Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain. Here we report that inhibition of S6K1 by A77 1726, the active metabolite of an anti-inflammatory drug leflunomide, induced mTOR feedback activation and ULK1S757 phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPKT172 and ULK1S555 phosphorylation. Similar observations were made with PF-4708671, a specific S6K1 inhibitor, or with S6K1 siRNA. Further studies showed that A77 1726 induced AMPK phosphorylation by activating the TGF-β-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1G93A protein aggregates with autophagosomes and accelerated SOD1G93A protein degradation, which was blocked by inhibition of autophagy through autophagy-related protein 7 (ATG7) siRNA. Our study suggests that S6K1 inhibition induces autophagy through TAK1-mediated AMPK activation in NSC34 cells, and that blocking S6K1 activity by a small molecule inhibitor such as leflunomide may offer a new strategy for ALS treatment.

Graphical passwords (GPWs) are convenient for mobile equipments with touch screen. Topological graphic passwords (Topsnut-gpws) can be saved in computer by classical matrices and run quickly than the existing GPWs. We research Topsnut-gpws by the matching of view, since they have many advantages. We discuss: configuration matching partition, coloring/labelling matching partition, set matching partition, matching chain, etc. And, we introduce new graph labellings for enriching Topsnut-matchings and show these labellings can be realized for trees or spanning trees of networks. In theoretical works we explore Graph Labelling Analysis, and show first that every graph admits our extremal labellings and set-type labellings in graph theory. Many of the graph labellings mentioned are related with problems of set matching partitions to number theory, and yield new objects and new problems to graph theory.

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Topological graphic passwords (Topsnut-gpws) are one of graph-type passwords, but differ from the existing graphical passwords, since Topsnut-gpws are saved in computer by algebraic matrices. We focus on the transformation between textbased passwords (TB-paws) and Topsnut-gpws in this article. Several methods for generating TB-paws from Topsnut-gpws are introduced; these methods are based on topological structures and graph coloring/labellings, such that authentications must have two steps: one is topological structure authentication, and another is text-based authentication. Four basic topological structure authentications are introduced and many text-based authentications follow Topsnut-gpws. Our methods are based on algebraic, number theory and graph theory, many of them can be transformed into polynomial algorithms. A new type of matrices for describing Topsnut-gpws is created here, and such matrices can produce TB-paws in complex forms and longer bytes. Estimating the space of TB-paws made by Topsnutgpws is very important for application. We propose to encrypt dynamic networks and try to face: (1) thousands of nodes and links of dynamic networks; (2) large numbers of Topsnut-gpws generated by machines rather than human's hands. As a try, we apply spanning trees of dynamic networks and graphic groups (Topsnut-groups) to approximate the solutions of these two problems. We present some unknown problems in the end of the article for further research.

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