ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin

A hallmark of Huntington's disease is the pronounced sensitivity of striatal neurons to polyglutamine-expanded huntingtin expression. Here we show that cultured striatal cells and murine brain striatum have remarkably low levels of phosphorylation of translation initiation factor eIF2 alpha, a stress-induced process that interferes with general protein synthesis and also induces differential translation of pro-apoptotic factors. EIF2 alpha phosphorylation was elevated in a striatal cell line stably expressing pathogenic huntingtin, as well as in brain sections of Huntington's disease model mice. Pathogenic huntingtin caused endoplasmic reticulum (ER) stress and increased eIF2 alpha phosphorylation by increasing the activity of PKR-like ER-localized eIF2 alpha kinase (PERK). Importantly, striatal neurons exhibited special sensitivity to ER stress-inducing agents, which was potentiated by pathogenic huntingtin. We could strongly reduce huntingtin toxicity by inhibiting PERK. Therefore, alteration of protein homeostasis and eIF2 alpha phosphorylation status by pathogenic huntingtin appears to be an important cause of striatal cell death. A dephosphorylated state of eIF2 alpha has been linked to cognition, which suggests that the effect of pathogenic huntingtin might also be a source of the early cognitive impairment seen in patients

Constructing the Cubus simus and the Dodecaedron simum via paper folding

The archimedean solids Cubus simus (snub cube) and Dodecaedron simum (snub dodecahedron) cannot be constructed by ruler and compass. We explain that for general reasons their vertices can be constructed via paper folding on the faces of a cube, respectively dodecahedron, and we present explicit folding constructions. The construction of the Cubus simus is particularly elegant. We also review and prove the construction rules of the other Archimedean solids.Comment: 13 pages, 12 figures, v2: as published in Geometriae Dedicat

Tetrakis(ferrocenylethynyl)ethene:synthesis, spectro)electrochemical and quantum chemical characterisation

Tetrakis(ferrocenylethynyl)ethene (1) has been prepared in four steps from ethynyl ferrocene (2). In a dichloromethane solution containing 10–1 M NBu4[PF6], only a single oxidation process is observed by cyclic voltammetry, corresponding to the independent oxidation of the four ferrocenyl moieties. However, in dichloromethane containing 10–1 M NBu4[BArF4] electrolyte, where [BArF4]– is the weakly associating anion [B{C6H3(CF3)2-3,5}4]–, four distinct oxidation processes are resolved, although further spectroelectrochemical investigation revealed essentially no through bond interaction between the individual ferrocenyl moieties. Quantum chemical treatment of 1 identified several energetic minima corresponding to different relative orientations of the ferrocenyl moieties and the plane of the all-carbon bridging fragment. Further computational investigation of the corresponding monocation [1]+ supported the notion of charge localisation with no evidence for significant through bond electronic interactions

Proteome-wide observation of the phenomenon of life on the edge of solubility

To function effectively proteins must avoid aberrant aggregation, and hence they are expected to be expressed at concentrations safely below their solubility limits. By analyzing proteome-wide mass spectrometry data of Caenorhabditis elegans, however, we show that the levels of about three-quarters of the nearly 4, 000 proteins analyzed in adult animals are close to their intrinsic solubility limits, indeed exceeding them by about 10% on average. We next asked how aging and functional self-assembly influence these solubility limits. We found that despite the fact that the total quantity of proteins within the cellular environment remains approximately constant during aging, protein aggregation sharply increases between days 6 and 12 of adulthood, after the worms have reproduced, as individual proteins lose their stoichiometric balances and the cellular machinery that maintains solubility undergoes functional decline. These findings reveal that these proteins are highly prone to undergoing concentration-dependent phase separation, which on aging is rationalized in a decrease of their effective solubilities, in particular for proteins associated with translation, growth, reproduction, and the chaperone system

General-Relativistic Curvature of Pulsar Vortex Structure

The motion of a neutron superfluid condensate in a pulsar is studied. Several theorems of general-relativistic hydrodynamics are proved for a superfluid. The average density distribution of vortex lines in pulsars and their general-relativistic curvature are derived.Comment: 18 pages, 1 figure

Sandwich and half-sandwich metal complexes derived from cross-conjugated 3-methylene-penta-1,4-diynes

The cross-conjugated ethynyl–vinylidene [Ph2CvC(CuCH){C(H)vCRu(PPh3)2Cp}]PF6 ([4a]PF6), and [FcC (H)vC(CuCH){C(H)vCRu(PPh3)2Cp}]PF6 ([4b]PF6), and ethynyl–alkynyl Ph2CvC(CuCH){CuCRu(PPh3)2Cp} (5a), and FcC(H)vC(CuCH){CuCRu(PPh3)2Cp} (5b) compounds (Cp = η5-cyclopentadienyl) have been prepared from reactions of the known 3-methylene-penta-1,4-diynes Ph2CvC(CuCH)2 (3a) and [FcCHvC(CuCH)2] (3b) with [RuCl(PPh3)2Cp]. The compounds derived from 3b incorporating the more electron-rich alkene proved to be unstable during work-up, and attempts to prepare bis(ruthenium) complexes from 3a and 3b or from transmetallation reactions of the bis(alkynylgold) complex FcCHvC(CuCAuPPh3)2 (7) with RuCl(PPh3)2Cp were unsuccessful. The related bis- and tris(ferrocenyl) derivatives Ph2CvC(CuCFc)2 (6a) and FcCHvC(CuCFc)2 (6b) were more readily obtained from Pd(II)/Cu(I) catalysed cross-coupling reactions of FcCuCH with the 1,1-dibromo vinyl complexes PhCvCBr2 (1a) and FcC(H)vCBr2 (1b). Cyclic voltammetry of 6a and 6b using n-Bu4N[PF6] as the supporting electrolyte shows broad, overlapping waves arising from the sequential oxidation of the ferrocenyl moieties in electronically and chemically similar environments. Electrostatic effects between the ferrocenyl moieties are enhanced in solutions of the weakly ion-pairing electrolyte n-Bu4N[B{C6H3(CF3)2-3,5}4], leading to better resolution of the individual electrochemical processes. The comparative IR spectroelectrochemical response of 6a and 6b suggest the vinyl ferrocene moiety in 6b undergoes oxidation before the ethynyl ferrocene fragments. There is no evidence of electronic coupling between the metallocene moieties and [6a]+, [6b]n+ (n = 1, 2) are best described as Class I mixed-valence compounds

Mitochondrial precursor proteins are imported through a hydrophilic membrane environment

We have analyzed how translocation intermediates of imported mitochondrial precursor proteins, which span contact sites, interact with the mitochondrial membranes. F1-ATPase subunit β(F1β) was trapped at contact sites by importing it into Neurospora mitochondria in the presence of low levels of nucleoside triphosphates. This F1β translocation intermediate could be extracted from the membranes by treatment with protein denaturants such as alkaline pH or urea. By performing import at low temperatures, the ADP/ATP carrier was accumulated in contact sites of Neurospora mitochondria and cytochrome b2 in contact sites of yeast mitochondria. These translocation intermediates were also extractable from the membranes at alkaline pH. Thus, translocation of precursor proteins across mitochondrial membranes seems to occur through an environment which is accessible to aqueous perturbants. We propose that proteinaceous structures are essential components of a translocation apparatus present in contact sites

Can Modal Skepticism Defeat Humean Skepticism?

My topic is moderate modal skepticism in the spirit of Peter van Inwagen. Here understood, this is a conservative version of modal empiricism that severely limits the extent to which an ordinary agent can reasonably believe “exotic” possibility claims. I offer a novel argument in support of this brand of skepticism: modal skepticism grounds an attractive (and novel) reply to Humean skepticism. Thus, I propose that modal skepticism be accepted on the basis of its theoretical utility as a tool for dissolving philosophical paradox

The statistical analysis of acoustic phonetic data: exploring differences between spoken Romance languages

The historical and geographical spread from older to more modern languages has long been studied by examining textual changes and in terms of changes in phonetic transcriptions. However, it is more difficult to analyze language change from an acoustic point of view, although this is usually the dominant mode of transmission. We propose a novel analysis approach for acoustic phonetic data, where the aim will be to statistically model the acoustic properties of spoken words. We explore phonetic variation and change using a time-frequency representation, namely the log-spectrograms of speech recordings. We identify time and frequency covariance functions as a feature of the language; in contrast, mean spectrograms depend mostly on the particular word that has been uttered. We build models for the mean and covariances (taking into account the restrictions placed on the statistical analysis of such objects) and use these to define a phonetic transformation that models how an individual speaker would sound in a different language, allowing the exploration of phonetic differences between languages. Finally, we map back these transformations to the domain of sound recordings, allowing us to listen to the output of the statistical analysis. The proposed approach is demonstrated using recordings of the words corresponding to the numbers from ``one'' to ``ten'' as pronounced by speakers from five different Romance languages.John Coleman appreciates the support of UK Arts and Humanities Research Council grant AH/M002993/1, “Ancient Sounds: mixing acoustic phonetics, statistics and comparative philology to bring speech back from the past”. John Aston appreciates the support of UK Engineering and Physical Sciences Research Council grant EP/K021672/2, “Functional Object Data Analysis and its Applications”