L-Lysine Decarboxylase and Cadaverine Gamma-Glutamylation Pathways in Pseudomonas Aeruginosa PAO1

In comparison to other Pseudomonas, P. aeruginosa grows poorly in L-lysine as a sole source of nutrient while fast growth mutants can be obtained. The proposed catabolic pathway involves lysine decarboxylation to cadaverine and its subsequent degradation through g-glutamylation pathway to d-aminovalerate and glutarate. The lysine decarboxylase A (ldcA) gene, previously identified as a member of the ArgR regulon of L-arginine metabolism, was found essential for L-lysine catabolism. The ldcA gene encodes a decarboxylase which takes L-lysine but not L-arginine as substrate. Contrarily, the ldcA expression was inducible by L-arginine but not by L-lysine. This peculiar arginine control on lysine utilization was also noted from uptake experiments. The lack of lysine-responsive control on lysine catabolism and its tight connection to arginine regulatory network provided an explanation of lysine as poor nutrient for P. aeruginosa. Catabolism of cadaverine, a product from lysine decarboxylation, was investigated and compared to that of putrescine, another diamine of similar biochemical properties that is derived from arginine and ornithine. While the g-glutamylation pathway was first reported in E. coli for putrescine utilization, an expanded version of this pathway was found in P. aeruginosa with redundant enzymes for polyamine degradation. The PauR protein was identified as a transcriptional repressor of genes for the catabolism of putrescine and cadaverine, as well as their corresponding downstream metabolites, g-aminobutyrate (GABA) and d-aminovalerate (AMV). PauR shows distinct dimer configuration after glutaraldehyde crosslinkage, and possible conformational changes could be triggered by the presence of putrescine and cadaverine, but not GABA. A newly identified ABC transport system, encoded by the agtABCD operon, was found important for the uptake of GABA and AMV; and expression of which is controlled by the AgtSR two-component system. The CbrAB two-component system was proposed to regulate the catabolite repression control protein Crc through a small RNA CrcZ. A consensus CbrB recognition sequence was proposed based on the conserved palindromic nucleotide sequence in the upstream activating sequence of the crcZ promoter. Genetic studies indicated utilization of arginine, lysine and diamines (but not histidine, GABA and AMV) might be under CbrAB regulation through the CbrAB/CrcZ/Crc system in P. aeruginosa

Cooperative order and excitation spectra in the bicomponent spin networks

A ferrimagnetic spin model composed of $S=1/2$ spin-dimers and $S=5/2$ spin-chains is studied by combining the bond-operator representation (for $S=1/2$ spin-dimers) and Holstein-Primakoff transformation (for $S=5/2$ spins). A finite interaction $J_{\rm DF}$ between the spin-dimer and the spin chain makes the spin chains ordered antiferromagnetically and the spin dimers polarized. The effective interaction between the spin chains, mediated by the spin dimers, is calculated up to the third order. The staggered magnetization in the spin dimer is shown proportional to $J_{\rm DF}$. It presents an effective staggered field reacting on the spin chains. The degeneracy of the triplons is lifted due to the chain magnetization and a mode with longitudinal polarization is identified. Due to the triplon-magnon interaction, the hybridized triplon-like excitations show different behaviors near the vanishing $J_{\rm DF}$. On the other hand, the hybridized magnon-like excitations open a gap $\Delta_A\sim J_{\rm DF}$. These results consist well with the experiments on Cu$_{2}$Fe$_{2}$Ge$_{4}$O$_{13}$.Comment: 7 pages, 5 figure

THE ROLE OF LGR5+ EPITHELIAL STEM-LIKE CELLS IN 3D-ORGANOID MODELING AND PATHOGENESIS OF AMELOBLASTOMA

Ameloblastoma (AM) is a benign yet locally aggressive tumor with high recurrences. Currently, the underlying pathophysiology remains elusive and radical surgery remains the most definitive treatment with severe morbidities. Our group first reported that AM harbors a subpopulation of tumor epithelial stem-like cells (AM-EpiSCs). Herein, this study further explored whether LGR5+ epithelial cells in AM possess unique stem-like cell properties and their potential contribution to the pathogenesis and recurrence of AM. Our findings demonstrated that LGR5 and stem cell-related genes were simultaneously expressed in a subpopulation of AM epithelial cells, both in vivo and in vitro, which were markedly enriched under the 3D-spheroid culture condition. As compared to LGR5- counterparts, LGR5+ AM epithelial cells showed increased expression of several critical genes involved in the regulation of epithelial-mesenchymal transition (EMT) and stem cell pluripotency, and functionally, exhibited enhanced capacity to form 3D-spheroids and generate human tumor 3D-organoids, which recapitulated characteristic histopathologic features of distinct subtypes of solid AM. Interestingly, AM derived mesenchymal stromal cells (AM-MSCs) and their secretomes or extracellular vesicles (EVs) significantly promoted the generation of LGR5+ AM-EpiSCs both in vitro and in vivo. Furthermore, treatment with a selective BRAFV600E inhibitor, Vemurafenib, unexpectedly enriched the proportion of LGR5+ AM-EpiSCs in AM 3D-organoids, which may explain the therapeutic resistant and recurrent properties of AM conferred by this unique subpopulation of AM-EpiSCs. Therefore, the tumor 3D-organoids generated by LGR5+ AM-EpiSCs provided a novel ex vivo platform for mechanistic studies of human AM and high throughput screening of targeted therapeutic drugs. These findings suggest that LGR5+ AM-EpiSCs play a pivotal role in pathogenesis and progression of AM and targeted inhibition of both BRAF and LGR5 potentially serves a novel non-surgical adjuvant therapeutic approach for this benign yet aggressively destructive jaw tumor