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

On a Conjecture of Rapoport and Zink

In their book Rapoport and Zink constructed rigid analytic period spaces $F^{wa}$ for Fontaine's filtered isocrystals, and period morphisms from PEL moduli spaces of $p$-divisible groups to some of these period spaces. They conjectured the existence of an \'etale bijective morphism $F^a \to F^{wa}$ of rigid analytic spaces and of a universal local system of $Q_p$-vector spaces on $F^a$. For Hodge-Tate weights $n-1$ and $n$ we construct in this article an intrinsic Berkovich open subspace $F^0$ of $F^{wa}$ and the universal local system on $F^0$. We conjecture that the rigid-analytic space associated with $F^0$ is the maximal possible $F^a$, and that $F^0$ is connected. We give evidence for these conjectures and we show that for those period spaces possessing PEL period morphisms, $F^0$ equals the image of the period morphism. Then our local system is the rational Tate module of the universal $p$-divisible group and enjoys additional functoriality properties. We show that only in exceptional cases $F^0$ equals all of $F^{wa}$ and when the Shimura group is $GL_n$ we determine all these cases.Comment: v2: 48 pages; many new results added, v3: final version that will appear in Inventiones Mathematica

Dimer, trimer and FFLO liquids in mass- and spin-imbalanced trapped binary mixtures in one dimension

We present a systematic investigation of attractive binary mixtures in presence of both spin- and mass-imbalance in one dimensional setups described by the Hubbard model. After discussing typical cold atomic experimental realizations and the relation between microscopic and effective parameters, we study several many-body features of trapped Fermi-Fermi and Bose-Bose mixtures such as density profiles, momentum distributions and correlation functions by means of numerical density-matrix-renormalization-group and Quantum Monte Carlo simulations. In particular, we focus on the stability of Fulde-Ferrell-Larkin-Ovchinnikov, dimer and trimer fluids in inhomogeneous situations, as typically realized in cold gas experiments due to the harmonic confinement. We finally consider possible experimental signatures of these phases both in the presence of a finite polarization and of a finite temperature.Comment: 19 pages, 25 figure

Ecological theatre and the evolutionary game: how environmental and demographic factors determine payoffs in evolutionary games

In the standard approach to evolutionary games and replicator dynamics, differences in fitness can be interpreted as an excess from the mean Malthusian growth rate in the population. In the underlying reasoning, related to an analysis of "costs" and "benefits", there is a silent assumption that fitness can be described in some type of units. However, in most cases these units of measure are not explicitly specified. Then the question arises: are these theories testable? How can we measure "benefit" or "cost"? A natural language, useful for describing and justifying comparisons of strategic "cost" versus "benefits", is the terminology of demography, because the basic events that shape the outcome of natural selection are births and deaths. In this paper, we present the consequences of an explicit analysis of births and deaths in an evolutionary game theoretic framework. We will investigate different types of mortality pressures, their combinations and the possibility of trade-offs between mortality and fertility. We will show that within this new approach it is possible to model how strictly ecological factors such as density dependence and additive background fitness, which seem neutral in classical theory, can affect the outcomes of the game. We consider the example of the Hawk-Dove game, and show that when reformulated in terms of our new approach new details and new biological predictions are produced

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

The electric two-echelon vehicle routing problem

Two-echelon distribution systems are attractive from an economical standpoint and help to keep large vehicles out of densely populated city centers. Large trucks can be used to deliver goods to intermediate facilities in accessible locations, whereas smaller vehicles allow to reach the final customers. Due to their reduced size, pollution, and noise, multiple companies consider using an electric fleet of terrestrial or aerial vehicles for last-mile deliveries. Route planning in multi-tier logistics leads to notoriously difficult problems. This difficulty is accrued in the presence of an electric fleet since each vehicle operates on a smaller range and may require planned visits to recharging stations. To study these challenges, we introduce the electric two-echelon vehicle routing problem (E2EVRP) as a prototypical problem. We propose a large neighborhood search (LNS) metaheuristic as well as an exact mathematical programming algorithm, which uses decomposition techniques to enumerate promising first-level solutions in conjunction with bounding functions and route enumeration for the second-level routes. These algorithms produce optimal or near-optimal solutions for the problem and allow us to evaluate the impact of several defining features of optimized battery-powered distribution networks. We created representative E2EVRP benchmark instances to simulate realistic metropolitan areas. In particular, we observe that the detour miles due to recharging decrease proportionally to 1/ρx with x ≈ 5/4 as a function of the charging stations density ρ; e.g., in a scenario where the density of charging stations is doubled, recharging detours are reduced by 58%. Finally, we evaluate the trade-off between battery capacity and detour miles. This estimate is critical for strategic fleet-acquisition decisions, in a context where large batteries are generally more costly and less environment-friendly

Hsp70 in mitochondrial biogenesis

The family of hsp70 (70 kilodalton heat shock protein) molecular chaperones plays an essential and diverse role in cellular physiology, Hsp70 proteins appear to elicit their effects by interacting with polypeptides that present domains which exhibit non-native conformations at distinct stages during their life in the cell. In this paper we review work pertaining to the functions of hsp70 proteins in chaperoning mitochondrial protein biogenesis. Hsp70 proteins function in protein synthesis, protein translocation across mitochondrial membranes, protein folding and finally the delivery of misfolded proteins to proteolytic enzymes in the mitochondrial matrix