Deletion of the trpc4 gene and its role in simple and complex strategic learning

The TRPC4 ion channel is expressed extensively in corticolimbic and a subpopulation of midbrain dopamine neurons. While TRPC4 knockout (KO) rats exhibit reduced sociability and social exploration, little is known about the role of TRPC4 in motivation and learning. To identify a function for TRPC4 channels in learning processes  we tested TRPC4 KO and normal wild type (WT) rats. TRPC4 KO and WT rats exhibited no differences in Y-­maze learning or simple discrimination learning. Furthermore, on a more complex serial reversal shift task designed  to assess strategic learning where the reward and non-­reward cues were repeatedly reversed between training sessions both TRPC4 KO and WT rats   performed equally well. Finally, we found no   performance differences when using a conditional reversal shift task where a tone signals the reversal of reward and non-reward cues within sessions. These data suggest that although TRPC4 channels may play a role in social interaction/anxiety  they exert a minimal role in simple and complex strategic learning

The Phases Differential Astrometry Data Archive. IV. The Triple Star Systems 63 Gem A and HR 2896

Differential astrometry measurements from the Palomar High-precision Astrometric Search for Exoplanet Systems (PHASES) are used to constrain the astrometric orbit of the previously known ≾2 day subsystem in the triple system 63 Gem A and have detected a previously unknown two-year Keplerian wobble superimposed on the visual orbit of the much longer period (213 years) binary system HR 2896. 63 Gem A was already known to be triple from spectroscopic work, and absorption lines from all three stars can be identified and their individual Doppler shifts measured; new velocities for all three components are presented to aid in constraining the orbit and measuring the stellar masses. In fact, 63 Gem itself is a sextuple system: the hierarchical triple (Aa1-Aa2)-Ab (in which Aa1 and Aa2 orbit each other with a rapid period just under 2 days, and Ab orbits these every two years), plus three distant common proper motion companions. The very small astrometric perturbation caused by the inner pair in 63 Gem A stretches the limits of current astrometric capabilities, but PHASES observations are able to constrain the orientation of the orbit. The two bright stars comprising the HR 2896 long-period (213 year) system have a combined spectral type of K0III and the newly detected object's mass estimate places it in the regime of being an M dwarf. The motion of the stars are slow enough that their spectral features are always blended, preventing Doppler studies. The PHASES measurements and radial velocities (when available) have been combined with lower precision single-aperture measurements covering a much longer time frame (from eyepiece measurements, speckle interferometry, and adaptive optics) to improve the characterization of the long-period orbits in both binaries. The visual orbits of the short- and long-period systems are presented for both systems and used to calculate two possible values of the mutual inclinations between inner and outer orbits of 152° ± 12° or a less likely value of 31° ± 11° for 63 Gem A and 10.°2 ± 2.°4 or 171.°2 ± 2.°8 for HR 2896. The first is not coplanar, whereas the second is either nearly coplanar or anti-coplanar

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I

Regulation of branching dynamics by axon-intrinsic asymmetries in Tyrosine Kinase Receptor signaling

Axonal branching allows a neuron to connect to several targets, increasing neuronal circuit complexity. While axonal branching is well described, the mechanisms that control it remain largely unknown. We find that in the Drosophila CNS branches develop through a process of excessive growth followed by pruning. In vivo high-resolution live imaging of developing brains as well as loss and gain of function experiments show that activation of Epidermal Growth Factor Receptor (EGFR) is necessary for branch dynamics and the final branching pattern. Live imaging also reveals that intrinsic asymmetry in EGFR localization regulates the balance between dynamic and static filopodia. Elimination of signaling asymmetry by either loss or gain of EGFR function results in reduced dynamics leading to excessive branch formation. In summary, we propose that the dynamic process of axon branch development is mediated by differential local distribution of signaling receptors

Isothiourea-catalysed enantioselective pyrrolizine synthesis : synthetic and computational studies

We thank Syngenta and the EPSRC (grant code EP/K503162/1) (DGS), and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) (ERG,SFM, RWFK) for funding. The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged (JET). ADS thanks the Royal Society for a Wolfson Research Merit Award.The catalytic enantioselective synthesis of a range of cis-pyrrolizine carboxylate derivatives with outstanding stereocontrol (14 examples,>95:5 dr, >98:2 er) through an isothiourea-catalyzed intramolecular Michael addition-lactonisation and ring opening approach from the corresponding enone acid is reported. An optimised and straightforward three-step synthetic route to the enone acid starting materials from readily available pyrrole-2-carboxaldehydes is delineated, with benzotetramisole (5 mol%) proving the optimal catalyst for the enantioselective process. Ring-opening of the pyrrolizine dihydropyranone products with either MeOH or a range of amines leads to the desired products in excellent yield and enantioselectivity. Computation has been used to probe the factors leading to high stereocontrol, with the formation of the observed cis-steroisomer predicted to be kinetically and thermodynamically favoured.Publisher PDFPeer reviewe