Two distinct but distantly related complementary DNAs encoding proteins sharing human interleukin-1 (IL-1) activity (termed IL-1 alpha and IL-1 beta), were isolated from a macrophage cDNA library. ...The primary translation products of the genes are 271 and 269 amino acids long, although expression in Escherichia coli of the carboxy-terminal 159 and 153 amino acids produces IL-1 biological activity.
Reliable modeling of conditional densities is important for quantitative scientific fields such as particle physics. In domains outside physics, implicit quantile neural networks (IQN) have been ...shown to provide accurate models of conditional densities. We present a successful application of IQNs to jet simulation and correction using the tools and simulated data from the Compact Muon Solenoid (CMS) Open Data portal.
To determine whether the production and secretion of TNF and IL-1 by human mononuclear phagocytes could be independently modulated, we examined secretion of TNF and IL-1 by fresh monocytes and ...monocytes pretreated with IFN-gamma or granulocyte macrophage CSF before LPS stimulation. TNF and IL-1 secretion were in part differentially modulated. Fresh monocytes secreted large amounts of TNF and IL-1 after LPS stimulation and less than 6% as much without LPS. The capacity to secrete TNF in response to LPS decreased slightly in cultured monocytes but was markedly augmented by IFN-gamma (approximately five-fold more than fresh monocytes). In contrast, cultured monocytes secreted less than 5% as much IL-1 as fresh monocytes and, although augmented by IFN-gamma, IL-1 secretion remained much less than by fresh monocytes. These differences in modulation were reflected by differences in the molecular mechanisms regulating TNF and IL-1 secretion. TNF secretion was regulated primarily by changes in the duration of increased transcription and by an apparent increase in translation or protein stability in response to LPS; greater than 95% TNF produced was secreted under all conditions. In contrast, the changes in IL-1 secretion reflected primarily post-transcriptional regulation of IL1-alpha mRNA, transcriptional and post-transcriptional regulation of IL-1 beta mRNA and a decrease in the fraction of IL-1 secreted by cultured compared with fresh monocytes (10 and 60%, respectively). Changes in translational efficiency or protein processing or stability appeared not to be important mechanisms regulating IL-1 secretion. Additional evidence that TNF and IL-1 can be differentially modulated was the selective decrease in TNF secretion and the failure of IFN-gamma to enhance TNF secretion by cultured monocytes from neonates, whereas results for IL-1 were similar with adult and neonatal monocytes. Results with tissue macrophages were similar to those with cultured monocytes. These results indicate that TNF and IL-1 production and secretion by mononuclear phagocytes can be differentially modulated, reflecting in part different mechanisms of regulation; this may allow them to play partially independent roles in the host immune response.
The MCR and half-disappearance time of exogenously administered somatostatin have been measured during and after cessation of a constant infusion. Studies were performed on normal volunteers and ...patients with chronic liver disease and failure. Immunoreactive somatostatin was measured by a sensitive and specific RIA using an antiserum directed against the core of the molecule. Normal subjects had a mean MCR of 1949 +/- 250 ml/min (28.4 +/- 4.2 ml/min . kg BW) (mean +/- SEM), similar to values found in five patients with chronic liver disease. However, patients with chronic renal failure showed a highly significant (P less than 0.001) lowering of the MCR (501 +/- 32.7 ml/min or 7.8 +/- 0.6 ml/min . kg). The rate of disappearance of somatostatin after infusion was linear for 7-10 min, after which a much slower component was observed. In normal subjects, the t 1/2 of the first component varied from 1.1-3.0 min, in patients with liver disease it varied from 1.2-4.8 min, and in patients with chronic renal failure it varied from 2.6-4.9 min. Exogenously administered somatostatin is rapidly cleared in normal subjects and patients with chronic liver disease, but the MCR in end stage chronic renal failure is markedly lowered. The kidney may have a role in the metabolic clearance of exogenously administered somatostatin, or uremia may impair catabolism nonspecifically.
Saturation mutagenesis of the mature human interleukin-1 alpha (IL-1 alpha) gene has been performed. Following expression
in Escherichia coli, the biological and receptor binding activities of the ...mutant proteins were examined. Most of the molecule
could be altered with little effect on either function. More than 3,500 mutants were examined, and only 23 unique amino acid
sequences were identified which resulted in an altered ratio of biological to binding activity when compared with wild-type
IL-1 alpha. These proteins possessed mutations at 38 of the 159 amino acid residues in IL-1 alpha. Random mutagenesis at several
of these positions identified further substitutions that affected activity. Examination of a model for IL-1 alpha localized
most of the residues which altered activity along one face of the molecule. This region appears to be distinct from areas
of IL-1 which have been postulated to make contact with IL-1 receptor.
A specific antiserum has been produced to haemocyanin conjugaed synthetic growth hormone release inhibiting hormone (GHRIH). This has allowed the development of a radioimmunoassay for GHRIH sensitive ...to 5 pg/tube. GHRIH content in 2 m acetic acid extracts of rat tissues have been measured and show the majority to be CNS-especially hypothalamus and septum and preoptic areas with substantial amounts in spinal cord and thalamus. Extra neurological localization in pancreas, gastric antrum, colon and thyroid have been demonstrated.
Somatostatin-like immunoreactivity (SLI) has been demonstrated by radioimmunoassay (RIA) in rat serum using an antiserum specific for somatostatin and cross-reacting maximally with the biologically ...important area on the peptide. The RIA has a sensitivity of 35 pg/ml. SLI dilutes in parallel with synthetic somatostatin standard in the RIA and shows characteristics similar to synthetic somatostatin on Sephadex G-25 (f) gel chromatography eluting largely as a single peak with 1 M acetic acid. Significant regional differences in serum SLI are present. A positive gradient was found in paired samples from aorta (mean+/-SEM, 0.304+/-0.024 ng/ml) and portal vein (0.495+/-0.047 ng/ml) consistent with the known presence of somatostatin in gut and pancreas, and a negative gradient was noted between paired samples from portal vein (0.523+/-0.076 ng/ml) and hepatic vein (0.290+/-0.048 ng/ml) indicating hepatic clearance. No significant differences were demonstrated between aorta and confluence of cerebral venous sinuses or between aorta and inferior vena cava (IVC). After intragastric glucose, a significant and marked elevation of portal SLI was observed, maximal at 5 min (0.416+/-0.137 vs. 1.55+/-0.30 ng/ml at 5 min). A significant biphasic elevation of portal SLI also occurred after intravenous glucose. After both routes of glucose administration, the patterns of portal SLI followed closely those of portal glucose and insulin. By contrast, IVC SLI failed to reflect these changes.Thus, SLI in the rat shows chromatographic similarity with synthetic somatostatin. Regional differences in serum levels are marked; the highest concentrations being found in the portal venous effluent of pancreas and gut. Furthermore, glucose causes elevation of portal SLI in a pattern similar to portal insulin and glucose and without concomitant elevation in IVC. This differential elevation of SLI after glucose is consistent with a hormonal action within the portal system as a direct effect of somatostatin on the liver has previously been demonstrated. In addition, the liver is important in the clearance of portal SLI, possibly to prevent extraportal effects in response to gut and pancreatic stimulation. Finally, it is clear that regional sampling of serum for SLI measurement may be critical in the investigation of the putative physiological roles for somatostatin.
Growth hormone (GH) has been shown to cause a dose-dependent increase in the release of immunoreactive somatostatin from the rat hypothalamus in vitro, thus providing further evidence that GH may be ...involved in a "short loop" feedback, controlling its own secretion via hypothalamic somatostatin release.
We describe the characterization of somatostatin-like immunoreactivity (SRIF-LI) found by radioimmunoassay (RIA) to be present in normal human serum. Degradation by serum of 125I-Tyr1 SRIF in the ...assay, as assessed by chromatoelectrophoresis and immunoprecipitation, was overcome by using EDTA in the assay buffer and Trasylol in the blood samples. Serum samples thus obtained from 48 normal subjects revealed a bimodal distribution of SRIF-LI; 92 per cent (group 1) had a mean level of 0.274 +/- 0.009 ng. per milliliter. What was measured in these sera showed identity to synthetic SRIF on serial dilutions, Sephadex G-25 chromatography, and thin-layer chromatography, and it was shown to be immunoreactive by an antibody-Sepharose affinity system. Higher levels (1.0 +/- 0.041 ng. per milliliter) were found in 8 per cent of the sera; 50 per cent of this material behaved identically as serum SRIF-LI from group 1. The remainder proved to be heterogeneous, consisting of two peaks of large molecular weight, both of which shared immunologic identity with synthetic SRIF as shown by binding to the antibody-Sepharose affinity system. Their further nature is unknown.
PDF
