Breakdown of supersaturation barrier links protein folding to amyloid formation

The thermodynamic hypothesis of protein folding, known as the “Anfinsen’s dogma” states that the native structure of a protein represents a free energy minimum determined by the amino acid sequence. However, inconsistent with the Anfinsen’s dogma, globular proteins can misfold to form amyloid fibrils, which are ordered aggregates associated with diseases such as Alzheimer’s and Parkinson’s diseases. Here, we present a general concept for the link between folding and misfolding. We tested the accessibility of the amyloid state for various proteins upon heating and agitation. Many of them showed Anfinsen-like reversible unfolding upon heating, but formed amyloid fibrils upon agitation at high temperatures. We show that folding and amyloid formation are separated by the supersaturation barrier of a protein. Its breakdown is required to shift the protein to the amyloid pathway. Thus, the breakdown of supersaturation links the Anfinsen’s intramolecular folding universe and the intermolecular misfolding universe

Multi-layer scintillation detector for the MOON double beta decay experiment: Scintillation photon responses studied by a prototype detector MOON-1

An ensemble of multi-layer scintillators is discussed as an option of the high-sensitivity detector Mo Observatory Of Neutrinos (MOON) for spectroscopic measurements of neutrino-less double beta decays. A prototype detector MOON-1, which consists of 6 layer plastic-scintillator plates, was built to study the sensitivity of the MOON-type detector. The scintillation photon collection and the energy resolution, which are key elements for the high-sensitivity experiments, are found to be 1835+/-30 photo-electrons for 976 keV electrons and sigma = 2.9+/-0.1% (dE/E = 6.8+/-0.3 % in FWHM) at the Qbb ~ 3 MeV region, respectively. The multi-layer plastic-scintillator structure with good energy resolution as well as good background suppression of beta-gamma rays is crucial for the MOON-type detector to achieve the inverted hierarchy neutrino mass sensitivity.Comment: 8 pages, 16 figures, submitted to Nucl.Instrum.Met

The selective elimination of messenger RNA underlies the mitosis–meiosis switch in fission yeast

The cellular programs for meiosis and mitosis must be strictly distinguished but the mechanisms controlling the entry to meiosis remain largely elusive in higher organisms. In contrast, recent analyses in yeast have shed new light on the mechanisms underlying the mitosis–meiosis switch. In this review, the current understanding of these mechanisms in the fission yeast Schizosaccharomyces pombe is discussed. Meiosis-inducing signals in this microbe emanating from environmental conditions including the nutrient status converge on the activity of an RRM-type RNA-binding protein, Mei2. This protein plays pivotal roles in both the induction and progression of meiosis and has now been found to govern the meiotic program in a quite unexpected manner. Fission yeast contains an RNA degradation system that selectively eliminates meiosis-specific mRNAs during the mitotic cell cycle. Mmi1, a novel RNA-binding protein of the YTH-family, is essential for this process. Mei2 tethers Mmi1 and thereby stabilizes the transcripts necessary for the progression of meiosis

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Beta-Arrestin Functionally Regulates the Non-Bleaching Pigment Parapinopsin in Lamprey Pineal

The light response of vertebrate visual cells is achieved by light-sensing proteins such as opsin-based pigments as well as signal transduction proteins, including visual arrestin. Previous studies have indicated that the pineal pigment parapinopsin has evolutionally and physiologically important characteristics. Parapinopsin is phylogenetically related to vertebrate visual pigments. However, unlike the photoproduct of the visual pigment rhodopsin, which is unstable, dissociating from its chromophore and bleaching, the parapinopsin photoproduct is stable and does not release its chromophore. Here, we investigated arrestin, which regulates parapinopsin signaling, in the lamprey pineal organ, where parapinopsin and rhodopsin are localized to distinct photoreceptor cells. We found that beta-arrestin, which binds to stimulated G protein-coupled receptors (GPCRs) other than opsin-based pigments, was localized to parapinopsin-containing cells. This result stands in contrast to the localization of visual arrestin in rhodopsin-containing cells. Beta-arrestin bound to cultured cell membranes containing parapinopsin light-dependently and translocated to the outer segments of pineal parapinopsin-containing cells, suggesting that beta-arrestin binds to parapinopsin to arrest parapinopsin signaling. Interestingly, beta-arrestin colocalized with parapinopsin in the granules of the parapinopsin-expressing cell bodies under light illumination. Because beta-arrestin, which is a mediator of clathrin-mediated GPCR internalization, also served as a mediator of parapinopsin internalization in cultured cells, these results suggest that the granules were generated light-dependently by beta-arrestin-mediated internalization of parapinopsins from the outer segments. Therefore, our findings imply that beta-arrestin-mediated internalization is responsible for eliminating the stable photoproduct and restoring cell conditions to the original dark state. Taken together with a previous finding that the bleaching pigment evolved from a non-bleaching pigment, vertebrate visual arrestin may have evolved from a “beta-like” arrestin by losing its clathrin-binding domain and its function as an internalization mediator. Such changes would have followed the evolution of vertebrate visual pigments, which generate unstable photoproducts that independently decay by chromophore dissociation

Modeling the Violation of Reward Maximization and Invariance in Reinforcement Schedules

It is often assumed that animals and people adjust their behavior to maximize reward acquisition. In visually cued reinforcement schedules, monkeys make errors in trials that are not immediately rewarded, despite having to repeat error trials. Here we show that error rates are typically smaller in trials equally distant from reward but belonging to longer schedules (referred to as “schedule length effect”). This violates the principles of reward maximization and invariance and cannot be predicted by the standard methods of Reinforcement Learning, such as the method of temporal differences. We develop a heuristic model that accounts for all of the properties of the behavior in the reinforcement schedule task but whose predictions are not different from those of the standard temporal difference model in choice tasks. In the modification of temporal difference learning introduced here, the effect of schedule length emerges spontaneously from the sensitivity to the immediately preceding trial. We also introduce a policy for general Markov Decision Processes, where the decision made at each node is conditioned on the motivation to perform an instrumental action, and show that the application of our model to the reinforcement schedule task and the choice task are special cases of this general theoretical framework. Within this framework, Reinforcement Learning can approach contextual learning with the mixture of empirical findings and principled assumptions that seem to coexist in the best descriptions of animal behavior. As examples, we discuss two phenomena observed in humans that often derive from the violation of the principle of invariance: “framing,” wherein equivalent options are treated differently depending on the context in which they are presented, and the “sunk cost” effect, the greater tendency to continue an endeavor once an investment in money, effort, or time has been made. The schedule length effect might be a manifestation of these phenomena in monkeys