Accumulating evidence indicates that defects in the molecular and cellular circuitries that underpin immune responses accelerate the course of chronic diseases, including hepatic cirrhosis and cancer. Along similar lines, the re-establishment of tissue homeostasis upon acute pathological insults such as ischemia appears to be delayed when normal immunological functions are naturally or experimentally

compromised. Here, we propose that immunosurveillance is a key regulator of tissue homeostasis.”
“A member of the family of hematopoietic cytokines human prolactin (hPRL) is a 23k kDa polypeptide hormone, which displays pH dependence in its structural and functional properties. The binding AZD1480 mw affinity of hPRL for the extracellular domain of its receptor decreases 500-fold over the relatively narrow, physiologic pH range from 8 to 6; whereas, the affinity of human growth hormone (hGH),

its closest evolutionary cousin, does not. Similarly, the structural stability of hPRL decreases from 7.6 to 5.6 kcal/mol from pH 8 to 6, respectively, whereas the stability of hGH is slightly increased selleck screening library over this same pH range. hPRL contains nine histidines, compared with hGH’s three, and they are likely responsible for hPRL’s pH-dependent behavior. We have systematically mutated each of hPRL’s histidines to alanine and measured the effect on pH-dependent global stability. Surprisingly, a vast majority of these mutations stabilize the native protein, by as much as 2-3 kcal/mol. Changes in the overall pH dependence to hPRL global stability can be rationalized according to the predominant structural interactions of individual histidines in the hPRL tertiary structure. Using double mutant cycles, we detect large interaction free energies within a cluster of nearby histidines, which are both stabilizing and destabilizing to the native state. Finally, by comparing the structural locations of hPRL’s nine histidines with their homologous residues in hGH, we speculate on the evolutionary

role of replacing structurally stabilizing residues with histidine to introduce pH dependence to cytokine function.”
“Human high-density lipoprotein (HDL) plays a key role in the reverse cholesterol transport pathway that delivers Idasanutlin excess cholesterol back to the liver for clearance. In vivo, HDL particles vary in size, shape and biological function. The discoidal HDL is a 140-240 kDa, disk-shaped intermediate of mature HDL. During mature spherical HDL formation, discoidal HDLs play a key role in loading cholesterol ester onto the HDL particles by activating the enzyme, lecithin: cholesterol acyltransferase (LCAT). One of the major problems for high-resolution structural studies of discoidal HDL is the difficulty in obtaining pure and, foremost, homogenous sample.