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

Rules for biological regulation based on error minimization

The control of gene expression involves complex mechanisms that show large variation in design. For example, genes can be turned on either by the binding of an activator (positive control) or the unbinding of a repressor (negative control). What determines the choice of mode of control for each gene? This study proposes rules for gene regulation based on the assumption that free regulatory sites are exposed to nonspecific binding errors, whereas sites bound to their cognate regulators are protected from errors. Hence, the selected mechanisms keep the sites bound to their designated regulators for most of the time, thus minimizing fitness-reducing errors. This offers an explanation of the empirically demonstrated Savageau demand rule: Genes that are needed often in the natural environment tend to be regulated by activators, and rarely needed genes tend to be regulated by repressors; in both cases, sites are bound for most of the time, and errors are minimized. The fitness advantage of error minimization appears to be readily selectable. The present approach can also generate rules for multi-regulator systems. The error-minimization framework raises several experimentally testable hypotheses. It may also apply to other biological regulation systems, such as those involving protein-protein interactions.Comment: biological physics, complex networks, systems biology, transcriptional regulation http://www.weizmann.ac.il/complex/tlusty/papers/PNAS2006.pdf http://www.pnas.org/content/103/11/3999.ful

Bose-Einstein distribution, condensation transition and multiple stationary states in multiloci evolution of diploid population

The mapping between genotype and phenotype is encoded in the complex web of epistatic interaction between genetic loci. In this rugged fitness landscape, recombination processes, which tend to increase variation in the population, compete with selection processes that tend to reduce genetic variation. Here we show that the Bose-Einstein distribution describe the multiple stationary states of a diploid population under this multi-loci evolutionary dynamics. Moreover, the evolutionary process might undergo an interesting condensation phase transition in the universality class of a Bose-Einstein condensation when a finite fraction of pairs of linked loci, is fixed into given allelic states. Below this phase transition the genetic variation within a species is significantly reduced and only maintained by the remaining polymorphic loci.Comment: (12 pages, 7 figures

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

The Newton stratification on deformations of local G-shtukas

Bounded local G-shtukas are function field analogs for p-divisible groups with extra structure. We describe their deformations and moduli spaces. The latter are analogous to Rapoport-Zink spaces for p-divisible groups. The underlying schemes of these moduli spaces are affine Deligne-Lusztig varieties. For basic Newton polygons the closed Newton stratum in the universal deformation of a local G-shtuka is isomorphic to the completion of a corresponding affine Deligne-Lusztig variety in that point. This yields bounds on the dimension and proves equidimensionality of the basic affine Deligne-Lusztig varieties.Comment: several improvements, definition of local G-shtuka is change

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