Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole genome DNA sequence and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NFκB signaling, chromatin remodeling, and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs vs. 1.0 somatic single nucleotide variants per CTCL). These findings have implications for novel therapeutics.
Remarkable progress in bioengineering over the past two decades has enabled the formulation of fundamental design principles for a variety of medical and non-medical applications. These advancements have laid the foundation for building multicellular engineered living systems (M-CELS) from biological parts, forming functional modules integrated into living machines. These cognizant design principles for living systems encompass novel genetic circuit manipulation, self-assembly, cell–cell/matrix communication, and artificial tissues/organs enabled through systems biology, bioinformatics, computational biology, genetic engineering, and microfluidics. Here, we introduce design principles and a blueprint for forward production of robust and standardized M-CELS, which may undergo variable reiterations through the classic design-build-test-debug cycle. This Review provides practical and theoretical frameworks to forward-design, control, and optimize novel M-CELS. Potential applications include biopharmaceuticals, bioreactor factories, biofuels, environmental bioremediation, cellular computing, biohybrid digital technology, and experimental investigations into mechanisms of multicellular organisms normally hidden inside the “black box” of living cells.
In both natural and applied contexts, investigating cell self-assembly and aggregation within controlled 3D environments leads to improved understanding of how structured cell assemblies emerge, what determines their shapes and sizes, and whether their structural features are stable.
Inflammatory bowel diseases are associated with a loss of epithelial barrier integrity that can lead to an imbalance in gut homeostasis and severe inflammation. Studies in mice have shown that CD1d, a lipid antigen-presenting molecule, and natural killer T (NKT) cells play important roles in forming and maintaining homeostasis in the intestines. However, it is currently unknown what specific lipids are presented to NKT cells during homeostasis or inflammation in the gut. We hypothesize that during inflammation, CD1d ligands are replaced with pathogenic lipids that alter the activation of NKT cells and contribute to inflammation. Mice were administered dextran sodium sulfate (DSS) in their drinking water for 7 days to induce colitis symptoms, then switched to normal water for an additional 7 days to recover. Lipid species were measured in colons from day 7 inflamed mice and day 14 recovered mice. Compared to control mice, the lipid composition of inflamed colon was significantly altered. Day 7 enriched ceramide and hexosylceramide species remained elevated at the recovery time-point. These lipids stimulated inflammatory cytokine production in lamina propria cultures in a CD1d-dependent manner. To determine if these lipids were being generated endogenously, we measured the gene expression of several key enzymes in the hexosylceramide synthesis pathway. Expression of Degs1 and Ugcg were up-regulated in lamina propria cells during colitis, suggesting that immune cells could be responsible for the altered lipid composition we observed in DSS treated mice. Overall, we have demonstrated that colitis-induced lipid alterations in lamina propria cells of the gut can contribute to intestinal inflammation through CD1d antigen presentation.
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