Correction of Aberrant Splicing of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) Gene by Antisense Oligonucleotides

The CFTR splicing mutation 3849 + 10 kb C --> T creates a novel donor site 10 kilobases (kb) into intron 19 of the gene and is one of the more common splicing mutations that causes cystic fibrosis (CF). It has an elevated prevalence among patients with atypically mild disease and normal sweat electrolytes and is especially prominent in Ashkenazi Jews. This class of splicing mutations, reported in several genes, involves novel splice sites activated deep within introns while leaving wild-type splice elements intact. CFTR cDNA constructs that modeled the 3849 + 10 kb C --> T mutation were expressed in 3T3 mouse fibroblasts and in CFT1 human tracheal and C127 mouse mammary epithelial cells. In all three cell types, aberrant splicing of CFTR pre-mRNA was comparable to that reported in vivo in CF patients. Treatment of the cells with 2'-O-methyl phosphorothioate oligoribonucleotides antisense toward the aberrant donor and acceptor splice sites or to the retained exon-like sequence, disfavored aberrant splicing and enhanced normal processing of CFTR pre-mRNA. This antisense-mediated correction of splicing was dose- and sequence-dependent and was accompanied by increased production of CFTR protein that was appropriately glycosylated. Antisense-mediated correction of splicing in a mutation-specific context represents a potential gene therapy modality with applicability to many inherited disorders

Cystic fibrosis gene mutations and pancreatitis risk: Relation to epithelial ion transport and trypsin inhibitor gene mutations

Abstract Background & Aims: Nonalcoholic chronic pancreatitis is usually idiopathic and often associated with cystic fibrosis gene (CFTR) mutations. It is unknown whether pancreatitis risk correlates with having 1 or 2 CFTR mutations, abnormal epithelial ion transport, or mutations of other genes. Methods: We tested 39 patients with idiopathic chronic pancreatitis (mean age at diagnosis, 33 years) for common mutations of CFTR and of genes encoding a trypsin inhibitor (PSTI) and trypsinogen (PRSS1). To exclude hereditary pancreatitis, we initially relied on family history and subsequently tested for PRSS1 mutations. Twenty subjects were tested for rare CFTR mutations (DNA sequencing) and 11 were tested for extrapancreatic CFTR function (clinical and physiologic evaluation). Results: Mutations were identified in 24 of 39 subjects. Nine patients had cystic fibrosis–causing mutations, 8 of whom also had mild-variable mutations. Eight others had only mild-variable mutations. Nine subjects had the N34S PSTI mutation and 1 had hereditary pancreatitis (R122H, PRSS1). Pancreatitis risk was increased approximately 40-fold by having 2 CFTR mutations (P < 0.0001), 20-fold by having N34S (P < 0.0001), and 900-fold by having both (P < 0.0001). Subjects with 2 CFTR mutations had abnormal nasal epithelial ion transport and clinical findings suggesting residual CFTR function between that in cystic fibrosis and in carriers. By contrast, subjects with only PSTI mutations had normal CFTR function. Conclusions: CFTR-related pancreatitis risk correlates with having 2 CFTR mutations and reduced extrapancreatic CFTR function. The N34S PSTI mutation increased risk separately. Testing for pancreatitis-associated CFTR and PSTI genotypes may be useful in nonalcoholic pancreatitis.GASTROENTEROLOGY 2001;121:1310-131

Association Between Maternal Diabetes in Utero and Age at Offspring's Diagnosis of Type 2 Diabetes

OBJECTIVE—The purpose of this study was to examine age of diabetes diagnosis in youth who have a parent with diabetes by diabetes type and whether the parent's diabetes was diagnosed before or after the youth's birth

AGN-Host Galaxy Connection: Morphology and Colours of X-ray Selected AGN at z < 2

The connection between AGN and their host galaxies has been widely studied over recent years, showing it to be of great importance for providing answers to some fundamental questions related with AGN fueling mechanisms, their formation and evolution. Using X-ray and one of the deepest broad-band optical data sets, we studied morphology and colours in relationship with X-ray properties for sources at redshifts z < 2.0, using a sample of 262 AGN in the Subaru/XMM-Newton Deep Survey (SXDS). Morphological classification was obtained using the galSVM code, one of the new methods useful especially when dealing with high-redshift sources and low-resolution data. Colour-magnitude diagrams were studied in relationship with redshift, morphology, X-ray obscuration, and X-ray-to-optical flux ratio. Finally, the significance of different regions was analysed on colour-magnitude diagrams, relating the observed properties of AGN populations with some models of their formation and evolution.Comment: 24 pages, 19 figures, accepted for publication in Astronomy&Astrophysic

Cancer risk in childhood-onset systemic lupus

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care

The XMM large scale structure survey: optical vs. X-ray classifications of active galactic nuclei and the unified scheme

Our goal is to characterize AGN populations by comparing their X-ray and optical classifications. We present a sample of 99 spectroscopically identified X-ray point sources in the XMM-LSS survey which are significantly detected in the [2-10] keV band, and with more than 80 counts. We performed an X-ray spectral analysis for all of these 99 X-ray sources. Introducing the fourfold point correlation coefficient, we find only a mild correlation between the X-ray and the optical classifications, as up to 30% of the sources have differing X-ray and optical classifications: on one hand, 10% of the type 1 sources present broad emission lines in their optical spectra and strong absorption in the X-rays. These objects are highly luminous AGN lying at high redshift and thus dilution effects are totally ruled out, their discrepant nature being an intrinsic property. Their X-ray luminosities and redshifts distributions are consistent with those of the unabsorbed X-ray sources with broad emission lines. On the other hand, 25/32 are moderate luminosity AGN, which are both unabsorbed in the X-rays and only present narrow emission lines in their optical spectra. The majority of them have an optical spectrum which is representative of the host galaxy. We finally infer that dilution of the AGN by the host galaxy seems to account for their nature. 5/25 have been defined as Seyfert 2. In conclusion, most of these 32 discrepant cases can be accounted for by the standard AGN unified scheme, as its predictions are not met for only 12% of the 99 X-ray sources. ABRIDGEDComment: 25 pages, 19 figures, Accepted for publication in A&

LoCuSS: Luminous infrared galaxies in the merging cluster Abell 1758 at z=0.28

We present the first galaxy evolution results from the Local Cluster Substructure Survey (LoCuSS), a multi-wavelength survey of 100 X-ray selected galaxy clusters at 0.15<z<0.30. LoCuSS combines far-UV through far-IR observations of cluster galaxies with gravitational lensing analysis and X-ray data to investigate the interplay between the hierarchical assembly of clusters and the evolution of cluster galaxies. Here we present new panoramic Spitzer/MIPS 24micron observations of the merging cluster Abell 1758 at z=0.279 spanning 6.5x6.5Mpc and reaching a 90% completeness limit of 400uJy. We estimate a global cluster SFR of 910\pm320 M_sun/yr within 3 Mpc of the cluster centre, originating from 42 galaxies with L_IR > 5x10^10 L_sun. The obscured activity in A1758 is therefore comparable with that in Cl 0024+1654, the most active cluster previously studied at 24um. The obscured galaxies faithfully trace the cluster potential as revealed by the weak-lensing mass map of the cluster, including numerous mass peaks at R~2-3Mpc that are likely associated with infalling galaxy groups and filamentary structures. However the core (R<500kpc) of A1758N is 2x more active in the IR than that of A1758S, likely reflecting differences in the recent dynamical history of the two clusters. The 24micron results from A1758 therefore suggest that dust-obscured cluster galaxies are common in merging clusters and suggests that obscured activity in clusters is triggered by both the details of cluster-cluster mergers and processes that operate at larger radii including those within in-falling groups. Our ongoing far-UV through far-IR observations of a large sample of clusters should allow us to disentangle the different physical processes responsible for triggering obscured star formation in clusters.Comment: 13 pages, 9 figures. Accepted for publication in MNRA

Scope for Credit Risk Diversification

This paper considers a simple model of credit risk and derives the limit distribution of losses under different assumptions regarding the structure of systematic risk and the nature of exposure or firm heterogeneity. We derive fat-tailed correlated loss distributions arising from Gaussian risk factors and explore the potential for risk diversification. Where possible the results are generalised to non-Gaussian distributions. The theoretical results indicate that if the firm parameters are heterogeneous but come from a common distribution, for sufficiently large portfolios there is no scope for further risk reduction through active portfolio management. However, if the firm parameters come from different distributions, then further risk reduction is possible by changing the portfolio weights. In either case, neglecting parameter heterogeneity can lead to underestimation of expected losses. But, once expected losses are controlled for, neglecting parameter heterogeneity can lead to overestimation of risk, whether measured by unexpected loss or value-at-risk

Decomposing Star Formation and Active Galactic Nucleus with Spitzer Mid-Infrared Spectra: Luminosity Functions and Co-Evolution

We present Spitzer 7-38um spectra for a 24um flux limited sample of galaxies at z~0.7 in the COSMOS field. The detailed high-quality spectra allow us to cleanly separate star formation (SF) and active galactic nucleus (AGN) in individual galaxies. We first decompose mid-infrared Luminosity Functions (LFs). We find that the SF 8um and 15um LFs are well described by Schechter functions. AGNs dominate the space density at high luminosities, which leads to the shallow bright-end slope of the overall mid-infrared LFs. The total infrared (8-1000um) LF from 70um selected galaxies shows a shallower bright-end slope than the bolometrically corrected SF 15um LF, owing to the intrinsic dispersion in the mid-to-far-infrared spectral energy distributions. We then study the contemporary growth of galaxies and their supermassive black holes (BHs). Seven of the 31 Luminous Infrared Galaxies with Spitzer spectra host luminous AGNs, implying an AGN duty cycle of 23+/-9%. The time-averaged ratio of BH accretion rate and SF rate matches the local M_BH-M_bulge relation and the M_BH-M_host relation at z ~ 1. These results favor co-evolution scenarios in which BH growth and intense SF happen in the same event but the former spans a shorter lifetime than the latter. Finally, we compare our mid-infrared spectroscopic selection with other AGN identification methods and discuss candidate Compton-thick AGNs in the sample. While only half of the mid-infrared spectroscopically selected AGNs are detected in X-ray, ~90% of them can be identified with their near-infrared spectral indices.Comment: ApJ Accepted. emulateapj style. 16 pages, 9 figures, 4 table

Seeking legitimacy through CSR: Institutional Pressures and Corporate Responses of Multinationals in Sri Lanka

Arguably, the corporate social responsibility (CSR) practices of multinational enterprises (MNEs) are influenced by a wide range of both internal and external factors. Perhaps most critical among the exogenous forces operating on MNEs are those exerted by state and other key institutional actors in host countries. Crucially, academic research conducted to date offers little data about how MNEs use their CSR activities to strategically manage their relationship with those actors in order to gain legitimisation advantages in host countries. This paper addresses that gap by exploring interactions between external institutional pressures and firm-level CSR activities, which take the form of community initiatives, to examine how MNEs develop their legitimacy-seeking policies and practices. In focusing on a developing country, Sri Lanka, this paper provides valuable insights into how MNEs instrumentally utilise community initiatives in a country where relationship-building with governmental and other powerful non-governmental actors can be vitally important for the long-term viability of the business. Drawing on neo-institutional theory and CSR literature, this paper examines and contributes to the embryonic but emerging debate about the instrumental and political implications of CSR. The evidence presented and discussed here reveals the extent to which, and the reasons why, MNEs engage in complex legitimacy-seeking relationships with Sri Lankan institutions