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Travis, S.

Publications and source records attributed to Travis, S..

4 recordsLinked to original sources

Two-Year Field Trial of Genetically Engineered American Chestnut Reveals Greater Fungal Blight Tolerance Compared to Wild-Type Full-Sibling Trees

The American chestnut (Castanea dentata [Marsh.] Borkh.) was a foundational forest canopy species in eastern North America until an accidentally imported fungal blight (caused by Cryphonectria parasitica [Murr.] Barr.) rendered it functionally extinct across its native range. Biotechnological approaches, such as the bioengineered Darling 54 line, have potential for future restoration of American chestnut, but field-based evaluations of blight tolerance have been limited. Progress has been slowed by the many years it takes for seedlings to grow to saplings, then to full-fledged trees. Current regulatory restrictions also constrain the testing of transgenic chestnuts to within permitted orchards. This research reports on a two-year field trial of Darling 54, their non-transgenic wild-type siblings and Chinese chestnut (Castanea mollissima Blume) controls deployed a randomized block design to test for blight tolerance. In the two years, three replicates each of 261 trees were branch-inoculated with EP-155, a highly virulent isolate of the fungal blight. Based on canker length, Darling 54 trees consistently outperformed their non-transgenic wild-type siblings and Chinese chestnut. To our knowledge, this is the first report of a multi-year field trial of fungal blight inoculations comparing advanced generation Darling 54 families. This field-based evaluation suggests that reintroduction programs using Darling 54 American chestnuts, which can commence after federal approval, may offer a promising path to success.

synthetic biology↗

A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.

immunology↗

Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

BACKGROUND & AIMSDysregulated immune responses are the cause of inflammatory bowel diseases. Studies in both mice and humans suggest a central role of IL-23 producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for select IL-23 targeting therapies as part of personalized medicine. METHODSWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA-sequencing to derive a transcriptomic signature of hyper-inflammatory monocytes. Using gene network correlation analysis, we deconvolve this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTSWe characterized monocyte subsets of healthy individuals and patients with inflammatory bowel disease that express IL-23. We identified auto- and paracrine sensing of IL-1/IL-1{beta} and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion, uptake of whole bacteria induced IL-23 production via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to anti-TNF therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSIONOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyper-inflammation-associated IL-23 production in patients with severe ulcerating active Crohns disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with inflammatory bowel disease that might benefit from IL-23p19 and/or IL-1/IL-1{beta}-targeting therapies upstream of IL-23. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/719492v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@16598faorg.highwire.dtl.DTLVardef@11e5116org.highwire.dtl.DTLVardef@15d831borg.highwire.dtl.DTLVardef@4a697e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗