Autophagy is a lysosomal degradation pathway wherein cytoplasmic components not needed by or harmful to the cell are degraded and recycled. BECN homologs are key autophagy proteins consisting of an intrinsically disordered region (IDR), flexible helical domain (FHD), coiled-coil domain (CCD) and β-α repeated, autophagy-specific domain (BARAD). Diverse proteins modulate autophagy by binding BECN1. Understanding the mechanisms by which these proteins regulate BECN1-mediated autophagy is important for developing therapeutics targeting these proteins. Toward this goal, we have developed purification protocols for multi-domain BECN1 fragments to explore the conformational flexibility and interactions. We show that a BECN1 helix transitions between mutually exclusive packing states, wherein it either forms part of the CCD homodimer or packs against the BARAD, but predominantly packs against the BARAD. The same set of residues on this helix contribute to the CCD homodimer or packing with the BARAD, and mutation of these residues abrogates starvation-induced up-regulation of autophagy. Next, we show the equatorial groove of GAPR-1 may be responsible for binding BECN1. The five conserved residues lining the GAPR-1 equatorial groove are essential for the interaction, as mutation of these residues disrupts GAPR-1:BECN1 interaction. We also solved the structure of this pentad mutant, which indicates the changes in the equatorial groove and the improved dimerization of pentad mutant likely abrogates BECN1-binding. We then show that BH3D is not required for BECN1 to up-regulate autophagy, though it is required for binding BCL2 homologs. Therefore, we investigated the interactions between BH3D-containing BECN1 fragments and the BCL2 homolog, M11. BECN1 regions outside the BH3D increase binding to M11 by 5-10 fold. In addition, M11-binding increases flexibility of the nuclear export sequence (NES). Further, homodimerization and thermostability of BECN1 BH3D-FHD-CCD increases upon M11-binding. Lastly, the M11:BH3D-FHD-CCD complex appears to fluctuate between two major types of conformations, which may be mediated by the increased flexibility of BECN1 NES upon binding M11. Lastly, we investigated the interactions between BH3D-containing BECN1 fragments and Bcl-XL. Our results indicate that BECN1 regions outside the BH3D do not affect BECN1 interaction with Bcl-XL. Together, these studies are important for better understanding how proteins down-regulate BECN1-mediate autophagy. / NIH: RO3 NS090939, R15 GM122035, P20 RR015566, and R21 AI078198 (S.S). R15 GM113227, P30 GM103332-01, P41 GM103622, and P41 GM103403.; NSF: MCB-1413525 (S.S.); ND Dept. of Commerce: Award #14-11-J1-73 (S.S.)

Many studies have focused on the effects of MNC subsidiaries' external relational embeddedness. Little attention has been given to its antecedents and especially to the potential effect that the business network context might have. We try to fill this gap and attempt to explain variation among subsidiaries' degree of relational embeddedness. Our results show a strong and robust effect of the business network context -- i.e. the network context in which the direct business relationships between the subsidiary and its partners are embedded -- on the degree of relational embeddedness. However, contrary to previous literature, we find an inverted u-shaped relationship. We discuss our findings with regard to the issue of over-embeddedness and the literature on the strength of weak versus strong ties.

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根據民國88至90年教育部統計處出版的資料，本文首先利用資料包絡分析法評估個別國立大學之技術效率；然後，以Tobit截斷迴歸模型探討可能造成國立大學技術效率差異之因素。技術效率評估結果顯示，在不同投入產出組合下，國立大學整體的技術效率平均值介於115.30﹪與122.17﹪之間，並且，規模效率平均值大於1，代表：台灣國立大學在產出上仍存在改善空間；且造成其不效率之原因，主要歸咎於純技術無效率及規模無效率。Tobit截斷迴歸實證結果顯示，大學部學生比例與技術效率之關係為負向，競爭程度的提高可提昇國立大學的經營效率，師範與科技類大學的技術效率低於其他大學。 關鍵詞：技術效率、資料包絡分析法、Tobit截斷迴歸方法 JEL Classification：L83、M11、M21