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The HIV‐1 protease is critical for the process of viral maturation and as such, it is one of the most well characterized proteins in the Protein Data Bank. There is some evidence to suggest that the HIV‐1 protease is capable of accommodating small molecule fragments at several locations on its surface outside of the active site. However, some pockets on the surface of proteins remain unformed in the apo structure and are termed "cryptic sites." To date, no cryptic sites have been identified in the structure of HIV‐1 protease. Here, we characterize a novel cryptic cantilever pocket on the surface of the HIV‐1 protease through mixed‐solvent molecular dynamics simulations using several probes. Interestingly, we noted that several homologous retroviral proteases exhibit evolutionarily conserved dynamics in the cantilever region and possess a conserved pocket in the cantilever region. Immobilization of the cantilever region of the HIV‐1 protease via disulfide cross‐linking resulted in curling‐in of the flap tips and the propensity for the protease to adopt a semi‐open flap conformation. Structure‐based analysis and fragment‐based screening of the cryptic cantilever pocket suggested that the pocket may be capable of accommodating ligand structures. Furthermore, molecular dynamics simulations of a top scoring fragment bound to the cryptic pocket illustrated altered flap dynamics of the fragment‐bound enzyme. Together, these results suggest that the mobility of the cantilever region plays a key role in the global dynamics of retroviral proteases. Therefore, the cryptic cantilever pocket of the HIV‐1 protease may represent an interesting target for future in vitro studies. [ABSTRACT FROM AUTHOR]

A study was conducted to determine the thermodynamic stabilities of a few Ln(PCTA) complexes. The trend of the stability constants is similar to that of the Ln(NOTA) and/or Ln[(DOTA).sup.-] complexes involving a large increase at the beginning of the series, practically constant values for [Ln.sup.3+] ions in the middle of the series, and a slight increase of the stability at the end for Yb(PCTA).

The metabolic mechanism of hepatic glucose overproduction was investigated in 3,3'-5-triiodo-L-thyronine ([T.sub.3])-treated rats and Zucker diabetic fatty (ZDF) rats (fa/fa) after a 24-h fast. [sup.2][H.sub.2]O and [U- [sup.13][C.sub.3]]propionate were administered intraperitoneally, and [3,4-[sub.13][C.sub.2]]glucose was administered as a primed infusion for 90 min under ketamine-xylazine anesthesia. [sup.13]C NMR analysis of monoacetone glucose derived from plasma glucose indicated that hepatic glucose production was twofold higher in both [T.sub.3]-treated rats and ZDF rats compared with controls, yet the sources of glucose overproduction differed significantly in the two models by [sup.2]H NMR analysis. In [T.sub.3]-treated rats, the hepatic glycogen content and hence the contribution of glycogenolysis to glucose production was essentially zero; in this case, excess glucose production was due to a dramatic increase in gluconeogenesis from TCA cycle intermediates. [sup.13]C NMR analysis also revealed increased phosphoenolpyruvate carboxykinase flux (4x), increased pyruvate cycling flux (4x), and increased TCA flux (5x) in [T.sub.3]-treated animals. ZDF rats had substantial glycogen stores after a 24-h fast, and consequently nearly 50% of plasma glucose originated from glycogenolysis; other fluxes related to the TCA cycle were not different from controls. The differing mechanisms of excess glucose production in these models were easily distinguished by integrated [sup.2]H and [sup.13]C NMR analysis of plasma glucose. gluconeogenesis; glycogenolysis; type 2 diabetes; thyroid hormone; isotopes; nuclear magnetic resonance

The pH-sensitive contrast agent, GdDOTA-4AmP (Gd1) is used to map tissue pH by MRI. The study shows that the complexation reaction run at a pH no lower than 9 to produce only the desired pH-sensitive, Type II product needed for imaging pH by MRI.

Paramagnetic chemical exchange saturation transfer (CEST) agents with a wide variety of chemical and physical properties can be designed by slight modification of the ligand structure or choice paramagnetic ion. It is reported for the first time that there is a possibility of mapping the distribution of glucose in tissue by MRI using the bulk water protons as antenna.

Metabolic imaging with hyperpolarized carbon-13 allows sequential steps of metabolism to be detected in vivo. Potential applications in cancer, brain, muscular, myocardial, and hepatic metabolism suggest that clinical applications could be readily developed. A primary concern in imaging hyperpolarized nuclei is the irreversible decay of the enhanced magnetization back to thermal equilibrium. Multiple methods for rapid imaging of hyperpolarized substrates and their products have been proposed with a multi-point Dixon method distinguishing itself as a robust protocol for imaging [1-13C]pyruvate. We describe here a generalized chemical shift decomposition method that incorporates a single-shot spiral imaging sequence plus a spectroscopic sequence to retain as much spin polarization as possible while allowing detection of metabolites that have a wide range of chemical shift values. The new method is demonstrated for hyperpolarized [1-13C]pyruvate, [1-13C]acetoacetate, and [2-13C]dihydroxyacetone. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]