Protein antigenic determinants have been classified as continuous or discontinuous. The continuous determinants are composed of residues which are local in the polypeptide sequence, while discontinuous determinants consist of residues from different parts of the sequence, brought together by the folding of the protein to its native structure. Searches made for protein determinants using peptide fragments which compete with protein-antibody complex formation, or peptides that can be used to raise antibodies which crossreact with the native protein, are limited to the simulation of continuous determinants. However, recent experiments suggest that most determinants are discontinuous. We now show, by consideration of protein surfaces, that if the recognition zone between a protein and antibody has the same dimensions as those found for the lysozyme-antibody complex, none of the protein's surface will be 'continuous'. We suggest that all determinants are discontinuous to some extent, and that crossreacting peptides mimic only the 'primary' interaction site. In addition, we show that the parts of a protein's surface which are most continuous fall predominantly in the loops and/or protruding regions. This explains why quantities such as hydrophilicity, accessibility, mobility and protrusion can be used to predict which parts of a polypeptide provide the 'best' antigenic peptides.

A simple method is described to locate 'antigenic' peptides from the a-carbon co-ordinates of a protein, based on protrusion from the protein's globular surface. A good correlation is found between those parts of a protein which protrude and the experimentally determined antigenic peptides in myoglobin, lysozyme and myohemerythrin. A comparison is made between the use of protrusion index, mobility, solvent accessibility and hydrophilicity for predicting the most likely antigenic peptides.

The mortality experience of 7,119 workers who were employed at a Beaumont, Texas, refinery for at least 1 year between 1945 and 1987 was investigated. Mortality analyses based on standardized mortality ratios (SMRs) and 95% confidence intervals (95%CI) showed overall mortality was significantly lower than expected compared with the U.S. general population (SMR <=;=> 82, 95%CI = 79–86). Total cancer mortality was also lower than expected (SMR = 92, 95% CI = 84–100). Significant mortality deficits from several malignant and nonmalignant diseases were reported. A significant mortality increase in the broad category of lymphatic and hematopoietic cancers was found (SMR = 133, 95%CI = 103–170). This increase was attributed to a nonsignificant elevation in leukemia of all cell types combined (SMR = 139, 95%CI = 92–201) and a borderline significant increase in other lymphatic tissue cancer (SMR = 158, 95%CI = 101–235). The elevation in leukemia was confined to workers hired before 1950. Furthermore, the leukemia excess was shown to have peaked during the 1960s, with mortality no longer elevated post‐1980. Analyses of cell type‐specific leukemias showed a similar temporal pattern for acute myeloid leukemia (AML) which was not significantly elevated (SMR = 136, 95%CI = 59–268). Mortality from other leukemia cell types was similar to or lower than expected. Mortality from non‐Hodgkin's lymphoma (NHL) (SMR = 140, 95%CI = 88–211) and multiple myeloma (MM) (SMR = 121, 95%CI = 55–230) were increased, but neither was statistically significant nor likely to be related to refinery employment. No death from asbestosis was reported, and mortality from mesothelioma and pulmonary fibrosis was lower than expected. Lung cancer mortality for the overall cohort was similar to expected. For the overall cohort, analyses by duration of employment and time since first employment showed no evidence of any trends for increasing cause‐specific mortality. Separate analyses of male workers employed in operator jobs showed mortality patterns that were more favorable than those of the total cohort. Maintenance craftworkers showed statistically significant elevations in mortality for prostate cancer (SMR = 145, 95%CI = 107–194), leukemia (SMR = 179, 95%CI = 111–273), and other lymphatic tissue cancer (SMR = 233, 95%CI = 138–368). Detailed analyses indicated that, among maintenance craftworkers, mortality was elevated for AML, NHL, and MM, but none was significant. Furthermore, no upward trend by duration of maintenance jobs was observed. A small increase of lung cancer was observed among maintenance craftworkers (SMR = 120, 95%CI = 99–145), which was borderline significant. No relationship between lung cancer and duration of maintenance employment was found. In contrast, a deficit of pulmonary fibrosis was reported among maintenance craftworkers (SMR = 62, 95%CI = 17–159). These findings are discussed in conjunction with results from other refinery studies, and the limitations of the study are discussed. Am. J. Ind. Med. 33:61–81, 1998. © 1...

Loop regions in proteins have traditionally been described as ‘random coil’, although they are known to adopt well‐defined conformations in most globular proteins. In this contribution we summarize the results of detailed analysis of the structures and sequences of these loop regions in proteins of known three‐dimensional structure. We also describe how these results can be used as an aid to protein design, modification and modelling.

To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a “Western-style diet” [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine- N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver. NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine- N-oxide in the liver.