Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Loss of Sphingosine Kinase 1/S1P Signaling Impairs Cell Growth and Survival of Neurons and Progenitor Cells in the Developing Sensory Ganglia

Background: Lysophospholipids such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are important signaling molecules that can regulate a wide range of cellular responses. We discovered that Sphingosine kinase 1 (Sphk1), a key enzyme that converts sphingosine to S1P, is expressed in neurons and progenitor cells in nascent trigeminal and dorsal root ganglia during mouse embryogenesis. Methods and Findings: Sphk1 null mouse embryos do not display overt deficits owing to compensation by Sphk2. Thus, we analyzed embryos that are deficient in both Sphk1 and Sphk2 (which essentially eliminates S1P function) in order to investigate the role(s) of Sphk1 during sensory ganglia formation. While animals lacking 1–3 alleles of Sphk1 and Sphk2 had no obvious phenotype, embryos without both genes displayed clear developmental defects. The complete absence of Sphk1 and Sphk2 resulted in trigeminal and dorsal root ganglia with fewer neurons and progenitor cells. The profound loss in cell number could be attributed to a decrease in cell proliferation as well as an increase in apoptosis. Furthermore, Sphk1/ 2 double mutants displayed an overall reduction in other sphingolipids as well as an imbalance of S1P/sphingosine and S1P/ ceramide ratio, thereby favoring cell death and reducing cell growth. Conclusions: Together, these results provide strong in vivo evidence that sphingosine kinase/S1P signaling plays a

Stellar and Gaseous Nuclear Disks Observed in Nearby (U)LIRGs

We present near-infrared integral field spectroscopy of the central kiloparsec of 17 nearby luminous and ultra-luminous infrared galaxies undergoing major mergers. These observations were taken with OSIRIS assisted by the Keck I and II Adaptive Optics systems, providing spatial resolutions of a few tens of parsecs. The resulting kinematic maps reveal gas disks in at least 16 out of 19 nuclei and stellar disks in 11 out of 11 nuclei observed in these galaxy merger systems. In our late-stages mergers, these disks are young (stellar ages $<30$ Myr) and likely formed as gas disks which became unstable to star formation during the merger. On average, these disks have effective radii of a few hundred parsecs, masses between $10^{8}$ and $10^{10} M_{Sun}$, and $v/\sigma$ between 1 and 5. These disks are similar to those created in high-resolution hydrodynamical simulations of gas-rich galaxy mergers, and favor short coalescence times for binary black holes. The few galaxies in our sample in earlier stages of mergers have disks which are larger ($r_{eff}\sim200-1800$ pc) and likely are remnants of the galactic disks that have not yet been completely disrupted by the merger.Comment: accepted for publication in Ap

Simplifying intensity-modulated radiotherapy plans with fewer beam angles for the treatment of oropharyngeal carcinoma.

The first aim of the present study was to investigate the feasibility of using fewer beam angles to improve delivery efficiency for the treatment of oropharyngeal cancer (OPC) with inverse-planned intensity-modulated radiation therapy (IP-IMRT). A secondary aim was to evaluate whether the simplified IP-IMRT plans could reduce the indirect radiation dose. The treatment plans for 5 consecutive OPC patients previously treated with a forward-planned IMRT (FP-IMRT) technique were selected as benchmarks for this study. The initial treatment goal for these patients was to deliver 70 Gy to &gt; or = 95% of the planning gross tumor volume (PTV-70) and 59.4 Gy to &gt; or = 95% of the planning clinical tumor volume (PTV-59.4) simultaneously. Each case was re-planned using IP-IMRT with multiple beam-angle arrangements, including four complex IP-IMRT plans using 7 or more beam angles, and one simple IMRT plan using 5 beam angles. The complex IP-IMRT plans and simple IP-IMRT plans were compared to each other and to the FPIMRT plans by analyzing the dose coverage of the target volumes, the plan homogeneity, the dose-volume histograms of critical structures, and the treatment delivery parameters including delivery time and the total number of monitor units (MUs). When comparing the plans, we found no significant difference between the complex IP-IMRT, simple IP-IMRT, and FP-IMRT plans for tumor target coverage (PTV-70: p = 0.56; PTV-59.4: p = 0.20). The plan homogeneity, measured by the mean percentage isodose, did not significantly differ between the IP-IMRT and FP-IMRT plans (p = 0.08), although we observed a trend toward greater inhomogeneity of dose in the simple IP-IMRT plans. All IP-IMRT plans either met or exceeded the quality of the FP-IMRT plans in terms of dose to adjacent critical structures, including the parotids, spinal cord, and brainstem. As compared with the complex IP-IMRT plans, the simple IP-IMRT plans significantly reduced the mean treatment time (maximum probability for four pairwise comparisons: p = 0.0003). In conclusion, our study demonstrates that, as compared with complex IP-IMRT, simple IP-IMRT can significantly improve treatment delivery efficiency while maintaining similar target coverage and sparing of critical structures. However, the improved efficiency does not significantly reduce the total number of MUs nor the indirect radiation dose

Shocked Gas in IRAS F17207-0014: ISM Collisions and Outflows

We combine optical and near-infrared AO-assisted integral field observations of the merging ULIRG IRAS F17207-0014 from the Wide-Field Spectrograph (WiFeS) and Keck/OSIRIS. The optical emission line ratios [N II]/H$\alpha$, [S II]/H$\alpha$, and [O I]/H$\alpha$ reveal a mixing sequence of shocks present throughout the galaxy, with the strongest contributions coming from large radii (up to 100% at $\sim$5 kpc in some directions), suggesting galactic-scale winds. The near-infrared observations, which have approximately 30 times higher spatial resolution, show that two sorts of shocks are present in the vicinity of the merging nuclei: low-level shocks distributed throughout our field-of-view evidenced by an H$_{2}$/Br$\gamma$ line ratio of $\sim$0.6-4, and strong collimated shocks with a high H$_{2}$/Br$\gamma$ line ratio of $\sim$4-8, extending south from the two nuclear disks approximately 400 pc ($\sim$0.5 arcsec). Our data suggest that the diffuse shocks are caused by the collision of the interstellar media associated with the two progenitor galaxies and the strong shocks trace the base of a collimated outflow coming from the nucleus of one of the two disks.Comment: accepted to MNRA

Following Black Hole Scaling Relations Through Gas-Rich Mergers

We present black hole mass measurements from kinematic modeling of high-spatial resolution integral field spectroscopy of the inner regions of 9 nearby (ultra-)luminous infrared galaxies in a variety of merger stages. These observations were taken with OSIRIS and laser guide star adaptive optics on the Keck I and Keck II telescopes, and reveal gas and stellar kinematics inside the spheres of influence of these supermassive black holes. We find that this sample of black holes are overmassive ($\sim10^{7-9}$ M$_{Sun}$) compared to the expected values based on black hole scaling relations, and suggest that the major epoch of black hole growth occurs in early stages of a merger, as opposed to during a final episode of quasar-mode feedback. The black hole masses presented are the dynamical masses enclosed in $\sim$25pc, and could include gas which is gravitationally bound to the black hole but has not yet lost sufficient angular momentum to be accreted. If present, this gas could in principle eventually fuel AGN feedback or be itself blown out from the system.Comment: accepted to Ap

Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus.

High titer, class-switched autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Dysregulation of the interferon (IFN) pathway is observed in individuals with active SLE, although the association of specific autoantibodies with chemokine score, a combined measurement of three IFN-regulated chemokines, is not known. To identify autoantibodies associated with chemokine score, we developed giant magnetoresistive (GMR) biosensor microarrays, which allow the parallel measurement of multiple serum antibodies to autoantigens and peptides. We used the microarrays to analyze serum samples from SLE patients and found individuals with high chemokine scores had significantly greater reactivity to 13 autoantigens than individuals with low chemokine scores. Our findings demonstrate that multiple autoantibodies, including antibodies to U1-70K and modified histone H2B tails, are associated with IFN dysregulation in SLE. Further, they show the microarrays are capable of identifying autoantibodies associated with relevant clinical manifestations of SLE, with potential for use as biomarkers in clinical practice

Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries.

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and inflammatory cell recruitment that differed between wild-type and mutant animals. Studies with isolated cells found that M292R-mutant Lox is retained in the endoplasmic reticulum and ultimately cleared through an autophagy/proteasome pathway. Because the mutant protein does not transit to the Golgi where copper incorporation occurs, the protein is never catalytically active. These studies show that the M292R mutation results in LOX loss-of-function due to a secretion defect that predisposes the ascending aorta in mice (and by extension humans with similar mutations) to arterial dilation when exposed to risk factors that impart stress to the arterial wall