Some of the NLRG show bipolar regions with roughly circumferential polarization vectors, revealing a large reflection nebula illuminated by a central source. Our observations powerfully support the hidden quasar hypothesis for some NLRG. Classification as NLRG, broad-line radio galaxy (BLRG), or quasar therefore depends on orientation. However, not all objects fit into this unification scheme. Our sample is biased towards objects known in advance to be polarized, but the combination of our results with those of Hill, Goodrich and DePoy (1996) show that at least 6 out of a complete, volume and flux-limited sample of 9 FR II NLRG have broad lines, seen either in polarization or P_alpha.Comment: To appear in November 1999 Astronomical Journal. 49 pages, 13 figure

Tests of model of color reconnection and a search for glueballs using gluon jets with a rapidity gap

Gluon jets with a mean energy of 22 GeV and purity of 95% are selected from hadronic Z0 decay events produced in e+e- annihilations. A subsample of these jets is identified which exhibits a large gap in the rapidity distribution of particles within the jet. After imposing the requirement of a rapidity gap, the gluon jet purity is 86%. These jets are observed to demonstrate a high degree of sensitivity to the presence of color reconnection, i.e. higher order QCD processes affecting the underlying color structure. We use our data to test three QCD models which include a simulation of color reconnection: one in the Ariadne Monte Carlo, one in the Herwig Monte Carlo, and the other by Rathsman in the Pythia Monte Carlo. We find the Rathsman and Ariadne color reconnection models can describe our gluon jet measurements only if very large values are used for the cutoff parameters which serve to terminate the parton showers, and that the description of inclusive Z0 data is significantly degraded in this case. We conclude that color reconnection as implemented by these two models is disfavored. The signal from the Herwig color reconnection model is less clear and we do not obtain a definite conclusion concerning this model. In a separate study, we follow recent theoretical suggestions and search for glueball-like objects in the leading part of the gluon jets. No clear evidence is observed for these objects.Comment: 42 pages, 18 figure

Search for the Standard Model Higgs Boson with the OPAL Detector at LEP

This paper summarises the search for the Standard Model Higgs boson in e+e- collisions at centre-of-mass energies up to 209 GeV performed by the OPAL Collaboration at LEP. The consistency of the data with the background hypothesis and various Higgs boson mass hypotheses is examined. No indication of a signal is found in the data and a lower bound of 112.7GeV/C^2 is obtained on the mass of the Standard Model Higgs boson at the 95% CL.Comment: 51 pages, 21 figure

A study of charm production in beauty decays with the OPAL detector at LEP

Using an inclusive method, BR(b -> D\bar{D}X) has been measured in hadronic Z^0 decays with the OPAL detector at LEP. The impact parameter significance of tracks opposite tagged b-jets is used to differentiate b -> D\bar{D}X decays from other decays. Using this result, the average number of charm and anti-charm quarks produced per beauty quark decay, n_c, is determined.Comment: 20 pages, 4 figure