Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store-operated calcium (Ca(2+)) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same compounds exerted neuroprotective effects in glutamate-toxicity assays with YAC128 medium spiny neurons primary cultures. We demonstrated a key role of TRPC1 channels in supporting SOC pathway in HD neurons. We concluded that the TRPC1-mediated neuronal SOC pathway constitutes a novel target for HD treatment and that the identified compounds represent a novel class of therapeutic agents for treatment of HD and possibly other neurodegenerative disorders.     

Synthesis of carbohydrates in mineral-guided prebiotic cycles

One present obstacle to the "RNA-first" model for the origin of life is an inability to generate reasonable "hands off" scenarios for the formation of carbohydrates under conditions where they might have survived for reasonable times once formed. Such scenarios would be especially compelling if they deliver pent(ul)oses, five-carbon sugars found in terran genetics, and exclude other carbohydrates (e.g., aldotetroses) that may also be able to function in genetic systems. Here, we provide detailed chemical analyses of carbohydrate premetabolism, showing how borate, molybdate, and calcium minerals guide the formation of tetroses (C(4)H(8)O(4)), heptoses (C(7)H(14)O(7)), and pentoses (C(5)H(10)O(5)), including the ribose found in RNA, in "hands off" experiments, starting with formaldehyde and glycolaldehyde. These results show that pent(ul)oses would almost certainly have formed as stable borate complexes on the surface of an early Earth beneath a humid CO(2) atmosphere suffering electrical discharge. While aldotetroses form extremely stable complexes with borate, they are not accessible by pathways plausible under the most likely early Earth scenarios. The stabilization by borate is not, however, absolute. Over longer times, material is expected to have passed from borate-bound pent(ul)oses to a branched heptulose, which is susceptible to Cannizzaro reduction to give dead end products. We show how this fate might be avoided using molybdate-catalyzed rearrangement of a branched pentose that is central to borate-moderated cycles that fix carbon from formaldehyde. Our emerging understanding of the nature of the early Earth, including the presence of hydrated rocks undergoing subduction to form felsic magmas in the early Hadean eon, may have made borate and molydate species available to prebiotic chemistry, despite the overall "reduced" state of the planet.     

Search for a dark matter annihilation signal from the galactic center halo with H.E.S.S

A search for a very-high-energy (VHE; ≥100 GeV) γ-ray signal from self-annihilating particle dark matter (DM) is performed towards a region of projected distance r～45-150 pc from the Galactic center. The background-subtracted γ-ray spectrum measured with the High Energy Stereoscopic System (H.E.S.S.) γ-ray instrument in the energy range between 300 GeV and 30 TeV shows no hint of a residual γ-ray flux. Assuming conventional Navarro-Frenk-White and Einasto density profiles, limits are derived on the velocity-weighted annihilation cross section (σv) as a function of the DM particle mass. These are among the best reported so far for this energy range and in particular differ only little between the chosen density profile parametrizations. In particular, for the DM particle mass of ～1 TeV, values for (σv) above 3×10(-25) cm(3)?s(-1) are excluded for the Einasto density profile.     

Use of perceptual weights to test a model of loudness summation

Leibold et al.[J. Acoust. Soc. Am. 121, 2822-2831 (2007)] examined the perceptual weight subjects assigned to individual components of a multitone complex while performing a loudness-matching task. Weights agreed with the Moore et al. loudness model [J. Audio Eng. Soc. 45, 224-237 (1997)], except when components were widely spaced in frequency. In an effort to account for the data, the just-noticeable-difference (jnd) for intensity discrimination was measured for each component and compared to the weight for that component. The model predicts greater improvement in intensity discrimination with increasing bandwidth than was observed in the data. jnds were not correlated with weights in the widest frequency-spacing condition.     

Modeling Reputational and Informational Influences in Threshold Models of Bandwagon Innovation Diffusion

Bandwagon innovation diffusion is characterized by a positive feedback loop where adoptions by some actors increase the pressure to adopt for other actors. In particular, when gains from an innovation are difficult to quantify, such as implementing quality circles or downsizing practices, diffusion is likely to occur through a bandwagon process. In this paper we extend Abrahamson and Rosenkopf&2018;s (1993) model of bandwagon diffusion to examine both reputational and informational influences on this process. We find that the distribution of reputations among the set of potential adopters affects the extent of bandwagon diffusion under conditions of moderate ambiguity, and we find that bandwagons occur even when potential adopters receive information about others&2018; unprofitable experiences with the innovation.