Modification of the L1-CAM carboxy-terminus in pancreatic adenocarcinoma cells

The neural cell adhesion molecule L1 has recently been shown to be expressed in pancreatic adenocarcinoma (PDAC) cells. In this report, we demonstrate that L1 is expressed by moderately- to poorly-differentiated PDAC cells in situ, and that L1 expression is a predictor of poor patient survival. In vitro, reduced reactivity of an anti-L1 carboxy-terminus-specific antibody was observed in the more poorly differentiated fast-growing (FG) variant of the COLO357 population, versus its well-differentiated slow-growing (SG) counterpart, even though they express equivalent total L1. The carboxy-terminus of L1 mediates binding to the MAP kinase-regulating protein RanBPM and mutation of T1247/S1248 within this region attenuates the expression of malignancy associated proteins and L1-induced tumorigenicity in mice. Therefore, we reasoned that the differential epitope exposure observed might be indicative of modifications responsible for regulating these events. However, epitope mapping demonstrated that the major determinant of binding was actually N1251; mutation of T1247 and S1248, alone or together, had little effect on C20 binding. Moreover, cluster assays using CD25 ectodomain/L1 cytoplasmic domain chimeras demonstrated the N1251-dependent, RanBPM-independent stimulation of erk phosphorylation in these cells. Reactivity of this antibody also reflects the differential exposure of extracellular epitopes in these COLO357 sublines, consistent with the previous demonstration of L1 ectodomain conformation modulation by intracellular modifications. These data further support a central role for L1 in PDAC, and define a specific role for carboxy-terminal residues including N1251 in the regulation of L1 activity in PDAC cells

Association between single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) and self-reported responses to alcohol in American Indians

Abstract Background Variation in response to the hedonic and adverse effects of a substance is in part an inherited factor that may influence its use, abuse and dependence. The mu opioid receptor is the primary site of action for opiates and individuals with polymorphisms in this receptor appear to have variation in the CNS effects of opiates. Several studies have suggested that this receptor may also mediate some of the effects of non-opioid drugs, such as alcohol. The purpose of this study was to investigate associations between 13 single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) with self-reported responses to alcohol, an endophenotype associated with the development of alcohol dependence, in American Indians living on eight contiguous reservations. Methods Each participant gave a blood sample and completed a structured diagnostic interview. Additionally, response to alcohol was indexed using the expectation version of the subjective high assessment scale (SHAS-E). SNPs were genotyped in 251 participants and data analyses were conducted using SOLAR. Results The estimated heritability (h2) for the SHAS-E phenotypes ranged from 0.01 to 0.28. Endorsing the expectation of a more intense response on one or more of the following items from the SHAS-E: buzzed, clumsy, dizzy, drunk, effects, high, nausea, sleepy, talkative, terrible, and/or uncomfortable after imbibing 2–3 drinks was significantly associated with having at least one minor allele for at least one of 7 SNPs (p < 0.01) in the OPRM1 receptor gene. Conclusion These studies provide data to suggest that the minor allele, for most of the polymorphisms in the OPRM1 receptor gene investigated, was found to be associated with a more intense, and/or more adverse, response to alcohol, traits that are significantly correlated with lowered quantity of alcohol consumption and less susceptibility to dependence in this Indian population. These data further suggest that making conclusions on the role of the mu opiod receptor gene in the development of alcohol dependence may be limited if only one polymorphism in the gene is evaluated in isolation

An Investigation of the Effect of the WADC 30,000-Horsepower Whirl Rig Upon the Static Characteristics of a Propeller

Tests have been made at the Langley Aeronautical Laboratory on a 6000-horsepower propeller dynamometer installed at a ground test facility to determine the effect of a half-scale model of the Wright Aeronautical Development Center 30,000-horsepower whirl rig upon the aerodynamic characteristics of a three-blade NACA 10-(3)(062)-045 propeller. The model of the whirl rig was mounted in front of the 6000-horsepower propeller dynamometer. Static propeller tests were made for 0deg, 5deg, 10deg, 15deg, and 20deg blade angles over a range of rotational speeds from 600 to 2200 rpm in 100-rpm increments. Measurements were made of propeller thrust and torque, stresses in the propeller blades, and static and total pressures over the surface of the model. Propeller thrust and torque were increased up to 33 percent by the presence of the model of the whirl rig, but the average increase was from 5 to 10 percent. Blade vibratory stresses were small

NACA Research Memorandums

"Tests have been made at the Langley Aeronautical Laboratory on a 6000-horsepower propeller dynamometer installed at a ground test facility to determine the effect of a half-scale model of the Wright Aeronautical Development Center 30,000-horsepower whirl rig upon the aerodynamic characteristics of a three-blade NACA 10-(3)(062)-045 propeller. The model of the whirl rig was mounted in front of the 6000-horsepower propeller dynamometer. Static propeller tests were made for 0deg, 5deg, 10deg, 15deg, and 20deg blade angles over a range of rotational speeds from 600 to 2200 rpm in 100-rpm increments" (p. 1)