Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2

The Ras oncogene products regulate the expression of genes in transformed cells, and members of the Ets family of transcription factors have been implicated in this process. To determine which Ets factors are the targets of Ras signaling pathways, the abilities of several Ets factors to activate Ras-responsive enhancer (RRE) reporters in the presence of oncogenic Ras were examined. In transient transfection assay, reporters containing RREs composed of Ets-AP-1 binding sites could be activated 30-fold in NIH 3T3 fibroblasts and 80-fold in the macrophage-like line RAW264 by the combination of Ets1 or Ets2 and Ras but not by several other Ets factors that were tested in the assay. Ets2 and Ras also superactivated an RRE composed of Ets-Ets binding sites, but the Ets-responsive promoter of the c-fms gene was not superactivated. Mutation of a threonine residue to alanine in the conserved amino-terminal regions of Ets1 and Ets2 (threonine 38 and threonine 72, respectively) abrogated the ability of each of these proteins to superactivate reporter gene expression. Phosphoamino acid analysis of radiolabeled Ets2 revealed that Ras induced normally absent threonine-specific phosphorylation of the protein. The Ras-dependent increase in threonine phosphorylation was not observed in Ets2 proteins that had the conserved threonine 72 residue mutated to alanine or serine. These data indicate that Ets1 and Ets2 are specific nuclear targets of Ras signaling events and that phosphorylation of a conserved threonine residue is a necessary molecular component of Ras-mediated activation of these transcription factors

Spin dynamics and disorder effects in the S=1/2 kagome Heisenberg spin liquid phase of kapellasite

We report $^{35}$Cl NMR, ESR, $\mu$SR and specific heat measurements on the $S=1/2$ frustrated kagom\'e magnet kapellasite, $\alpha-$Cu$_3$Zn(OH)$_6$Cl$_2$, where a gapless spin liquid phase is stabilized by a set of competing exchange interactions. Our measurements confirm the ferromagnetic character of the nearest-neighbour exchange interaction $J_1$ and give an energy scale for the competing interactions $|J| \sim 10$ K. The study of the temperature-dependent ESR lineshift reveals a moderate symmetric exchange anisotropy term $D$, with $|D/J|\sim 3$%. These findings validate a posteriori the use of the $J_1 - J_2 - J_d$ Heisenberg model to describe the magnetic properties of kapellasite [Bernu et al., Phys. Rev. B 87, 155107 (2013)]. We further confirm that the main deviation from this model is the severe random depletion of the magnetic kagom\'e lattice by 27%, due to Cu/Zn site mixing, and specifically address the effect of this disorder by $^{35}$Cl NMR, performed on an oriented polycrystalline sample. Surprisingly, while being very sensitive to local structural deformations, our NMR measurements demonstrate that the system remains homogeneous with a unique spin susceptibility at high temperature, despite a variety of magnetic environments. Unconventional spin dynamics is further revealed by NMR and $\mu$SR in the low-$T$, correlated, spin liquid regime, where a broad distribution of spin-lattice relaxation times is observed. We ascribe this to the presence of local low-energy modes.Comment: 15 pages, 11 figures. To appear in Phys. Rev.

Valproate Protein Binding Is Highly Variable in ICU Patients and Not Predicted by Total Serum Concentrations: A Case Series and Literature Review

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/1/phar1912-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/2/phar1912_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/3/phar1912.pd

Let’s celebrate recovery. Inclusive Cities working together to support social cohesion

Recovery from illicit drug and alcohol use takes place over time and is characterised by a dynamic interaction between internal and external components. An integral part of all recovery journeys is effective community reintegration. After all, recovery is not mainly an issue of personal motivation rather it is about acceptance by family, by friends and by a range of organisations and professionals across the community. Therefore to support pathways to recovery, structural and contextual endeavours are needed to supplement individually-oriented interventions and programmes. One way to do this, is by introducing Inclusive Cities. An Inclusive City promotes participation, inclusion, full and equal citizenship to all her citizens, including those in recovery, based on the idea of community capital. The aim of building recovery capital at a community level through connections and 'linking social capital' to challenge stigmatisation and exclusion, is seen as central to this idea. Inclusive Cities is an initiative to support the creation of Recovery-Oriented Systems of Care at a city level, that starts with but extends beyond substance using populations. This paper describes (and gives examples of) how it is possible to use recovery as a starting point for generating social inclusion, challenging the marginalisation of other excluded populations as well by building community connections

A luminescent 1D silver polymer containing [2.2]paracyclophane ligands

Funding: UK EPSRC Grant Number(s) EP/P014082/1, EP/M02105X/1, EP/R035164/1).[2.2]Paracyclophane scaffolds have seen limited use as building blocks in supramolecular chemistry. Here, we report the synthesis and characterization of a 1D coordination polymer consisting of silver(I) ions bound to a [2.2]paracyclophane scaffold functionalized with two 4-pyridyl units. The structure of the polymer has been determined from single crystal X-ray diffraction analysis and reveals two different silver coordination motifs that alternate along the 1D coordination polymer. The coordination polymer exhibits strong blue and sky-blue fluorescence in solution and in the crystalline solid state, respectively.Publisher PDFPeer reviewe

Gridmapping the northern plains of Mars: Geomorphological, Radar and Water-Equivalent Hydrogen results from Arcadia Plantia

A project of mapping ice-related landforms was undertaken to understand the role of sub-surface ice in the northern plains. This work is the first continuous regional mapping from CTX (“ConTeXt Camera”, 6 m/pixel; Malin et al., 2007) imagery in Arcadia Planitia along a strip 300 km across stretching from 30°N to 80°N centred on the 170° West line of longitude. The distribution and morphotypes of these landforms were used to understand the permafrost cryolithology. The mantled and textured signatures occur almost ubiquitously between 35° N and 78° N and have a positive spatial correlation with inferred ice stability based on thermal modelling, neutron spectroscopy and radar data. The degradational features into the LDM (Latitude Dependent Mantle) include pits, scallops and 100 m polygons and provide supporting evidence for sub-surface ice and volatile loss between 35-70° N in Arcadia with the mantle between 70-78° N appearing much more intact. Pitted terrain appears to be much more pervasive in Arcadia than in Acidalia and Utopia suggesting that the Arcadia study area had more wide-spread near-surface sub-surface ice, and thus was more susceptible to pitting, or that the ice was less well-buried by sediments. Correlations with ice stability models suggest that lack of pits north of 65-70° N could indicate a relatively young age (~1Ma), however this could also be explained through regional variations in degradation rates. The deposition of the LDM is consistent with an airfall hypothesis however there appears to be substantial evidence for fluvial processes in southern Arcadia with older, underlying processes being equally dominant with the LDM and degradation thereof in shaping the landscape

Kallikrein-kininogen system activation and bradykinin (B2) receptors in indomethacin induced enterocolitis in genetically susceptible Lewis rats

Background—The plasma kallikrein-kinin (K-K) system is activated in acute and chronic relapsing intestinal inflammation induced in Lewis rats by intramural injection of exogenous bacterial components. Aims—To determine whether this effect is model specific, K-K system activation was investigated in a modified indomethacin induced enterocolitis model, as well as bradykinin 2 (B2) receptor distribution in the normal and acutely inflamed intestine. Methods—Lewis rats injected with daily sublethal doses of indomethacin for two days developed acute (two days) and chronic (14 days) intestinal inflammation. Plasma prekallikrein (amidolytic), high molecular weight kininogen (HK, coagulant) and cleavage of HK (western blot) were assayed to detect K-K activation. Results—Liver and spleen weights were significantly higher, and body weights and haematocrit values were significantly lower in the indomethacin group than in the control group. During both acute and chronic phases, rats displayed K-K system activation manifested by a significant decrease in plasma prekallikrein and HK functional levels, and by HK cleavage. Plasma T kininogen (a major acute phase protein) was significantly elevated. B2 receptors were identified in both normal and inflammatory intestine with more prominent specific immunohistochemical staining in the acutely inflamed tissue. Conclusions—K-K system activation occurs in association with both acute and chronic phases of intestinal injury, regardless of the triggering agent, suggesting that activation of this system is integrally involved in intestinal inflammation in genetically susceptible hosts. Localisation of B2 receptors across intestinal layers provides a structural basis for the kinin function in the intestine

14-3-3 Proteins Regulate a Cell-Intrinsic Switch from Sonic Hedgehog-Mediated Commissural Axon Attraction to Repulsion after Midline Crossing

SummaryAxons must switch responsiveness to guidance cues during development for correct pathfinding. Sonic Hedgehog (Shh) attracts spinal cord commissural axons ventrally toward the floorplate. We show that after crossing the floorplate, commissural axons switch their response to Shh from attraction to repulsion, so that they are repelled anteriorly by a posterior-high/anterior-low Shh gradient along the longitudinal axis. This switch is recapitulated in vitro with dissociated commissural neurons as they age, indicating that the switch is intrinsic and time dependent. 14-3-3 protein inhibition converted Shh-mediated repulsion of aged dissociated neurons to attraction and prevented the correct anterior turn of postcrossing commissural axons in vivo, an effect mediated through PKA. Conversely, overexpression of 14-3-3 proteins was sufficient to drive the switch from Shh-mediated attraction to repulsion both in vitro and in vivo. Therefore, we identify a 14-3-3 protein-dependent mechanism for a cell-intrinsic temporal switch in the polarity of axon turning responses