Integrating and mining the chromatin landscape of cell-type specificity using self-organizing maps

We tested whether self-organizing maps (SOMs) could be used to effectively integrate, visualize, and mine diverse genomics data types, including complex chromatin signatures. A fine-grained SOM was trained on 72 ChIP-seq histone modifications and DNase-seq data sets from six biologically diverse cell lines studied by The ENCODE Project Consortium. We mined the resulting SOM to identify chromatin signatures related to sequence-specific transcription factor occupancy, sequence motif enrichment, and biological functions. To highlight clusters enriched for specific functions such as transcriptional promoters or enhancers, we overlaid onto the map additional data sets not used during training, such as ChIP-seq, RNA-seq, CAGE, and information on cis-acting regulatory modules from the literature. We used the SOM to parse known transcriptional enhancers according to the cell-type-specific chromatin signature, and we further corroborated this pattern on the map by EP300 (also known as p300) occupancy. New candidate cell-type-specific enhancers were identified for multiple ENCODE cell types in this way, along with new candidates for ubiquitous enhancer activity. An interactive web interface was developed to allow users to visualize and custom-mine the ENCODE SOM. We conclude that large SOMs trained on chromatin data from multiple cell types provide a powerful way to identify complex relationships in genomic data at user-selected levels of granularity

Comparison of diametric and volumetric changes in Stanford type B aortic dissection patients in assessing aortic remodeling post-stent graft treatment

Background: The study aims to analyze the correlation between the maximal diameter (both axial and orthogonal) and volume changes in the true (TL) and false lumens (FL) after stent-grafting for Stanford type B aortic dissection. Method: Computed tomography angiography was performed on 13 type B aortic dissection patients before and after procedure, and at 6 and 12 months follow-up. The lumens were divided into three regions: the stented area (Region 1), distal to the stent graft to the celiac artery (Region 2), and between the celiac artery and the iliac bifurcation (Region 3). Changes in aortic morphology were quantified by the increase or decrease of diametric and volumetric percentages from baseline measurements. Results: At Region 1, the TL diameter and volume increased (pre-treatment: volume =51.4±41.9 mL, maximal axial diameter =22.4±6.8 mm, maximal orthogonal diameter =21.6±7.2 mm; follow-up: volume =130.7±69.2 mL, maximal axial diameter =40.1±8.1 mm, maximal orthogonal diameter =31.9+2.6 mm, P<0.05 for all comparisons), while FL decreased (pre-treatment: volume =129.6±150.5 mL; maximal axial diameter =43.0±15.8 mm; maximal orthogonal diameter =28.3±12.6 mm; follow-up: volume =66.6±95.0 mL, maximal axial diameter =24.5±19.9 mm, maximal orthogonal diameter =16.9±13.7, P<0.05 for all comparisons). Due to the uniformity in size throughout the vessel, high concordance was observed between diametric and volumetric measurements in the stented region with 93% and 92% between maximal axial diameter and volume for the true/false lumens, and 90% and 92% between maximal orthogonal diameter and volume for the true/false lumens. Large discrepancies were observed between the different measurement methods at regions distal to the stent graft, with up to 46% differences between maximal orthogonal diameter and volume. Conclusions: Volume measurement was shown to be a much more sensitive indicator in identifying lumen expansion/shrinkage at the distal stented region

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Background and aimsFatty streaks initiating the formation of atheromatous plaque appear in the tunica intima. The tunica media is not known to be a nidus for lipid accumulation initiating atherogenesis. We assessed changes to the tunica media in response to a micro-injury produced in the pig aorta. In addition, we assessed human carotid endarterectomy plaques for indication of atheroma initiation in the tunica media.MethodsThree healthy landrace female pigs underwent laparotomy to inject autologous blood and create micro-hematomas at 6 sites within the tunica media of the infrarenal abdominal aorta. These pigs were fed a high-fat diet (HFD) for 4–12 weeks. Post-mortem aortas from all pigs, including a control group of healthy pigs, were serially stained to detect lipid deposits, vasa vasora (VV), immune cell infiltration and inflammatory markers, as well as changes to the vascular smooth muscle cell (vSMC) compartment. Moreover, 25 human carotid endarterectomy (CEA) specimens were evaluated for their lipid composition in the tunica media and intima.ResultsHigh lipid clusters, VV density, and immune cell infiltrates were consistently observed at 5 out of 6 injection sites under prolonged hyperlipidemia. The hyperlipidemic diet also affected the vSMC compartment in the tunica media adjacent to the tunica adventitia, which correlated with VV invasion and immune cell infiltration. Analysis of human carotid specimens post-CEA indicated that 32% of patients had significantly greater atheroma in the tunica media than in the arterial intima.ConclusionThe arterial intima is not the only site for atherosclerosis initiation. We show that injury to the media can trigger atherogenesis

Fragmentation in the Massive Star-Forming Region IRAS 19410+2336

The Core Mass Functions (CMFs) of low-mass star-forming regions are found to resemble the shape of the Initial Mass Function (IMF). A similar result is observed for the dust clumps in high-mass star forming regions, although at spatial scales of clusters that do not resolve the substructure found in them. The region IRAS 19410+2336 is one exception, having been observed at spatial scales on the order of ~2500AU, resolving the clump substructure into individual cores. We mapped that region with the PdBI in the 1.4mm and 3mm continuum and several transitions of H2CO and CH3CN. The H2CO transitions were also observed with the IRAM 30m Telescope. We detected 26 continuum sources at 1.4mm with a spatial resolution down to ~2200 AU, distributed in two protoclusters. With the lines emission we derived the temperature structure of the region, ranging from 35 to 90K. With them we calculated the core masses of the detected sources, ranging from ~0.7 to ~8 M_sun. These masses were strongly (~90%) affected by the interferometer spatial filtering. Considering only the detected dense cores we derived a CMF with a power-law index b=-2.3+-0.2. We resolve the Jeans length of the protoclusters by one order of magnitude, and only find little velocity dispersion between the different subsources. Since we cannot unambiguously differentiate protostellar and prestellar cores, the derived CMF is not prestellar. Also, because of the large missing flux, we cannot establish a firm link between the CMF and the IMF. This implies that future high-mass CMF studies will need to complement the interferometer continuum data with the short spacing data, a task suitable for ALMA. We note that the method of extracting temperatures using H2CO lines becomes less applicable when reaching the dense core scales of the interferometric observations because most of the H2CO appears to originate in the envelope structure.Comment: 17 pages, 12 figures, accepted by A&

The cooling of atomic and molecular gas in DR21

We present an overview of a high-mass star formation region through the major (sub-)mm, and far-infrared cooling lines to gain insight into the physical conditions and the energy budget of the molecular cloud. We used the KOSMA 3m telescope to map the core ($10'\times 14'$) of the Galactic star forming region DR 21/DR 21 (OH) in the Cygnus X region in the two fine structure lines of atomic carbon CI and four mid-$J$ transitions of CO and $^{13}$CO, and CS J=7\TO6. These observations have been combined with FCRAO J=1\TO0 observations of $^{13}$CO and C$^{18}$O. Five positions, including DR21, DR21 (OH), and DR21 FIR1, were observed with the ISO/LWS grating spectrometer in the \OI 63 and 145 $\mu$m lines, the \CII 158 $\mu$m line, and four high-$J$ CO lines. We discuss the intensities and line ratios at these positions and apply Local Thermal Equilibrium (LTE) and non-LTE analysis methods in order to derive physical parameters such as masses, densities and temperatures. The CO line emission has been modeled up to J=20. From non-LTE modeling of the low- to high-$J$ CO lines we identify two gas components, a cold one at temperatures of T_\RM{kin}\sim 30-40 K, and one with T_\RM{kin}\sim 80-150 K at a local clump density of about n(H$_2$)$\sim 10^4-10^6$ cm$^{-3}$. While the cold quiescent component is massive containing typically more than 94 % of the mass, the warm, dense, and turbulent gas is dominated by mid- and high-$J$ CO line emission and its large line widths. The medium must be clumpy with a volume-filling of a few percent. The CO lines are found to be important for the cooling of the cold molecular gas, e.g. at DR21 (OH). Near the outflow of the UV-heated source DR21, the gas cooling is dominated by line emission of atomic oxygen and of CO

Imaging chemical differentiation around the low-mass protostar L483-mm

This paper presents a millimeter wavelength aperture-synthesis study of the spatial variations of the chemistry in the envelope around the deeply embedded low-mass protostar L483-mm on 1000 AU (5") scales. Lines of 8 molecular species including CN, C18O, CS, C34S, HCN, H13CN, HCO+ and N2H+ have been observed using the Owens Valley Radio Observatory Millimeter Array. Continuum emission at 2.7-3.4 millimeter is well-fit by a pure envelope model down to the sensitivity of the interferometer without introducing a disk/compact source, in contrast to what is seen for other protostars. A velocity gradient in the densest material is traced by HCN, CS and N2H+, and is perpendicular to the large-scale CO outflow, with a pattern consistent with rotation around a 1 solar mass central object. Velocity gradients in the propagation direction of the outflow suggest a clear interaction between the outflowing material and "quiescent" core. The C18O observations are fit with a "drop" abundance profile where CO is frozen-out in a region of the envelope with temperatures lower than 40 K and densities higher than 1.5e5 cm^{-3}, which is also required to reproduce single-dish observations. The N2H+ emission strongly resembles that of NH3 and is found to be absent toward the central continuum source. This is a direct consequence of the high CO abundances in the inner region as illustrated by a chemical model for the L483 envelope. The observed CN emission forms a spatial borderline between the outflowing and quiescent material probed by, respectively, HCO+ and N2H+, and also shows intermediate velocities compared to these two species. A scenario is suggested in which CN is enhanced in the walls of an outflow cavity due to the impact of UV irradiation either from the central protostellar system or related to shocks caused by the outflow.Comment: Accepted for publication in A&A. 14 pages, 14 figure

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685