Transcriptome Analysis of Targeted Mouse Mutations Reveals the Topography of Local Changes in Gene Expression.

The unintended consequences of gene targeting in mouse models have not been thoroughly studied and a more systematic analysis is needed to understand the frequency and characteristics of off-target effects. Using RNA-seq, we evaluated targeted and neighboring gene expression in tissues from 44 homozygous mutants compared with C57BL/6N control mice. Two allele types were evaluated: 15 targeted trap mutations (TRAP); and 29 deletion alleles (DEL), usually a deletion between the translational start and the 3' UTR. Both targeting strategies insert a bacterial beta-galactosidase reporter (LacZ) and a neomycin resistance selection cassette. Evaluating transcription of genes in +/- 500 kb of flanking DNA around the targeted gene, we found up-regulated genes more frequently around DEL compared with TRAP alleles, however the frequency of alleles with local down-regulated genes flanking DEL and TRAP targets was similar. Down-regulated genes around both DEL and TRAP targets were found at a higher frequency than expected from a genome-wide survey. However, only around DEL targets were up-regulated genes found with a significantly higher frequency compared with genome-wide sampling. Transcriptome analysis confirms targeting in 97% of DEL alleles, but in only 47% of TRAP alleles probably due to non-functional splice variants, and some splicing around the gene trap. Local effects on gene expression are likely due to a number of factors including compensatory regulation, loss or disruption of intragenic regulatory elements, the exogenous promoter in the neo selection cassette, removal of insulating DNA in the DEL mutants, and local silencing due to disruption of normal chromatin organization or presence of exogenous DNA. An understanding of local position effects is important for understanding and interpreting any phenotype attributed to targeted gene mutations, or to spontaneous indels

Retrieving Bulge and Disk Parameters and Asymptotic Magnitudes from the Growth Curves of Galaxies

We show that the growth curves of galaxies can be used to determine their bulge and disk parameters and bulge-to-total luminosity ratios, in addition to their conventional asymptotic magnitudes, provided that the point spread function is accurately known and signal-to-noise ratio is modest (S/N$\gtrsim30$). The growth curve is a fundamental quantity that most future large galaxy imaging surveys will measure. Bulge and disk parameters retrieved from the growth curve will enable us to perform statistical studies of luminosity structure for a large number of galaxies.Comment: 28 pages including 13 PS figures; accepted for publication in PAS

Immune Reconstitution Inflammatory Syndrome and the Influence of T Regulatory Cells: A Cohort Study in the Gambia

The factors associated with the development of immune reconstitution inflammatory syndrome in HIV patients commencing antiretroviral therapy have not been fully elucidated. Using a longitudinal study design, this study addressed whether alteration in the levels of T regulatory cells contributed to the development of IRIS in a West African cohort of HIV-1 and HIV-2 patients. Seventy-one HIV infected patients were prospectively recruited to the study and followed up for six months. The patients were categorized as IRIS or non-IRIS cases following published clinical guidelines. The levels of T regulatory cells were measured using flow cytometry at baseline and all follow-up visits. Baseline cytokine levels of IL-2, IL-6, IFN-(Gamma), TNF-(Alpha), MIP-1(Beta), IL-1, IL-12, IL-13, and IL-10 were measured in all patients

A Novel Technique for Risk Calculation of Anastomotic Leakage after Thoracoscopic Repair for Esophageal Atresia with Distal Fistula

Purpose: This study was designed to determine the risk of anastomotic leakage after thoracoscopic repair for esophageal atresia by digitally measuring the length of the proximal esophagus and distance of carina to proximal esophagus. Methods: With the use of Picture Archiving and Communication System (PACS), the length of the proximal esophagus from the top of the first thoracic vertebra was measured on the preoperative chest x-ray, as well as the distance from the carina to the proximal esophagus. The chest x-rays of 27 neonates, born with esophageal atresia with distal fistula, were examined. Furthermore, the tapes from the procedures were reviewed. Statistical analysis was performed with the t test for equality of means by using SPSS® 12.0.1 for Windows. Results: Both groups were comparable, and there was a statistical significant difference in both length of the proximal esophagus (p<0.023) and distance of carina to proximal esophagus (p<0.022) in patients who did and did not leak postoperatively. There seems to be a tendency toward a shorter proximal esophagus in recent years that was not obvious earlier. Conclusions: The digital measurement of the length of the proximal esophagus (M<7 mm) and distance of carina to proximal esophagus (M<13.5 mm) with the use of PACS gives a good risk calculation for postoperative leakage

Hubble Space Telescope Observations of NGC 6240: a Case Study of an Ultra-Luminous Infrared Galaxy with Obscured Activity

We present results from an HST study of the morphology and kinematics of NGC 6240. This merging galaxy with a double nucleus is one of the nearest and best-studied ultraluminous infrared galaxies. HST resolves both nuclei into seperate components. The distance between the northern and southern optical/near-infrared components is greater than that observed in radio and X-ray studies, arguing that even in K-band we may not be seeing all the way through the dust to the true nuclei. The ionized gas does not display rotation around either of the nuclei, or equilibrium motion in general. There is a strong velocity gradient between the nuclei, similar to what is seen in CO data. There is no such gradient in our stellar kinematics. The velocity dispersion of the gas is larger than expected for a cold disk. We also map and model the emission-line velocity field at an off-nuclear position where a steep velocity gradient was previously detected in ground-based data. Overall, the data indicate that line-of-sight projection effects, dust absorption, non-equilibrium merger dynamics, and the possible influence of a wind may be playing an important role in the observed kinematics. Chandra observations of hard X-rays have shown that both of the nuclei contain an Active Galactic Nucleus (AGN). The HST data show no clear sign of the two AGNs: neither continuum nor narrow-band imaging shows evidence for unresolved components in the nuclei, and there are no increased emission line widths or rapid rotation near the nuclei. This underscores the importance of X-ray data for identifying AGNs in highly dust-enshrouded environments.Comment: LaTeX, 32 pages, 9 figures, 2 tables, accepted for publication in The Astronomical Journal (Jan 2004). Paper with high-resolution (non-compressed) color figures in gzipped postscript format available at http://www.stsci.edu/~marel/psgzdir/ngc6240v11.ps.g

The role of pancreatoscopy in the diagnostic work-up of intraductal papillary mucinous neoplasms : a systematic review and meta-analysis

Background Confirming the diagnosis, invasiveness, and disease extent of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas is challenging. The aim of this study was to summarize the literature on the efficacy and safety of peroral pancreatoscopy (POP) in the diagnosis of IPMN, including the impact of pre- and intraoperative POP on the management of IPMN. Methods The EMBASE, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar databases were systematically searched for articles. Eligible articles investigated cohorts of patients who underwent POP for (suspected) IPMN. Results 25 articles were identified and included in this review; with 22 of these reporting on the diagnostic yield of POP in IPMN and 11 reporting on the effect of pre- or intraoperative POP on clinical decision-making. Cannulation and observation rates, and overall diagnostic accuracy were high across all studies. Frequently reported visual characteristics of IPMN were intraductal fish-egg-like lesions, hypervascularity, and granular mucosa. Overall, the adverse event rate was 12 %, primarily consisting of post-endoscopic retrograde cholangiopancreatography pancreatitis, with a pooled rate of 10 %, mostly of mild severity. Regarding the impact of POP on clinical decision-making, POP findings altered the surgical approach in 13%- 62% of patients. Conclusion POP is technically successful in the vast majority of patients with (suspected) IPMN, has a consistently high diagnostic accuracy, but an adverse event rate of 12 %. Data on intraoperative pancreatoscopy are scarce, but small studies suggest its use can alter surgical management. Future studies are needed to better define the role of POP in the diagnostic work-up of IPMN.Peer reviewe

The accretion origin of the Milky Way's stellar halo

We have used data from the Sloan Digital Sky Survey (SDSS) Data Release 5 to explore the overall structure and substructure of the stellar halo of the Milky Way using about 4 million color-selected main sequence turn-off stars. We fit oblate and triaxial broken power-law models to the data, and found a `best-fit' oblateness of the stellar halo 0.5<c/a<0.8, and halo stellar masses between Galactocentric radii of 1 and 40kpc of (3.7+/-1.2)x10^8 M_sun. The density profile of the stellar halo is approximately r^{-3}; it is possible that the power law slope is shallower inside 20kpc and steeper outside that radius. Yet, we found that all smooth and symmetric models were very poor fits to the distribution of stellar halo stars because the data exhibit a great deal of spatial substructure. We quantified deviations from a smooth oblate/triaxial model using the RMS of the data around the model profile on scales >~100pc, after accounting for the (known) contribution of Poisson uncertainties. The fractional RMS deviation of the actual stellar distribution from any smooth, parameterized halo model is >~40%: hence, the stellar halo is highly structured. We compared the observations with simulations of galactic stellar halos formed entirely from the accretion of satellites in a cosmological context by analysing the simulations in the same way as the data. While the masses, overall profiles, and degree of substructure in the simulated stellar halos show considerable scatter, the properties and degree of substructure in the Milky Way's halo match well the properties of a `typical' stellar halo built exclusively out of the debris from disrupted satellite galaxies. Our results therefore point towards a picture in which an important fraction of the Milky Way's stellar halo has been accreted from satellite galaxies.Comment: Submitted to the Astrophysical Journal. 14 pages; 11 figure

BioDiVinE: A Framework for Parallel Analysis of Biological Models

In this paper a novel tool BioDiVinEfor parallel analysis of biological models is presented. The tool allows analysis of biological models specified in terms of a set of chemical reactions. Chemical reactions are transformed into a system of multi-affine differential equations. BioDiVinE employs techniques for finite discrete abstraction of the continuous state space. At that level, parallel analysis algorithms based on model checking are provided. In the paper, the key tool features are described and their application is demonstrated by means of a case study

Backward bifurcation, equilibrium and stability phenomena in a three-stage extended BRSV epidemic model

In this paper we consider the phenomenon of backward bifurcation in epidemic modelling illustrated by an extended model for Bovine Respiratory Syncytial Virus (BRSV) amongst cattle. In its simplest form, backward bifurcation in epidemic models usually implies the existence of two subcritical endemic equilibria for R 0 &lt; 1, where R 0 is the basic reproductive number, and a unique supercritical endemic equilibrium for R 0 > 1. In our three-stage extended model we find that more complex bifurcation diagrams are possible. The paper starts with a review of some of the previous work on backward bifurcation then describes our three-stage model. We give equilibrium and stability results, and also provide some biological motivation for the model being studied. It is shown that backward bifurcation can occur in the three-stage model for small b, where b is the common per capita birth and death rate. We are able to classify the possible bifurcation diagrams. Some realistic numerical examples are discussed at the end of the paper, both for b small and for larger values of b