Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes.

See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article.Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington's disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington's disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington's disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-associated behavioural phenotypes in a knock-in Huntington's disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington's disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington's disease drug discovery by targeting Gpr52

Apparent timing and duration of the Matuyama-Brunhes geomagnetic reversal in Chinese loess

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; The Matuyama-Brunhes (MB) geomagnetic reversal in Chinese loess has been studied extensively as an important boundary for land-ocean stratigraphic and paleoclimatic correlations. However, the apparent timing and duration of the MB boundary remain controversial in Chinese loess deposits due to its inconsistent stratigraphic position and the uncertain chronologies. Here we synthesized high-resolution paleomagnetic records from four loess sequences in the central Chinese Loess Plateau and synchronized the loess-paleosol chronology by matching the grain-size variations to orbitally tuned grain-size time series. The synthesized paleomagnetic results reveal consistent features of the MB transition in Chinese loess, including the stratigraphic position (L8/S8 transition), timing (&sim;808&ndash;826 ka), duration (&sim;14&ndash;16 ka), and rapid directional oscillations. Compared with the MB transition in marine records (770&ndash;775 ka), the timing of the MB transition is relatively older and longer in Chinese loess, due to a complex interplay between different remanence acquisition mechanisms which occurred during the course of postdepositional physical and chemical processes.</p

Structure of hadron resonances with a nearby zero of the amplitude

We discuss the relation between the analytic structure of the scattering amplitude and the origin of an eigenstate represented by a pole of the amplitude.If the eigenstate is not dynamically generated by the interaction in the channel of interest, the residue of the pole vanishes in the zero coupling limit. Based on the topological nature of the phase of the scattering amplitude, we show that the pole must encounter with the Castillejo-Dalitz-Dyson (CDD) zero in this limit. It is concluded that the dynamical component of the eigenstate is small if a CDD zero exists near the eigenstate pole. We show that the line shape of the resonance is distorted from the Breit-Wigner form as an observable consequence of the nearby CDD zero. Finally, studying the positions of poles and CDD zeros of the KbarN-piSigma amplitude, we discuss the origin of the eigenstates in the Lambda(1405) region.Comment: 7 pages, 3 figures, v2: published versio