Molecular Dynamics on a Model for Nascent High-Density Lipoprotein: Role of Salt Bridges

AbstractThe results of an all-atom molecular dynamics simulation on a discoidal complex made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and a synthetic α-helical 18-mer peptide with an apolipoprotein-like charge distribution are presented. The system consists of 12 acetyl-18A-amide (Ac-18A-NH2) (Anantharamaiah et al., 1985. J. Biol. Chem. 260:10248–10255) molecules and 20 molecules of POPC in a bilayer, 10 in each leaflet, solvated in a sphere of water for a total of 28,522 atoms. The peptide molecules are oriented with their long axes normal to the bilayer (the “picket fence” orientation). This system is analogous to complexes formed in nascent high-density lipoprotein and to Ac-18A-NH2/phospholipid complexes observed experimentally. The simulation extended over 700ps, with the last 493ps used for analysis. The symmetry of this system allows for averaging over different helices to improve sampling, while maintaining explicit all-atom representation of all peptides. The complex is stable on the simulated time scale. Several possible salt bridges between and within helices were studied. A few salt bridge formations and disruptions were observed. Salt bridges provide specificity in interhelical interactions

Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos

Wnt ligands and Frizzled (Fz) receptors have been shown to activate multiple intracellular signaling pathways. Activation of the Wnt–β-catenin pathway has been described in greatest detail, but it has been reported that Wnts and Fzs also activate vertebrate planar cell polarity (PCP) and Wnt–Ca2+ pathways. Although the intracellular protein Dishevelled (Dsh) plays a dual role in both the Wnt–β-catenin and the PCP pathways, its potential involvement in the Wnt–Ca2+ pathway has not been investigated. Here we show that a Dsh deletion construct, XDshΔDIX, which is sufficient for activation of the PCP pathway, is also sufficient for activation of three effectors of the Wnt–Ca2+ pathway: Ca2+ flux, PKC, and calcium/calmodulin-dependent protein kinase II (CamKII). Furthermore, we find that interfering with endogenous Dsh function reduces the activation of PKC by Xfz7 and interferes with normal heart development. These data suggest that the Wnt–Ca2+ pathway utilizes Dsh, thereby implicating Dsh as a component of all reported Fz signaling pathways

Compact Symmetric Objects -- I Towards a Comprehensive Bona Fide Catalog

Compact Symmetric Objects (CSOs) are jetted Active Galactic Nuclei (AGN) with overall projected size <1 kpc. The classification was introduced to distinguish these objects from the majority of compact jetted-AGN in centimeter wavelength very long baseline interferometry observations, where the observed emission is relativistically boosted towards the observer. The original classification criteria for CSOs were: (i) evidence of emission on both sides of the center of activity, and (ii) overall size <1 kpc. However some relativistically boosted objects with jet axes close to the line of sight appear symmetric and have been mis-classified as CSOs, thereby undermining the CSO classification. This is because two essential CSO properties, pointed out in the original papers, have been neglected: (iii) low variability, and (iv) low apparent speeds along the jets. As a first step towards creating a comprehensive catalog of ``bona fide'' CSOs, we identify 79 bona fide CSOs, including 15 objects claimed as confirmed CSOs here for the first time, that match the CSO selection criteria. This sample of bona fide CSOs can be used for astrophysical studies of CSOs without contamination by mis-classified CSOs. We show that the fraction of CSOs in complete flux density limited AGN samples with S$_{\rm 5\,GHz}$ >700 mJy is between $(6.8\pm1.6)$% and $(8.5\pm1.8)$%.Comment: 28 pages, 9 figures, 3 tables, accepted for publicatio

Compact Symmetric Objects -- II Confirmation of a Distinct Population of High-Luminosity Jetted Active Galaxies

Compact Symmetric Objects (CSOs) are compact (<1 kpc), jetted Active Galactic Nuclei (AGN), whose jet axes are not aligned close to the line of sight, and whose observed emission is not predominantly relativistically boosted towards us. Two classes of CSOs have previously been identified: approximately one fifth are edge-dimmed and designated as CSO 1s, while the rest are edge brightened and designated as CSO 2s. This paper focuses almost exclusively on CSO 2s. Using complete samples of CSO 2s we present three independent lines of evidence, based on their relative numbers, redshift distributions, and size distributions, which show conclusively that the vast majority (> 99%) of CSO 2s do not evolve into larger-scale radio sources. These CSO 2s belong to a distinct population of jetted-AGN, which should be characterized as ``short-lived'' compared to the classes of larger jetted-AGN, as opposed to ``young''. We show that there is a sharp upper cutoff in the CSO 2 size distribution at $\approx 500$ pc. The distinct differences between most CSO 2s and other jetted-AGN provides a crucial new time domain window on the formation and evolution of relativistic jets in AGN and the supermassive black holes that drive them.Comment: 29 pages, 10 figures, 7 tables, accepted for publicatio

High-resolution VLA low radio frequency observations of the Perseus cluster: radio lobes, mini-halo and bent-jet radio galaxies

We present the first high-resolution 230-470 MHz map of the Perseus cluster obtained with the Karl G. Jansky Very Large Array. The high dynamic range and resolution achieved has allowed the identification of previously-unknown structures in this nearby galaxy cluster. New hints of sub-structures appear in the inner radio lobes of the brightest cluster galaxy NGC 1275. The spurs of radio emission extending into the outer X-ray cavities, inflated by past nuclear outbursts, are seen for the first time at these frequencies, consistent with spectral aging. Beyond NGC 1275, we also analyze complex radio sources harbored in the cluster. Two new distinct, narrowly-collimated jets are visible in IC 310, consistent with a highly-projected narrow-angle tail radio galaxy infalling into the cluster. We show how this is in agreement with its blazar-like behavior, implying that blazars and bent-jet radio galaxies are not mutually exclusive. We report the presence of filamentary structures across the entire tail of NGC 1265, including two new pairs of long filaments in the faintest bent extension of the tail. Such filaments have been seen in other cluster radio sources such as relics and radio lobes, indicating that there may be a fundamental connection between all these radio structures. We resolve the very narrow and straight tail of CR 15 without indication of double jets, so that the interpretation of such head-tail sources is yet unclear. Finally, we note that only the brightest western parts of the mini-halo remain, near NGC 1272 and its bent double jets.Comment: 17 pages, 12 figures, Accepted for publication in MNRA

Compact Symmetric Objects -- III Evolution of the High-Luminosity Branch and a Possible Connection with Tidal Disruption Events

We use a sample of 54 Compact Symmetric Objects (CSOs) to confirm that there are two unrelated CSO classes: an edge-dimmed, low-luminosity class (CSO~1), and an edge-brightened, high-luminosity class (CSO~2). Using blind tests, we show that CSO~2s consist of three sub-classes: CSO 2.0, having prominent hot-spots at the leading edges of narrow jets and/or narrow lobes; CSO~2.2, without prominent hot-spots, and with broad jets and/or lobes; and CSO~2.1, which exhibit mixed properties. Most CSO 2s do not evolve into larger jetted-AGN, but spend their whole life-cycle as CSOs of size $\lesssim$500 pc and age $\lesssim$5000 yr. The minimum energies needed to produce the radio luminosity and structure in CSO~2s range from $\sim~10^{-4}\,M_\odot{c}^2$ to $\sim7\,M_\odot{c}^2$. We show that the transient nature of most CSO~2s, and their birthrate, can be explained through ignition in the tidal disruption events of giant stars. We also consider possibilities of tapping the spin energy of the supermassive black hole, and tapping the energy of the accretion disk. Our results demonstrate that CSOs constitute a large family of AGN in which we have thus far studied only the brightest. More comprehensive CSO studies, with higher sensitivity, resolution, and dynamic range, will revolutionize our understanding of AGN and the central engines that power them.Comment: 44 pages, 16 figures, 9 tables, accepted for publicatio

Beta-Catenin Signaling Plays a Disparate Role in Different Phases of Fracture Repair: Implications for Therapy to Improve Bone Healing

In a study in mice Benjamin Alman and colleagues show that β-catenin functions differently in different stages of fracture repair; moreover, activation of β-catenin by lithium improves fracture healing when used in later phases of repair

Reorganisation of Wnt-response pathways in colorectal tumorigenesis

In most colorectal tumours, APC mutation stabilises β-catenin and mimics elements of Wnt growth factor signalling, but the high frequency of epigenetic loss of Wnt antagonists indicates an additional role for ligand-mediated Wnt signalling. Here, we have investigated the expression of key components of β-catenin-independent Wnt response pathways to determine whether their profiles change during the transition from normal mucosa to colorectal adenomas. Transcription of the Wnt/planar cell polarity pathway determinant NKD1 (naked cuticle homologue 1) was induced in adenomas by a median 135-fold and in cancers by 7.4-fold. While some Frizzleds (FZDs) were downregulated in adenomas, the Wnt/Ca2+ receptors FZD3 and FZD6 were induced by a median factor of 6.5 and 4.6, respectively. Naked cuticle homologue 1, FZD3 and FZD6 expression were coordinated in pre-malignant disease, but this relationship was lost in invasive cancers, where FZD induction was seen less frequently. Naked cuticle homologue 1 expression was associated with nuclear localisation of phospho-c-Jun in adenomas. In cultured cells, NKD1 transcription was induced by lithium chloride but FZD3 expression required Wnt growth factor treatment. These data show that Wnt responses are consistently directed towards both β-catenin-independent routes in early colorectal tumorigenesis and elements of this are retained in more advanced cancers. These β-catenin-independent Wnt signalling pathways may provide novel targets for chemoprevention of early colorectal tumours