Innate-like T cells in liver disease.

Mammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner.

The Polar Flagellar Transcriptional Regulatory Network in Vibrio campbellii Deviates from Canonical Vibrio Species.

Swimming motility is a critical virulence factor in pathogenesis for numerous Vibrio species. Vibrio campbellii DS40M4 is a wild-type isolate that has been recently established as a highly tractable model strain for bacterial genetics studies. We sought to exploit the tractability and relevance of this strain for characterization of flagellar gene regulation in V. campbellii. Using comparative genomics, we identified homologs of V. campbellii flagellar and chemotaxis genes conserved in other members of the Vibrionaceae and determined the transcriptional profile of these loci using differential RNA-seq. We systematically deleted all 63 predicted flagellar and chemotaxis genes in V. campbellii and examined their effects on motility and flagellum production. We specifically focused on the core regulators of the flagellar hierarchy established in other vibrios: RpoN (σ54), FlrA, FlrC, and FliA. Our results show that V. campbellii transcription of flagellar and chemotaxis genes is governed by a multitiered regulatory hierarchy similar to other motile Vibrio species. However, there are several critical differences in V. campbellii: (i) the σ54-dependent regulator FlrA is dispensable for motility; (ii) the flgA, fliEFGHIJ, flrA, and flrBC operons do not require σ54 for expression; and (iii) FlrA and FlrC coregulate class II genes. Our model proposes that the V. campbellii flagellar transcriptional hierarchy has three classes of genes, in contrast to the four-class hierarchy in Vibrio cholerae. Our genetic and phenotypic dissection of the V. campbellii flagellar regulatory network highlights the differences that have evolved in flagellar regulation across the Vibrionaceae. IMPORTANCE Vibrio campbellii is a Gram-negative bacterium that is free-living and ubiquitous in marine environments and is an important global pathogen of fish and shellfish. Disruption of the flagellar motor significantly decreases host mortality of V. campbellii, suggesting that motility is a key factor in pathogenesis. Using this model organism, we identified >60 genes that encode proteins with predicted structural, mechanical, or regulatory roles in function of the single polar flagellum in V. campbellii. We systematically tested strains containing single deletions of each gene to determine the impact on motility and flagellum production. Our studies have uncovered differences in the regulatory network and function of several genes in V. campbellii compared to established systems in Vibrio cholerae and Vibrio parahaemolyticus.

Lysine Deprivation Induces AKT-AADAT Signaling and Overcomes EGFR-TKIs Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells.

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in non-small cell lung cancer (NSCLC), especially in the Asian population. Although EGFR-tyrosine kinase inhibitors (TKIs) are influential in the treatment of EGFR-mutant NSCLC patients, acquired resistance inevitably occurs. Therefore, there is an urgent need to develop strategies to overcome this resistance. In addition, cancer cells with particular mutations appear more vulnerable to deficiency related to the availability of specific amino acids. However, it is still unknown which amino acid is affected in the case of EGFR-mutant NSCLC. In the present study, we established a screening platform based on amino acid deprivation and found that EGFR-mutant NSCLC cells are sensitive to short-term lysine deprivation. Moreover, we found that expression of the gene for the lysine catabolism enzyme α-aminoadipate aminotransferase (AADAT) increased under lysine deprivation, revealing that AADAT can be regulated by EGFR-AKT signaling. Finally, we found that lysine reduction can not only enhance the cytostatic effect of single-agent osimertinib but also overcome the resistance of EGFR-TKIs in EGFR-mutant NSCLC cells. In summary, our findings suggest that the introduction of lysine stress might act as an advancement in EGFR-mutant NSCLC therapy and offer a strategy to overcome EGFR-TKI resistance.