Publications by authors named "E George Salter"

178 Publications

When First We Practice to Deceive.

Am J Bioeth 2021 05;21(5):15-17

Albert Gnaegi Center for Health Care Ethics, Saint Louis University.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15265161.2021.1906998DOI Listing
May 2021

Can Parents Restrict Access to Their Adolescent's Voice?: Deciding About a Tracheostomy.

Pediatrics 2021 04;147(4)

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.

Parents are the default decision-makers for their infants and children. Their decisions should be based on the best interests of their children. Differing interpretations of children's best interests may be a source of conflict. Providers' biased evaluations of patients' quality of life may undermine medicine's trustworthiness. As children mature, they should participate in medical decision-making to the extent that is developmentally appropriate. In this month's Ethics Rounds, physicians, a philosopher, and a lawyer consider parents' demand, supported by the hospital's legal department, that their 17-year-old son be excluded from a potentially life-and-death medical decision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2021-050358DOI Listing
April 2021

Chemical and Biochemical Reactivity of the Reduced Forms of Nicotinamide Riboside.

ACS Chem Biol 2021 04 30;16(4):604-614. Epub 2021 Mar 30.

All life forms require nicotinamide adenine dinucleotide, NAD, and its reduced form NADH. They are redox partners in hundreds of cellular enzymatic reactions. Changes in the intracellular levels of total NAD (NAD + NADH) and the (NAD/NADH) ratio can cause cellular dysfunction. When not present in protein complexes, NADH and its phosphorylated form NADPH degrade through intricate mechanisms. Replenishment of a declining total NAD pool can be achieved with biosynthetic precursors that include one of the reduced forms of nicotinamide riboside (NR), NRH. NRH, like NADH and NADPH, is prone to degradation via oxidation, hydration, and isomerization and, as such, is an excellent model compound to rationalize the nonenzymatic metabolism of NAD(P)H in a biological context. Here, we report on the stability of NRH and its propensity to isomerize and irreversibly degrade. We also report the preparation of two of its naturally occurring isomers, their chemical stability, their reactivity toward NRH-processing enzymes, and their cell-specific cytotoxicity. Furthermore, we identify a mechanism by which NRH degradation causes covalent peptide modifications, a process that could expose a novel type of NADH-protein modifications and correlate NADH accumulation with "protein aging." This work highlights the current limitations in detecting NADH's endogenous catabolites and in establishing the capacity for inducing cellular dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.0c00757DOI Listing
April 2021

The anabolic effect of inorganic polyphosphate on chondrocytes is mediated by calcium signalling.

J Orthop Res 2021 Mar 14. Epub 2021 Mar 14.

Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.

Inorganic polyphosphates (polyP) are polymers composed of phosphate residues linked by energy-rich phosphoanhydride bonds. As polyP can bind calcium, the hypothesis of this study is that polyP enters chondrocytes and exerts its anabolic effect by calcium influx through calcium channels. PolyP treatment of cartilage tissue formed in 3D culture by bovine chondrocytes showed an increase in proteoglycan accumulation but only when calcium was also present at a concentration of 1.5 mM. This anabolic effect could be prevented by treatment with either ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid or the calcium channel inhibitors gadolinium and nifedipine. Calcium and polyP cotreatment of chondrocytes in monolayer culture resulted in calcium oscillations that were polyP chain length specific and were inhibited by gadolinium and nifedipine. The calcium influx resulted in increased gene expression of sox9, collagen type II, and aggrecan which was prevented by treatment with either calphostin, an inhibitor of protein kinase C, and W7, an inhibitor of calmodulin; suggesting activation of the protein kinase C-calmodulin pathway. Tracing studies using  4',6-diamidino-2-phenylindole, Mitotracker Red, and/or Fura-AM staining showed that polyP was detected in the nucleus, mitochondria, and intracellular vacuoles suggesting that polyP may also enter the cell. PolyP colocalizes with calcium in mitochondria. This study demonstrates that polyP requires the influx of calcium to regulate chondrocyte matrix production, likely via activating calcium signaling. These findings identify the mechanism regulating the anabolic effect of polyP in chondrocytes which will help in its clinical translation into a therapeutic agent for cartilage repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jor.25032DOI Listing
March 2021

Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers.

Nat Commun 2021 01 8;12(1):172. Epub 2021 Jan 8.

Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, MA, 02139, USA.

The dimeric transporter, EmrE, effluxes polyaromatic cationic drugs in a proton-coupled manner to confer multidrug resistance in bacteria. Although the protein is known to adopt an antiparallel asymmetric topology, its high-resolution drug-bound structure is so far unknown, limiting our understanding of the molecular basis of promiscuous transport. Here we report an experimental structure of drug-bound EmrE in phospholipid bilayers, determined using F and H solid-state NMR and a fluorinated substrate, tetra(4-fluorophenyl) phosphonium (F-TPP). The drug-binding site, constrained by 214 protein-substrate distances, is dominated by aromatic residues such as W63 and Y60, but is sufficiently spacious for the tetrahedral drug to reorient at physiological temperature. F-TPP lies closer to the proton-binding residue E14 in subunit A than in subunit B, explaining the asymmetric protonation of the protein. The structure gives insight into the molecular mechanism of multidrug recognition by EmrE and establishes the basis for future design of substrate inhibitors to combat antibiotic resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20468-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794478PMC
January 2021
-->