Universal Accessible Biomarkers of Drug-Induced Tissue Injury and Systemic Inflammation in Rat: Performance Assessment of TIMP-1, A2M, AGP, NGAL, and Albumin.

The ability to monitor for general drug-induced tissue injury (DITI) or systemic inflammation in any tissue using blood-based accessible biomarkers would provide a valuable tool in early exploratory animal studies to understand potential drug liabilities. Here we describe the evaluation of 4 biomarkers of tissue remodeling and inflammation (α2-macroglobulin [A2M], α1-acid glycoprotein [AGP], neutrophil gelatinase-associated lipocalin [NGAL], and tissue inhibitor of metalloproteinases [TIMP-1]) as well as the traditional serum parameter albumin as potential blood-based biomarkers of DITI and systemic inflammatory response (SIR). Biomarker performance was assessed in 51 short-term rat in vivo studies with various end-organ toxicities or SIR and receiver operating characteristic curves were generated to compare relative performances.

Climate-associated drivers of plasma cytokines and contaminant concentrations in Beaufort Sea polar bears (Ursus maritimus).

Assessing polar bear (Ursus maritimus) immune function in relation to environmental stressors, including habitat change, nutritional stress, pathogen prevalence, and pollution, has been identified as critical for improved understanding of the species' health. The objectives of this study were two-fold: 1) to assess the role of climate-associated factors (habitat use, body condition) in explaining the plasma concentrations of contaminants in southern Beaufort Sea (SB) polar bears, and 2) to investigate how climate-associated factors, contaminant concentrations, and pathogen sero-prevalence influence the plasma concentrations of immune-signaling proteins called cytokines. A commercially available multiplex canine cytokine panel was validated for the quantification of five pro- and anti-inflammatory cytokines in polar bear plasma: tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-8, IL-10, and interferon gamma-induced protein 10 (IP-10).

Fatty acid-based diet estimates suggest ringed seal remain the main prey of southern Beaufort Sea polar bears despite recent use of onshore food resources.

Polar bears () from the southern Beaufort Sea (SB) subpopulation have traditionally fed predominantly upon ice-seals; however, as the proportion of the subpopulation using onshore habitat has recently increased, foraging on land-based resources, including remains of subsistence-harvested bowhead whales () and colonial nesting seabirds has been observed. Adipose tissue samples were collected from this subpopulation during the springs of 2013-2016 and analyzed for fatty acid signatures. Diet estimates were generated for the proportional consumption of ringed seal (), bearded seal (), and beluga whale (), relative to onshore foods, including bowhead whale remains and seabird, as represented by black guillemot () nestlings and eggs.

Structure of mandelate racemase with bound intermediate analogues benzohydroxamate and cupferron.

Mandelate racemase (MR, EC 5.1.2.

Mutational analysis of the active site flap (20s loop) of mandelate racemase.

Mandelate racemase from Pseudomonas putida catalyzes the Mg2+-dependent 1,1-proton transfer that interconverts the enantiomers of mandelate. Residues of the 20s and 50s loops determine, in part, the topology and polarity of the active site and hence the substrate specificity. Previously, we proposed that, during racemization, the phenyl ring of mandelate moves between an S-pocket comprised of residues from the 50s loop and an R-pocket comprised of residues from the 20s loop [Siddiqi, F.

Intermediate analogue inhibitors of mandelate racemase: N-Hydroxyformanilide and cupferron.

Mandelate racemase (MR) catalyzes the 1,1-proton transfer that interconverts the enantiomers of mandelate. The transition state/intermediate analogues N-hydroxyformanilide (K(i)=2.79+/-0.

Perturbing the hydrophobic pocket of mandelate racemase to probe phenyl motion during catalysis.

Mandelate racemase (MR, EC 5.1.2.