Computing by nowhere increasing complexity

A cellular automaton is presented whose governing rule is that the Kolmogorov complexity of a cell's neighborhood may not increase when the cell's present value is substituted for its future value. Using an approximation of this two-dimensional Kolmogorov complexity the underlying automaton is shown to be capable of simulating logic circuits. It is also shown to capture trianry logic described by a quandle, a non-associative algebraic structure. A similar automaton whose rule permits at times the increase of a cell's neighborhood complexity is shown to produce animated entities which can be used as information carriers akin to gliders in Conway's game of life

The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1. DOI: http://dx.doi.org/10.7554/eLife.12278.00

GSK3-mediated raptor phosphorylation supports amino acid-dependent Q2 mTORC1-directed signalling

The mammalian or mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a ubiquitously expressed multimeric protein kinase complex that integrates nutrient and growth factor signals for the co-ordinated regulation of cellular metabolism and cell growth. Herein, we demonstrate that suppressing the cellular activity of glycogen synthase kinase-3 (GSK3), by use of pharmacological inhibitors or shRNA-mediated gene silencing, results in substantial reduction in amino acid (AA)-regulated mTORC1-directed signalling, as assessed by phosphorylation of multiple downstream mTORC1 targets. We show that GSK3 regulates mTORC1 activity through its ability to phosphorylate the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Ser(859). We further demonstrate that either GSK3 inhibition or expression of a S859A mutated raptor leads to reduced interaction between mTOR and raptor and under these circumstances, irrespective of AA availability, there is a consequential loss in phosphorylation of mTOR substrates, such as p70S6K1 (ribosomal S6 kinase 1) and uncoordinated-51-like kinase (ULK1), which results in increased autophagic flux and reduced cellular proliferation

The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1

The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP bound for the interaction to occur. We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 activation and a molecular function for the FLCN tumor suppressor.United States. National Institutes of Health (CA103866)United States. National Institutes of Health (AI47389)United States. Department of Defense (W81XWH-07-0448)National Cancer Institute (U.S.) (F30CA180754

mTORC1 Senses Lysosomal Amino Acids Through an Inside-Out Mechanism That Requires the Vacuolar H+-ATPase

The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H+–adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid–sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. Results obtained in vitro and in human cells suggest that amino acid signaling begins within the lysosomal lumen. These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing.Damon Runyon Cancer Research FoundationMillennium Pharmaceuticals, Inc.American Lebanese Syrian Associated CharitiesHoward Hughes Medical Institut

Different fiber materials as reinforcement for geopolymer composite

For the last two centuries, Ordinary Portland Cement (OPC) is the most popular building material in the world due to its high mechanical properties, ease of handling and low cost. However, the concrete industry is known to leave an enormous environmental footprint. Therefore, the development of sustainable materials that could replace the OPC is essential. One of such recent developments is an aluminosilicate based material that can be activated in an alkaline medium to form a hardened sustainable product, known as ‘Geopolymer’. Geopolymers exhibit equal or better engineering properties as compared to conventional concrete with better environmental foot print. However, geopolymer\u27s main disadvantage, as concrete, is its brittleness and low tensile properties. One way to overcome this limitation is by addition of fibers, as they can control cracking by crack bridging, resulting in an increase of the tensile properties of the geopolymeric composite. The purpose of this research was to develop a high performance geopolymer composite by addition of short fibers. Three different types of fibers were added to the matrix with two different fiber contents (0.5% and 1%). The idea was to add fibers of significant difference in their chemical nature and tensile properties: PP and Carbon fibers which are both hydrophobic, but have significant differently tensile behavior, and PVA which is hydrophilic like the geopolymeric matrix, and has moderate tensile properties. Their influence on the geopolymer flexural behavior was examined. The microstructure of the composite at the fracture surface was also studied to better understand the role of the fibers. The results of this research showed that all fibers improved the ductility and toughness of the matrix. Geopolymeric composites with 1% carbon fibers showed the highest flexural strength, +216% compared to plain matrix, followed by the PVA fiber composites. Different failure modes were observed – fiber pull-out for the PP and carbon composites, and fiber rupture for the PVA fiber composite. This can be explained based on the different chemical nature of the fibers which produce a different matrix-fiber interface

Biosynthesis of UDP-xylose and UDP-arabinose in Sinorhizobium meliloti 1021: first characterization of a bacterial UDP-xylose synthase, and UDP-xylose 4-epimerase

Sinorhizobium meliloti is a soil bacterium that fixes nitrogen after being established inside nodules that can form on the roots of several legumes, including Medicago truncatula. A mutation in an S. meliloti gene (lpsB) required for lipopolysaccharide synthesis has been reported to result in defective nodulation and an increase in the synthesis of a xylose-containing glycan. Glycans containing xylose as well as arabinose are also formed by other rhizobial species, but little is known about their structures and the biosynthetic pathways leading to their formation. To gain insight into the biosynthesis of these glycans and their biological roles, we report the identification of an operon in S. meliloti 1021 that contains two genes encoding activities not previously described in bacteria. One gene encodes a UDP-xylose synthase (Uxs) that converts UDP-glucuronic acid to UDP-xylose, and the second encodes a UDP-xylose 4-epimerase (Uxe) that interconverts UDP-xylose and UDP-arabinose. Similar genes were also identified in other rhizobial species, including Rhizobium leguminosarum, suggesting that they have important roles in the life cycle of this agronomically important class of bacteria. Functional studies established that recombinant SmUxs1 is likely to be active as a dimer and is inhibited by NADH and UDP-arabinose. SmUxe is inhibited by UDP-galactose, even though this nucleotide sugar is not a substrate for the 4-epimerase. Unambiguous evidence for the conversions of UDP-glucuronic acid to UDP-α-d-xylose and then to UDP-β-l-arabinose (UDP-arabinopyranose) was obtained using real-time 1H-NMR spectroscopy. Our results provide new information about the ability of rhizobia to form UDP-xylose and UDP-arabinose, which are then used for the synthesis of xylose- and arabinose-containing glycans