Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates.

Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1) linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt) induces p62 phosphorylation at its ubiquitin-association (UBA) domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington's disease.

The Directional Distance Function and Measurement of Super-Efficiency: An Application to Airlines Data

Lovell and Rouse (LR) have recently proposed a modification of the standard DEA model that overcomes the infeasibility problem often encountered in computing super-efficiency. In the LR procedure one appropriately scales up the observed input vector (scale down the output vector) of the relevant super-efficient firm thereby usually creating its inefficient surrogate. An alternative procedure proposed in this paper uses the directional distance function introduced by Chambers, Chung, and Färe and the resulting Nerlove-Luenberger (NL) measure of super-efficiency. The fact that the directional distance function combines features of both an input-oriented and an output-oriented model, generally leads to a more complete ranking of the observations than either of the oriented models. An added advantage of this approach is that the NL super-efficiency measure is unique and does not depend on any arbitrary choice of a scaling parameter. A data set on international airlines from Coelli, Perelman, and Griffel-Tatje (2002) is utilized in an illustrative empirical application.

Institutional Infrastructure to Support 'Super Growth' in Kenya: Governance Thresholds, Reversion Rates and Economic Development

Kenya Growth Vision 2030 proposes policy and institutional reforms that make it possible for the country to achieve development status of a middle income country by 2030. This paper outlines the institutional framework necessary to achieve ÈSuper Growth,É which describes the character of growth required to meet targets stipulated in the Vision. The paper provides evidence confirming the importance of improving the quality of governance to the achievement of the Vision. The paper also demonstrates that the country is characterized by a high probability of reverting to poor governance. It is argued that, to achieve super growth, the country must attain an institutional tipping point which associates with low reversion rates to weaker institutions. The paper provides suggestions for institutional reforms that result in the achievement of an institutional tipping point and super growth.

Ms. Barth. 55 - Postilla super quattuor evangelia

Vorbesitzer: Bartholomaeusstift Frankfurt am Main

Ms. Barth. 39 - Scriptum super quartum Sententiarum

Vorbesitzer: Bartholomaeusstift Frankfurt am Main

Ms. Praed. 71 - Postilla super Evangelia dominicalia et in praecipuis festivitatibus sanctorum

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. Praed. 27 - Sermones de tempore super evangelia dominicalia

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. Praed. 141 - Casus summarii super Decretales

Vorbesitzer: Heinrich Brinzel (Brunsel); Johannes Usungen; Johannes Styrne; Dominikanerkloster Frankfurt am Main

Ms. Praed. 72 - Quaestiones super Tegni Galeni

Vorbesitzer: Georg von Breidenbach; Dominikanerkloster Frankfurt am Main

Ms. Praed. 66 - Scriptum super quartum Sententiarum

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. Praed. 90 - Summa super titulis Decretalium

Vorbesitzer: Johannes Smizkil; Dominikanerkloster Frankfurt am Main

Ms. Praed. 109 - Postilla super evangelia dominicalia

Vorbesitzer: Johannes Beinhauer; Dominikanerkloster Frankfurt am Main;

Ms. Praed. 117 - Opus tabulare super quattuor specula Vincentii Bellovacensis

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. Praed. 127 - Summa super V libros Decretalium

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. Praed. 126 - Sermones super Magnificat

Vorbesitzer: Dominikanerkloster Frankfurt am Main