Publications by authors named "Stephen Kunkel"

3 Publications

  • Page 1 of 1

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Nat Commun 2020 02 5;11(1):722. Epub 2020 Feb 5.

Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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http://dx.doi.org/10.1038/s41467-019-14172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002453PMC
February 2020

Part I: the development of the catalytic Wittig reaction.

Chemistry 2013 Nov 25;19(45):15281-9. Epub 2013 Sep 25.

School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9 (Ireland) http://webpages.dcu.ie/∼obrienc/OBrien_Group/Home.html.

We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1. Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N-diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di- and trisubstituted olefins in moderate-to-high yields (60-96%) by using a precatalyst loading of 4-10 mol%. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β-unsaturated products was achieved through a phosphane-mediated isomerization event. The CWR was applied to the synthesis of 54, a known precursor to the anti-Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74% yield). In addition, to our knowledge, the described CWR is the only transition-/heavy-metal-free catalytic olefination process, excluding proton-catalyzed elimination reactions.
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http://dx.doi.org/10.1002/chem.201301444DOI Listing
November 2013

Recycling the waste: the development of a catalytic wittig reaction.

Angew Chem Int Ed Engl 2009 ;48(37):6836-9

Department of Chemistry and Biochemistry, The University of Texas at Arlington, Box 19065, Arlington, TX 76019, USA.

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http://dx.doi.org/10.1002/anie.200902525DOI Listing
December 2009