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The Mammalian Disaggregase Machinery: Hsp110 Synergizes with Hsp70 and Hsp40 to Catalyze Protein Disaggregation and Reactivation in a Cell-Free System

Bacteria, fungi, protozoa, chromista and plants all harbor homologues of Hsp104, a AAA+ ATPase that collaborates with Hsp70 and Hsp40 to promote protein disaggregation and reactivation. Curiously, however, metazoa do not possess an Hsp104 homologue. Thus, whether animal cells renature large protein aggregates has long remained unclear. Here, it is established that mammalian cytosol prepared from different sources possesses a potent, ATP-dependent protein disaggregase and reactivation activity, which can be accelerated and stimulated by Hsp104. This activity did not require the AAA+ ATPase, p97. Rather, mammalian Hsp110 (Apg-2), Hsp70 (Hsc70 or Hsp70) and Hsp40 (Hdj1) were necessary and sufficient to slowly dissolve large disordered aggregates and recover natively folded protein. This slow disaggregase activity was conserved to yeast Hsp110 (Sse1), Hsp70 (Ssa1) and Hsp40 (Sis1 or Ydj1). Hsp110 must engage substrate, engage Hsp70, promote nucleotide exchange on Hsp70, and hydrolyze ATP to promote disaggregation of disordered aggregates. Similarly, Hsp70 must engage substrate and Hsp110, and hydrolyze ATP for protein disaggregation. Hsp40 must harbor a functional J domain to promote protein disaggregation, but the J domain alone is insufficient. Optimal disaggregase activity is achieved when the Hsp40 can stimulate the ATPase activity of Hsp110 and Hsp70. Finally, Hsp110, Hsp70 and Hsp40 fail to rapidly remodel amyloid forms of the yeast prion protein, Sup35, or the Parkinson's disease protein, alpha-synuclein. However, Hsp110, Hsp70 and Hsp40 enhanced the activity of Hsp104 against these amyloid substrates. Taken together, these findings suggest that Hsp110 fulfils a subset of Hsp104 activities in mammals. Moreover, they suggest that Hsp104 can collaborate with the mammalian disaggregase machinery to rapidly remodel amyloid conformers

The Number and Transmission of [PSI+] Prion Seeds (Propagons) in the Yeast Saccharomyces cerevisiae

Yeast (Saccharomyces cerevisiae) prions are efficiently propagated and the on-going generation and transmission of prion seeds (propagons) to daughter cells during cell division ensures a high degree of mitotic stability. The reversible inhibition of the molecular chaperone Hsp104p by guanidine hydrochloride (GdnHCl) results in cell division-dependent elimination of yeast prions due to a block in propagon generation and the subsequent dilution out of propagons by cell division.Analysing the kinetics of the GdnHCl-induced elimination of the yeast [PSI+] prion has allowed us to develop novel statistical models that aid our understanding of prion propagation in yeast cells. Here we describe the application of a new stochastic model that allows us to estimate more accurately the mean number of propagons in a [PSI+] cell. To achieve this accuracy we also experimentally determine key cell reproduction parameters and show that the presence of the [PSI+] prion has no impact on these key processes. Additionally, we experimentally determine the proportion of propagons transmitted to a daughter cell and show this reflects the relative cell volume of mother and daughter cells at cell division.While propagon generation is an ATP-driven process, the partition of propagons to daughter cells occurs by passive transfer via the distribution of cytoplasm. Furthermore, our new estimates of n(0), the number of propagons per cell (500-1000), are some five times higher than our previous estimates and this has important implications for our understanding of the inheritance of the [PSI+] and the spontaneous formation of prion-free cells

Assessing Internet addiction using the parsimonious Internet addiction components model - a preliminary study [forthcoming]

Internet usage has grown exponentially over the last decade. Research indicates that excessive Internet use can lead to symptoms associated with addiction. To date, assessment of potential Internet addiction has varied regarding populations studied and instruments used, making reliable prevalence estimations difficult. To overcome the present problems a preliminary study was conducted testing a parsimonious Internet addiction components model based on Griffiths’ addiction components (2005), including salience, mood modification, tolerance, withdrawal, conflict, and relapse. Two validated measures of Internet addiction were used (Compulsive Internet Use Scale [CIUS], Meerkerk et al., 2009, and Assessment for Internet and Computer Game Addiction Scale [AICA-S], Beutel et al., 2010) in two independent samples (ns = 3,105 and 2,257). The fit of the model was analysed using Confirmatory Factor Analysis. Results indicate that the Internet addiction components model fits the data in both samples well. The two sample/two instrument approach provides converging evidence concerning the degree to which the components model can organize the self-reported behavioural components of Internet addiction. Recommendations for future research include a more detailed assessment of tolerance as addiction component

Short-Term Trends in Bastardy in Taiwan

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68002/2/10.1177_036319908000500303.pd

Immigrant fertility in West Germany: is there a socialization effect in transitions to second and third births?

In this paper on immigrant fertility in West Germany, we estimate the transition rates to second and third births, using intensity-regression models. The data come from the German Socio-Economic Panel Study. We distinguish women of the first and the second immigrant generations originating from Turkey, the former Yugoslavia, Greece, Italy, and Spain, and compare their fertility levels to those of West German women. In the theoretical framework, we discuss competing hypotheses on migrant fertility. The findings support mainly the socialization hypothesis: the transition rates of first-generation immigrants vary by country of origin, and the fertility patterns of migrant descendants resemble more closely those of West Germans than those of the first immigrant generation. In addition, the analyses show that fertility differentials between immigrants and women of the indigenous population can largely, though not in full, be explained by compositional differences.Dans cet article relatif à la fécondité des immigrées en Allemagne, le passage du premier au deuxieme enfant et dans celui du deuxieme au troisieme enfant est estimé à partir de modèles de régression à risques instantanés. Les données utilisées proviennent de l’étude de Panel socio-économique allemand. On distingue les femmes immigrées de première ou de seconde génération originaires de Turquie, d’ex-Yougoslavie, de Grèce, d’Italie et d’Espagne, et leurs niveaux de fécondité sont comparés à ceux des femmes ouest-allemandes d’origine. Des hypothèses concurrentes sur la fécondité des immigrés sont discutées dans le cadre théorique. Les résultats vérifient principalement l’hypothèse de la socialisation : le passage au deuxieme et au troisieme enfant de la première génération d’immigrés varie selon le pays d’origine, et le profil de fécondité par âge des descendantes d’immigrées se rapproche plus de celui des femmes ouest-allemandes que de celui des immigrées de première génération. De plus, les analyses montrent que les différences de fécondité entre les immigrées et les femmes ouest-allemandes peuvent être en grande partie, mais pas totalement, expliquées par des différences de structure

Volatile chemical emission as a weapon of rearguard action: a game-theoretic model of contest behavior

We use a game-theoretic model to explore whether volatile chemical (spiroacetal) emissions can serve as a weapon of rearguard action. Our basic model explores whether such emissions serve as a means of temporary withdrawal, preventing the winner of the current round of a contest from translating its victory into permanent possession of a contested resource. A variant of this model explores an alternative possibility, namely, that such emissions serve as a means of permanent retreat, attempting to prevent a winner from inflicting costs on a fleeing loser. Our results confirm that the underlying logic of either interpretation of weapons of rearguard action is sound; however, empirical observations on parasitoid wasp contests suggest that the more likely function of chemical weapons is to serve as a means of temporary withdrawal. While our work is centered around the particular biology of contest behavior in parasitoid wasps, it also provides the first contest model to explicitly consider self-inflicted damage costs, and thus responds to a recent call by empiricists for theory in this area

Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]

Prions are proteins that can access multiple conformations, at least one of which is beta-sheet rich, infectious and self-perpetuating in nature. These infectious proteins show several remarkable biological activities, including the ability to form multiple infectious prion conformations, also known as strains or variants, encoding unique biological phenotypes, and to establish and overcome prion species (transmission) barriers. In this Perspective, we highlight recent studies of the yeast prion [PSI+], using various biochemical and structural methods, that have begun to illuminate the molecular mechanisms by which self-perpetuating prions encipher such biological activities. We also discuss several aspects of prion conformational change and structure that remain either unknown or controversial, and we propose approaches to accelerate the understanding of these enigmatic, infectious conformers